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MAXILLARY viagra doses and effects viagra dosage canada PRIMARY DENTITION ANSWERS: 1—distal cusp ridge of buccal cusp; 2—buccal (cusp) ridge; 3—mesial cusp ridge of buccal cusp; 4—mesial marginal ridge; 5—mesial cusp ridge of lingual cusp; 6—distal cusp ridge of lingual cusp; 7—distal marginal ridge; 8—triangular ridge of buccal cusp; 9—triangular ridge of lingual cusp. viagra directions 100mg viagra deaf 14 19 9 viagra cialis legitimate dealers 2.8G 2.5 2.1 1.1 0.9 0.7 viagra cialis herbal substitutes 0.97 1.6 1.5 1.6 0.6 0.5 0.2 0.2 0.2 0.80 viagra cialis buy safe paypal Posterior t eet h viagra cialis and relationships viagra cheap india pharmacy D. ARCH TRAITS THAT DISTINGUISH MAXILLARY FROM MANDIBULAR INCISORS viagra causing high blood pressure LOCATION OF PROXIMAL CONTACTS (PROXIMAL HEIGHT OF CONTOUR) ON INCISORS (BEST SEEN FROM FACIAL VIEW) viagra canadain Cingulum centered Same length mesial and distal marginal ridges 62 viagra best taken when Chapter 2 | Morphology of the Permanent Incisors viagra antacid viagra and nitrites Adult dentition with the Universal numbers for canines highlighted in red. viagra and hemroids • Determine whether the canine is maxillary or mandibular. You should never rely on only one characteristic difference between teeth to name them; rather, make a list of many arch traits that suggest the tooth is a maxillary canine as opposed to only one trait that makes you think it belongs in the mandible. Refer to the arch traits in Figures 3-4 through 3-8 as needed. • If you determine that the tooth is maxillary, position the root up; if it is mandibular, position the root down. • With the tooth aligned correctly, use characteristic traits for each surface to identify the facial surface. This will permit you to view the tooth as though you were looking into a patient's mouth. • Finally, determine which surface is the mesial. (Refer to the right/left traits in Figs. 3-4 through 3-8 as needed.) While viewing the tooth from the facial and picturing it within the appropriate arch (upper or lower), the mesial surface can be positioned toward the midline in only one quadrant, the right or left. • Once you have determined the quadrant, assign the appropriate Universal number for the canine in that quadrant. For example, the canine in the upper right quadrant is tooth No. 6. viagra and avalide Maxillary right canine with a deep notch in the mesial cusp ridge. viagra alternative and woman 11.0 15.9 25.9 6.8 5.2 7.7 7.5 2.4 1.6 MAXILLARY FIRST PREMOLAR MAXILLARY SECOND PREMOLAR viagra across the counter F. viagra 25 mg order s Po tri mix and viagra to enhance effects of cialis B side effects if viagra L B sex during viagra search viagra viagra find generic buy Chapter 5 | Morphology of Permanent Molars the usual relative cusp size from largest to smallest is the same as in the first and second molars: first, the mesiolingual cusp is largest and longest; followed by the mesiobuccal cusp, which is wider and usually longer than the distobuccal cusp; followed by the smallest distolingual cusp (if present). The oblique ridge is poorly developed and often absent (maxillary molars in Fig. 5-32). From the occlusal view, the maxillary third molar crown outline usually tapers from buccal to lingual, being narrower on the lingual side, and tapers from mesial to distal, being considerably larger faciolingually in its mesial half due to a prominent mesiobuccal cervical ridge and large mesiolingual cusp (Fig. 5-32). Also, the buccal surface can be distinguished from the lingual because the buccal surface is relatively more flat. Although the crown of a mandibular third molar may exhibit great variance in size and shape and look like no other tooth (as seen in Fig. 5-34), its crown quite often resembles that of the mandibular second molar (with four cusps) or the crown of the mandibular first molar (with five cusps). For example, the occlusal outline of a mandibular third molar crown is rectangular or oval and wider mesiodistally than buccolingually.FF The crown of the four-cusp type tapers from mesial to distal and from buccal to lingual (but only slightly) (occlusal aspect).EE As on mandibular first and second molars, the lingual cusps of mandibular third molars are often larger and longer than the buccal cusps, with real life cialis REFERENCES 1. Everett FG, Jump EG, Holder TD, et al. The intermediate bifurcation ridge: a study of the morphology of the bifurcation of the lower first molar. J Dent Res 1958;37:162. 2. Tratman EK. A comparison of the teeth of people. IndoEuropean racial stock with Mongoloid racial stock. Dent Record 1950;70:31–53, 63–88. 3. Masters DH, Hoskins SW. Projection of cervical enamel into molar furcations. J Periodontol 1964;35:49–53. 4. Tratman EK. Three-rooted lower molars in man and their racial distribution. Br Dent J 1938;64:264–274. 5. Brand RW, Isselhard DE. Anatomy of orofacial structures. 6th ed. St. Louis, MO: C.V. Mosby, 1998:438. 6. Ash MM, Nelson SJ. Wheeler's dental anatomy, physiology and occlusion. Philadelphia, PA: Saunders, 2003. 7. Lundeen HC. Introduction to occlusal anatomy. Gainesville, FL: L&J Press, 1973. 8. Brand RW, Isselhard DE. Anatomy of the orofacial structures. Vol. 159. St. Louis, MO: C.V. Mosby, 1982:163. 9. Bath-Balogh M, Fehrenbach MJ. Illustrated dental embryology, histology, and anatomy. Philadelphia, PA: W.B. Saunders. 10. Chiles DG, Cosentino BJ. Third molar question: report of 522 cases. J Am Dent Assoc 1987;115:575–576. 11. Jordan R, Abrams L. Kraus's dental anatomy and occlusion. St. Louis, PA: Mosby Year Book, 1992. 12. Dahlberg AA. The evolutionary significance of the protostylid. Am J Phys Anthropol 1950;8:NS:15. q buy cialis online purchase viagra medication 6.4 7.4 7.6 6.0 6.4 K purchase kamagra in u s a pics of generic cialis FIGURE 6-17. penis after taking viagra MAXILLARY LATERAL INCISOR Chapter 7 | Periodontal Anatomy penes con viagra paroxetine and cialis PERIODONTAL DISEASE THERAPIES36–38 overnight shipping of professional cialis B over counter viagra sales B order viagra today 1 1 1 2 (buccal and lingual) or 1 1 3 (mesiobuccal, distobuccal, and lingual) 3 (mesiobuccal, distobuccal, and lingual) 1 1 1 (but has 2 roots more often than other anterior teeth: buccal and lingual) 1 1 2 (mesial and distal) 2 (mesial and distal) order viagra air travel Periapical radiolucency. Radiograph of a maxillary first premolar with the dark area (red arrows) surrounding the root apices indicating the pulp has become necrotic. A granuloma or cyst has developed in the bone, probably as a result of the exposure of the pulp to deep decay that was removed and restored with a large amalgam filling (seen as a white outline) that covers the distal and occlusal surfaces of this tooth. Each of the following questions may have more than one correct answer. 1. Which teeth are NOT likely to have root depressions on both the mesial and distal surfaces of the root? a. Maxillary central and lateral incisor b. Maxillary canine c. Maxillary second premolar d. Mandibular second premolar 2. Maxillary anterior teeth are most likely to have how many root canals? a. One b. Two c. Three d. One or two 3. Maxillary first molars are most likely to have _____ roots and _____ root canals? a. Two, two b. Two, three c. Two, four d. Three, three e. Three, four 4. The one premolar most likely to have two roots (and two root canals) is the a. Maxillary first premolar. b. Maxillary second premolar. c. Mandibular first premolar. d. Mandibular second premolar. 5. The two roots of a maxillary first premolar are called a. Mesial and lingual. b. Mesial and distal. c. Buccal and mesial. d. Buccal and lingual. e. Mesiobuccal and distobuccal. 6. On a tooth with severe bone loss due to periodontal disease, a probe can access the root furcation of a maxillary first molar on which of the following surfaces? a. Buccal surface b. Lingual surface c. Mesial surface d. Distal surface order generic cialis softtabs order chinese viagra Temporal order 5mg cialis online INCISOR AND CANINE OVERLAP OF 1114 STUDENTS C online medicine rx cialis viagra order olga viagra A. Radiograph of a class I lesion (arrow) on tooth No. 31. By the time the lesion appeared this deep on the radiograph, the caries had destroyed dentin to such a depth that a thermal-insulating base of some type of dental cement will possibly be needed to protect the pulp from thermal conductivity through the metal filling. This pit and fissure caries should have been detected earlier with a good clinical examination. (There is also a large distal class II lesion on tooth No. 4, which appears to be rotated [top right]). B. Spread pattern of class I decay: The occlusal lesion at the arrow (class I, pit and fissure) is small externally, widening toward the depth of the fissure as it approaches the DEJ. Once within dentin, the caries spreads out laterally, as well as progressing toward the pulp. FIGURE 10-24. non prescription cialis from canada 318 natural viagra for woman natural forms of cialis Part 2 | Application of Tooth Anatomy in Dental Practice natural equivalent ingredient in cialis Occipital naked female viagra chin (Fig. 14-13). No other mammal has a chin. Two mental tubercles lie on either side of the midline near the inferior border of the mandible. The mental protuberance is centered on the midline between the two mental tubercles but is about 10 mm superior. The protuberance and the tubercles are more prominent on men than on women. An external oblique [ob LEEK] ridge (Fig. 14-12) extends from the anterior border of the ramus toward the canine region. The nearly horizontal ledge of bone in the molar region between the external oblique ridge and alveolar process is named the buccal shelf. The buccal (or buccinator) nerve is located in the cheek just superior to this shelf. The mental foramen is located near the root end (apex) of the second premolar (Fig. 14-12). The nerve within the mandible (inferior alveolar nerve) gives off a branch (mental branch of the inferior alveolar nerve) that exits through this mental foramen to supply skin filling the space between incongruous articulating surfaces of the convex condyle and concave-convex articular fossa and articular eminence.12 The disc cushions the articulating bones of the joint at the areas of contact (like a shock absorber). The cushioning and lubrication reduce physical wear and strain on joint surfaces. As the mandible moves forward, the discs move forward with the mandible due, in part, to the thickened borders of each disc, which conforms to the shape of the condyles, and because the muscles that pull the mandible forward (lateral pterygoids) are attached to the neck of each condyles (in the pterygoid fovea) as well as to the discs. When the thicker peripheral portions of the discs become flattened or the center of the disc thickens, the disc fails to move synchronously with the condyle, resulting in a popping or grating noise (crepitus), which is quite an annoying yet a fairly common occurrence. The frequency of this occurrence is presented in Table 14-1. With an elastic posterior attachment, the money online order save viagra Part 3 | Anatomic Structures of the Oral Cavity mail order viagra without prescription Chapter 14 | Structures that Form the Foundation for Tooth Function macular degeneration cialis B. VEINS lyrics viagra in the water Human skull with maxilla painted red, the palatine bone (barely visible) is green, and the sphenoid bone is yellow. A pipe cleaner, representing the PSA nerve, passes out of the pterygomandibular space superiorly, toward the alveolar canals on the posterior surface of the maxilla. lowest prices for professional cialis lifestyle pharmaceuticals cialis e. These bacteria allow the adherence of other organisms like filamentous bacteria,which are unable to adhere directly to the tooth surface. Proliferation of new invading bacteria produce entangled masses of filaments forming "corncob" like structure. kgr 100 kamagra kamagra review tablet Smooth enamel surfaces kamagra on line pharmacy B. is cialis beter dan viagra 2. 3. 4. 5. 6. 7. internet viagra reviews 199 Preface i took viagra and cialis how to maximize resutts of levitra 27 how to make your own cialis The Thorax At the base of the transverse mesocolon, this double peritoneal sheet divides once again; the upper leaf passes upwards over the posterior abdominal wall to reflect on to the liver (at the bare area), the lower leaf passes over the lower part of the posterior abdominal wall to cover the pelvic viscera and to link up once again with the peritoneum of the anterior wall. This posterior layer is, however, interrupted by its being reflected along an oblique line running from the duodenojejunal flexure, above and to the left, to the ileocaecal junction, below and to the right, to form the mesentery of the small intestine. The mesentery of the small intestine, the lesser and greater omenta and mesocolon all carry the vascular supply and lymph drainage of their contained viscera. The lesser sac (Fig. 48) is the extensive pouch lying behind the lesser omentum and the stomach and projecting downwards (although usually this space is obliterated) between the layers of the greater omentum. Its left how does cialis taste GB Quad rate Porta R Caudate how does cialis affect a woman Sacral (caudal) anaesthesia ginko biloba viagra generic viagra uk online pharmacy Relations generic viagra super active plus 2◊◊The uterosacral ligaments, which pass backwards from the posterolateral aspect of the cervix at the level of the isthmus and from the lateral vaginal fornices deep to the uterosacral folds of peritoneum in the lateral boundaries of the pouch of Douglas, are attached to the periosteum in front of the sacroiliac joints and the lateral part of the third piece of the sacrum. 3◊◊The pubocervical fascia extends forward from the cardinal ligament to the pubis on either side of the bladder, to which it acts as a sling. These three ligaments act as supports to the cervix of the uterus and the vault of the vagina, in conjunction with the important elastic muscular foundation provided by levator ani. In prolapse these ligaments lengthen (in procidentia — complete uterine prolapse — they may be 6 in (15 cm) long) and any repair operation must include their reconstitution. Two other pairs of ligaments take attachments from the uterus. 1◊◊The broad ligament is a fold of peritoneum connecting the lateral margin of the uterus with the side wall of the pelvis on each side. The uterus and its broad ligaments, therefore, form a partition across the pelvic floor dividing off an anterior compartment, containing bladder (the uterovesical pouch), from a posterior compartment, containing rectum (the pouch of Douglas or recto-uterine pouch). The broad ligament contains or carries (Figs 104, 106): •◊◊the Fallopian (uterine) tube in its free edge; •◊◊the ovary, attached by the mesovarium to its posterior aspect; •◊◊the round ligament; •◊◊the ovarian ligament, crossing from the ovary to the uterine cornu (see ovary); •◊◊the uterine vessels and branches of the ovarian vessels; •◊◊lymphatics and nerve fibres. The ureter passes forwards to the bladder deep to this ligament and lateral to and immediately above the lateral fornix of the vagina. 2◊◊The round ligament —a fibromuscular cord—passes from the lateral angle of the uterus in the anterior layer of the broad ligament to the internal inguinal ring; thence it traverses the inguinal canal to the labium majus. Taken together with the ovarian ligament, it is equivalent to the male gubernaculum testis and can be thought of as the pathway along which the female gonad might have, but in fact did not, descend to the labium majus (the female homologue of the scrotum). Compare this process to descent of the testis, (page 121). The relations of the vagina to the other pelvic organs must be constantly borne in mind when carrying out a vaginal examination. Inspection (by means of a speculum) enables the vaginal walls and cervix to be examined and a biopsy or cytological smear to be taken. Inspection of the introitus while straining detects prolapse and the presence of stress incontinence. •◊◊Anteriorly—the urethra, bladder and symphysis pubis are felt. •◊◊Posteriorly — the rectum (invasion of the vagina by a rectal neoplasm generic viagra pages edinburgh find generic viagra online a href pharmacy The aorta enters the abdomen via the aortic hiatus in the diaphragm at the level of the 12th thoracic vertebra and ends at L4 in the transcristal plane (Fig. 42). It lies throughout this course against the vertebral bodies and is easily palpable in the midline. Anteriorly, from above down, it is related to the pancreas (separating it from the stomach), the third part of the duodenum and coils of small intestine. It is crossed by the left renal vein. A large tumour of pancreas or stomach, a mass of enlarged para-aortic nodes, or a large ovarian cyst may transmit the pulsations of the aorta and be mistaken for an aneurysm. The branches of the aorta are: 1◊◊three anterior unpaired branches passing to the viscera: (a) the coeliac axis —giving off the The external iliac artery runs along the brim of the pelvis on the medial side of psoas major. The artery passes below the inguinal ligament to form the femoral artery, giving off, immediately before its termination, the inferior epigastric artery, which demarcates the medial edge of the internal inguinal ring (Fig. 45) and also the deep circumflex iliac artery. The internal iliac artery passes backwards and downwards into the pelvis, sandwiched between the ureter anteriorly and the internal iliac vein posteriorly. At the upper border of the greater sciatic notch it divides into an anterior and posterior division, which give off numerous branches to supply the pelvic organs, perineum, buttock and sacral canal. generic viagra canadian pharmacy no prescription generic india viagra with paypal The breasts develop as an invagination of chest wall ectoderm, which forms a series of branching ducts. Shortly before birth this site of invagination everts to form the nipple. At puberty, alveoli sprout from the ducts and considerable fatty infiltration of the breast tissue takes place. With pregnancy there is tremendous development of the alveoli which, in lactation, secrete the fatty droplets of milk. At the menopause the gland tissue atrophies. 190 generic cialis in stock The upper limb generic cialis from india buying generac for viagra •◊◊artery—aneurysm of the femoral artery; •◊◊vein—varix of the great saphenous vein; •◊◊nerve—neuroma of the femoral nerve or its branches; •◊◊femoral canal—femoral hernia; •◊◊psoas sheath—psoas abscess; •◊◊lymph nodes—any of the causes of lymphadenopathy. fucking on viagra video Course and distribution of nerves The tongue and floor of the mouth free viagra program Fig. 234◊The spinal cord —transverse section through a thoracic segment. free sample viagra womens The central nervous system flowmax and cialis xiv find viagra free online search female viagra to be released The medical student, in addition to being a member of the medical team, must interact with members of the professional team of nurses, dietitians, pharmacists, social workers, and all others who provide direct care for the patient. Good working relations with this group of professionals can make your work go more smoothly; bad relations with them can make your rotation miserable. Nurses are generally good-tempered, but overburdened. Like most human beings, they respond very favorably to polite treatment. Leaving a mess in a patient's room after the performance of a floor procedure, standing by idly while a 98-lb licensed practical nurse struggles to move a 350-lb patient onto the chair scale, and obviously listening to three ringing telephones while room call lights flash are acts guaranteed not to please. Do not let anyone talk you into being an acting nurse's aide or ward secretary, but try to help when you can. You will occasionally meet a staff member who is having a bad day, and you will be able to do little about it. Returning hostility is unwarranted at these times, and it is best to avoid confrontations except when necessary for the care of the patient. When faced with ordering a diet for your first sick patient, you will no doubt be confronted with the inadequacy of your education in nutrition. Fortunately for your patient, dietitians are available. Never hesitate to call one. In matters concerning drug interactions, side effects, individualization of dosages, alteration of drug dosages in disease, and equivalence of different brands of the same drug, it never hurts to call the pharmacist. Most medical centers have a pharmacy resident who follows every patient on a floor or service and who will gladly answer any questions you have on medications. The pharmacist or pharmacy resident can very often provide pertinent articles on a requested subject. female viagra legal THE WRITTEN HISTORY AND PHYSICAL female naked viagra Description T1 C6 femail viagra * fast acting cialis (See Chapter 20 for a sample ICU progress note.) 1. List each medical, surgical, psychiatric problem separately: pneumonia, pancreatitis, congestive heart failure, etc. 2. Give each problem a call number: 1, 2, 3, . . . (as on page 31). 3. Retain the number of each problem throughout the hospitalization. 4. When the problem is resolved, mark it as such and delete it from the daily progress note. 5. Evaluate each problem by number in the following SOAP format. Or, you may do a separate assessment and plan for each problem eli lily cialis This type of progress note is written several hours after or the night of surgery. Procedure: Indicate the operation performed. Level of Consciousness: Note if the patient is alert, drowsy, etc. levitra warfarin levitra professional.uk 3 Differential Diagnosis: Symptoms, Signs, and Conditions Increased: (Hypergonadotropic >40 IU/L) postmenopausal, surgical castration, gonadal levitra free voucher how often to take levitra 4 Laboratory Diagnosis: Chemistry, Immunology, and Serology levitra 20mg tab + levitra ratings • Adult <40 mg/dL (1.93 mmol/L) • Child <25 mg/dL (1.21 mmol/L) • Collection: Lavender, navy, or green top tube; lab-specific Neurologic findings can be detected at 15 mg/dL in children and 30 mg/dL in adults; severe symptoms (lethargy, ataxia, coma) are present >60 mg/dL. quanto custa o levitra 8.5–14.5 levitra bayer-original • 1–20 ng/mL (mg/L) • Collection: Tiger top tube Useful for following patients with nonmedullary thyroid carcinomas generique levitra 20 Decreased: Hypothyroidism, euthyroid sick syndrome, any cause of decreased TBG THYROXINE-BINDING GLOBULIN (TBG) can you buy levitra over the counter 42.9–49.1 37.9–43.9 levitra identification Neutrophils, Segmented (% WBC count) levitra austria 56 As above 51 50 39 30 28 30 39–52 58 levitra cost cvs Decreased: Acute rheumatic fever, pregnancy, after radiation, steroid therapy, thyrotoxicosis, stress levitra precio en chile Intrinsic (Prekallikrein + Surface contact) Factor XII Factor XIIa 129 levitra trial offer how long does levitra stay in system Procedure buy brand name levitra S. pneumoniae oral flora, including anaerobes (eg, Fusobacterium, Bacteroides sp.) Enterobacteriaceae S. pneumonia, coliforms, Pseudomonas, Legionella Pneumocystis Others as above TB, fungi S. pneumoniae H. influenzae M. catarrhalis Anaerobes In nosocomial, nasal intubations, etc: S. aureus Pseudomonas spp. Enterobacteriaceae Propionibacterium acne Possible skin mite S. aureus, Enterobacteriaceae, 7 can a woman take levitra levitra professional reviews 164 Actual bicarbonate is 6 mmol/L, which is very close to the expected of 5 mmol/L. Thus, a pure metabolic gap acidosis is present from DKA. levitra retail price 189 levitra reviews side effects Treatment: Clinical hypermagnesemia requiring therapy is infrequently encountered in levitra generico prezzi levitra generique 20mg Low-sodium levitra costco price physician must be certain to evaluate the patient for other causes of diarrhea. Formularelated causes include contamination, excessively cold temperature, lactose intolerance, osmolality, and an incorrect method or route of delivery. Eliminate potential causes before using antidiarrheal medications. can you buy levitra online 2. 45–80 2/3 serum levitra 40 mg dose 13 levitra vs levitra professional Green/red marbled does levitra work on women levitra prices in australia Angiography: A rapid series of films obtained after a bolus contrast injection via percutaneous catheter. Used to image the aorta, major arteries and branches, tumors, and venous drainage via late "run-off" films. Helical CT scans are now capable of generating angiographic images. levitra trial voucher BE: Examining the colon and rectum. Indications include diarrhea, crampy abdominal pain, heme-positive stools, change in bowel habits, and unexplained weight loss Most useful in the diagnosis of gynecologic pathology (uterus, ovaries) levitra 5 mg ohne rezept vente levitra france Scrubbing technique depends somewhat on local custom. Some ORs want a timed scrub in which the duration of scrubbing is determined by watching the clock. Other ORs use an "anatomic" scrub in which the duration of scrubbing is determined by counting strokes. Either is acceptable, and you should find out what the custom is at your institution. INTRODUCTION levitra generika paypal levitra side effects forum Copyright 2002 The McGraw-Hill Companies, Inc. Click Here for Terms of Use levitra lawsuit FIGURE 19–20 conduction. V3 levitra cost uk ⇓ ⇓ ⇓ ⇓ ⇓ levitra greece Clinician's Pocket Reference, 9th Edition levitra doctissimo generic levitra canada pharmacy 439 451 levitra for daily use 1 mg/mL in 5-mL vial Adults. 5 mg slow IV q 5 min, total 15 mg levitra original-bayer levitra bez recepty Antihistamines levitra kaufen in holland Cephalosporins, Fourth-Generation levitra bayer kaufen Letrozole Levcovorin Levamisole Mitotane Mitoxantrone Paclitaxel Pentostatin levitra efficacy Thyroid/Antithyroid does levitra work women tericin B Cefoperazone (Cefobid) cheap levitra online uk real levitra online Clotrimazole (Lotrimin, Mycelex) Delavirdine (Rescriptor) levitra hearing loss 1.1–1.4 0.8–1 0.5–0.7 <0.4 levitra sale canada 537 levitra priser Gentamicin and Prednisolone, Ophthalmic (Pred-G Ophthalmic) where can i buy levitra in the philippines buy levitra singapore 22 what is levitra prescribed for 22 Commonly Used Medications levitra mk Herpes simplex Competitive inhibitor of DNA polymerase Apply topically at first sign of lesions, then q2h for 4 d SUPPLIED: Cream 1% COMMON USES: ACTIONS: buy levitra 20 mg online <60 ≥60–<70 ≥70–<80 ≥80–<90 ≥90 levitra picture of pill COMMON USES: ACTIONS: levitra upotreba 615 levitra buy singapore levitra orders 22 levitra coffee 126 generic levitra vardenafil 20mg THE TRANSCENDENTAL MEDITATION TECHNIQUE AS A CORNERSTONE OF VEDIC MEDICINE In practical terms, the means of experience of pure awareness is by a mental technique. The regular experience of pure awareness is a cornerstone of ayurveda, and more specifically of the Vedic approach to health as recently introduced by Maharishi Mahesh Yogi. In recent clinical and scientific literature, it is often referred to as the Maharishi Vedic Approach to Health (MVAH) or Maharishi Vedic Medicine (MVM). The experience of pure awareness is by means of a systematic mental technique, whereby a thought is experienced on finer and finer levels of its inception, until thought itself is transcended, and one is aware, but without an object of awareness. This is the experience of 'pure awareness' or 'pure consciousness'. It is often referred to as the source of levitra 10 mg forum HISTORY OF HYPNOSIS Conventionally, the starting point for the history of hypnosis begins with Dr Franz Anton Mesmer's discovery and practice of animal magnetism in 1774, although the role of hypnosis in religious and healing practices has been inferred from medical papyri dating back to the Ancient Egyptians. Mesmer's theory of animal magnetism proposed, among other things, that a universal fluid permeated all space and that certain diseases were due to a lack of harmony in the distribution of the flow of this fluid. Although Mesmer's early work incorporated the use of magnets in a similar manner to other healers of the time, he soon proposed that one could distinguish animal magnetism from mineral magnetism and relegated the properties of the latter to a metaphorical framework for the former: 'I set forth the nature and action of ANIMAL MAGNETISM and the analogy between its properties and those of the magnet and electricity. I added that all bodies were, like the magnet, capable of communicating this magnetic principle; that this fluid penetrated everything; that it could be stored up and concentrated, like the electric fluid…'4 Mesmer's healing practices involved both touching and passing his hands over the bodies of the afflicted, which generated 'restorative crises' involving convulsive seizures. The powerful influence of the mesmerist could be applied to many people at once, and even at great distances or through thick walls. The curative powers of animal magnetism could also be stored and transferred via any object. Trained at the Vienna Medical School, Mesmer eventually moved to pre-revolutionary Paris where he found his fame and fortune. He was convinced about the importance of his discoveries, and tried for many years in vain to establish recognition from the Royal Society of Medicine, though always on his own terms. Eventually, in 1784, King Louis XVI commissioned a number of scientific luminaries to investigate the claims of animal magnetism. The Royal Commission, which included Benjamin Franklin, Joseph Guillotin and Antoine Lavoisier, elected to test the existence of animal magnetism itself rather than the cures—they argued that its utility could be taken up only after the question of its existence had been answered. A disciple of Mesmer's, Charles D'Eslon, served as the mesmerist for the commission. The commission, after demonstrating that people fell under the influence of animal magnetism when there was none and failing to show any effect when it should have been present, concluded: 'Touching, imagination, imitation, these then are the real causes of the effects attributed to this new agent, known under the name Animal Magnetism, to this fluid said to circulate in the body & to spread from individual to individual.'(p. 359)5 Thus, the mechanism by which Mesmer claimed to effect cures was discredited by the Royal Commission, giving official support to the growing opposition to mesmerism. Mesmer fell into disrepute. Although some supporters remained, Mesmer's dream of the Ignoring spiritual leads The praying patient The patient with religious jewelry, texts, etc The patients who asks, 'Why is God punishing me?' Rushing the discussion Responding to interruptions (e.g. pagers) Going beyond expertise and role In these circumstances, obtain appropriate consultation (e.g. chaplain) Proselytizing Attempting to answer questions that cannot be answered Using unhelpful phrases 'It's God's will' 'Nothing more can be done' 'It could be worse' cost of levitra at costco MIGRAINE HEADACHES Elimination of triggers Avoidance of triggers can dramatically reduce the frequency of attacks. An excessive amount of caffeine in the diet (for a headache sufferer, more than one drink a day) or in over-the-counter or prescription medications is one of the most common triggers. Some of the foods that can provoke migraine headaches include yogurt, bananas, dried fruit, beans, aged cheese, pickled and marinated foods and buttermilk. Monosodium glutamate and aspartame should be avoided. Among the alcoholic beverages red wine and beer are more likely to induce a migraine headache than vodka. Lack of sleep or excessive amounts of sleep (e.g. on weekends) can trigger a migraine attack in a susceptible individual. Nutritional therapies Dietary approaches to the treatment of migraines are widely advocated and are in the category of complementary therapies but have very little scientific evidence. Tyraminecontaining foods can trigger migraine headaches in susceptible individuals, as can skipping meals and some food additives and sugar substitutes. Some patients report that their headaches get better with elimination of wheat products, sugar or milk products from their diets. While we do not have scientific proof, it is possible to speculate on why these dietary changes may work. If the patient is so inclined there is no reason to discourage her from trying these dietary changes, which are usually safe and inexpensive. Strict vegetarian and other unusual diets can lead to vitamin B12 and other deficiencies, which can make headaches worse and cause other problems. Biofeedback Biofeedback is one of the therapies where definitive proof is difficult to obtain. Biofeedback is used by most of the specialty headache clinics; this does not prove its efficacy, but strongly suggests that a large number of patients benefit from it. Many clinical trials have shown effectiveness of biofeedback and relaxation techniques3–7. Results of these studies indicate higher response rates than those seen in placebo arms of prophylactic drug trials. Long-term follow-up studies suggest that biofeedback can have sustained efficacy for years after the completion of training3,7. The essence of biofeedback, which is often combined with behavior modification, is to teach a patient how to encounter stress without adverse physiological effects. A typical course of biofeedback consists of 8–10 weekly 30–45 min sessions. Learning to control one's physiological functions such as temperature or electromyographic activity can be achieved only by first learning to relax the skeletal muscles. This is achieved through progressive relaxation, visualization and breathing techniques. Most important, though, is the daily practice of these techniques. The practice sessions can be only a few seconds or minutes long, but they have to be very frequent. A conscious effort is required in the first levitra quanto custa 26. Pfaffenrath V, Diener HC, Fischer M, Friede M, Henneicke-von Zepelin HH. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis—a double-blind, multicenter, randomized placebo-controlled dose-response study. Cephalalgia 2002; 22: 523–32 27. Vogler BK, Pittler MH, Ernst E. Feverfew as a preventive treatment for migraine: a system-atic review. Cephalalgia 1998; 18:704–8 28. Grossman M, Schmidramsl H. An extract of Petasites hybridus is effective in the prophy-laxis of migraine. Int J Clin Pharmacol Ther 2000; 38:430–5 29. Lipton RB, Gobel H, Wilkes K, Mauskop A. A special extract from Petasites hybrid root is effective as a preventive treatment for mi-graine. Headache 2002; 42:406–7 30. Danesch U, Rittinghausen R. Safety of a patented special butterbur root extract for migraine prevention. Headache 2003; 43:76–8 31. Gobel H, Schmidt G, Soyka D. Effect of peppermint and eucalyptus oil preparations on neurophysiological and experimental algesimetric headache parameters. Cephalalgia 1994; 14:228–34 32. Gobel H, Heinze A, Dworschak M, et al. Oleum menthae piperitae significantly reduces the symptoms of tension-type head-ache and its efficacy does not differ from that of acetaminophen. In Olesen J, Tfelt-Hansen P, eds. In Headache Treatment: Trial Methodology and New Drugs. Philadelphia: Lippincott-Raven, 1997:169–74 33. Bruhn P, Olesen J, Melgaard B. Controlled trial of EMG feedback in muscle contraction headache. Ann Neurol 1979; 6:34–7 34. Leone M, D'Amico D, Moschiano F, et al. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia 1996; 16:494–6 35. Peres MFP, Rozen TD. Melatonin in the preventive treatment of chronic cluster headache. Cephalalgia 2001; 21:993–5 36. Fogan L. Treatment of cluster headache. A double-blind comparison of oxygen v air inhalation. Arch Neurol 1985; 43:362–3 37. Kudrow L. Response of cluster headache attacks to oxygen inhalation. Headache 1981; 21:1–4 38. Fitzgerald M. Capsaicin and sensory neurons—a review. Pain 1983; 15:109–30 39. Sicuteri F, Fusco BM, Marabini S, et al. Beneficial effect of capsaicin application to the nasal mucosa in cluster headache. Clin J Pain 1989; 5:49–53 40. Marks DR, Papoport A, Padla D, et al. A double-blind placebo-controlled trial of intranasal capsaicin for cluster headache. Cephalalgia 1993; 13:114–16 41. Fusco BM, Marabini S, Maggi C, et al. Preventative effect of repeated nasal applications of capsaicin in cluster headache. Pain 1994; 59: 321–5 42. Fusco BM, Fiore G, Gallo F, et al. 'Capsaicinsensitive' sensory neurons in cluster headache: pathophysiological aspects and therapeutic indication. Headache 1994; 34:132–7 43. Mauskop A, Altura BT, Cracco RQ, Altura BM. Intravenous magnesium sulfate relieves cluster headaches in patients with low serum ionized magnesium levels. Headache 1995; 35: 597–600 levitra expiry date weeks; twice-weekly physical therapy sessions; and continued care by a general practitioner (analgesics, counseling and education). The principal outcome measure (percentage of patients reporting significant improvement or resolution of symptoms) was measured 1 -week post-treatment; pain scores and disability were secondary outcome measures. Mobilization was found to be significantly better than the other two methods of treatment in terms of recovery, pain and disability, although the difference in disability was fairly small. The authors concluded that manual therapy was a good option for the treatment of neck pain. The second study by Hurwitz and colleagues40 randomized 336 patients with neck pain in a managed care organization to one of eight treatment groups: spinal mobilization with and without heat; spinal mobilization with and without electrical muscle stimulation; spinal manipulation with and without heat; spinal manipulation with and without electrical muscle stimulation. Over the 6 months of observation, the treatment groups showed improvement over baseline in terms of pain and disability, with no statistically significant differences between groups. The authors concluded that spinal manipulation and mobilization were equally effective in the treatment of neck pain40. Because all patients received treatment, it is unknown whether the observed results were due to the treatment received or simply the natural history of neck pain. Mobilization summary Mobilization procedures for neck pain have substantial literature support, appear to be significantly better than conventional medical management and compare favorably with spinal manipulation. However, it remains to be determined whether mobilization procedures are of benefit for low back pain, since there have been few direct studies of lumbar spinal mobilization procedures for low back pain and almost none in which mobilization was the sole treatment. Manipulation Spinal manipulation is the application of force to a hypomobile joint through the use of a high-velocity, low-amplitude thrusting procedure aimed at moving a joint into its paraphysiological range of motion (see Chapter 3). There are several important issues that must be considered when reviewing this literature. The first is that, much like other medical therapies for low back pain, the methodological quality of the clinical trials has varied greatly from study to study41. Appropriate placebos for manipulative treatments are not well established and may be particularly difficult to validate. Most of the existing studies have therefore compared manipulation to other forms of therapy rather than to pure (i.e. no treatment) placebo groups. This has the potential effect of minimizing differences between groups. Additionally, there is significant variation in the delivery of manipulation amongst buy levitra philippines para que es el medicamento levitra 328 levitra kaufen schweiz no effect OTHER ORTHOMOLECULAR AND HERBAL REMEDIES There are a large number of agents that have been tested in limited clinical trials or animal experiments. Although oxidative injury may be important in the pathogenesis of Alzheimer's disease, there are no significant clinical data on other antioxidants (e.g. zinc and selenium). A specific extract from cat's claw (Uncaria tomentosa) was found to inhibit amyloid fibrillogenesis in vitro and in preliminary animal studies158. Huperzine A is a potent cholinesterase inhibitor that has been used in China, but the clinical data are very limited159–161. A large American trial is currently planned. Coenzyme Q is an antioxidant that is an essential cofactor of the electron transport chain and has potential for treatment of neurodegenerative disorders162. There is evidence for benefit from a human trial in Parkinson's disease (see Chapter 19), but there are no clinical data for Alzheimer's disease. A single small trial of vinpocetine demonstrated no efficacy for Alzheimer's disease163, although there are some animal and in vitro data suggesting potential benefit164,165. There wasa single well-designed trial of 50 mg/kg per day Nacetylcysteine in 43 patients with probable Alzheimer's disease that did not demonstrate effects on the primary outcome measures of MMSE score and an activities of daily living scale, but there were changes in some of the secondary measures166. Curcumin, the main yellow pigment in turmeric, has antioxidant properties167,168 and, in the amyloid precursor protein Alzheimer's disease mouse model, this has been shown to reduce oxidative damage, β-amyloid and plaque burden169. Salvia officinalis (sage) has been reported to have beneficial effect in a single double-blind placebo-controlled trial in 42 patients with mild to moderate Alzheimer's disease using the ADAS-cognitive subtest and Clinical Dementia Rating (CDR) scale Sum of the Boxes170. Choto-san, a traditional Japanese medicine, had some beneficial effect on global ratings as well as on functional measures in patients with vascular dementia as diagnosed by defined criteria and using imaging studies171. These investigators also found that the main ingredient in Choto-san, Uncaria sinensis, was protective in glutamate-induced cerebellar granule cell death. Nicotine skin patches had some beneficial effect in a placebocontrolled crossover trial of eight subjects with Alzheimer's disease as assessed by a continuous performance task, but there was no improvement on measures of memory function172. Pyritinol, a pyridoxine derivative, was reported to be useful in Alzheimer's disease as well as vascular dementia in a randomized trial of 164 patients using standard cognitive and functional outcome measures173. There was an earlier trial also reporting positive effects in 40 hospitalized patients with modestly severe dementia174, but no more recent large trial. Various forms of aromatherapy have also been evaluated for management of behavioral symptoms in dementia with some benefit reported in pilot studies175–181. Extracts of Bacopa monniera have been used in ayurvedic medicine as a cognitive enhancer. It appears to induce antioxidant activity in the brain182 and produced some protection from scopolamine- and phenytoin-induced cognitive deficits in mice32,183. There have been small trials in healthy humans suggesting some beneficial effect on levitra kaufen preis levitra ricetta medica vibration perception threshold. There have been no controlled trials for acupuncture, although there have been uncontrolled trials26. levitra 10 mg orodispersibile Leathwood et al.24 49. Bernstein IL. Enzyme allergy in population exposed to long-term, low-level concentra tions of household laundry products. J Allerg Clin Immunol 1972; 49:219–37 50. Dexter D Jr. Magnetic therapy is ineffectiv for the treatment of snoring and obstructiv sleep apnea syndrome. Wis Med J 1997; 96 35–7 where to buy levitra in singapore 467 levitra 20mg generique Peyotism or peyote religion: Native American Church Lophophora williamsi (peyote) is obtained from the top of the peyote cactus. The substance contains mescaline, which is noted for its hallucinogenic and other mental effects. While substance abuse and self-exploration aspects of this preparation have been popularized, its most important use occurs in the Native American Church as part of a religious ritual which contains Native American and Christian components, and which promotes brotherly love, family care, self-support and avoidance of alcohol. The US Supreme Court has established a legal precedent that has significant implications for the religious use of peyote, and for sacramental use of all traditional drugs other than alcohol. It has been estimated that there are more than 225 000 members of the Native American Church. Peyote religion is a Native American pan-tribal religious system that employs the use of the peyote cactus—a practice depicted on tombs dating back to 100 BC. Research on this topic is generally difficult, because of the multi-component nature of the 'treatment', the self-selection of the church members, lack of explicit standardization of the treatment and other factors such as the formation of social networks to help prevent relapse into alcoholism, and the participation by many in dance ceremonies held several times a year in various parts of the country. 'Treatment' may be a social system that has peyote as only one of its probable 'active' ingredients. The range of related practices includes sweat lodges, other herbs, cultural re-education and sun dances, among others. Research results have been contradictory, and recommendations that have been drawn from historical and epidemiological data have not been investigated by controlled research. Several factors probably contribute to outcome success in this area, as they do in all substance abuse research. Many health workers in the Indian Health Service of the US Public Health Service (USPHS) have seen long-term sobriety associated with Native American Church attendance by former inebriates. Physicians should note that participants and believers have a powerful conviction of its benefits. Many have experienced personal evidence for its salutary effects on not only substance abuse but also health, mental health and spiritual wholeness111,112. Regarding potential negative effects, three cases of botulism have been reported in members of the Native American Church who consumed peyote113. Thirteen church members ingested peyote from a communal jar during a ceremony. Two to four days' afterward, three men (40, 42 and 72 years old) noted the onset of bilaterally symmetric, moderate, flaccid weakness in all extremities. The ceremonial tea the patients had drunk was made from buttons of the dried, alkaline-ground peyote cactus, which had been covered with water and stored in a closed jar for 2 months under refrigeration. The author of the report believed that this prolonged, non-traditional storage of unsterilized peyote produced an anaerobic and alkaline environment that favored the growth and production of toxin from spores of Clostridium botulinum that were probably on the cactus. It was concluded that all ingested substances, including herbal medications and religious sacraments, must be considered as sources when botulism is suspected. levitra gsk (41–49°C). CMH responses are affected by stimuli history and are subject to fatigue and sensitization modulation (see later and chapter 5 on hyperalgesia). levitra 60 mg levitra 10mg rezeptfrei kaufen Definitions 2 levitra and hearing loss Gene: An ordered sequence of nucleotides located in a particular position (locus) on a particular chromosome, which encodes a specific functional product (the gene product, i.e. a protein or RNA molecule). Exon: A protein-coding DNA sequence of a gene. Intron: A DNA base sequence that can be transcribed into RNA but are cut out of the message before it is translated into protein. However, introns may contain sequences involved in regulating gene expression. Codon: Crick (1963) proposed this term now recognised to be a triplet of nitrogenous bases in DNA or RNA that specifies a single amino acid. levitra professional vs levitra • • ASIC1–3, VR1 levitra package insert TrkB NMDA-R Naϩ cAMP Src PKA PKA Ca2؉ COX/LOX PGE2 NO Gs EP cAMP AC AMPA-R KA-R levitra prices australia levitra potency Increased excitability Tachykinins activate several intracellular pathways such as: average cost of levitra levitra non funziona Tissue damage induces inflammation, causing release of numerous inflammatory mediators that activate and sensitize 1° afferent nociceptors. Many pro-inflammatory substances promote the release of and accentuate the actions of other inflammatory mediators. Resultant electrophysiological changes lead to inflammatory hyperalgesia. The augmented afferent barrage to the spinal cord from this peripheral (1°) sensitization drives central (2°) sensitization. Degranulation of mast cells releases not only inflammatory mediators that act directly and indirectly on 1° afferent nociceptors, but also powerful chemotactic substances to promote influx of neutrophils and macrophages. These recruited immune • • • • • • • levitra 10 mg prezzo in farmacia Ligand-gated ion channels levitra trial coupon warfarin and levitra Glutamate levitra 10 mg orodispersible M E A S U R E M E N T O F PA I N I N A N I M A L S Pain behaviours levitra cost costco • original levitra 20mg Table 10.5 Characteristics of common experimental pain stimuli Electrical Tissue depth Anatomical structure Afferent selectivity Temporal characteristics Spatial characteristics Clinical relevance Quantifiable stimulus Superficial or deep Skin, muscle, viscera Poor Brief, repeatable Small area, localized pain Poor Yes Thermal Superficial Skin Good Brief or tonic, repeatable Variable area, localized pain Moderate Yes Mechanical Superficial and deep Skin, muscle, viscera Moderate Brief or tonic, repeatable Variable area, localized pain Moderate Yes Cold pressor Superficial and deep Skin, muscle Moderate Tonic Variable area, diffuse pain Moderate Somewhat Ischaemic Primarily deep Muscle Moderate Tonic Large area, diffuse pain Good Somewhat Chemical Superficial or deep Skin, muscle Good Tonic Variable area diffuse pain Good Somewhat cialis when drunk cialis the weekender Figure 11.1 Example of a VAS for pain assessment. A 10 cm line is anchored at either end with a description of the pain level appropriate to mark at that site. No other descriptions are given. The patient is asked to mark the line at the level that best describes their pain. The assessor then measures the distance along the line. As shown in this VAS, the scale can be manipulated to demonstrate pain (lower anchors) or degree of pain relief (upper anchors). india cialis manufacturers • • • • • • • • cialis utah Simple measures are important to maintain patient comfort and should include: Nervous system: – No effect on intracranial pressure (ICP). – No effect on neuro-muscular junction activity. Minimal cardiovascular effects, which may be: – Primary effects on the myocardium or vascular resistance. – Secondary effects, consequent upon chemical release (e.g. histamine causing vasodilatation and hypotension). No effects on the respiratory tract, which may be: – Central (depressed respiratory drive). – Peripheral (bronchconstriction). No effects on renal system consequent upon: – Inadequate perfusion. – Altered cellular function. No adverse gastrointestinal effects, including: – Abnormal smooth muscle peristalsis. – Muscle sphincter contraction. – Deranged hepatic/pancreatic function. cialis bangladesh Renal (10%); not removed by dialysis Renal (90%); not removed by dialysis Renal (60%), bile (10%); not removed by dialysis cialis lloyds pharmacy Withdrawal problems are most likely to be avoided by the use of careful unit protocols. These should include the following features: cialis how to pronounce Many patients with chronic pain express their frustration that nobody understands them; including health care providers, partners, family and friends. The unpredictability of chronic pain means the patients abilities will vary quite considerably on a day-to-day basis. One day they may be able to go shopping and clean the house, whereas the next day the best they para que sirve el cialis de 20 mg cialis generico madrid FMS patients may display increased pain sensitivity to other stimuli (heat, cold and ischaemia). Pain intensity and pain thresholds are affected by ketamine, an NMDA receptor antagonist. Substance P is increased in cerebrospinal fluid. Single photon emission computed tomography (SPECT) imaging of the thalamic and caudate Incidence buy generic cialis europe cialis stamina Injection therapy Epidural injections Tricyclic antidepressants or antiepileptics in neuropathic pain. High dose steroids for raised intracranial pressure headache. getting cialis prescription online cialis and amphetamine • • The most common cause is a bony or fibrous band (i.e. cervical rib). If the band is fibrous it may be difficult to detect on X-ray. Ischaemic pain (from interruption of the brachial artery) may only be present when the arm is exercised, or raised above the head, cialis dose size cialis is not working for me beyond the initial event. An understanding of the impact of developmental neurobiology and pharmacology is essential for safe and effective pain management in the neonate and infant. Pain is a subjective experience and psychological factors greatly influence perceptions of the unpleasantness, quality and intensity of pain. Childrens' pain and related behaviour is modified by a complex interaction of emotional, situational, familial and developmental factors. Age appropriate treatment includes not only the selection of suitable analgesics at the correct dosage, but also non-pharmacological measures designed to reduce pain. These include: • immune to cialis A MDT is only as good and useful as its ability to communicate between the disciplines. It requires regular meetings with transference of information between disciplines sharing a common philosophy and goal, in order to achieve effect. The patient journey in a multidisciplinary pain clinic is one of change. Often one treatment will support and make possible another, for example analgesia and physical therapy. Hence the necessity for individualized treatment regimes and regular review of patient progress. Clinics vary considerably in what they offer patients, depending upon the skills of their team members and the resources available. One may make an initial assessment, another recommend a plan of care and someone else support pain management on an on-going basis. Team members have to be consistent in their explanations, helping the patient to accept the chronicity of their problems and encouraging self-management. Some hospitals have pain management programmes (PMPs) where groups of patients interact with the MDT. This improves insight, explains why they are experiencing pain and what it means, in addition to offering help and advice. The aim of such programmes is not to remove the pain. Rather they help patients to change their behaviour and improve their functioning and quality of life, while experiencing on-going pain. This biopsychosocial approach is used often in conjunction with treatments based in cognitive behavioural therapy. Programmes are usually for outpatients on a weekly or bi-weekly basis. Inpatient programmes are costly and are usually reserved for those who need more intensive intervention and rehabilitation. how long does 10mg of cialis last commander cialis en ligne functioning in this system may be implicated in addiction and some psychiatric diseases. However, orphanin FQ subserves a different role in the spinal cord, where it is involved in the regulation of inhibitory inter-neurones in laminae I, II and V. Here it acts in a similar fashion to the MOP agonists, producing pre-synaptic inhibition and analgesia. • • how do you pronounce cialis cialis pill looks like 21 flomax and cialis interactions theory, the behavioral, physiological and electrical correlates of concussion arise as a consequence of this brief but intense generalized neuronal firing. Concussion is therefore conceived as a kind of epileptic seizure and the mechanisms responsible for the development of its symptoms must be basically the same as those for a spontaneous seizure or one which is generated artificially by chemical, electrical or other means. If the pathophysiology of concussion primarily involves mechanicallyinduced convulsive activity, then the question arises as to what is the sequence of events which leads to sudden massive breakdown of the cell membrane potential. Drawing upon the early studies of Gurdjian (Gurdjian & Webster, 1945) as well as those of Scott (1940), Walker et al. demonstrated that the concussive blow creates a zone of increased ICP at the point of impact. This sets in motion vigorous high frequency pressure waves which are transmitted throughout the brain. Such mechanical stresses deform and thereby depolarize neural tissue. Walker et al. cite the findings of Krems et al. (1942) on nerve concussion in support of this contention. In this it was demonstrated that mechanical stimulation of the frog sciatic nerve tissue produced temporary excitation. Walker appeared to believe that linear acceleration was instrumental in generating the pressure waves within the brain. The recent discoveries of Holbourn (1943) on the role of rotational acceleration in producing shearing forces operating principally at the surface of the brain are acknowledged. Nonetheless, the authors remain skeptical of their value when dealing with animals possessing comparatively small heads and brains. Still, it is conceded that either angular or translational acceleration could be responsible for creating ICP waves which ultimately produce a state of traumatic excitation. Fifty years later, in a commemorative article, Walker revisited the convulsive theory and the problem of the physiology of concussion, in general (Walker, 1994). Judging by this paper, he appeared to have lost confidence in the convulsive hypothesis as a credible explanation for concussion during the intervening years. In particular, he is cognizant of the fact that at the time of publication in 1944, it was still some years before Moruzzi, Magoun, Lindsley and others first established the role of the BSRF/ARAS in the control of wakefulness and responsiveness. 3.5.2. Post-Traumatic Loss of Consciousness get cialis fast information is, likewise, quite useful for athletes at other levels of skill and in other sports where a concussion may occur. Early in the history of formal concussion management, the symptom report of the injured athlete was the only basis upon which practitioners could determine whether the athlete was recovered and when he or she could return to contact sport safely. Currently, there remain practitioners who will evaluate the athlete once after concussion and release the athlete to return to play when he or she is "feeling back to normal." Other earlier methods relied upon concussion grading scales, of which there are currently at least 25 different, though relatively similar versions (see Johnston, McCrory, Mohtadi, & Meeuwisse, 2001). Generally concussion grading scales were designed to rate concussion severity, but were not based upon research, rather upon clinical experiences. The American Academy of Neurology is one of the most frequently used concussion grading scales (AAN, 1997). In this scale, a Grade 1 concussion involves no LOC and fewer than 15 minutes of symptoms. A Grade 2 concussion is characterized by no LOC and greater than 15 minutes of symptoms. Grade 3 concussions are any concussions involving LOC, no matter how brief. The revised Cantu grading scale is the most evidence-based scale in common use (Cantu, 2001). In this scale a Grade 1 concussion involves symptoms lasting less than 30 minutes and no LOC or amnesia. Grade 2 concussions are characterized by less than 1 minute LOC and amnesia or symptoms lasting between 30 minutes and 24 hours prior to resolving. A Grade 3 concussion in this scale involves LOC greater than one minute LOC or amnesia lasting more than 24 hours, and post-concussion symptoms lasting more than one week. cialis tabs 10mg 9 (15%) 1 (4%) cialis online yahoo 110 n 100 cialis ssri lilly cialis coupon When EEG activity is recorded in relation to a specific stimuli, it is called an event related or evoked potential. For example, if a flash of light is viewed by a subject who has one electrode on the rear of his scalp and another on his earlobe, a predictable sequence of voltage variations will be recorded. A very small positive deflection (less than a microvolt) will follow the flash by about 40 msec. This response will be followed by a large negative deflection lasting 10 to 30 msec and peaking around 60 msec after the flash. Immediately following this wave there appears a fairly large, positive wave with a maximum amplitude occurring about 80 msec after the flash. This pattern is quite predictable; it follows each successive light flash, although, it should be stressed, with some variability from flash to flash. By averaging individual stimulus presentations into a grand average, it is possible to note stable response patterns to a variety of stimuli. This succession of waveforms to visual stimulation is termed the visual evoked response. When the distribution of the responses is examined, it is found to be of maximum amplitude over the occipital area of the brain, and to be less widely distributed than most spontaneous rhythms. Other sensory evoked responses also can be demonstrated. A sharp sound reliably produces an auditory evoked response. The response is maximal over the vertex of the brain and usually entirely absent from the occipital area. It has been shown that the brain's response to discrete sounds can be traced from the brain stem to the cortex in recordings from an electrode on the scalp. In such records (termed brain stem evoked responses, or BSERs), a distinct wave of positive voltage reflects each level of neural activity as the effects of the stimulus move through the brain. In the same manner, local stimulation of the skin surface in most body locations results in a somatic evoked potential, the waveform and distribution of which are dependent upon the area stimulated. In general, evoked responses regardless of the nature of the stimulus are referred to as event-related responses or ERPs. Unlike the spontaneous EEG which is recorded in a continuous fashion over a period of time, ERPs are time locked to specific stimuli or responses. In the literature a distinction is sometimes made between endogenous and exogenous ERPs. Exogenous ERPs are seen to be controlled largely by the physical nature of the stimulus itself. Endogenous ERPs, on the other hand, are those that are influenced by the individual's perception or interpretation of the event. Overall, the ERP is smaller in voltage than the EEG and requires averaging procedures over many trials for patterns to be clearly seen. The most common ERP procedure is to time lock the EEG signal to a particular tone or visual stimulus. The basic procedure is to repeat the stimulus a number of times and then average the electrocortical signal to each of these stimuli. This results in a wave that is seen to represent 5.1. generic cialis shipping canada active during different types of processing. Since PET can measure almost any molecule that can be radioactively labeled, it can be used to answer specific questions about perfusion, metabolism, and neurotransmitter turnover. Some of PET's main disadvantages include expense, the need for a cyclotron to create radioactive agents, the injection of radioactive tracers which limit the number of experimental sessions that can be run for a given individual, and limited temporal resolution. Like PET, functional magnetic resonance imaging (fMRI) is based on the fact that blood flow increases in active areas of the cortex. However, it uses a different technology from PET in that in fMRI local magnetic fields are measured in relation to an external magnet. Specifically, hemoglobin which carries oxygen in the bloodstream has different magnetic properties before and after oxygen is absorbed. Thus by measuring the ratio of hemoglobin with and without oxygen, the fMRI is able to map changes in cortical blood and infer neuronal activity. Although fMRI has the same temporal disadvantage as PET, it has a number of advantages including better spatial resolution and the ability to do repeated images on one individual. costo cialis in svizzera Barth, J., Macciocchi, S and Giordani, B. (1983). Neurospsychological sequelae of minor head injury. Neurosuregery, 13, 529-537. Rimel, R., Giodani, B., Barth, J. Boll, T. and Jane, J. (1981). Disability caused by monor head injury. Neurosurgery, 9, 221-223. Thatcher, R.W. & John, E.R. (1997). Functional Neuroscience, Vol /, New Jersey: Erlbaum Associates. Nuwer, M.R. (1997). Assessment of digital EEG, quantitative EEG and EEG brain mapping report of the American Academy of Neurology and the American Clinical Neurophysiology Society. Neurology, 49, 277-292. Hughes, J.R., & John, E.R. (1999). Conventional and quantitative electroencephalography in psychiatry. Neuropsychiatry, 11(2), 190-208. Hoffman, D.A., Lubar, J.F., Thatcher, R.W., Sterman, B.M., Rosenfeld, P.J., Striefel, S., Trudeau, D., and Stockdale, S. (1999). Limitation of the American Academy of Neurology and American Clinical Neurophysiology Society Paper on QEEG. Journal of Neuropsychiatry, and Clinical Neurosciences, 11(3), 401-407. Thatcher, R.W., Moore, N., John, E.R., Duffy, F., Hughes, J.R. and Krieger, M. (1999). QEEG and traumatic brain injury: Rebuttal of the American Academy of Neurology 1997 Report by the EEG and Clinical Neuroscience Society. Clinical Electroencephalograph, 30(3), 94-98. Cooper, R., Osselton, J.W. and Shaw, J.G. (1974). EEG Technology. Butterworth & Co, London. Woody, R.H. (1966). Intra-judge Reliability in Clinical EEG. Journal of Clinical Psychology, 22, 150-161. Woody, R.H. (1968). Inter-judge Reliability in Clinical EEG. Journal of Clinical Psychology, 2^, 151-161. Volavaka, J., Matousek, M., Roubicek, J., Feldstein, S., Brezinova, N., Prior, P. I., Scott, D.F. and Synek, V. (1971). The reliability of visual EEG assessment. Electroenceph. Clin. Neurophysiol., 31,294-302. Majkowski, J., Horyd, W., Kicinska, M., Narebski, J., Goscinski, I., and Darwaj, B. (1971). Reliability of electroencephalography. Polish Medical Journal, 10, 1223-1230. Niedermeyer, E. & Ds Silva, F.L.(1995). Electroencephalography: Basic principles, clinical applications and related fields. Baltimore: Williams & Wilkins. Thatcher, R.W., Biver, C, and North, D. (2003). Quantitative EEG and the Frye and Daubert Standards of Admissibility. Clinical Electroencephalography, 34(2), 39-53. Berger, H. (1929). Uber das Electrenkephalogramm des Menschen. Archiv. Fur. Psychiatric und Neverkrankheiten, 87, 527-570. Nunez, P. (1981). Electrical Fields of the Brain^ Oxford University Press, Cambridge. Nunez, P. (1995). Neocortical dynamics and human EEG rhythms, Oxford University Press, New York. Thatcher, R.W., Krause, P., & Hrybyk, M. (1986). Corticocortical associations and EEG coherence: a two compartmental model. Electroencephalography and Clinical Neurophysiology, 64, 123-143. Arruda, J.E., Weiler, M.D., Valentino, D., Willis, W.G., Rossi, J.S., Stem, R.A., Gold, S.M., Costa, L. (1996). A guide for applying principal-components analysis and confirmatory factor analysis to quantitative electroencephalogram data. International Journal of Psychophysiology, 23(1-2), 63-81. Burgess A, and Gruzelier J. (1993). Individual reliability of amplitude distribution in topographical mapping of EEG. Electroencephalography and Clinical Neurophysiology, 86(4), 219-223. Corsi-Cabrera, M., Solis-Ortiz, S., Guevara, M.A. (1997). Stability of EEG inter- and intrahemispheric correlation in women. Electroencephalography and Clinical Neurophysiology, 102(3), 248-255. cialis alle erbe Kontos, Elbin and Collins cialis prescription toronto Participants were asked to complete a questionnaire regarding height, weight, position, age, grade, and playing status (i.e., starter or non-starter). Information regarding exposures (i.e., attendance and participation in contact practices and games) for each athlete was also obtained weekly from coaches. what happens if a female takes cialis cialis 2.5 reviews To aid with the discussion that follows I will note a few key terms used in the field of EEG. Frequency analysis divides the EEG into its frequency components measured in cycles per second (cps), or hertz (Hz). These can be in any size but are usually in 1 Hz or pre-set standard divisions (eg. 0.53.5, 3.5-8, 8-12, 12-20, 20-30). It is a measure of the amount of energy in each division and is referred to either as power or amplitude (the square root of power). Quantitative EEG (QEEG) refers to measures performed on the raw EEG recording. It encompasses any statistical or mathematical analysis made on the raw EEG recording. The QEEG can also provide graphical representations of the recorded electrical activity showing areas of the head in which specific EEG features are present. A recent development that has greatly advanced the utility of EEG in localizing cortical damage is low-resolution brain electromagnetic tomography (LORETA). The Key Institute for Brain-Mind Research in Switzerland developed the LORETA inverse solution. This procedure computes, from the recorded EEG, the three-dimensional distribution of the electrically active neuronal generators in the brain as a current density value (amplitude/m^) at each voxel (a voxel is the basic unit of computed tomography reconstruction, represented as a pixel in a computed tomography image display) (Korn et al., 2005). Three-dimensional LORETA images consist of 2,394 voxels in total and give a graphic representation of cortical gray matter similar to that of CT and MRI. Computations for source localization of EEG frequencies are limited to cortical gray matter and the hippocampus according to a digitized Probability Atlas (Brain Imaging Centre, Montreal Neurologic Institute). LORETA has been shown to be accurate in its generation of instantaneous scalp potential distribution maps to within 7mm (Korn et al., 2005). For a complete explanation of the LORETA inverse solution and its validation, please refer to Pascual-Marqui et al. (1994), Pascual-Marqui (1999), and Pascual-Marqui et al. (2002). By integrating LORETA into concussion assessment the clinician is given a tool that can detect the location of gray matter damage post MTBI even in the absence of cortical lesions, a process that until now has not been possible. A 16 year old high school linebacker, who has no history of previous concussion or head trauma, runs over to the sideline during the end of the second quarter. He jogs over to the athletic trainer with tears streaming from his face. Known as a hard hitter and the strongest physical player on the team, he has never sought help from the medical team. His only complaint tonight is that he can not stop crying and has no idea why he is doing so. He denies any pain or injury as well as any emotional or psychological stressors at home. He also denies having conflict with any coach or teammate over his play that game. He reports that all he remembers is hitting the running back early in the first quarter to end the drive on a goal line stand. Retrospectively, he also notes that he had some difficulty in making the play call and adjustments during the second quarter. He denies any headache, or other symptom suggestive of a concussion. Upon exam, the player has normal SAC and denies any symptom increase with activity. He has intact memory and recall. The player was removed from the game despite his adamant protest. His coach also was angered and verbally pressured the trainer to return his all-state linebacker to the game. The athlete's parents came down from the stands and also stated matter-of-factly to the medical team that their son was fine and needed to play. Despite this pressure, the medical team stood fast to the decision to remove the athlete from the game. The following day, the athlete's parents took him to his pediatrician, who cleared the athlete because "his symptoms were improving" and recommended that he ease back into things over the next 3 to 4 days. The reason given for the pediatrician's recommendation was that this is the way he did things. Despite the pediatrician's recommendations, the team physician referred the football player for formal neuropsychological testing, the results of which showed major declines in visual speed processing. The athlete also reported a headache following the testing procedure. He was monitored over the course of the next several days, and his emotional state and all other symptoms returned to baseline. He then had an unremarkable exercise challenge. After missing the next seven days of practice and a game, he returned to the season and had no further sequelae. order real cialis by attending practice and communicating with his teammates. He opened the lines of communication between himself and the experimental team which allowed for casual psychological counseling. All of the members of the experimental team possessed a background in Sports Psychology. The athlete received compassion from the experimental team as well as understanding. The experimental team worked diligently to alter the athlete's perspective of his injury. It was important to emphasize the severity of the impact in order to stress the need for a longer recovery. Additionally, in order to decrease the athlete's tendency to engage in bracing behaviors upon return to play, we extensively discussed avoidance and dependency behaviors. This intervention allowed the athlete to return to play with a healthy mentality and continued on to have a successful athletic career. The athlete was coached mentally to revisit the impact that caused the injury, then to take that image and change his perspective from fear to power. Instructing the athlete that bracing or avoidance behaviors increases the risk of injury is essential for an athlete's mental rehabilitation from concussion. If athletic trainers and physicians start incorporating psychological skills training into rehabilitation we may begin to observe fewer cases of multiple concussions among athletes. adcirca vs cialis cialis weekender Guskiewicz, K.M., Ross, S.E., Marshall, S.W. (2001). Postural Stability and Neuropsychological Deficits After Concussion in Collegiate Athletes. Journal of Athletic Training, 36(3), 263-273. Guskiewicz, K. (2003). Assessment of postural stability following sport-related concussion. Current Sport Medicine Reports, 2(1), 24-30. Rieman, B. & Guskiewicz, K. (2002). Effect of mild head injury on postural stability as measured through clinical balance testing. Journal of Athletic Training, 35, 19-25. Valovich, T., Periin, D., Gansneder, B. (2003). Repeat administration elicits a practice effect with the balance error scoring system but not with the standardized assessment of concussion in high school athletes. Journal of Athletic Training, 38(10), 51-56. Peterson, C, Ferrara, M., Mrazik, M., Piland, S., Elliott, R. (2003). Evaluation of neuropsychological domain scores and postural stability following cerebral concussion in sport. Clinical Journal of Sport Medicine, 13(4), 230-237. Kushner, D. (1998). Mild traumatic brain injury: Toward understanding manifestations and tYQdXmtni. Archive of Internal Medicine, 158, 10-24. Povlishock, J. T., Erb, D. E. , & Astruc, J. (1992). Axonal response to traumatic brain injury: reactive axonal change, deafferentation and neuroplasticity, Journal of Neurotrauma, Pfsuppl.l), 189-200. Jahanshahi, M., & Hallett, M. (2003). The Bereitschaftpotential: Movement-related cortical potentials. Kluger Academic/Plenum Publishers. NY. Jasper, H., & Penfield, W. (1949). Electrocorticograms in man: effect of voluntary movement upon the electrical activity of the precentral gyrus. Arch.Psychiat. Vol.183, pp. 163-174. Pfurtscheller, G. (1981). Central beta rhythm during sensory motor activities in man. EEC and Clinical Neurophysiology, 51, 253-264. Sheer,D.E. (1976). Focused arousal and 40 Hz-EEG. In R. M. Knight and D. J.Bakker (Eds.), The Neuropsychology of Leaning Disorders, (pp. 71-87). University Park Press, Baltimore. Basar,E., & Demiralp, T. (1995). Fast rhythms in the hippocampus are a part of the diffuse gamma response system. Hippocampus, 5, 240-241. Tallon-Baudry, C , Bertrand, O., Delpuech, C, & Pernier, J. (1996). Stimulus specificity of phase-locked and non-phase-locked 40 Hz visual responses in human. Journal of Neuroscience,16(3), 4240-4249. Tallon-Baudry,C., Bertrand, O., Delpuech, C, & Pernier, J. (1997). Oscillatory gamma-band (30-70 Hz) activity induced by a visual search task in humans. Journal ofNeuroscience, 17(2), 722-734. Slobounov, S., Tutwiler, R. Slobounova, E. (1998c). Perception of postural instability as revealed by wavelet transform. IEEE Signal Processing, 12(5), 234-238. Geets,W., & Louette, N (1985). Early EEG in 300 cerebral concussions. EEC and Clinical Neurophysiology, 14(4 ),333-33S. Tebano, T. M., Cameroni, M., Gallozzi ,G., Loizzo, A., Palazzino, G., Pessizi, G., & Ricci, G. F. (1988). EEG spectral analysis after minor head injury in man. EEG and Clinical Neurophysiology, 70, 185-189. Pratar-Chand, R., Sinniah, M., & Salem, F. A. (1988). Cognitive evoked potential (P300): a metric for cerebral concussion. Acta Neurologia Scandinavia, 78, 185-189. Watson, W. R., Fenton, R. J. , McClelland, J., Lumbsden, J., Headley, M., & Rutherford, W. H. (1995). The post-concussional state: Neurophysiological aspects. British Journal of Psychiatry, 167, 514-521. Thatcher, R. W., Biver, C , McAlister, R., Camacho, M., Salazar, A. (1998). Biophysical linkage between MRI and EEG amplitude in closed head injury. Neuroimage, 7, 352367. Thornton, K. E. (1999). Exploratory investigation into mild brain injury and discriminant analysis with high frequency bands (32-64 Hz). Brain Injury, 13(7), 477-488. improved during the same time frame. More importantly, Echemendia et al found that while neuropsychological test scores could statistically differentiate between concussed and non-concussed athletes at 48 hours, post concussion symptoms as measured by the standard Post-Concussion Symptom Scale, could not differentiate the groups. This finding was important because it helped to expose the problems with relying exclusively on symptoms to determine return to play. McCrae and his colleagues (2002) used a "sideline" cognitive screening instrument (Standardized Assessment of Concussion-SAC) in combination with selected traditional neuropsychological measures with college students and found that concussed athletes' SAC scores were significantly lower than baseline when compared to non-concussed athletes. Individual measures revealed lower scores in memory and concentration. All scores returned to baseline within 48 hours of injury, which stands in contrast to the findings from all previously reported studies using neuropsychological batteries, which showed deficits in functioning up to 7 days following injury. The findings highlight the complimentary nature of brief screening instruments and the more comprehensive batteries. Screening instruments are useful on the sideline and during the acute phase of recovery whereas test batteries more effectively identify enduring neurocognitive deficits. The advent of computerized test platforms helped to revolutionize Sports Neuropsychology. At present there are four major computerized platforms that have been used in sport concussion management: ImPACT (Immediate Post Concussion Assessment and Cognitive Testing), CogSport, Headminder Concussion Resolution Index, and the Automated Neuropsychological Assessment Metrics Sports Medicine Battery AMSB). Each of these batteries is thoroughly discussed elsewhere (Echemendia, 2006). In general, these batteries provide distinct advantages over the traditional "paper and pencil" measures because they allow for relatively rapid standardized assessment of large numbers of athletes in a cost-effective manner (Schatz & Zillmer, 2003; McKeever & Schatz, 2003). Although different in their content, each of these batteries allows for a thorough assessment of simple and complex information processing speed, which has been shown to be a key deficit following concussion. While exceedingly useful, computer-based assessment minimizes interactions between the athlete and the neuropsychologist thereby reducing qualitative information about the player's cognitive functioning. Similarly, computer-based assessment is limited in the ability to examine the process by which injured athletes solve problems, learn and remember information, which has been shown to be useful in the assessment of concussed athletes (e.g. Bruce & Echemendia, 2006). Hybrid concussion management programs, such as that used at Penn State and Princeton University, employ a combination of paper and pencil and computer based assessment. The Princeton program, which has been buy cialis once day enalapril y cialis quite useful clinically, uses computer based assessment at baseline with computer-based and paper and pencil tests used following injury. Computer based assessment has generated a rich literature in the neuropsychological study of concussion. For example, Collins et al. (2003) examined on-field predictors of neuropsychological functioning and symptom complaints in a large sample of concussed high school and college athletes. Using ImPACT at 3 days post injury, they found that athletes with "poor" outcome were 10-times more likely to have exhibited on-field retrograde amnesia and four times more likely have demonstrated any onfield traumatic amnesia. No effect was found for loss of consciousness. Erlanger and colleagues employed the Headminder CRI computer battery and found that cognitive impairment at initial post-concussion assessment (when compared to baseline) is a significant predictor of duration of postconcussion symptoms (Kaushik & Erlanger, 2006). Bleiberg and colleagues have used the ASMB replicate earlier findings by Echemendia et al (2001), showing that impairment in cognitive functioning was apparent on the day of injury and 1-2 days postinjury, with recovery over a 3-7 day period. They noted that the differences between the groups were not necessarily due to a decrement in functioning in the concussed group but either absent or restricted practice effect in the concussed group when compared to controls (Bleiberg et al., 2004). The same pattern was observed when concussed athletes with a history of concussion were compared to those with no history of concussion. When examined 24 hours after injury, control subjects and injured athletes with no history of concussion showed practice effects but concussed athletes with a history or previous concussions did not (Bleiberg et al, 2006). Neuropsychological test batteries with children have corroborated animal laboratory studies (McDonald & Johnson, 1990; McDonald, Silverstein & Johnson, 1988) that have suggested that the effects of MTBI in children are quite different from the effects in adults. Several studies (Field et al., 2003, Lovell et al., 2003; Moser & Schatz, 2002) reported that high school students have an extended period of neurocognitive recovery when compared to college athletes. Field et al. found significant memory impairment in high school students 7 days following injury whereas their college sample recovered memory functioning within 24 hours of injury. Similarly, Lovell et al. (2003) found that younger athletes may be more vulnerable to concussion when compared to college students with high school students requiring at least 7 days for full neurocognitive recovery and a minimum of 4 days for symptom resolution following a minor "ding." Neuropsychological testing with children also requires more frequent administration of "baseline" tests due to the effects of cognitive maturation. acheter cialis en ligne forum Dialog with Collegiate Coaches cialis one a day cost It is the responsibility of all to make ethical and moral decisions about how best to make use of the results of scientific investigations. OH acheter cialis en suisse I. Human Organization cialis youtube commercial comment utiliser le cialis Mader: Human Biology, Seventh Edition is it safe to buy cialis from canada Lipids are varied in structure and function. Fats and oils, which function in long-term energy storage, contain glycerol and three fatty acids. Fatty acids can be saturated or unsaturated. Plasma membranes contain phospholipids that have a polarized end. Certain hormones are derived from cholesterol, a complex ring compound. 2.8 Nucleic Acids buy cialis japan song from cialis commercial 2011 Electron micrographs of nuclear envelope showing pores. environmental change how much is cialis in australia canine (1) incisors (2) a. b. does cialis work first time Maintenance of the Human Body cialis fast acting cialis taken with food Maintenance of the Human Body cialis campaign Maintenance of the Human Body once a day cialis reviews Red blood cells (erythrocytes) are small, biconcave disks that lack a nucleus when mature. They occur in great quantity; there are 4 to 6 million red blood cells per mm3 of whole blood. The absence of a nucleus provides more space for hemoglobin. Hemoglobin is called a respiratory pigment because it carries oxygen, and is red. A red blood cell contains about 200 million hemoglobin molecules. If this much hemoglobin were suspended within the plasma rather than enclosed within the cells, blood would be so viscous that the heart would have difficulty pumping it. In a hemoglobin molecule, the iron portion of hemoglobin carries oxygen, a molecule that cells require for cellular respiration (Fig. 6.3c). The equation for oxygenation of hemoglobin is usually written as lungs Hb + O2 tissues The hemoglobin on the right, which is combined with oxygen, is called oxyhemoglobin. Oxyhemoglobin, which forms in the lungs, has a bright red color. The hemoglobin on the left, which has given up oxygen to tissue fluid, is called deoxyhemoglobin. Deoxyhemoglobin is a dark maroon color. Unfortunately, as discussed in the Ecology Focus on page 114, carbon monoxide combines with hemoglobin more readily than does oxygen, and it stays combined for several hours, making hemoglobin unavailable for oxygen transport. HbO2 cialis black 800 mg reviews multipotent stem cells lymphoid stem cells red blood cell anti-Rh antibody generic cialis shipping to canada a. Muscle contraction exerts pressure against the vein, and blood moves past the valve. b. Blood cannot flow back once it has moved past the valve. cialis profesional generico cialis medication interactions renal vein cialis sicher online kaufen Does an employer who provides you with health insurance have the right to require you to have a healthy lifestyle? 148 cialis drunk brand cialis 10mg 150 cialis maximum daily dosage heavy chain 9. Respiratory System cialis peak effect time b. tadalista vs cialis In females, there is no connection between the reproductive and urinary systems. In males, the urethra carries urine during urination and sperm during ejaculation. This double function of the urethra in males does not alter the path of urine (Fig. 10.2). Only the urinary system, consisting of the kidneys, the urinary bladder, the ureters, and the urethra, holds urine. comprare cialis 5 mg proximal convoluted tubule podocyte glomerulus afferent arteriole juxtaglomerular apparatus distal convoluted tubule glomerular capsule efferent arteriole is cialis prescription only overdose cialis effects Chapter 11 cialis 1mg Figure 11.1 Anatomy of a long bone, from the macroscopic to the microscopic level. cheapest cialis 10mg compact bone cialis philippines price Jaws contain teeth that chew food Key Term Flashcards vocabulary quiz Chapter Quiz objective quiz covering all chapter concepts price of cialis in singapore cialis negative effects peroneus longus cialis sans ordonnance paris Skeletal Muscles of the Body how much is cialis uk Marieb, E. N. 1999. Human anatomy and physiology. 4th ed. Redwood City, Calif.: Benjamin/Cummings Publishing. A thorough anatomy and physiology text that can safely be used as a complete and accurate reference. Marion, R. September 1999. Emergency room terror. Discover 20(9):44. Article discusses osteogenesis imperfecta, a disease that results in easily fractured bones in children. Melton, L. July 2000. Age breakers. Scientific American 283(1):16. A compound has been developed that might rejuvenate hearts and muscles by breaking the sugar-protein bonds that accumulate with aging. Pennisi, E. March 6, 1998. Bone marrow cells may provide muscle power. Science 279(5356):1456. Researchers show that bone marrow cells can move into damaged muscle and grow into new muscle fibers in mice. Rogers, M. J. January 2000. Statins: Lower lipids and better bones? Nature Medicine 6(1):21. A recent study suggests that statins could be developed into new treatments for common metabolic bone diseases such as osteoporosis. Rome, L. C. July/August 1997. Testing a muscle's design. American Scientist 85(4):356. Muscular systems adapt to specific functions, such as the specialized muscles found in frogs. Science, September 1, 2000. Bone remodeling and repair. 289(5484):1497. Several articles in this section discuss bones, bone repair, and the future of tissue engineering in bone repair. Tortora, G. J. 1996. Atlas of the human skeleton. New York: HarperCollins Publishers. This supplement contains carefully selected and labeled photographs of the human skeleton. White, R. J. September 1998. Weightlessness and the human body. Scientific American 279(3):58. Space medicine is providing new ideas about treatment of osteoporosis and anemia. Wolkomir, R. August 1998. Oh, my aching back. Smithsonian 29(5):36. 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Still, the two cerebral hemispheres are connected by a bridge of tracts within the corpus callosum. Shallow grooves called sulci (sing., sulcus) divide each hemisphere into lobes (Fig. 13.10). The frontal lobe is toward the front of a cerebral hemisphere, and the parietal lobe is toward the back. The occipital lobe is dorsal to (behind) the parietal lobe, and the temporal lobe lies below the frontal and parietal lobes. The Cereal Cortex The cerebral cortex is a thin but highly convoluted outer layer of gray matter that covers the cere- price cialis philippines retina choroid sclera ciliary body retinal blood vessels optic nerve lens iris pupil fovea centralis cornea anterior compartment filled with aqueous humor posterior compartment filled with vitreous humor youtube cialis commercial IV. 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Niacin (a component of vitamin B complex) occasionally is used to dilate blood vessels in the hope that this will reduce the problem. Benzodiazepines, the class of medications that includes diazepam (Valium®), clonazepam (Klonopin®), and oxazepam (Serax®), directly suppress the structures of the inner ear that stimulate dizziness. They are potent antidizziness treatments but they cialis eu kaufen Glossary cialis cardiovascular t r i g g e r s cialis for women canada c o n t r o l Ia Q Ia Soleus Post- activation depression H reflex MEP PAD INs Sol MN Contraction Rest Fig. 2.12. Evidence for post-activation depression in normal subjects. (a ) Sketch of the pathway for post-activation depression at the Ia-motoneurone (MN) synapse of soleus (Sol), and of heteronymous Ia facilitation from quadriceps (Q) to Sol. The pathway of presynaptic inhibition of Ia terminals is also represented (PAD INs). (b) The size of the Sol H reflex (●) and the amount of femoral-induced facilitation (1 MT, – 5.4 ms ISI, ❍) of the Sol H reflex, both expressed as a percentage of their control value, are plotted against the time after the end of a passive dorsiflexion (dotted line at the bottomof the panel, 10 ◦ in 600 ms, too slowand too small to evoke any EMG activity). (c ) The size of the soleus H reflex (as a percentage of its value when elicited at an interstimulus interval [ISI] of 15 s) is plotted against the ISI between two consecutive stimuli at rest (●) and during Sol voluntary contraction (❍). (d ), (e ) The size of the Sol H reflex at ISIs of 1, 2 and 15 s (as a percentage of its value at the 15-s ISI) at rest () and during voluntary contraction () before (d ) and 25 minutes after ischaemia by cuff around the upper part of the leg (e). (f) Sketch of the pathways explored in (g )–(j ). (g )–(j) The size of the MEP ((g ), (h )) and of the H reflex ((i ), (j )) of the flexor carpi radialis (FCR) are compared before (, (g ) and (i )) and 2 s after passive wrist extension (filled columns, (h ) and (j )). Modified from Hultborn & Nielsen (1998), with permission. Post-activation depression 99 subthreshold for the H reflex or tendon jerk (T´ abor´ıkov´ a & Sax, 1969; Katz et al., 1977; Crone & Nielsen, 1989). Depression during voluntary contraction During voluntary contraction of the tested muscle the depression is attenuated (Rothwell, Day &Mars- den, 1986; Burke, Adams & Skuse, 1989; Hultborn & Nielsen, 1998; Fig. 2.12c). The most parsimonious explanation for this is that the enhanced Ia firing during voluntary contraction (see Chapter 3, pp. 133–5) causes a background level of post-activation depression, and this can only be enhanced slightly by the additional depression caused by a preced- ing H reflex. This interpretation is supported by the finding that the difference between the amount of post-activation depression observed at rest and during contraction (Fig. 2.12(d ), , ) disappears when the activity of Ia afferents is blocked by ischaemia (Hultborn & Nielsen, 1998; Fig. 2.12(e )). That the H reflex is still facilitated during con- traction indicates that other mechanisms outweigh the reduction caused by the background post- activation depression. These mechanisms include increased motoneurone excitability and, for the H reflex, decreased inhibitory mechanisms gating the test volley. Driving spindle afferents by vibration of the muscle tendon does not similarly abolish post- activation depression of the H reflex (Van Boxtel, 1986) but this could be due to the additional presy- naptic inhibition of Ia terminals produced by vibra- tion (see Chapter 8, p. 341). Reflexes elicited in small motoneurones Reflexes elicited in small motoneurones are more sensitive to post-activation depression, in agree- ment with animal data (see above). As a result, the decline of the reflex response when increasing the stimulus rate is greater for soleus H reflexes of small than of large size (Floeter & Kohn, 1997). This difference in susceptibility to homosynaptic depression may serve to concentrate the damping effect upon those motoneurones that are the most likely to be activated by small stretches or pertur- bations, without disabling the stretch responses of higher-threshold motoneurones. The weaker sen- sitivity to post-activation depression of reflexes elicited in high-threshold motoneurones could also account for the lesser susceptibility of FCR H reflexes to high stimulus rates (Rossi-Durand et al., 1999). Post-activation depression in spastic patients Decreased post-activation depression in spastic patients The depression produced by passive dorsiflex- ion is much less pronounced in spastic patients with spinal cord lesion(s), whether due to trauma or multiple sclerosis, than in healthy subjects (Fig. 2.13(a ); Nielsen & Hultborn, 1993; Nielsen, Petersen & Crone, 1995; Hultborn & Nielsen, 1998). Similarly, the amount of post-activation depression of the FCRand soleus Hreflexes, assessed as the size of the H reflex elicited every 2 s and expressed as a percentage of its value when elicited every 8 s, is significantly reduced on the affected side of hemi- plegic patients. In contrast, the depression is sim- ilar on their unaffected side and in normal subjects (Fig. 2.13(b ), (c ); Aymard et al., 2000). Post-activation depression and pathophysiology of spasticity The reduction of post-activation depression would enhance the synaptic efficacy of trains of Ia impulses and could contribute to the stretch reflex exag- geration that characterises spasticity. As empha- sised by Hultborn and Nielsen (1998), the decreased depression seen in patients with a lesion of the central nervous system does not necessarily imply that post-activation depression is under direct control by descending pathways. Several lines of evidence suggest that adaptive changes in the 100 Monosynaptic Ia excitation (a) (b) (c) Fig. 2.13. Reduction of post-activation depression in spastic patients. (a) The mean value (±SEM) of the soleus H reflex (expressed as a percentage of its control value) plotted against the time after the onset of passive dorsiflexion of the foot (illustrated by the dotted line at the bottom of the panel, 10 ◦ in 600 ms, too slow and too small to evoke any EMG activity) in 30 healthy subjects (●) and 17 spastic patients with multiple sclerosis or spinal cord injury (❍). (b), (c) The mean value (÷SEM) of the FCR (b ) and soleus (c ) H reflex elicited every 2 s, and expressed as a percentage of its value when elicited every 8 s, is compared in 16 normal subjects () and on the affected () and unaffected (dashed columns) of hemiplegic patients (n =16 in (b), and 10 in (c)). Modified from Hultborn & Nielsen (1998) (a ), and Aymard et al. (2000) ((b ), (c )), with permission. efficacy of the Ia-motoneurone synapse develop following the changes in activity of motoneurones and Ia fibres resulting from the impairment of the motor command. (i) The fact that spastic- ity progresses during weeks or months after the causal lesion (whether a spinal lesion or stroke) fits this hypothesis, because such adaptive changes develop over time. (ii) In this respect, a longitu- dinal study of one patient with spinal cord injury found that the reduction of post-activation depres- sion developed with the transition from flaccid to spastic paralysis, even though reduced post- activation depression preceded clinically observ- able spasticity (Schindler-Ivens & Shield, 2000). (iii) Contrary to several other electrophysiological changes explored (see Chapter 12, pp. 577–9), post- activation depression is unchanged on the unaf- fected side of patients with hemiplegia (Fig. 2.12(b ), (c ), dashed columns). (iv) The synaptic efficacy of primary afferents can be up- or down-regulated by disuse or use of synapses, respectively (Gallagoet al., 1979). Conclusions Role of monosynaptic Ia excitation in natural motor tasks The short-latency spinal stretch reflex This reflex has beenextensively investigatedinankle extensors, where it contributes to rapid automatic load compensation in various motor tasks such as running, hopping, landing, walking and standing by helping the stabilisation of the supporting limb. Available data concerning the functional role of the stretch reflex in other muscles are more sparse, and it would be important to investigate the role of the short-latency spinal stretch reflexes for muscles operating at knee and hip level in natural tasks. In the upper limb, the well-developed homonymous monosynaptic Ia excitation of muscles operating at the wrist and elbow suggests that these connections could be used to compensate rapidly and automat- ically for errors in the programmed movement, but R´ esum´ e 101 so far experiments have focused on the role of the long-latency stretch reflex rather than the spinal reflex pathway. Heteronymous monosynaptic Ia connections In the cat and the baboon hindlimb these connec- tions link motoneurones of muscles acting syner- gistically at the same joint but, in the human lower limb, these connections are more widespread and transjoint connections are almost the rule. The more widespread distribution of Ia connections found in the human lower limb could have evolved to pro- vide the more elaborate reflex assistance required for bipedal stance and gait, inwhichthe equilibrium is less stable than in quadrupeds. In the upper limb, there is also a different organisation, with absence of the proximal-to-distal projections used in feline locomotion, but withstrong projections fromintrin- sic hand muscles to muscles acting at the wrist and elbow, projections which serve to stabilise the limb for manipulatory tasks. Changes in monosynaptic Ia excitation in patients Reflex attenuation A decrease in the amplitude (and an increase in the latency) of the H reflex ocurs in various radicu- lopathies, plexus and nerve lesions, and in polyneu- ropathies, and will occur when there is loss of con- ducting afferents and/or dispersion of the afferent volley. Spasticity In spasticity the H max /M max ratio is increased in soleus, but is largely unchanged in FCR. Post- activation depression following previous activation of Ia fibres is reduced in spastic patients. This reduc- tion could be a consequence of altered use due to motor impairment, and may be an important spinal mechanism underlying spasticity. R´ esum´ e Importance of studies of Ia connections Several reasons account for the continuing interest instudies of monosynapticIaexcitationof motoneu- rones. (i) One objective of the study of reflexes is to trace the effects of a given input. The monosynaptic exci- tationof Iaafferents occurs without aninterneurone, and therefore constitutes the simplest example of reflex function. (ii) It is a challenging problem to understand how different feedback systems have adapted to evolu- tionarydemands for changedpatterns of movement, and here again investigations of the distribution of monosynaptic Ia connections provides the easiest way to approach evolutionary changes. (iii) They are technically the easiest to study because Ia effects are the first to appear inmotoneu- rones after peripheral stimulationanddosowiththe lowest threshold. (iv) ␥-innervation modulates the sensitivity of spindle endings and the resulting Ia discharges, and it is likely that this modulationhelps maintainmove- ment (see Chapter 3). (v) Reduction of post-activation depression at the Ia-motoneurone synapse could be one of the main spinal mechanisms underlying spasticity. As discussed below, there is little doubt that the monosynaptic Ia pathway contributes to the spinal stretch reflex, but whether it is the sole input driving the reflex discharge is debatable. With this caveat, the following focuses on the Ia contribution. Background fromanimal experiments Ia afferents originate from the primary endings of muscle spindles, and are sensitive to muscle stretch and high-frequency vibration. They have excitatory monosynaptic projections to homony- mous motoneurones, and this constitutes the exci- tatory pathway underlying the tendon jerk and the 102 Monosynaptic Ia excitation short-latency spinal stretch reflex. Projections are stronger on motoneurones innervating slow-twitch units than on those of fast-twitch units. Heterony- mous projections are weaker than homonymous projections, and exist to motoneurones of close syn- ergists operating at the same joint. Transjoint con- nections are more developed in the forelimb than in the hindlimb of the cat. Methodology Homonymous monosynaptic Ia excitation Evidence for a two-neurone arc in the human soleus Stimulation of the posterior tibial nerve produces a synchronised response in the soleus muscle, and this has become known as the Hoffmann reflex or H reflex. Recordings of the action potentials fromboth dorsal and ventral roots intrathecally have demon- strated that the first motoneurones discharging in the soleus H reflex may do so at a latency consistent with a monosynaptic pathway. Besides the mono- synaptic latency, several arguments indicate that the pathway is fed by Ia afferents: low electrical thresh- old, similar excitationelicitedby atapontheAchilles tendon, facilitation by a homonymous volley to the inferior branch of the soleus nerve, and simulta- neous blockade by ischaemia of the homonymous facilitation and of the Achilles tendon jerk. Routine diagnostic studies In routine studies there is a number of advantages of studying the H reflex during voluntary contrac- tion, because it is then possible to record the reflex invirtually all accessible limb muscles, to reduce the latency variability, to increase the stimulus rate, and to direct the reflex response to the active motoneu- rone pool. PSTH method Stimulation of the parent nerve evokes an early peak in PSTHs with the characteristics of homonymous monosynapticIaexcitationinall limbmuscles tested (same latency as the H reflex after allowance for the trigger delay of the unit, lowthreshold, elicitation by tendon taps). Critique By analogy with the soleus H reflex, the H reflex and the early peak in the PSTHs of single units in other muscles are probably evoked by Ia afferents with a monosynaptic linkage. However, so far, unequivo- cal evidence for a 'two-neurone-arc' in humans has been presented only for the soleus H reflex. Heteronymous monosynaptic Ia excitation Heteronymous facilitation of the H reflex H reflex studies do not allow reliable assessment of the central delay of the resulting facilitation. PSTHs of single motor units The principle is to compare the latencies of the early facilitation evoked in the same unit by stimulation of homonymous and heteronymous nerves. The dif- ference between the two latencies must reflect the differences in the afferent conduction times and in the central (synaptic) delay of the Ia effects of the homonymous and heteronymous volleys. If, like homonymous excitation, heteronymous excitation is mediated through a monosynaptic pathway, the difference in latencies between heteronymous and homonymous peaks should be explained by the dif- ference in afferent conduction times. Afferent con- ductiontimes for the Ia homonymous andheterony- mous volleys can be estimated from the distance from stimulation sites to the arrival of the afferent volleys at the spinal cord, as measured on the skin, andtheconductionvelocityinIaafferents. Thevalid- ity of the calculation depends on the reliability of these estimates. Bidirectional connections To eliminate uncertainties inestimates of peripheral conduction times, studies have been performed on R´ esum´ e 103 Ia connections linking a pair of motor units in two different muscles (e.g. soleus and peroneus brevis). Inthis case, thehomonymous volleyfor onemember of the pair is the heteronymous volley for the other, and vice versa. The absolute value of the difference in afferent conduction times is the same for the two members of the pair. Such studies provide cogent evidence for heteronymous monosynaptic connec- tions, independent of estimates of peripheral affer- ent conduction times. Facilitation of the on-going EMG Some heteronymous monosynaptic Ia connections described in PSTH experiments are sufficiently strong to be demonstrable in averages of unrectified on-going voluntary EMG activity. Ia afferent origin Besides the monosynaptic connection, several fea- tures argue that the heteronymous pathway is fed by Ia afferents: low electrical threshold, similar excita- tion elicited by a tendon tap, increase in the thresh- oldof theexcitationbylong-lastingvibrationapplied to the tendon of the 'conditioning' muscle, a man- oeuvre that raises the threshold of Ia afferents, and inability of cutaneous stimulation to reproduce the early peak of excitation. The difference between the stimulus intensity required for the full recruitment of Ia afferents in cat and human experiments (2 Ia threshold and 8 Ia threshold, respectively) is due to the fact that, in human experiments, the afferents are stimulated through surface electrodes at a distance from the nerve. This factor is important because: (i) the 'true monosynaptic latency' can only be disclosed at intensities much greater than 1 MT; and (ii) if some Ia afferents are only activated by such strong stimuli, the potential Ia reflex contri- bution may have been underestimated in previous human studies performed with stimulus intensities ≤1 MT. Organisation and pattern of connections Homonymous monosynaptic Ia excitation In virtually all limb muscles, stimulation of the par- ent nerve can elicit an H reflex and a peak of mono- synaptic Ia excitation in PSTHs of single motor units during voluntary contractions. At rest, H reflexes can be recorded from the soleus, quadriceps and FCR in healthy subjects. The ease with which the H reflex can be elicited at rest and the size of the peak of excitation elicited by stimulation subthresh- oldfor thecompoundHreflexarecloselyrelated. The efficacy of the monosynaptic Ia input in activating motoneurones depends on its preferential distribu- tiontoearly recruited(small) motoneurones inmost muscles (Henneman's size principle), and inhibitory mechanisms limiting the efficacy of the Ia volley (e.g. presynaptic inhibition of Ia terminals; contamina- tionof monosynaptic EPSPs by oligosynaptic IPSPs). Heteronymous monosynaptic Ia excitation Lower limb In the human lower limb, in striking contrast with datafor thecat hindlimb, connectionsbetweensome close synergists operating at the same joint (e.g. the different heads of triceps surae) are weak or absent. This pattern is consistent with weaker connec- tions in the baboon than the cat. Conversely, trans- joint connections are rare in the cat and baboon hindlimb, but are almost the rule inthe humanlower limb. These transjoint connections can be strong, e.g. gastrocnemius medialis to biceps femoris. They often link a muscle or group of muscles to a pair of antagonistic muscles operating at another joint, e.g. quadriceps onto all tested muscles acting at the ankle. Upper limb The upper limb lacks the proximal-to-distal trans- joint connections used in feline locomotion, while distal-to-proximal connections, in particular from 104 Monosynaptic Ia excitation intrinsic hand muscles, are stronger and more widespread than in the cat. Maturation of Ia connections during development It has been reported that, in the normal newborn baby, atendontapmayelicit short-latencyheterony- mous excitatory responses in antagonistic muscle pairsintheupper andlower limbs(e.g. bicepsandtri- ceps brachii) at monosynaptic latencies. However, it would be prudent to retain reservations about these conclusions (see p. 86). This 'reciprocal excitation' disappears during the first years of life. Motor tasks and physiological implications Muscle stretch elicits a reflex response from the corresponding motoneurone pool, and this has at least two separate components: the classical short- latency spinal reflex (M1), the latency of which is compatible with monosynaptic Ia excitation, and a medium-latency component (M2) of more complex origin. The short-latency spinal stretch reflex during natural motor tasks The spinal stretch reflex utilises the simplest reflex pathway and interacts with pre-programmed and other reflex mechanisms to compensate for distur- bances during natural motor tasks. There is con- siderable literature about the contribution of the short-latencystretchreflexof triceps suraetovarious natural movements, but few data for other muscles. Running, hopping and landing Duringthestancephaseof runningandhoppingand after the impact of landing, the short-latency spinal stretch reflex of the triceps surae is superimposed on pre-programmed activity and contributes to the musclecontractionresponsiblefor thepushingoff of the foot. There is probably also a concomitant short- latency stretch response in the quadriceps. Walking The spinal stretch reflex can produce a mechani- cally effective contraction and provides a pathway through which rapid automatic load compensation to an unexpected disturbance can be generated. Short-latency stretch reflexes in triceps surae, trig- gered by unexpected ankle joint displacement, con- tribute significant stabilisation of the supporting limb during walking. Heteronymous Ia connections between ankle muscles that are not synergistic in flexion–extension movements probably contribute further to the stability of the ankle. Perturbations of upright stance Perturbationsof theupright stanceinsubjectsstand- ing on a rotating platform produce an early spinal stretch reflex response (M1), which is prominent in soleus. After loss of large-diameter muscle spindle afferents, M1 is absent but posture is quite stable, suggesting that M1 is not essential for equilibrium control during quiet stance. Spinal and transcortical stretch reflexes The medium-latency (M2) response to stretch fol- lowing the early spinal (M1) response has a different origininvarious muscles: intheflexor pollicis longus (and intrinsic muscles of the hand) the long latency is due to a transcortical pathway fed by Ia afferents, whereas infoot and leg muscles the stretchresponse is mediated through a spinal pathway fed by slowly conductinggroupII afferents. Bothtranscortical and spinal group II pathways could contribute to the M2 response in proximal upper limb muscles, such as the biceps brachii. Heteronymous monosynaptic Ia excitation There are little experimental data on the functional role of heteronymous Ia connections. However, the R´ esum´ e 105 different organisation of these connections in the cat and baboon hindlimb and the human lower limb suggests that the connections are functionally important, having adapted to provide the particular reflex assistance required in each species. Weak connections between ankle extensors The weakness of the connections between ankle extensors in human subjects may be related to the role of triceps surae in walking: it resists and brakes the passive ankle dorsiflexion produced by extrinsic forces (kinetic force and gravity), but must be over- come by these forces if the body is to be brought forward. It would then be undesirable to have exces- sive activity fromthe triceps surae stretchreflex, and weak Ia connections between the different heads of the muscle would help ensure this. Transjoint connections Widespreadtransjoint connections inthe lower limb have probably evolved to provide the more elabor- ate reflex assistance required in bipedal stance and gait, inwhichequilibriumis muchless stable thanin quadrupedal stance and gait. Some of these connec- tions are weak, but their strength has been under- estimated in experimental studies and, in any case, this would not prevent them from modulating the excitability of motoneurones that are already depo- larised. During the stance phase of running, hop- ping and landing, all extensors undergo a lengthen- ingcontractionthat evokes astrongIadischarge, and it is probable that the extensive Ia connections link- ing muscles across joints modulate the role played by the different muscles in load compensation. Projections onto antagonists operating at another joint These projections are desirable functionally because of the versatile synergisms required to accomplish the various tasks of the human lower limb (e.g. co-contraction of quadriceps and gastrocnemius- soleus in running and hopping, but of quadriceps and tibialis anterior when leaning backward). On the other hand, diffuse Iaconnections couldbecome functionally inconvenient, because the activation of Iaafferents fromacontractingmusclemight result in theautomaticunwantedactivationof muscleslinked by Ia synergism. Suppressionof unwantedheterony- mous Ia discharges canbe achievedthroughfocused corticospinal control of presynaptic inhibition of Ia terminals and of recurrent inhibition. The need for this control suggests that the heteronymous Ia discharge does play a functional role, because it must be suppressed in tasks for which it is not required. Upper limb The diffuse distribution of the Ia projections from intrinsic hand muscles and the finding that they are stronger on muscles operating at the wrist than on long flexors and extensors of the fingers suggest that these projections might be used to stabilise the wrist to provide a firm support to hand muscles during manipulatory movements. Studies in patients and clinical implications In practice, assessing Ia connectivity involves meas- urements of the H reflex. There are a number of advantages of doing so during voluntary contrac- tions (see above). Modulation of the on-going EMG by a heteronymous volley may allow access to a motoneurone pool by afferent inputs that donot tra- verse the same nerve or nerve root as homonymous afferents. Peripheral neuropathies, mononeuropathies and nerve lesions These may be accompanied by a decrease in the amplitude and an increase in the latency of the H reflex. Reflex depression usually results from an afferent abnormality and will occur when there is either a loss of conducting afferents or dispersion of 106 Monosynaptic Ia excitation the afferent volley. Tests of reflex function provide a tool todistinguishbetweenisolatedperipheral nerve lesions and lesions involving roots or plexus. Spasticity The ratio H max /M max is, on average, increased in soleus but not, or hardly so, in FCR in hemiplegics. Post-activation depression at the Ia-motoneurone synapse Background fromanimal experiments It has long been known that the size of the mono- synaptic reflex decreases when it is repeatedly elicited. This results from a decrease in transmit- ter release due the repetitive activation of the Ia- motoneurone synapse. The results from a variety of preparations indicate the presence of an early facili- tationof relativelyshort durationsuperimposedona depressionof muchlonger duration. Post-activation depressionhelps tomaintainthe synaptic efficacy of the Ia-motoneurone synapse at a relatively low level during voluntary movements. Methodology Passive stretch Passive stretch of the tested muscle depresses the H reflex, a phenomenon confined to the Ia pathway activated by the passive stretch. There is experimen- tal evidence that this depression is not due to pre- synaptic inhibition of Ia terminals with primary afferent depolarisationor topost-synapticinhibition of the motoneurones. Increasing the stimulus rate This produces a reflex depression that is prominent at relatively high stimulus rates (>0.3 Hz), lessens when the stimulus rate is decreased, and disappears at stimulus rates below 0.1 Hz. 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P. & Stein, R. B. (1999). What function do reflexes have during human locomotion? Progress in Neurobiology, 58, 185–205. Zhu, Y., Starr, A., Su, S. H., Woodward, K. G. & Haldeman, S. (1992). The H-reflex to magnetic stimulation of lower-limb nerves. Archives of Neurology, 49, 66–71. 3 Muscle spindles and fusimotor drive: microneurography and other techniques The muscle spindle has intrigued physiologists since it was first described anatomically more than 100 years ago. Its in-parallel response during twitch contractionsof musclewasdefinedin1933byB. H. C. Matthews. The fascination has been heightened by the fact that the muscle spindle is a sensory organ that receives a motor innervation, an unusual but not unique property. The attention paid to the mus- cle spindle in the control of movement has often been at the expense of the Golgi tendon organ (cf. Chapter 6), intramuscular free nerve endings and, in particular, cutaneous mechanoreceptors (cf. Chap- ter 9), all of whichplayimportant roles inmodulating motor output and (probably) in generating appro- priate movement or contraction-related sensations. The attention paid to the muscle spindle/fusimotor system may be disproportionate for its role in the control of normal andpathological movement. How- ever, despite this attention, its role is still the sub- ject of debate, possibly because no unitary hypo- thesissatisfactorilyexplainsthefindingsinall animal species. Humanmusclespindlesareinnervated, asin the cat, by ␥ and  motoneurones, the former exclu- sively motor to the 'intrafusal' muscle fibres within the muscle spindle, the latter motor to both the con- tractile ('extrafusal') muscle as well as the spindle. Theterm'fusimotor' (i.e. motor tothefusiformstruc- ture) was coined by Hunt and Paintal (1958) to refer to the ␥ efferent innervation of the muscle spindle, and 'skeleto-fusimotor' by Emonet-D´ enand, Jami & Laporte (1975) for  innervation. The latter may be more important in small muscles where the spindle is more likely to be close to the motor point. Background fromanimal experiments Data fromanimal experiments are reviewedindetail elsewhere (e.g. Matthews, 1972, 1981; Hulliger, 1984; see the book edited by Taylor, Gladden & Durbaba, 1995), and the following is restricted to background data relevant to controversies concerning muscle spindle behaviour and fusimotor functioninhuman subjects. Initial investigations During an ischaemic block of large (␣) motor axons innervating muscle, it proved possible to stimulate small ␥ motor axonsselectivelytoproduceacontrac- tion of intrafusal muscle fibres without contraction of extrafusal muscle fibres (Leksell, 1945). Selective fusimotor stimulation (whether during ischaemic block of ␣ motor axons or following dissection and isolation of single ␥ axons) increases the discharge of spindle afferents (Kuffler, Hunt & Quillian, 1951), and peripheral afferent inputs may alter spindle discharge reflexly by altering the discharge of ␥ motoneurones(e.g. Hunt, 1951; Hunt &Paintal, 1958; Grillner, 1969). A conceptual leap occurred with the landmark studies of P. B. C. Matthews in the 1960s demonstrating that the static and dynamic sensi- tivity of muscle spindle primary endings can be controlled independently by two kinds of ␥ effer- ents, static (␥ s ) and dynamic (␥ d ), respectively (see Matthews, 1972). 113 114 Muscle spindles and fusimotor drive Fromfollow-up length servo to servo assistance That the activation of ␥ motoneurones could lead to muscle spindle activation and, thereby, to excita- tion of ␣ motoneurones led Merton (1951, 1953) to postulate that some movements might be controlled as in a follow-up length servo. The hypothesis that thecentral commandfirst activated␥ motoneurones and that this then led to ␣ motoneurone recruit- ment dominated the literature for many years. This hypothesis was invalidated as a mechanismfor driv- ing movement, but retained in modified form, in which movements receive 'servo assistance' from spindleinputs (seeMatthews, 1972). Therearediffer- ent supraspinal projections onto ␣ and ␥ motoneu- rones, but there are alsostriking parallels, andGranit (1955) therefore suggestedthat voluntary movement involved an ␣-␥ linkage (or co-activation), a sugges- tion that received some support from human stud- ies using microneurography (e.g. Hagbarth &Vallbo, 1968; Vallbo, 1971, 1974; Vallbo et al., 1979), but has beenroundly criticised(Prochazka &Hulliger, 1983). Current views of spindle structure and function Intrafusal fibres Muscle spindles contain modified muscle fibres (intrafusal fibres) with nuclei collected into a cen- tral bulbous region ('nuclear bag' fibres, usually 1–2/spindle in the cat) or arranged serially along the central region of the fibre ('nuclear chain' fibres, usually 3–5/spindle) (see Fig. 3.1). There are two types of bag fibre, the bag 1 and the bag 2 fibre withmorphological and functional differences. The dynamic bag 1 fibre receives terminals from only the primary ending and is innervated by dynamic fusimotor (␥ d ) axons, which can increase the dynamic sensitivity of the ending. The bag 2 fibre has terminals of both primary and secondary endings and is innervated by static fusimotor (␥ s ) axons, which increase the static sensitivity of the primary and secondary endings. There are two types of sensory endings Theprimaryendingspirals aroundthecentral region of the bag and chain fibres and gives rise to a sin- gle large group Ia afferent (i.e. there is only one pri- mary ending and one group Ia afferent per spindle). Secondary endings are more distal, on either side of the central region, mainly onchainfibres but alsoon one of the bag fibres (the static bag 2 fibre), and give rise to several group II afferent axons/spindle (i.e. there may be several secondary endings and several group II afferents per spindle). Primary endings are sensitivetoboththestaticanddynamiccomponents of muscle stretch and also to high-frequency vibra- tion, while secondary endings are similarly sensitive to the static component of stretch, but are much less sensitive to the dynamic component of stretch and less sensitive to vibration (see Matthews, 1972). The properties of the bag 2 fibre (not the bag 1 fibre) largely determine both the background firing rate of the group Ia afferent and the dynamic response to stretch of passive spindles (Gioux, Petit & Proske, 1991; Scott, 1991; Proske, 1997). The chain fibres are largely responsible for the static response to stretch of both the primary and secondary endings. ␥ innervation Fusimotor (␥) efferents cause the peripheral regions of intrafusal muscle fibres to contract and increase the stiffness of the intrafusal fibre, thereby exciting spindle endings and increasing their sensitivity to stretch. There are two types of fusimotor efferents: static fusimotor (␥ s ) axons, which increase the static sensitivity of the primary and secondary endings by causing contraction in bag 2 and chain fibres; dynamic fusimotor (␥ d ) axons, which can increase the dynamic sensitivity of the primary ending by causing contraction in bag 1 fibres (see Matthews, 1972; Fig. 3.1). The(skeleto-fusimotor) innervation is considered below (p. 117). Note that the dynamic response of primary endings in passive spindles arises from the bag 2 fibre, but the increase in the dynamic response due to ␥ d action comes from the bag 1 fibre. Background fromanimal experiments 115 Capsule Bag fibre Bag fibre Chain fibres Ia α β γ s γ d Extra- fusal muscle fibre Primary endings Secondary endings II 1 2 Fig. 3.1. Sketch of the muscle spindle and its afferent and efferent innervation. The capsule of the spindle (dotted line) contains intra-fusal muscle fibres – the so-called nuclear bag (bag 1 and bag 2 ) and chain fibres. The primary ending spirals around the central region of the bag and chain fibres and gives rise to a single large group Ia afferent. Secondary endings are more distal (asterisks), on either side of the central region (although shown on only one side, for simplicity), mainly on chain fibres but also on the static bag 2 fibre, and give rise to several group II afferent axons. Chain fibres and static bag 2 fibres receive efferent innervation from static fusimotor (␥ s ) neurones, while dynamic bag 1 fibres receive efferent innervation from dynamic fusimotor (␥ d ) neurones.  (skeleto-fusimotor) efferents innervate both intra- and extra-fusal muscle fibres. Only the  innervation of bag 1 fibres is represented, but some bag 2 fibres also receive  innervation. The main innervation of extra-fusal muscle fibres comes from large (␣) efferents. Differences in spindles In the cat, there are differences in spindle morphology in different muscles Complex spindles involving more than one spindle or a spindle/tendon organ combination, and spin- dles in tandem with two or more spindles end to end, are common in neck muscle. There are also differences in conduction velocity of the afferent axons innervating muscle spindles in different mus- cles, slower, for example, for spindles in jawmuscles than for spindles in the hindlimb (where most stud- ies have focussed). These morphological differences within a single species seem to be greater than the morphological differences between species. Morphological differences between feline and human spindles The differences are summarised by Prochazka & Hulliger (1983) and Gandevia & Burke (2004). Some may be of some functional relevance. (i) The size of the muscle spindle varies with the muscle in which it is located, often some 7–10 mm (but only 1–3 mm in the lumbrical muscles). How- ever, overall, the human spindle is slightly longer 116 Muscle spindles and fusimotor drive Fig. 3.2. Ambiguous responses of a spindle afferent during graded twitch-induced contractions of tibialis anterior. (a ) Sketch of the experimental paradigm: recording with a microelectrode in the common peroneal nerve (CPN) from a tibialis anterior (TA) muscle spindle ending (a presumed primary ending). (b )–(d ) Single sweeps showing the responses during graded twitch contractions produced by intrafascicular stimulation. Upper traces, neural activity from the afferent; lower traces, rectified EMG, with the amplification for (b ) twice that for (c ) and (d ). (b) Liminal twitch involving three motor units. (c ) Moderately strong but submaximal twitch. (d ) Near-maximal twitch. (e) Superimposed responses to three maximal twitch contractions produced by stimulation at the motor point using EMG electrodes. Upper trace, afferent potentials; lower trace, twitch force, calibration: 1 Nm. (f ) Superimpositions of all afferent potentials recorded during intrafascicular stimulation. The potentials (upper trace) are displayed without filtering, after passage through a digital delay line. The oscilloscope sweep was triggered by the potential, filtered as in (b )–(e ) (lower trace). From Burke, Aniss & Gandevia (1987), with permission. than the feline spindle. The spindle is always shorter than the muscle fibres with which it is associated, but muscle fibres are longer in human muscles. (ii) There seem to be more fascial connections between human spindles and nearby muscle fibres, and sometimes muscle fibres insert into the spindle capsule. This would produce a greater tendency for human spindles to be stimulated when nearby mus- cle fibres contract (Burke, Aniss & Gandevia, 1987). The muscle afferent in Fig. 3.2 was classified as of spindle origin using maximal twitch contractions produced by strong stimuli to the peroneal nerve (panel (e )). However, weaker twitch contractions in Fig. 3.2(b), (c ) and (d ) reveal an in-series coupling with some motor units, such that the spindle affer- ent discharges during the rising phase of the con- traction when a truly 'in-parallel' receptor would be unloaded (to appreciate the timing, see the twitch contraction in panel (e )). (iii) The human spindle contains more intrafusal fibres (1–4 bag fibres and up to 14 chain fibres) than in the cat, and (iv) thefusimotor innervationmaybeless selective in primates (and human subjects) than in the cat. (v) There is evidence suggesting that the primary ending of the human spindle is distributed more around bag fibres than chain fibres. (vi) The unmyelinated afferent terminal is longer than in the cat, perhaps allowing greater sensitivity to metabolites that have accumulated in the intra- capsular space around the spindle. (vii) The afferent and efferent axons appear to be of similar size in the two species, but the conduction velocities of human axons, afferent at least, appear to be much lower than in the cat. This implies that the 'Hursh constant' (the relationship between con- duction velocity and diameter for large myelinated axons) is lower in humans than the cat. Methodology 117 Spindle density The facial muscles and the digastric lack identifi- able muscle spindles or spindle-like structures. The number of spindles in other muscles varies from <50 for intrinsic muscles of the hand to >1000 for quadriceps femoris. However, spindle density seems to be greatest for the muscles of the neck (where theymayhaveacomplexmorphology, particularlyin deep paraspinal muscles, see above) and the intrin- sic muscles of the hand.  (skeleto-fusimotor) neurones Theseneurones innervatebothintra- andextra-fusal muscle fibres (Bessou, Emonet-D´ enand & Laporte, 1965) and, in the cat hindlimb, perhaps 30% spin- dles receive such innervation. Their activity would obligatorily result in a coupling of spindle excitation and muscle contraction. However, this is unlikely to account for the consistent finding that voluntary effort results in parallel activation of muscle and muscle spindle endings because (i) during pressure block experiments to the point of paralysis (presum- ably blocking large ␣ axons before small ␥ axons), voluntary effort can still activate spindle endings (Burke, Hagbarth & Skuse, 1979); (ii) specific search for a coupling of spindle discharge to EMG activity using spike-triggered averaging has been unreward- ing inone study (Gandevia, Burke &McKeon, 1986a) though not in a subsequent study (Kakuda, Miwa & Nagaoka, 1998); and (iii) there have been anecdotal reports of changes in spindle discharge that could be produced in relaxed muscles without the appear- anceof detectableEMG(Gandeviaet al., 1986b, 1994; Aniss et al., 1990a; Ribot-Ciscar et al., 1991). There is anatomical evidence of  innervation of human spindles and suggestive evidence that this may be physiologically significant: corticospinal volleys and voluntary effort seem capable of activating  effer- ents (Rothwell, Gandevia & Burke, 1990; Kakuda & Nagaoka, 1998, respectively), as also may volleys in low-threshold cutaneous afferents (Aniss, Gandevia & Burke, 1988). In general,  efferents innervate the dynamic bag 1 fibre (cf. Fig. 3.1) and their action is therefore to increase the dynamic sensitivity of the primaryending. However, therearealsostaticeffer- ents (not representedinFig. 3.1), whichareof slightly larger size than the dynamic  efferent and, when present, they innervate the long chain fibre, so alter- ing the static behaviour of the primary ending. Methodology Discredited techniques Comparisons of tendon jerk and Hreflex as measures of fusimotor drive Underlying principle Based onthe fact that the Hreflex bypasses the mus- cle spindle while the tendon jerk does not, many authors have, following Paillard (1955), implicitly accepted that comparisons of the H reflex and ten- don jerk can be used to provide a reliable measure of fusimotor activity. As a result of such comparisons, and of the uncritical use of local anaesthetic nerve blocks, it became accepted that (i) there is a sig- nificant level of background fusimotor drive in the relaxedstate, particularly indynamic ␥ motor axons; (ii) this background fusimotor drive sensitises spin- dleendingstopercussionintherelaxedstate; and(iii) without thisbackgroundfusimotordrivetherewould be no tendon jerk. These views have been the sub- ject of critical reappraisal, as have many of the con- clusions about motor control mechanisms in health and disease that were based on them (Burke, 1983; e.g. see Fig. 3.11). Each of the above statements is probably erroneous: there is nowsubstantial experi- mental evidence to support the view that valid con- clusions about fusimotor function cannot be drawn fromsuchcomparisons (e.g. Burke, McKeon&Skuse, 1981a,b; Burke, Gandevia & McKeon, 1983, 1984; Morita et al., 1998). Differences in the afferent volleys of the two reflexes Tendon jerk Because of the properties of the tendon, tendon percussion presents an oscillatory stimulus to the 118 Muscle spindles and fusimotor drive muscle spindle, and sensitive primary endings discharge multiple times to a single percussion, responding to the damped oscillating disturbance that reaches the ending. The afferent volley for the soleus tendon jerk reaches the popliteal fossa some 4–5 ms after percussion on the Achilles tendon, reaches a peak some 5–10 ms later and lasts some 30–40 ms (Burke, Gandevia & McKeon, 1983). Due to the extreme sensitivity of primary spindle end- ings, it is not necessary to percuss the appropri- ate tendon directly: percussion on a bony protu- berance will result in a vibration wave that trav- els along the bone exciting muscle spindles in nearby muscles and, in subjects with brisk ten- don jerks, may produce tendon jerks in multiple muscles throughout the limb – the phenomenon of 'reflex irradiation', best seen in patients with spas- ticity (Lance & de Gail, 1965). The muscle spin- dle is not the only receptor responsive to ten- don percussion, even when the mechanical stimu- lus is delivered carefully only to the appropriate muscle: sensitive muscle and cutaneous receptors throughout the limb, even those in antagonists, may be excited and the extent of this will be dependent only on effective transmission of the mechanical stimulus (Burke, Gandevia & McKeon, 1983; Ribot- Ciscar, Vedel & Roll, 1989). H reflex On the other hand, a 1-ms current pulse will excite axons only once, producing a more synchronised afferent volley, but one that involves group Ib as well as group Ia afferents. In addition, the stimu- latednerveusuallyinnervates manymuscles: e.g. the posterior tibial nerve innervates calf muscles other than triceps surae and the intrinsic muscles of the foot, the afferents of which(bothIa andIb) have het- eronymous projections tosoleus motoneurones (see Table 2.1; Chapter 10, p. 497). Presynaptic inhibition of Ia terminals This is more effective on the afferent volley of the H reflex than on that eliciting the tendon jerk (Morita et al., 1998; Chapter 8, pp. 354–5). Differences at the motoneurone pool level The dispersed afferent volley produced by ten- don percussion results in a long-lasting compound EPSP, the rising phase of which may be some 5– 10 ms, much longer than the 1–2 ms rising phase of the EPSP produced by a single electrical stimu- lus to the tibial nerve (Burke, Gandevia & McKeon, 1984). There is thus greater opportunity for oligo- synaptic inputs to affect the motoneurone discharge withthetendonjerkthantheHreflex. Notwithstand- ing, the rising phase of the electrically evoked EPSP is briefer than might be expected given the opportu- nity for dispersion of the volley created by the long conduction pathway (much longer than in the cat), theslower conductionvelocities of groupIaafferents (maximally∼60–70ms −1 inthelower limb, i.e. much lower than in the cat hindlimb) and the likely range of Ia conduction velocities (∼60–70 m s −1 down to ∼48 m s −1 ; see Chapter 7, pp. 302–3). It has been suggested that group Ib afferents curtail the electri- callyevokedEPSPandthat theHreflexcanbealtered by altering transmission across the Ib inhibitory interneurone, a situation not equally applicable to the tendon jerk (Burke, Gandevia & McKeon, 1984). There is now direct experimental support for this suggestion (Marchand-Pauvert et al., 2002; Chapter 1, pp. 14–15). Conclusions The tendonjerk and the Hreflex are bothdependent on the monosynaptic excitation from homonymous Ia afferents, but they differ inso many other respects that comparison of them as a measure of fusimotor function is invalid. Nerve blocks Underlying principle Inthe cat, Matthews &Rushworth(1957a,b) demon- strated that it is possible to block ␥ efferents using local anaesthetic applied directly to the nerve because they are smaller than ␣ efferents. Rushworth (1960) then showed that injections of Methodology 119 dilute procaine into the motor point reduced both spasticity and rigidity, an effect attributed, not unreasonably, to ␥ efferent blockade (however, see below). Situation in human subjects The situation in human subjects is quite differ- ent fromthe controlled experimental circumstances possible in the cat. Given the larger size of human nerves, diffusion of the local anaesthetic through perineural and fascicular tissues will result in non- selective effects because of involvement of closer rather than smaller axons, and this will also be so when the injection is into the motor point. The anaesthetic will not differentiate between affer- ents and efferents and, theoretically at least, reflex depression could result from loss of small afferent inputs rather than loss of fusimotor function. Loss of the tendon jerk but preservation of near-normal strength does not constitute an adequate control for the integrity of ␣ motor axons because consider- able denervation is required before the triceps surae muscles become weak to clinical testing. Finally, microneurographic studies have shown that, in gen- eral, the sequence of cutaneous afferent blockade by local anaesthetics is from small afferents to large afferents, but they have also demonstrated that the blocks are extremely difficult to control and their sequence not exactly the same in different experi- ments (Torebj ¨ ork & Hallin, 1973; Mackenzie et al., 1975). It is likely that greater involvement of ␥ effer- ents occurs during the recovery from a complete local anaesthetic block than during its induction, but this remains to be proven. Pressure blocks seem to produce a more reliable sequence of axon block, large before small, possibly because their temporal development can be controlled, at least in part, by adjusting pressure. Conclusion Local anaesthetic nerve blocks cannot be used to produce selective de-efferentation of muscle spindles. Acceptable techniques Microneurography Microelectrode The first definitive reports of microneurography were publishedby Vallbo&Hagbarth(1968) oncuta- neous afferents and Hagbarth & Vallbo (1968) on muscle afferents. The technique is illustrated in the sketch in Fig. 3.3(a ), and a recording from a pre- sumed secondary spindle afferent innervating the fourth dorsal interosseous muscle of the hand is shown in Fig. 3.3(b ). The basic technique has not changed greatly since then, and adequate descrip- tions are available (e.g. Hagbarth, 1979; Vallbo et al., 1979; Burke, 1981; Gandevia & Burke, 1992). The traditional microelectrode is a monopolar tungsten electrode with a shaft diameter of ∼200 m, insu- lated to the tip, with an optimal impedance in situ of ∼100–150 kfor single unit recordings and perhaps ∼50 k for multi-unit recordings. Some authorities prefer concentricneedleelectrodes withor without a bevelled tip, but the electrode has a wider shaft and, inpractice, thereis probably littleadvantageover the traditional electrode. Basic methodology Themicroelectrodeis insertedmanuallythroughthe skininto the peripheral nerve trunk andthenguided into an appropriate nerve fascicle. In most labora- tories this is facilitated by delivering weak electrical stimuli through the electrode to produce radiating cutaneous paraesthesiae (whentrying tohome inon a fascicle innervating skin) or a twitchcontractionof the innervated muscle (when focussing on a fasci- cle innervating muscle). When the tip is within the fascicle, gentle stroking of the skin or tapping on the appropriate muscle tendon will activate mechano- receptors in skin or muscle, respectively, and audi- tory feedback is then used to make further small adjustments of the electrode to bring the desired neural activityintofocus. Theelectrodeisleft floating free, securedbytissueresistanceat therecordingend 120 Muscle spindles and fusimotor drive Fig. 3.3. Unitary recording from a human muscle spindle. (a ) Sketch of the technique for the recording in (b ): the tungsten microelectrode was inserted percutaneously into a motor fascicle of the ulnar nerve at the wrist. The microelectrode was introduced manually. When in situ, it was supported without rigid fixation at one end by its connecting lead and at the other by the skin and subcutaneous tissue. Its position was adjusted within the nerve until the tip penetrated the desired nerve fascicle. Minor adjustments were made to bring the desired neural activity into focus. Note that the microelectrode has a shaft diameter of ∼200 m and that the largest axons have a diameter of ∼20 m. The target muscle was identified by the responses to intraneural electrical stimulation and the responses to passive and active movements of the digits. (b ) A recording from the afferent of a spontaneously active presumed secondary spindle ending in the fourth dorsal interosseous. Lower trace: action potentials; upper trace: instantaneous frequency of the afferent's discharge. The ending increased its discharge during extension and passive abduction (not shown) at the fourth metacarpophalangeal joint, the responses to stretch and shortening being essentially static. From Burke, Gandevia & Macefield (2003), with permission. and by a coiled insulated copper wire to the pream- plifier at the other. This is preferable to external fix- ation because movement by the subject cannot be avoided, andexternal fixationthenleads toelectrode dislodgement. Even so, the stability of the recording can be jeopardised by minor movements, particular those that displace skin at the recording site. Identification If a recording is obtained from a single axon it is necessary to identify the axon as an afferent and thentocharacterise its response tovarious stimuli in order to clarify its origin (e.g. from a primary or sec- ondary ending or a Golgi tendon organ). This can be time-consuming, andoftenrecordingsfrompartially or completely identified afferents are lost before experimental manipulations canbe studied. Criteria to differentiate muscle spindle afferents from Golgi tendonorganafferentsincludetheclassical response to a twitch contraction of the receptor-bearing mus- cle (unloading with spindles: Figs. 3.2(e ), 3.4(b ) and 3.5(c ); activation with tendon organs: Fig. 3.6(e )). This is now incorporated into the usual identifica- tion processes. The twitch contractions can be pro- duced by stimuli delivered through the recording microelectrode, transiently switching off the record- ing to do so (McKeon & Burke, 1980; Burke, Aniss & Gandevia, 1987) or by using external stimuli to the nerve trunk (e.g. Edin & Vallbo, 1987). How- ever, responses to twitch contractions are some- times ambiguous, possibly because of the above- mentionedfascial interconnections betweennearby motor units and the spindle (see Burke, Aniss & Methodology 121 Fig. 3.4. Identification of spindle endings in tibialis anterior. (a ) Sketch of the experimental paradigm: recording with a microelectrode in the common peroneal nerve (CPN) from a muscle spindle primary ending and a muscle spindle secondary ending in tibialis anterior (TA). (b ) Twitch test for the primary ending showing afferent potentials in the original neurogram (upper trace) and the torque produced by the twitch contraction of the receptor-bearing muscle (lower trace). Five superimposed sweeps. Note that an early discharge occurs before torque starts to rise (associated with the ␣ volley, cf. Hunt & Kuffler, 1951). Spindle discharge pauses as torque rises. (c ) 'Instantaneous' frequency plots of spindle responses to ramp stretch and shortening of 3–4 ◦ at 7.5 ◦ / s for a primary ending (upper trace) and a secondary ending / (middle trace). In both (c ) and (d ) the movement of the ankle joint is shown in the lower trace, but for simplicity, the goniometer record for the primary ending has been omitted. A downward deflexion represents stretch of the receptor-bearing muscle. In (d) the imposed movements for the two endings were very similar, but not quite identical in amplitude, so that occasionally the discharge of the primary ending appears slightly out of phase. From Burke et al. (1976a), with permission. Gandevia, 1987; Fig. 3.2(c ), (d ); p. 116). Additional criteria include the presence or absence of back- ground activity, the regularity of any background discharge, behaviour during voluntary contractions and on abrupt relaxation, and the responses to stretch and vibration (e.g. Edin & Vallbo, 1990a,b,c). These criteria also help distinguish group Ia affer- ents and primary endings from group II affer- ents and secondary endings. Figure 3.4 summarises some of these features. Both primary and secondary 122 Muscle spindles and fusimotor drive (a) (b) (e) (f ) (d) (c) Fig. 3.5. The effects of isometric voluntary contractions on background discharge rate of a secondary ending in extensor digitorum longus. (a ) Sketch of the experimental paradigm: during voluntary contraction of the extensor digitorum longus (EDL), there is descending activation of both ␣ and ␥ motoneurones (MNs) innervating EDL. Recording with a microelectrode in the common peroneal nerve (CPN) from an EDL muscle spindle secondary ending. (b ) Response of the ending to imposed joint movement. (c) An electrically induced twitch delivered at the arrow produces a twitch contraction, recorded by the myograph (lower trace), and a typical pause in spindle discharge, seen in the original neurogram (upper trace). In (b ), (d ), (e ) and (f ), traces are from top to bottom: instantaneous frequency; joint angle (downward deflection represents stretch of the receptor-bearing muscle); EMG of EDL; EMG of tibialis anterior (TA). The regularity of the background discharge in (d )–(f ) and the close parallelism between imposed joint movement and discharge rate in (b) suggest that the ending was a secondary ending. In (d ) contraction of the receptor-bearing muscle (EDL) accelerates the spindle (after a brief unloading). In (e ) contraction of predominantly TA (a synergist) decreases discharge rate. In (f ) contraction of both muscles, the opposing effects largely cancelling out. Note that in (d ) spindle discharge remains enhanced after EDL EMG has subsided, probably due to the thixotropic properties of intrafusal fibres. Modified from Burke et al. (1976b), with permission. endings should be unloaded by a maximal twitch contractionof the receptor-bearing muscle andacti- vatedonthefallingphaseof thetwitch(panel (b ), see alsoFig. 3.2(e )). However, theprimaryending(upper traces) has a more prominent dynamic response to stretch (indicated by a downward movement of the joint angle in the lower trace in Fig. 3.4(c ), (d )) than the secondary ending (middle traces). Figure 3.5(b ) illustrates anessentially static response tostretchfor another presumed secondary ending. Methodology 123 (a) (c) (e) (d) (b) Fig. 3.6. Effects of tendon vibration at 110 Hz on a Golgi tendon organ in tibialis anterior. (a ) Sketch of the experimental paradigm: recording with a microelectrode in the common peroneal nerve (CPN) from a Golgi tendon organ (GTO) in tibialis anterior (TA). (b ) Responses to vibration at constant muscle length, and (c ), during alternating passive movements. Upper traces: frequency plots. Middle traces: ankle position. Lower traces: EMG of tibialis anterior. Note the EMG silence throughout the traces. Vibration indicated by bar in (b), but is constant throughout the sweep in (c ). (d ) Individual vibration cycles taken fromthe position indicated by the arrow in (b ) with the spikes superimposed on the vibration wave to demonstrate phase-locking and subharmonic activation of the GTO. Note that these responses to vibration were recorded for a non-contracting muscle (see flat EMG traces in (b ) and (c ). (e ) Electrical twitch test. Three superimposed sweeps, showing discharge of the ending (upper trace) during the rising phase of torque (lower trace). Contrast (e ) with the spindle behaviour during twitch tests in Figs. 3.2(e ), 3.4(b ), 3.5(c) and 3.7(d ). Modified from Burke et al. (1976a), with permission. Sampling bias There is a bias in microneurographic recordings towards axons that are large and have a background discharge. The former is because the action poten- tial must be discriminated from noise, and action potential amplitude is a function of the square of axonal diameter. The latter is because, if you can- not hear action potentials, you may not know that you have a suitable recording site. Accordingly, most studies have been dominated by recordings from group Ia afferents, and it is possible that the sam- ple of group Ib afferents studied to date are fromthe more mechanically responsive end of the spectrum of tendon organs. This might explain the sensitivity tovibrationof thethreetendonorgans inthestudyof Burke et al. (1976a), as illustrated in Fig. 3.6(b )–(d ). These results do not necessarily imply that human tendon organs as a group are more stretch-sensitive than in the cat. More group Ib afferents might be isolated if searching was undertaken during a back- ground voluntary contraction rather than at rest. Nevertheless, Fig. 3.6 indicates that at least some tendon organs are vibration-sensitive. This ending responded appropriately in a twitch test (e ) but was sensitive to vibration at rest (as verified by the qui- escent EMG in panels (b ) and (c )), discharging at subharmonics of the vibration frequency (d ). Uncertainties of the technique Muscle spindle endings are extremely sensitive to minute perturbations, but small disturbances to the spindle's environment withinthe muscle may not be apparent to inspection. EMG electrodes and force andlengthtransducers must be usedif one wishes to have reasonable certainty that the receptor-bearing muscle is truly relaxed. However, the very same recordings may not be appropriate if one wishes to know whether only the receptor-bearing muscle is active (in which case intramuscular needles or wires should be used to record EMG). No one EMG set-up can guarantee the recording from every motor unit 124 Muscle spindles and fusimotor drive in a muscle, no length transducer can detect motor unit activity that does not produce movement, and no force transducer will keep a limb absolutely iso- metric. Hence, it is impossible to generate data with the same degree of precision as in animal experi- ments. This disadvantage is offset by the ability to study volitional processes in co-operative human subjects, capable of generating or changing motor drives on request. Nevertheless, the uncertainties must be kept in mind when assessing the validity of evidence for, e.g. selective activation of ␥ motoneu- rones during different manoeuvres, a controversial topic discussed further below (pp. 131–3). Studies that exploit the thixotropic properties of intrafusal fibres Underlying principle Thixotropy refers to the change in passive stiffness of muscle, analogous to the behaviour of certaingels whichcanbecome fluidwhenstirredor shaken, only to set into a gel again when allowed to stand. Both extrafusal and intrafusal muscle fibres can manifest thixotropic behaviour. This behaviour is important because intrafusal thixotropy can dramatically alter thedischargeof primaryandsecondaryspindleend- ings. For example, thethixotropicproperties of intra- fusal fibres underlie (i) the 'initial burst' from a pri- mary ending in response to abrupt ramp stretch, a response that has been termed an acceleration- like response (Brown, Goodwin & Matthews, 1969; Edin &Vallbo, 1990a), (ii) the after-effects of fusimo- tor activationonspindledischarge(Brown, Goodwin & Matthews, 1969), and (iii) stretch sensitisation of spindle endings (Edin & Vallbo, 1988; Edin, 1991). The effects of changes in the thixotropic proper- ties of muscle spindles on spindle discharge have been studied extensively by Proske and colleagues in the cat and in human subjects (Proske, Morgan & Gregory, 1993). They depend upon the formation, breakdownandre-formationof actin-myosinbonds in the intrafusal fibres, with consequent changes in stiffness of the fibres and an alteration in the stretchplacedonspindle endings. Prolongedstretch or fusimotor activity will cause bonds to form at the prevailing muscle length. Thus, if a muscle is held ina stretched positionand thenabruptly short- ened, intrafusal fibres will develop slack, and this will lead to a reduced spindle discharge. The 'slack' can be removed by activating fusimotor neurones to the spindle and, if the muscle is then slowly stretched back to the original length, spindle dis- charge and responsiveness will be greater than ori- ginally even though the fusimotor activity may have long ceased. The type of fusimotor axon stimulated will determine which intrafusal fibre is activated, and this will determine how spindle responsiveness changes. Thixotropy in human investigations In human subjects, the ␥ activity associated with a voluntary contraction can induce long-lasting enhancements in spindle discharge, changes that persist long after the contraction(Fig. 3.7(c ); see also Fig. 3.5(d )). The discharge of the spindle primary ending in Fig. 3.7(c ) continues long after the ces- sation of EMG and the return of contraction force to the control level. The discharge of the secondary endinginFig. 3.5(d ) declines slowlyandremains ele- vated for some seconds after EMG has disappeared. The latter ending is illustrated because many of the thixotropic after-effects of fusimotor activity in the literature involve primary endings rather than sec- ondary endings (Brown, Goodwin&Matthews, 1969; Matthews, 1972; Edin &Vallbo, 1988, 1990a). In both instances, the after-discharge is not evidence of con- tinuing ␥ drive but of a long-lasting change in stiff- ness of intrafusal fibres that contractedunder ␥ drive during the voluntary contraction (Jahnke, Proske & Struppler, 1989; Ribot-Ciscar et al., 1991; Wilson, Gandevia & Burke, 1995). As actin–myosin bonds break down and re-form at the prevailing muscle length, the discharge slowly declines. Inother words, the enhanced spindle discharge is a lasting mem- ory of past ␥ efferent activity, not evidence of the current level of fusimotor drive, and the enhanced discharge can be abolished by stretch sufficient to break the persistent actin-myosinbonds. Proske and Methodology 125 (a) (b) (c) (d) Fig. 3.7. Muscle spindle primary ending in tibialis anterior during and after a voluntary contraction illustrating the effects of thixotropy on spindle discharge. (a ) Sketch of the experimental paradigm: recording with a microelectrode in the common peroneal nerve (CPN) froma muscle spindle primary ending in tibialis anterior (TA). (b ) and (c ) showthe start and end of a 1 min submaximal contraction of ankle dorsiflexors at ∼20 % maximal voluntary force (MVC). 30 s have been omitted between (b ) and (c ). The traces are from top to bottom raw neurogram, force, and integrated EMG of tibialis anterior. The spindle was initially silent, maintained a discharge at ∼12 Hz throughout the 60-s contraction. There was a high-frequency burst of impulses on relaxation of the contraction, and the discharge continued at ∼8 Hz in the absence of EMG following the contraction. This persistent discharge probably results from intrafusal thixotropy. (d ) Upper two panels show the twitch test for the unit (three traces superimposed). The lowest panel shows superimposed action potentials from the unit on a faster time base. Modified from Macefield et al. (1991), with permission. colleagues have exploited this behaviour to study fusimotor action in human subjects indirectly, have documented appropriate changes in spinal reflexes, and have used the behaviour to confirm the role of muscle afferents in kinaesthesia (Proske, Morgan & Gregory, 1993; Wood, Gregory & Proske, 1996; Gregory et al., 1998; Wise, Gregory & Proske, 1998). For example, tendon jerks recorded at the same test muscle length can be enhanced or depressed fol- lowing a voluntary contraction, if the contraction is performedat amusclelengththat isshorterorlonger, respectively, than the test muscle length. Perspectives Potentially, this approach could be used to docu- ment fusimotor function during contractions that are too strong for microneurography or in patients unsuitable for microneurography, and there is one such recent report on patients spastic following 126 Muscle spindles and fusimotor drive stroke (Wilsonet al., 1999b). Acomplicating factor is that extrafusal muscle fibres also display thixotropic behaviour. This serves as a warning that careful controls are required even with this experimental paradigm. A further lesson is that the thixotropic properties of intrafusal muscle can distort spin- dle discharge and must be considered when inter- preting unexpected changes in spindle discharge, reflex behaviour or perception, especially whenthey occur after a muscle contraction. The history of what the spindle was subjected to can influence how it responds to a new stimulus. Critique of the tests to study muscle spindle afferent discharge and fusimotor drive Microneurography Necessity for careful controls Microneurography is less indirect than other tech- niques, but it is possible to make valid conclusions about fusimotor activity from recordings of mus- cle spindle discharge only if all disturbances to the spindle are rigidly controlled. This is possible in feline experiments but is rarely so in human sub- jects, in whom spindle endings have been noted to respond to mechanical stimuli that are not imme- diately obvious, such as respiration and the arterial pulse (Hagbarthet al., 1975a; McKeon&Burke, 1981) or the mechanical twitch produced by single motor units (McKeon &Burke, 1983). It is absolutely essen- tial that all possible perturbations to the highly sen- sitive spindle ending be controlled, whether they be external or internal. Uncertainties about identification The identification of an axonal recording as affer- ent rather than efferent (or vice versa) and then the subclassificationof the afferent (or efferent) must be beyond dispute, particularly when the conclusions are based ononly a couple of 'positive' findings from a larger sample. For example, it has been suggested that some of the findings on ␣/␥ co-activation from human studies can be attributed to incorrect iden- tification of Ib afferents as Ia (Prochazka & Hulliger, 1983). Sensitivity to displacements Even small movements of the skin at the recording site can disturb the microelectrode and disrupt the recording. As a result the movement repertoire that can be studied with this technique is quite limited. The need to apply restraints to prevent, or transdu- cers to measure perturbations that could be trans- mitted to the endings creates artificial conditions, andit is conceivablethat this couldalter theexplored fusimotor 'set'. The technique is traumatic It involves insertion of a needle electrode into the nervetrunkand, whiletherisksareverysmall indeed, some oedema is inevitable and there are theoretical risks of infection or of intraneural bleeding from a small vessel. The technique is technically demanding It is not unusual to spend a couple of hours search- ing in vain for a specific afferent type, having been unable to hold promising recordings for sufficiently long to gain meaningful data. Thixotropy Studies of intrafusal thixotropy can allow stronger contractions to be assessed and can be of value in patients for assessing fusimotor activity. While reflex studies using thixotropy to change behaviour do not involve comparing dissimilar reflexes (as with the discreditedcomparisonof mechanically andelectri- cally evoked reflexes), the technique is much more indirect than microneurography, and it is important to exclude other possible causes of variable reflex function. Organisation and pattern of connections 127 Organisation and pattern of connections Background fusimotor drive Static fusimotor drive There is now considerable evidence that human spindle endings behave as if passive receptors with- out active fusimotor drive in the relaxed state. The evidence is more cogent for static fusimotor (␥ s ) drive (see Vallboet al., 1979; Burke, 1981; Gandevia & Burke, 1992) than for dynamic fusimotor (␥ d ) drive. In relaxed muscle, human primary spindle endings maintainmuchlower firingrates andtheir responses to stretch are smaller than those of passive spindle endings in the cat (Vallbo, 1974; Vallbo et al., 1979; Burke, Skuse & Stuart, 1979; Prochazka & Hulliger, 1983; Gandevia &Burke, 1992). The regularity of dis- charge is similar to that of de-efferented feline end- ings (Burke, Skuse & Stuart, 1979; Nordh, Hulliger & Vallbo, 1983), and there is no evidence of a nega- tive serial correlation between successive interspike intervals (i.e. that long interspike intervals tendtobe followedby short ones, something that is a feature of ␥ s drive(Matthews &Stein, 1969) andappears during a voluntary contraction). In addition, de-efferenting spindles by blocking the nerve completely with local anaesthetic or by pressure does not alter muscle spindle discharge or the responses tomuscle stretch, tendon vibration or tendon percussion (Burke et al., 1976b; Burke, Hagbarth & Skuse, 1979; Burke, McKeon & Skuse, 1981b). Thus, when the spindle primary ending in Fig. 3.8(b ), (c ) was de-efferented by a complete block of the peroneal nerve proximal to the recording site, there was no detectable effect on the ending's background discharge rate or on its responses to stretch (downward movement of the angle trace) and shortening (upward movement), as can be confirmed by comparing the discharge fre- quencies in (b) and (c). These findings do not prove that there is no background activity in ␥ motoneu- rones, but they suggest a very low level of activity, at least in ␥ s motoneurones, insufficient to affect the background spindle discharge or the response to stretch materially. Dynamic fusimotor drive Thereis adifficultyincomparingdynamic responses in relaxed muscles with those when the state of the muscle changes due to, e.g. a background contrac- tion, because the muscle and tendon stiffen and this could dampen or enhance the stimulus actually reaching the receptors in the muscle. The responses to muscle stretch or to tendon percussion do not change in relaxed muscle when subjects perform reinforcement manoeuvres, are provided with alert- ing stimuli or anticipate the need to contract the test muscle, providedthat thereceptor-bearingmus- cle remains relaxed (Hagbarth et al., 1975a; Burke et al., 1980; Burke, McKeon & Skuse, 1981a; Gande- via & Burke, 1985; see, however, Ribot-Ciscar, Rossi- Durand &Roll, 2000). This argues against significant ␥ d drive to resting muscles, in agreement with the nerve block studies discussed above. Nevertheless, there is some evidence to suggest that there may be some background ␥ d activity (Aniss et al., 1990a; Gandevia et al., 1994), and this would be consistent withsomeviews onthemechanisms of reflexreinfor- cement (Ribot, Roll &Vedel, 1986; Ribot-Ciscar et al., 2000; see, however, the critique below: pp. 131–3). Effects of cutaneous afferents on fusimotor neurones There is extensive literature on the reflex effects of cutaneous afferents on ␥ motoneurones in different feline preparations, dating back to Hunt (1951) and Hunt & Paintal (1958), and there are now detailed studies in locomoting animals (see the book edited by Taylor, Gladden & Durbaba, 1995). Lower limb Evidence for reflex activation of ␥ motoneurones by inputs from cutaneous mechanoreceptors has been sought without success in lower limb muscles of reclining human subjects, who were at rest or 128 Muscle spindles and fusimotor drive (a) (b) (c) Fig. 3.8. The effect of de-efferentation on the responses to stretch and shortening of a primary ending in the relaxed peroneus longus muscle. (a ) Sketch of the experimental paradigm: recording with a microelectrode in the common peroneal nerve (CPN) from a muscle spindle primary ending in peroneus longus (PL). De-efferentation was achieved by complete nerve block with lignocaine proximal to recording site (horizontal double-headed dashed line in (a)). In (b ) and (c ) upper trace: 'instantaneous' frequency plot; lower trace: joint position. A downward deflexion indicates stretch of the receptor-bearing muscle. Responses of the ending are identical before (b ) and during (c ) the nerve block. Modified from Burke et al. (1976b), with permission. performing isometric voluntary contractions. How- ever, whensubjects were performing an appropriate task (active standing), muscle spindle endings could be activated by the same volleys without producing EMG activity. The tibialis anterior spindle ending in Fig. 3.9(b ) had no background discharge when the subject was standing without support and with eyes closed, and was therefore activated by steady pres- sure applied to the tendon. The absence of vision and external support ensured that the subject was maximally dependent on proprioceptive cues for stability. A train of five non-painful stimuli to the ipsilateral sural nerve activated the spindle ending (PSTH in the second trace), but produced no EMG in the silent tibialis anterior. The stimuli produced a reflex response insoleus (fourthtrace) anda forward body sway (fifth and six traces) but this would have unloadedthespindleending, andcannot explainthe spindle activation. Findings suchas this suggest that fusimotor reflexes are task-dependent, only active when subjects are performing an appropriate motor task (Aniss et al., 1990a; Burke & Gandevia, 1992), when their role may lie more in setting the back- ground operating level of fusimotor drive than in the moment-to-moment control of movement (see p. 138). Organisation and pattern of connections 129 (b) (a) Fig. 3.9. Poststimulus increase in discharge of a muscle spindle ending in tibialis anterior after non-painful trains of stimuli to the sural nerve during unsupported standing with eyes shut. (a ) Sketch of the presumed pathways: cutaneous afferents in the sural nerve reflexly excite ␥ motoneurones in tibialis anterior (TA). Recording with a microelectrode in the common peroneal nerve (CPN) from a TA muscle spindle ending. (b ) The ending was silent at rest but was given a background discharge of 9.5 Hz by applying steady pressure to the tendon of TA (not illustrated). Traces are, from above, CUSUM of the PSTH with the onset of the increase in discharge indicated by the arrowat the 84 ms latency; PSTHof spindle discharge; stimulus-triggered averages of rectified surface EMG of TA, of rectified surface EMG of soleus, of force and of ankle-joint angle. The histogram is based on 500 successive trials. Count ratio between the CUSUMand the histogramis 5. Vertical bars represent 10 V for EMGtraces, 2Nfor force, and 0.25 ◦ for the ankle-joint angle. Pre-trigger EMG level for soleus was 21 V. In this figure, stretch of pretibial flexors (i.e. backward body sway) is shown as an upward deflection in force and angle traces. Modified from Aniss et al. (1990a), with permission. Relaxed forearmextensor muscles In these muscles cutaneous afferents can change the muscle spindle response to tendon percussion, though this has been demonstrated for only four afferents – for two, the discharge increased and for two, it decreased (Gandevia et al., 1994). It is likely that, in the upper limb, such reflexes may be active even at rest. More importantly, the decreased response to percussion of two spindle endings suggests that there must have been some back- ground fusimotor drive to the resting muscles, in 130 Muscle spindles and fusimotor drive this case ␥ d activity. Contrary to the hypothesis that, because of temporal and spatial facilitation, natural cutaneous volleys would have more powerful effects on ␥ motoneurones than artificially synchronised electrically evoked volleys, natural activity of cuta- neous afferents evokedby skinstroking or taps failed to affect spindle discharge in these studies. Corticospinal volleys Motor cortex stimulation using single transcranial magnetic or electrical stimuli canalter the discharge of muscle spindle endings, presumably through effects on ␥ and probably  motoneurones (Roth- well, Gandevia & Burke, 1990). However, it does not do so at a lower threshold than that required to pro- duce the MEP, and these findings suggest that an effective ␥ discharge cannot be generated by cor- ticospinal volleys without discharging ␣ motoneu- rones and producing EMG activity in the test muscle. Effects of muscle vibration on human muscle spindles Muscle vibration has been employed extensively in humansubjects toproduce reflex effects or todistort proprioceptive sensations. It has been used to pro- duce reflex contractions (the tonic vibration reflex, TVR), to suppress the H reflex or tendon jerk, and to alter the excitability of group Ia afferents. For these reasons the specificity of vibration for primary spin- dle endings needs to be addressed. There are many fallacious or over-interpreted reports in the litera- turebasedontheassumptionthat transversetendon vibration in intact human subjects can be a selec- tive stimulus for primary spindle endings, driving them to respond 1:1 with the vibration frequency. When applied transversely to a muscle tendon of an intact subject, vibration is commonly not selective for muscle spindle receptors and, in intact human subjects, it may not excite only the primary spindle ending. Relaxed muscles Primary endings The dominant input produced by vibration of a ten- don will be from primary spindle endings in the vibrated muscle. The majority of human primary endings will respond vigorously to vibration and may discharge 1:1, i.e. at the frequency of vibration (120 Hz in Fig. 3.10(b )), particularly during muscle stretch. However, the discharge is often at subhar- monics of the vibration frequency, particularly if the amplitude of tendon vibration is kept small in order to make it as selective as possible. A frequency of ∼80 Hz seems the optimal frequency for most vibration-inducedperceptual andmotor effects (see Roll & Vedel, 1982; Roll, Vedel & Ribot, 1989), whether the vibration is applied using an eccentri- cally weighted motor or as high-frequency tendon taps (using, e.g. a Br¨ uel and Kjaer shaker). Secondary endings Humansecondaryendings mayrespondtovibration (Burke et al., 1976a), virtually always discharging at relatively low rates at subharmonics of the vibration frequency, rarely if ever reaching 1:1, even during muscle stretch (Fig. 3.10(d )). Again, this depends on the amplitude of vibration (Roll & Vedel, 1982; Roll, Vedel & Ribot, 1989). With low-amplitude vibration it should be possible to avoid activating secondary endings, but the lower the amplitude the less secure the driving of primary endings. Tendon organs Some tendon organs can respond to tendon vibra- tion in relaxed muscles and many do so during vol- untary contractions. Indeed, all three tendon organs in the study of Burke et al. (1976a) responded to vibrationwhenthemuscles wererelaxed(Fig. 3.6(b ), (c )). That all did so may be the result of a sam- pling bias of microneurography towards stretch- responsive receptors (see p. 123). Further studies isolating Ib afferents during a voluntary contrac- tion might produce a more representative sample, Motor tasks – physiological implications 131 possibly less responsive to vibration. Nevertheless, the data in Figs. 3.6(b ), (c ) and 3.10(d ) indicate that mechanoreceptors other than the primary spindle ending may be activated by tendon vibration. Cutaneous mechanoreceptors Most cutaneous mechanoreceptors respond to vibration (e.g. Ribot-Ciscar, Vedel & Roll, 1989), and it is probable that Ruffini endings in joints do so as well. Like any mechanical stimulus, vibration of a ten- donwill spreadwidely throughbone, exciting recep- tors in skin, muscles (see Chapter 8, p. 344), fascia andjointsremotefromthesiteof vibration. Thisphe- nomenon has been invoked to explain 'reflex irradi- ation' in spastic patients (see Lance & De Gail, 1965; Chapter 2, pp. 86, 96). Contracting muscles Incontractingmuscles, fusimotor drivecanenhance the spindle response to vibration (Burke et al., 1976b), but contractions may unload spindle end- ings and thereby decrease the spindle discharge for three reasons. First, the application of the vibra- tor to the tendon is not exactly the same as in the relaxed state, secondly, the spread of the vibration wave to the muscle belly is altered when the mus- cle contracts andthe tendonstiffens, andthirdly, the contraction may not be associated with a sufficient increase in ␥ drive to offset these effects. Indeed, if thecontractionisareflexcontractiontothevibration (tonic vibrationreflex, TVR), unloading is the rule, in human subjects (Burke et al., 1976b) and in the cat (Clark, Matthews & Muir, 1981). These problems are even greater if overt movement occurs at the joint, because movement can displace the vibrator and because the responses of different endings are not modulated identically by the change in length. For example, the response of primary endings is maxi- mal duringthestretchingphaseof passiveoscillating movements (Fig. 3.10(b )), while that of secondary endings is more statically related to muscle length (Fig. 3.10(c ); Burke et al., 1976a). Because the response of the primary ending switches off during shortening, while that of the secondary decrea- ses through subharmonics (Fig. 3.10(b ), (d )), there could, paradoxically, be a greater vibration-induced discharge from secondary endings during slow pas- sive muscle shortening. Responses during voluntary movements will not be accurately predictable, par- ticularly if the vibrator is not servo-controlledsothat there is a constant force of application to the mov- ing tendon (Cordo et al., 1993). The final discharge pattern will be determined by: (i) the stability of the vibrator, (ii) the sensitivity of the endings to vibra- tion, (iii) the potency of any fusimotor drive directed to the endings (see pp. 133–5), and (iv) whether the movement is eccentric or concentric, slow or rapid, performed against a load or not. Motor tasks and physiological implications Reflex reinforcement by remote muscle contraction: the Jendrassik manoeuvre Remote contractions may be of limited functional significance, but the mechanisms responsible for the widespread reflex enhancement accompanying such contractions have long been a matter of dis- pute, and the manoeuvre is important in the clin- ical examination. It was previously thought that per- formance of the Jendrassik manoeuvre potentiated tendonjerks inuninvolvednon-contractingmuscles duetowidespreadactivationof dynamic␥ motoneu- rones. Similarly, the reflex potentiation accompany- ing other alerting stimuli, such as a warning cue, has been attributed to the same mechanism. However, attractive as it may be, this hypothesis is seriously flawed for a number of reasons. (i) It is based on the belief that the H reflex is not potentiated to the same extent by the reinforcement manoeuvre. Infact, this is not so: tendonjerks and H reflexes of similar size undergo similar potentiation (e.g. Landau & Clare, 1964; Bussel, Morin & Pierrot- Deseilligny, 1978; Zehr & Stein, 1999). 132 Muscle spindles and fusimotor drive (b) (d) (c) (a) Fig. 3.10. The effects of alternating passive movements on the spindle response to vibration. (a ), (c ) Sketches of the experimental paradigm: recording with a microelectrode in the common peroneal nerve (CPN) from a muscle spindle primary ending in tibialis anterior (TA) and from a muscle spindle secondary ending in peroneus longus (PL). (b ), (d ) Upper trace: 'instantaneous' frequency plot from the recorded afferent (the dashed horizontal line indicates the absence of discharge of the unit); lower trace: goniometer, stretch is indicated by a downward movement of the goniometer trace (the lower trace in each panel). (b ) Vibration of the primary ending in TA at 120 Hz produces a 1:1 response during the stretch phases of the passive movement and silence during the shortening phases. (d ) Vibration of a secondary ending in PL at 100 Hz. The response increases more gradually through subharmonics during the stretching phase to 1:2. With shortening, the response gradually decreases again through subharmonics. Modified from Burke et al. (1976a), with permission. (ii) It is based on the belief that the increased excitability of the motoneurone pool depends on a muscle spindle input fromthe test muscle. However, the H reflex is still potentiated when the Ia input fromthetest muscleis blockedby ischaemia(Bussel, Morin & Pierrot-Deseilligny, 1978). (iii) It ignores the fact that increased background activityinIaafferents wouldproducepost-activation depressionof transmissionfromthose afferents (see Chapter 2, pp. 96–9). (iv) It assumes that increased dynamic ␥ drive would be sufficient to potentiate the spindle response to percussion and that this would be suffi- cient to enhance the discharge of the motoneurone pool, assumptions that have been questioned (see Morgan, Prochazka & Proske, 1984; Wood et al., 1994). (v) A ␥ role for reflex reinforcement cannot be demonstrated in studies that have controlled for post-activationdepressionandthethixotropicprop- erties of muscle spindles (Gregory, Wood & Proske, 2001). (vi) Many (but not all) recordings from spindle afferents using microneurography have failed to demonstrate that the Jendrassik manoeuvre pro- duces (i) anincreasedbackgrounddischarge of mus- cle spindles; (ii) an increase in their response to stretch; (iii) a change in ␣–␥ balance (see Hagbarth Motor tasks – physiological implications 133 et al., 1975a; Burke, 1981; Burke, Gandevia & Mace- field, 2003; however, see also Burg et al., 1973, 1974; Ribot, Roll &Vedel, 1986; Ribot-Ciscar, Rossi-Durand & Roll, 2000). If a ␥ mechanism was responsible for the reflex reinforcement, one would expect the effects on spindle activity to be large, not small, not restricted to a few afferents, and one would expect all studies to have no difficulty demonstrating this same finding. Some studies have demonstrated that there are central changes in the gain of the tendon jerk, changes which, together with the sensitivity of the H reflex (see above), indicate that the reflex enhance- ment involves central processes (e.g. Burke, McKeon & Skuse, 1981b). This is illustrated in Fig. 3.11 with data from a single subject. Panel (b ) plots the size of the muscle afferent volley from soleus against the intensity of tendon percussion. The round symbols represent data when the subject was at rest and the triangles when the subject performed the Jendrassik manoeuvre. There is no difference in the relation- ships. However, the manoeuvres were effective re- inforcing manoeuvres because a tendon jerk occurred (filled symbols) with weaker percussion and a lesser afferent volley. Panel (c ) plots, for the same data, the size of the reflex response against the intensity of the afferent volley. When performing the Jendrassikmanoeuvre(triangles), thereflexresponse was obtained at lower threshold than at rest (circles) and was larger for any given size of afferent volley. The question then arises about which spinal circuits contribute to the reflex enhancement. Decreased presynaptic inhibitionof Ia terminals has been suggested (Zehr & Stein, 1999), but, if any- thing, presynapticinhibitionof Iaterminals tosoleus motoneurones is slightly increased at the onset of a brisk ECR contraction (Meunier & Morin, 1989; Chapter 8, p. 362). Teethclenchinghas beenreported to enhance the H reflexes of both soleus and tibialis anterior (as might be expected for a reinforcement manoeuvre) but also to decrease peroneal-induced reciprocal Ia inhibitionof the soleus Hreflex (Takada et al., 2000; Chapter 5, p. 227). However, reciprocal Ia inhibition is only one of a number of circuits that could be involved in the reflex potentiation due to a remote muscle contraction. Effects of voluntary effort on fusimotor drive to the contracting muscle Increased spindle discharge during contraction Evidence for activation of γ motoneurones When movement is prevented so that contractions are quasi-isometric, there is, during a deliberate vol- untary contraction, an increase in the discharge of active endings (Fig. 3.5(d )), activation of previously silent spindleendings(Fig. 3.7(b )), andanincreasein overall musclespindledischarge(Hagbarth&Vallbo, 1968; Vallbo, 1971, 1974; Vallbo et al., 1979; Edin & Vallbo, 1990b). As mentioned above (p. 117), pres- sure block experiments suggest that this increase in spindle discharge is mediated, at least in part, by the activation of ␥ motoneurones (Burke, Hagbarth & Skuse, 1979). Theunloadingreflex provides evidence that muscle afferent feedback (presumably mainly of spindle origin) contributes to the maintenance of ␣ motor firing during a tonic isometric contrac- tion. When a muscle is pulling against a fixed resis- tancethat suddenlygivesway, asilent periodappears in the EMG of the contracting muscle at a latency appropriate for the withdrawal of Ia afferent support to the active motoneurones (see Hagbarth, 1967). Thus, overall the fusimotor-driven inflow from pri- maryandsecondaryendings duringavoluntarycon- tractionhas anautogenetic excitatoryeffect at spinal level. Spindle acceleration after the onset of EMG With brisk phasic contractions, the increase in spin- dle discharge follows the appearance of EMG in the contracting muscle by up to 50 ms (Vallbo, 1971), evidence that is inconsistent with the follow-up length servo hypothesis (Merton, 1951, 1953; see Matthews, 1972). Attempts to produce consistent spindle activation in advance of EMG by, e.g. pro- viding a warning cue, by using biofeedback train- ing or in learning paradigms, have been unsuc- cessful (Burke, McKeon, Skuse & Westerman, 1980; Gandevia & Burke, 1985; Al-Falahe & Vallbo, 1988; 134 Muscle spindles and fusimotor drive (b) (a) (c) Fig. 3.11. Effects of the Jendrassik manoeuvre on muscle afferent discharge and the size of the tendon jerk. (a ) Sketch of the presumed pathways. During the Jendrassik manoeuvre, there is a descending excitatory influence that enhances reflex transmission to ␣ motoneurones (MN), but not (or minimally) to ␥ MNs. (b) Relationship between intensity of tendon percussion (in arbitrary units) and amplitude of the rectified and smoothed neural afferent responses to percussion (also in arbitrary units) for one subject. (Circles =sequences when the subject was relaxed; triangles =those for which the subject performed reinforcement manoeuvres; filled symbols =tendon taps that produced a tendon jerk; open symbols =no reflex response.) (c) Relationship between amplitude of the rectified and smoothed afferent volley and peak-to-peak amplitude of the resulting reflex EMG bursts for the data in (b). Taps that failed to produce a tendon jerk are shown as open symbols alongside the appropriate afferent volley size. Dashed lines are linear regression lines for the taps that produced reflex EMG. The data obtained during reinforcement manoeuvres (filled triangles) differ significantly (P <0.01) from those obtained during relaxation (filled circles). From Burke, McKeon & Skuse (1981b), with permission. Motor tasks – physiological implications 135 Al-Falahe, Nagaoka & Vallbo, 1990a,b; Vallbo & Al-Falahe, 1990). Spindle activation The degree of spindle activation increases with the degree of effort (Vallbo, 1974) and occurs only or predominantly for spindles in the contracting mus- cle. Spindles in nearby inactive synergists may be unloaded (Vallbo, 1973, 1974; Burke et al., 1976b; Fig. 3.5(e )). Unloading, as in Fig. 3.5(e ), would not be expected if reinforcement manoeuvres produced widespread activation of ␥ motoneurones sufficient to enhance the muscle spindle discharge from inac- tive muscles (see above). The discharge of muscle spindle endings in the contracting muscle declines during long-lasting contractions by about one-third over 60 s, evenwhenthe presence of increasing EMG activityindicatessomefatigue(Fig. 3.7(b ), (c ); Mace- field et al., 1991). This indicates that the fusimotor system has a limited role in compensating for mus- clefatigue, contrarytoearlysuggestions(e.g. Merton, 1951, 1953). Concentric and eccentric contractions The efficacy of ␥ drive in activating spindle end- ings during a voluntary contraction depends on whether thecontractionproduces changes inlength, that shorten or stretch the spindle (Burke, Hagbarth & L¨ ofstedt, 1978a,b). Shortening (in a 'concentric' contraction) will unload spindle endings, and an increase in spindle discharge will then occur only in slow contractions or when the contracting mus- cle is working against a load so that greater effort is required to perform the same movement. During unloaded phasic shortening contractions, it is likely that muscle spindle endings in the contracting mus- cle will be silenced, andany perceptual or reflex cues will come from other receptors, particularly spin- dles inthe antagonist (see Ribot-Ciscar &Roll, 1998). Spindle endings in the contracting muscle may dis- charge, but this occurs after the appearance of the first EMGpotentials andbefore the limbhas actually commenced moving. When a contracting muscle is shortening against a load, the discharge pattern becomes less modulated by the change in muscle length, and spindle endings may behave less like length-transducing receptors andmore like tension- transducing organs (Burke, Hagbarth & L¨ ofstedt, 1978b). During an 'eccentric' contraction, the spin- dle discharge is much higher than when the relaxed muscle is subjected to passive stretch of similar amplitudeandvelocitybecausethefusimotor effects are potentiated by stretch. More complex responses are seen with two-dimensional limb movements. Again, these responses come essentially from the stretched antagonistic muscles, and they correlate with the direction of vibration-induced illusions of movement (Bergenheim, Ribot-Ciscar & Roll, 2000; Roll, Bergenheim & Ribot-Ciscar, 2000). Co- contractions may involve greater fusimotor drive to the contracting muscles than occurs during isolated contractions producing equivalent EMG (Nielsen et al., 1994). Primary and secondary spindle endings 'Dynamic' and 'static' endings, presumably primary and secondary endings respectively, behave in a qualitatively similar manner in the different con- tractions tested: shortening and lengthening con- tractions, with or without additional load (Burke, Hagbarth & L¨ ofstedt, 1978b). Fusimotor activity when reliant on proprioceptive feedback during standing When a subject is standing freely on a horizontal platform, there is little or no EMG activity in the pretibial muscles, there is a poorly sustained spin- dle afferent activity, and manoeuvres that increase the reliance on the proprioceptive feedback do not significantly alter the fusimotor drive in the absence of muscle contraction. However, when the receptor- bearing muscles are activated tonically or phasically to maintain balance their contraction is accompan- ied by an increase in fusimotor drive sufficient to affect spindle discharge (Aniss et al., 1990b). 136 Muscle spindles and fusimotor drive Activation of fusimotor neurones during voluntary effort Static fusimotor motoneurones The discharge of both primary and secondary spin- dle endings increases during voluntary contractions (Figs. 3.7(b ), (c ) and 3.5(d ), respectively), and this constitutes evidence that the increase in ␥ drive involves ␥ s neurones. Further evidence indicating a ␥ s action consists of an increase in static sensitivity, a decrease in the dynamic response of primary end- ings to stretch (though this could be due to a change in the damping effect of the stiffness of muscle and tendon), and a loss of the pause in discharge that primary endings undergofollowing passive shorten- ing (Vallbo, 1973, 1974; Vallbo et al., 1979). In addi- tion, there is an increase in the variability of spindle discharge, and the appearance of a negative serial correlation between successive interspike intervals (Burke, Skuse & Stuart, 1979), something that is a feature of ␥ s drive (see Matthews & Stein, 1969; p. 127). Dynamic fusimotor motoneurones There is some evidence that ␥ d drive is increased in addition to ␥ s (Kakuda & Nagaoka, 1998). How- ever, the study compared the dynamic responses to stretchof spindle endings inrelaxedandcontracting muscles. The experiments were well controlled, the results appear sound, and the conclusions may well becorrect, but it wouldbewisetoretainareservation in mind because it is difficult to be certain that spin- dle endings are subjected to identical stimuli when the muscle and tendon are stiff and when they are slack. Skeleto-fusimotor motoneurones There is also some evidence that voluntary activity activates motoneurones inadditionto␥ motoneu- rones during wrist extension (Kakuda, Miwa & Nagaoka, 1998). This finding relied on the use of spike-triggeredaveragingtodefineanEMGpotential closely linked to the afferent spikes, a technique that had previously yielded negative findings (Gandevia, Burke & McKeon, 1986a). Possible role of the fusimotor system during normal movement The role of the fusimotor system is still the subject of debate, and it is likely that its importance in the moment-to-moment control of movement differs in the cat and man – in part because of the species dif- ferences discussed earlier (see pp. 115–16). The view that some movements can be initiated by first acti- vating ␥ efferents is now rejected for both species, but the extent to which the fusimotor system pro- vides a necessary support to voluntary contractions has not been clarified. Microneurography has been used for ∼35 years, but in this time we have learnt a lot about what the fusimotor systemdoes not doand relatively little about its essential contribution to the control of human movement. Role of afferent feedback Is movement possible without afferent feedback? Movement is possible without any afferent feed- back from the contracting muscle. This has been demonstrated in patients with large-fibre sensory neuropathies (Rothwell et al., 1982; Sanes et al., 1985; Cole & Sedgwick, 1992; Gordon, Ghilardi & Ghez, 1995; Ghez, Gordon & Ghilardi, 1995) and in exper- iments in which the activity of ␣ motor axons was recorded proximal to a complete block of the motor nerve using local anaesthetic (Gandevia et al., 1990, 1993; Macefield et al., 1993). Subjects were still able to activate ␣ motor axons directed to acutely dener- vated muscles and could voluntarily modulate their firing rates. Necessity for afferent feedback However, in the absence of afferent feedback, sub- jects were unable to maintain a steady discharge of ␣ motoneurones, and the discharge rates in weak, Motor tasks – physiological implications 137 moderate and strong contractions were less than those reached in control experiments on the same subjects. Clearly, not every aspect of even a simple unperturbed contraction can be programmed cen- trally. Afferent feedback is also critical when there areunexpecteddisturbancestomovement, suchthat there is a mismatch between the intended and the achieved movement. Disturbances to the expected movement trajectory may be external (due, e.g. to an obstruction or its release) or internal (due, e.g. to a glitch in the motor programme, tremor or unex- pectedstiffness of moving parts). Some formof feed- back is necessary for skilled movement particularly when in novel circumstances, such as walking over an uneven terrain. Which feedback? The above data do not identify whether the neces- sary feedback is of cutaneous, muscle or joint (or even visual) origin. It is likely that the inputs from all appropriately responding mechanoreceptors are integrated to provide a consistent view of the pre- vailing circumstances and that all can play a role in shaping the compensatory motor response. The evidence is cogent for cutaneous and muscle affer- ents, but less convincing for human joint afferents, which seem to act more as multi-directional stress detectors: fewjoint afferents arecapableof encoding joint movement throughout the physiological range (Burke, Gandevia & Macefield, 1988). Much infor- mation about the role of different afferent inputs has come fromremoving individual afferent cues by blocking specific nerves or from artificially boosting the impulse traffic in a selected group of afferents (e.g. by using vibration to activate muscle spindles). It is important to remember that these manoeuvres create anartificial environment andcouldgive a dis- torted view of the importance of different afferent inputs. For example, exclusiononebyoneof thecues contributing to the control of upright quiet stance may be compensated for in normal subjects with a minimal increase in body sway (see Chapter 11, p. 536). This does not mean that the excluded cues were not important or that there was redundancy. It merely indicates that the nervous systemwill always compensateas well as it canbeforethesystembreaks down. Speculations on the functional role of ␥ drive in various motor tasks Accepting that muscle afferent feedback is critical to normal motor control and to movement-related sensations, it is still not clear the extent to which it is important to retain an ability to adjust muscle spin- dle responsiveness and, in particular, an ability to make such adjustments independently of the drive on␣motoneurones. Somespeculationsaretherefore in order. All movements are learnt While this book focuses on spinal circuitry and its role in movement, it should be remembered that muscle spindles are sensory receptors, that they project to higher centres including the sensorimo- tor cortex, and that they contribute significantly to kinaesthetic sensations. It is likely that the impor- tance of ␥ drive involves more than its spinal reflex role. ␥ drive is likely to be critical for the mainten- ance of a coherent input to the supraspinal cen- tres involved in formulating and crafting the motor programme. Lower-limb muscles Contractions of lower-limb muscles are usually weight-bearing and often cyclical, often eccentric. Normal gait is relatively slow, so that many muscles undergo slow loaded contractions that may be con- centric or eccentric. These are circumstances when the co-activated ␥ drive can represent a powerful input to muscle spindle endings (see Chapter 11, p. 544). Hand and forearm muscles The muscles of the handandforearmare requiredto performdiscrete manual tasks, while more proximal 138 Muscle spindles and fusimotor drive upper-limb muscles have a load-bearing and limb- positioning function (see Chapter 11, pp. 521–2). Skilled tasks such as playing the piano involve rapid essentially unloaded movements in which afferent- induced changes in motoneurone discharge could lagfar behindthe phase of movement that generated the feedback. Reflex feedback would have deleteri- ous effects, unless it was based on prediction rather thanactual performance. It wouldbe sensible if such movements wereperformedunder feedforwardcon- trol, because feedback could be disruptive. Under these circumstances, the limited efficacy of ␥ drive inmaintaining spindle discharge whenmovement is rapid and unloaded is not inappropriate: indeed, for it to be otherwise could do more harm than good. Awareness of limb position and movement would thendependmore onthe activity instretchedantag- onistic muscles thanintheactively contractingmus- cles (see p. 135). Motor learning Whenlearning a discrete motor task, movements are slower and often involve co-contraction of antag- onists to brace the joint. Such contractions are asso- ciatedwithaneffectiveincreasein␥ drivetothecon- tracting muscles, and there is evidence suggesting even greater fusimotor drive to co-contracting mus- cles (Nielsen et al., 1994). The feedback fromspindle endings would be important, not only for smooth- ing the movement trajectory but also for providing the sensory cues that allowa more refined voluntary drive. Setting up and maintaining a motor program depends on detailed information from both the re- afferent cues activated by the movement and the spinal circuitry ('the lower motor centres') fed by thesecues (seeChapter 11, pp. 530–1). It is not unrea- sonable to postulate that ␥ drive is important in motor learning. As skill is acquired, its importance would lessen, in parallel with a change in move- ment performance that decreases the efficacy of the ␥ drive. Unfortunately, as mentioned above (p. 133), attempts by Vallbo's group to demonstrate that ␥ drive plays an important role in the acquisition of the skill necessary to perform an initially unfamiliar manual task have been unsuccessful. However, it is possible that this was due to the difficulty of design- ing a task that would test the hypothesis but still allow full control over experimental variables, and the hypothesis remains attractive. Cutaneous control of gamma drive Cutaneous reflex control of ␥ drive is unlikely to play a significant role in the moment-to-moment control of cyclical movements because of the extra lags in the reflex pathway. Cutaneous (and joint) afferent inputs to ␥ motoneurones are more likely to play a role in setting the operating level of the system, such that it is more responsive to changes in supraspinal drives. Separate control of γ d and γ s That there is separate control of ␥ d and ␥ s suggests that thenervous systemrelies onandcandistinguish betweenthestaticanddynamiccomponentsof mus- cle spindle afferent discharge. As discussed above, the available evidence for human subjects does not favour a role for ␥ d in alerting responses or the pre- par-zation for movement. It is likely that the role of ␥ d is to maintain the dynamic responsiveness of pri- mary spindle endings so that they can signal irreg- ularities in movement, and appropriately adjust the timing of motor unit discharge when there is a mis- matchbetweentheintendedandtheachievedmove- ment (see pp. 136–7). However, in human experi- ments, it is technically difficult to infer ␥ d activity frommusclespindledischarge, andtheseviewsmust be advanced with caution. On the other hand, ␥ s couldfunctionto provide anincrease inbackground dischargeandtherebysupportiveexcitationtoactive muscles. Studies in patients and clinical implications Four decades ago, it was popularly held that dis- turbances of muscle tone occurred because of Studies in patients 139 overactivity of ␥ motoneurones (spasticity, rigidity) or their underactivity(hypotonia). Thebasisfor these views has been discussed above, and have been the subject of anumber of reviews(e.g. Burke, 1983, 1988; Van der Meche & Van Gijn, 1986). Intellectually sat- isfying at the time, the ␥ hypothesis of motor distur- bance corresponded with the view that some move- ments couldbe driventhroughthe fusimotor action, like a follow-up servo. Potentially, fusimotor dysfunctioninpatients with motor disturbances could include the following. Increased background fusimotor drive In spasticity, heightened ␥ d drive might result in tendon jerk hyperreflexia and a spastic increase in muscle tone, with loss of dexterity because of the resulting interference with voluntary movement. In parkinsonianrigidity, heightened␥ s drivemight pro- duce the more plastic increase in tone typical of rigidity. Disordered fusimotor activation In attempts to contract paretic, spastic or rigid mus- cles, this might leadtoaninappropriatelevel of spin- dle activity for EMG (or effort), and thereby to dis- turbed reflex support to the contraction. Disinhibited cutaneo-fusimotor reflexes Reflex disinhibition might lead to a fusimotor con- tribution to spasms and spasticity, particularly in spinal patients, in whom these manifestations are more prominent. Though the database of spindle recordings from such patients is restricted, there are cogent argu- ments against the view that fusimotor dysfunction drives these motor disturbances. This conclusion is consistent with other data suggesting that merely increasing spindle discharge with, e.g. vibration, does not produce spasticity or rigidity (Matthews, 1976; Burke, 1983). Spasticity Hemiplegia Absence of γ hyperactivity Someearlyrecordings basedonthetimingof spindle discharge on the falling phase of electrically evoked twitch contractions led Szumski et al. (1974) to sug- gest that there was heightened background ␥ d activ- ity in spastic patients. However, it is likely that these findings were due to changes in the twitch proper- ties of triceps surae rather than fusimotor action. Recordings have been made from spindle afferents in triceps surae of two hemiplegic patients (Hag- barth, Wallin & L¨ ofstedt, 1973) and in the forearm extensor muscles of 14 hemiplegic patients (Wilson et al., 1999a). In neither study was the background discharge or the response to stretch of spindle end- ings in relaxed muscles greater than those in con- trol subjects. In addition, there was no evidence of 'inappropriate' spindle behaviour (i.e. changes in discharge that could not be correlated with a change in muscle length or the development of EMG in the receptor-bearing muscles), and there was no evi- dencethat reinforcement manoeuvrescouldactivate spindle endings without causing contraction of the relevant muscle. Most of the patients suffered from tendonjerkhyperreflexia, withor without anobvious increase in muscle tone, and these findings there- fore support the view that spasticity occurs through mechanisms largely independent of the level of ␥ drive (Chapter 12; see also Burke, 1983, 1988). These results argue against a contribution of ␥ overactiv- ity to spasticity. However, it would be imprudent to discard completely heightened fusimotor excitabil- ity as a possible contributing factor to spasticity in stroke patients: (i) only in two patients were triceps surae afferents studied; (ii) in the upper limb, spas- ticity is preferentially distributed on forearmflexors, not extensors (see Chapter 12, pp. 564–5). Absence of α/γ co-activation in clonus Spindle activity has been recorded during ankle clonus in patients with hemiplegic spasticity 140 Muscle spindles and fusimotor drive (Hagbarthet al., 1975c). Spindles were activateddur- ing the stretching phase of the oscillating clonic movement, and their activation appeared to drive the next clonic contraction, presumably through the same spinal pathways that underlie the tendon jerk reflex. The contraction itself was not accompanied by spindle activation, though this was seen when normal subjects made rapid alternating contrac- tionsmimickingclonus(Hagbarth, Wallin&L¨ ofstedt, 1975b). This led Hagbarth and colleagues to suggest that proprioceptivespinal reflexes donot involvesig- nificant activation of ␥ motoneurones in addition to ␣ motoneurones, i.e. that these reflexes constituted an exception to the principle of ␣/␥ co-activation. This view was supported by similar findings with the tonic vibration reflex (Burke et al., 1976b), and is consistent withrelatively weak (or absent) excitatory projections of group Ia afferents onto ␥ motoneu- rones. Fusimotor dysfunction probably contributes little to the motor deficit A hypothesis of the study of Wilson et al. (1999a) had been that the corticospinal lesion might disrupt the balance normally present between the ␣ and ␥ drives to a voluntarily contracting muscle, but they foundnoevidenceof greater easeor greater difficulty in activating spindle endings voluntarily in paretic muscles. Disappointingly, therewasalsonoevidence for disinhibition of cutaneous reflex pathways to ␥ motoneurones. Spinal spasticity Reflex activation of γ motoneurones There are, as yet, no published reports of recordings fromspindle endings inpatients withspinal spastic- ity, though intuitively one might expect there to be disinhibition of reflex pathways acting on ␥ and  motoneurones, such that normally innocuous stim- uli such as stroking the skin would cause a height- ened spindle discharge. If this proved to be the case, it is possible that the skin, joint, bladder and bowel complications of paraplegia would result in a steady afferent input to ␥ motoneurones in such patients, producing widespread␥ activity eveninthe absence of EMG activity. It remains to be proven whether heightened ␥ drive contributes to spinal spasticity and to flexor and extensor spasms. Possible group II excitation of γ motoneurones In patients with spinal cord lesions, there is evi- dence that increased group II excitation might be an important spinal mechanism underlying spas- ticity (cf. Chapter 12, p. 581). The disinhibition of pathways mediating group II excitation is proba- bly due to damage to descending monoaminergic pathways that gate the transmission of group II excitation. The absence of a correlation between the increased electrically-induced group II excita- tion and the stretch reflex exaggeration could be because the former does not test the projections of group II-activated lumbar propriospinal neurones to ␥ motoneurones (see Chapter 7, p. 325). Reflex activation of ␥ motoneurones because of disinhibi- tion of group II pathways deserves to be mentioned separately to disinhibition of cutaneous pathways to ␥ motoneurones (cf. above) because the former would cause positive feedback if the target neurones were ␥ s . Parkinson's disease The data are particularly sparse for Parkinson's disease: multi-unit recordings that have been pre- sumed to be dominated by muscle spindle activ- ity (Hagbarth, Hongell & Wallin, 1970; Wallin, Hongell &Hagbarth, 1973), a subsequent re-analysis of precisely the same data (Burke, Hagbarth & Wallin, 1977), and some single-unit recordings dur- ing parkinsonian tremor (Hagbarth et al., 1975c). Rigidity In these recordings, fluctuations in rigidity were associated with parallel fluctuations in muscle Conclusions 141 afferent activity andEMG, but withthe latter leading the former. Voluntary efforts were associated with the increase in muscle afferent discharge expected fromstudiesinnormal subjects. Inother words, there was no evidence of selective or disproportionate ␥ drive to spindle endings in these patients, and no evidence that the rigidity was driven by enhanced fusimotor drive. However, as inthe case of spasticity, it wouldbeimprudent todiscardcompletelythepos- sibility that fusimotor neurones play a role inparkin- sonian rigidity. Any enhanced ␥ motoneurone dis- charge need not result from enhanced descending drive onto fusimotor neurones: it could also result fromabnormal gating of the transmissionof groupII excitation to ␥ motoneurones (see Chapter 12, p. 584). Clarification of this issue requires detailed studies under identical conditions of the responses of single spindle afferents in patients and control subjects. Parkinsonian resting tremor In parkinsonian resting tremor, muscle spindles dis- charged during two phases: during the shortening phase of the tremor cycle, with the EMG burst, and again in the opposite phase of the cycle as the end- ings werestretched(Hagbarthet al., 1975c). This pat- ternis similar to that seenwithvoluntary alternating movements (Hagbarth, Wallin&L¨ ofstedt, 1975b) but not clonus (Hagbarth et al., 1975c). Such behaviour suggeststhat thesupraspinal activitydrivingtherest- ingtremor of Parkinson'sdiseaseactivatesboth␣and ␥ motoneurones. Conclusions The sensitivity of the muscle spindle The muscle spindle is a more sensitive transducer of changes in muscle length and in the derivatives of lengththancouldbe constructedby humans or fixed to the limbs of volunteers. This complicates experi- ments that use muscle spindle activity as a measure of ␥ efferent drive. Evidence for selective activation of ␥ motoneurones should be viewed with an open mind, scepticismbeing warrantedwhenthe data are basedononly anoccasional recording fromanaffer- ent that could have been misclassified. Background ␥ efferent drive to relaxed muscles There is considerable evidence suggesting that there is little activity instatic ␥ motoneurones innervating resting muscles and, if there is any, it is insufficient to alter muscle spindle discharge materially. The tendon jerk does not require that spindle endings be sensitised by ␥ d drive to be sufficiently respon- sive that percussionevokes a tendonjerk. Regardless of whether reinforcement manoeuvres can activate some ␥ d motoneurones, the reflex potentiation pro- duced by the Jendrassik manoeuvre or in response to some other alerting stimulus is not mediated by selective activation of ␥ d motoneurones. ␥ efferent activation by corticospinal drives Corticospinal drives, whether associated with vol- untary effort or produced by transcranial magnetic or electrical stimulation of the motor cortex, can increase the discharge of spindle endings due, pri- marily, toactivationof ␥ motoneurones (but alsodue to activation of  motoneurones), largely in paral- lel with ␣ motoneurones. In voluntary contractions, the spindle activationparallels the effort put intothe contraction, and an effective increase in ␥ drive is directedonlytothecontractingmuscle. Theincrease in␥ drive is translatedinto anenhancedspindle dis- charge when the contraction is near-isometric. The ␥ drive is even more effective when the contracting muscleis lengthening, andis muchless soif themus- cleis shortening. Increasedspindlefeedbackaccom- panies shortening contractions only when the con- tractions are relatively slowor the muscle is working against a load. There will probably be little increase in spindle feedback from the contracting muscle in unloaded rapid shortening movements, i.e. proprio- ceptive cues probably then come fromthe stretched antagonists. 142 Muscle spindles and fusimotor drive ␥ efferent activity in patients with motor disturbances There are few studies in patients, but these do not support the viewthat an abnormality of ␥ motoneu- rone activity is the primary disturbance responsible for the clinical manifestations. This leads to the con- clusion that, if there is an abnormality of fusimo- tor function in patients, it is unlikely to represent a causal association. R´ esum´ e Background fromanimal experiments The number of spindles in different muscles varies from<50 for intrinsic muscles of the hand to >1000 for quadriceps femoris, but the density is higher in the former. Muscle spindles contain modified muscle fibres (intrafusal fibres). The bag 1 intrafusal fibre is innervated by dynamic fusimotor (␥ d ) axons, and the bag 2 and chain fibres by static fusimotor (␥ s ) axons. There are two types of sensory endings: primary endings wrap around both the bag and chain fibres, and are sensitive to both the static and dynamic components of muscle stretch and to high- frequency vibration; secondary endings are located on chain fibres and the static bag 2 fibre, are sensi- tive to the static component of stretch, are less sen- sitive to the dynamic component of stretch, and are much less sensitive to vibration. The primary end- ing gives rise to a single large group Ia afferent, while the secondary endings give rise to several group II afferent axons per spindle. Theproperties of thebag 2 fibre largely determine both the background firing rate of Ia afferents and the dynamic response to stretch of passive spindles. The fusimotor-induced enhancement of therestingdynamicresponsiveness depends on activation of bag 1 fibre. The static and dynamic sensitivity of muscle spindle primary end- ings can be controlled independently by ␥ s and ␥ d , respectively. There are different supraspinal projec- tions onto ␣ and ␥ motoneurones, but there are also striking parallels, and this led to the suggestion that voluntary movement involved an␣-␥ linkage (or co- activation), a suggestion supported by microneu- rographic studies.  (skeleto-fusimotor) efferents innervate both intra- and extra-fusal muscle fibres. Methodology Discredited methods (i) There is now substantial evidence against the viewthat comparisonsof theHreflexandtendonjerk can be used to provide a reliable measure of fusimo- tor activity. While the tendon jerk and the H reflex are both dependent on the monosynaptic excitation fromhomonymousIaafferents, theHreflexbypasses the muscle spindle while the tendon jerk does not. However, the two reflexes differ in so many other respects that comparison of them as a measure of fusimotor function is invalid. (ii) Local anaesthetic nerve blocks: because of the large size of human nerves, diffusion of local anaesthetic through perineural and fascicular tis- sues results in non-selective effects because of involvement of closer rather than smaller axons. Microneurographic studies have shown that anaes- thetic blocks are extremely difficult to control and cannot be used as a technique for selective denerva- tion of muscle spindles. Acceptable methods (i) Microneurography is the most reliable tech- nique for determining the level of fusimotor activity. Themicroelectrodeis insertedmanuallythroughthe skin into the peripheral nerve trunk. When the tip is withinanappropriatefascicle, tappingontheappro- priate muscle tendon will activate mechanorecep- tors, andauditory feedback is thenusedto make fur- ther small adjustments of the electrode to bring the desired neural activity into focus. Criteria to iden- tify spindle endings and Golgi tendon organs include the response to a twitch contraction of the R´ esum´ e 143 receptor-bearing muscle, the presence or absence of background activity, the regularity of any back- ground discharge, behaviour during voluntary contractions and on abrupt relaxation, and the responses to stretch and vibration. There is a bias inmicroneurographic recordings towards axons that are large and have a background discharge. Muscle spindle endings are extremely sensitive to minute perturbations. Small disturbance to the spindle's environment withinthemusclemaynot beapparent to inspection. EMG electrodes and force and length transducers must be used to be certain that the receptor-bearing muscle is truly relaxed when seek- ing evidence for selective activation of ␥ motoneu- rones. (ii) Studies that exploit the thixotropic properties of intrafusal fibres. In human subjects, voluntary activity can produce long-lasting enhancements in spindle discharge. These changes may persist long after the contraction and are due to the thixotropic properties of the intrafusal fibres that contracted under ␥ drive during the voluntary contraction. This behaviour canbeexploitedtostudyfusimotor action in human subjects indirectly. The thixotropic prop- erties of intrafusal muscle fibres can distort spindle discharge and must be considered when interpret- ing unexpected changes in spindle discharge, reflex behaviour or perception. Critique of the tests to study fusimotor drive Microneurography Conclusions about fusimotor activity from record- ings of muscle spindle discharge are valid only if all disturbances to the spindle are rigidly con- trolled, and this is rarely possible inhumansubjects; the identification of an axonal recording must be beyond dispute, particularly when the conclusions are based ononly a couple of 'positive' findings from alarger sample; themovement repertoirethat canbe studied is quite limited; the technique is traumatic and technically demanding. Studies of intrafusal thixotropy These studies can allow stronger contractions to be assessed and can be of value in patients for assessing fusimotor activity. However, the tech- nique is indirect, and a complicating factor is that extrafusal muscle fibres also display thixotropic behaviour. Organisation and pattern of connections Background fusimotor drive Human spindle endings behave as if passive recep- tors without static fusimotor drive in the relaxed state. There may be some background ␥ d activity. Firing rates are much lower and responses to stretch smallerthaninthecat, andtheregularityof discharge is similar to that of de-efferented feline endings. In addition, de-efferenting spindles does not alter the muscle spindle behaviour. This suggests a very low level of ␥ drive, insufficient to affect spindle dis- charge materially. Inaddition, the responses tomus- cle stretch or to tendon percussion do not change in relaxed muscle when subjects perform reinforce- ment manoeuvres, are provided with alerting stim- uli or anticipate the needto contract the test muscle, provided that the receptor-bearing muscle remains relaxed. Effects of cutaneous afferents on fusimotor neurones Evidencefor reflex activationof ␥ motoneurones has been found for human lower limb muscles, but only when subjects were standing without support. This finding suggests that fusimotor reflexes may be task- dependent, active when performing an appropriate motor task. Inthe relaxedforearmextensor muscles, such reflexes may be active even at rest. There may be some background ␥ d drive to the resting forearm muscles. 144 Muscle spindles and fusimotor drive Corticospinal volleys Single transcranial magnetic or electrical stimuli can alter the discharge of muscles spindles, presumably through effects on ␥ and probably  motoneurones. However, an effective ␥ discharge cannot be gener- ated without discharging ␣ motoneurones and pro- ducing EMG activity in the test muscle. Effects of muscle vibration on human mechanoreceptors When applied transversely to a muscle tendon of an intact subject, vibration is usually not selective for musclespindleprimaryendings inthevibratedmus- cle. Themajorityof humanprimaryendings respond vigorously to tendon vibration, though often at sub- harmonics of the vibration frequency, particularly if the amplitude of vibration is small. Human sec- ondary endings may respond to vibration, discharg- ing at highsubharmonics of the vibrationfrequency. Some tendon organs can respond to tendon vibra- tion in relaxed muscles and many probably do so during voluntary contractions. Most cutaneous mechanoreceptors respond to vibration, and it is probable that Ruffini endings in joints do so as well. Like any mechanical stimulus, vibration of a tendon will spread widely through bone, exciting receptors in skin, muscles, fascia and joints remote from the site of vibration. In contracting muscles, fusimotor drive canenhance the spindle response to vibration, but the contractionitself may unloadthe ending and thereby decrease the spindle discharge. Motor tasks and physiological implications Reinforcement of tendon jerks by remote muscle contraction Performance of the Jendrassik manoeuvre poten- tiates tendon jerks in uninvolved non-contracting muscles, but there is now cogent evidence that this is not due to widespread activation of ␥ d motoneu- rones. There are central changes in the gain of the tendon jerk, changes which, together with the fact that the H reflex is also potentiated by the manoeu- vre, indicate that the reflex enhancement involves central processes. Effects of voluntary effort on fusimotor drive to the contracting muscle (i) Deliberate voluntary contractions increase the discharge of primary and secondary spindle end- ings due, at least in part, to the activation of ␥ motoneurones. This afferent inflow has an overall autogenetic excitatory effect at spinal level and con- tributes tomaintainingthefiringof ␣motoneurones. It increases with the degree of effort but only or pre- dominantly for spindles inthe contracting muscle. It hasalimitedroleincompensatingformusclefatigue. (ii) The increase in spindle discharge follows the appearance of EMG in the contracting muscle. Attempts toproduce consistent spindle activationin advance of EMG by, e.g. providing a warning cue, by using biofeedback training or inlearning paradigms, have been unsuccessful. (iii) The efficacy of ␥ drive in activating spindle endings depends on whether the contraction pro- duces changes in length of the spindle. Shortening (as inaconcentriccontraction) unloads spindleend- ings, andanincreaseinspindledischargeoccursonly inslowcontractionsor whengreater effort isrequired to performthe same movement. There will probably be little increase in spindle feedback from the con- tracting muscle inunloaded rapid shortening move- ments and it is then likely that proprioceptive cues come from stretched antagonists. Stretching a con- tracting muscle (an eccentric contraction) greatly enhances any fusimotor effect on spindle discharge. There is some evidence that voluntary activity acti- vates  motoneurones in addition to ␥ motoneu- rones, and that ␥ d drive is increased in addition to ␥ s . (iv) The exact role of the fusimotor system in nor- mal motor control remains speculative. However, it is possible that the ␥-driven feedback from muscle spindles plays an important role in learning motor tasks. References 145 Changes in fusimotor activity in patients There are cogent arguments against the view that fusimotor dysfunction drives motor disturbances, but the database of spindle recordings frompatients is restricted. Spasticity No abnormal spindle behaviour could be identified for spindle afferents fromtriceps surae and the fore- arm extensor muscles of patients with hemiplegia. These findings support the view that spasticity in stroke patients occurs through mechanisms largely independent of the level of ␥ drive. During ankle clonus, spindles are activated during the stretching phase of the oscillating clonic movement, and their activation drives the next clonic contraction. This suggests that spinal proprioceptive reflexes do not involve significant activation of ␥ motoneurones in addition to ␣ motoneurones, i.e. that these reflexes areanexceptiontotheprincipleof ␣/␥ co-activation. There are, as yet, no published reports of recordings from spindle endings in patients with spinal spas- ticity, but the possibility exists that reflex activation of ␥ motoneurones by, e.g. cutaneous afferents and group II muscle afferents, contributes to the reflex disturbances of these patients. Parkinson's disease The data consist of multi-unit recordings, presumed tobedominatedbymusclespindleactivityandsome single-unit recordings during parkinsonian tremor. These have revealed no evidence of selective or dis- proportionately increased ␥ drive in these patients, but the question needs to be addressed quantita- tively using a large number of single unit record- ings from identified afferents. In parkinsonian rest- ing tremor, spindle discharge occurs in two phases: during the shortening phase of the tremor cycle, with the EMG burst, and again as the endings were stretched, a pattern similar to that seen with volun- tary alternating movements but not clonus. REFERENCES Al-Falahe, N. A. &Vallbo, Å. B. (1988). Role of the humanfusimo- tor systemina motor adaptationtask. Journal of Physiology (London), 401, 77–95. Al-Falahe, N. A., Nagaoka, M. & Vallbo, Å. B. (1990a). Lack of fusimotor modulation in a motor adaptation task in man. Acta Physiologica Scandinavica, 140, 23–30. 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Experimental Brain Research, 98, 101– 9. Wood, S. A., Gregory, J. E. & Proske, U. (1996). The influence of muscle spindle discharge on the human H reflex and the monosynaptic reflex in the cat. Journal of Physiology (London), 497, 279–90. Zehr, E. P. & Stein, R. B. (1999). Interaction of the Jendrassik maneuver with segmental presynaptic inhibition. Experi- mental Brain Research, 124, 474–80. 4 Recurrent inhibition Recurrent inhibition was the first spinal pathway identified, and there was detailed knowledge of its morphology, physiology and pharmacology from animal experiments well before other spinal path- ways could be investigated. After reciprocal Ia inhi- bition, the recurrent pathway was the first pathway for which a reliable selective method of investiga- tion became available for use in human subjects. This is due to the simplicity of its organisation and to its unique feature of being activated by the final motor output rather than by a special afferent input. Human experiments have helped understand what could be the functional role of this form of neg- ative feedback, but its exact function(s) remain(s) debated. Background from animal experiments Initial findings Renshaw (1941) demonstrated that, in animals with dorsal roots sectioned, antidromic impulses in motor axonscouldevokeashort-latencylong-lasting inhibition of the monosynaptic reflex in homony- mous and synergistic motoneurones. The inhibition depends on motor axon recurrent collaterals activa- ting interneurones, that have been called Renshaw cells, the discharge of which inhibits motoneu- rones (Eccles, Fatt & Koketsu, 1954). The following description of the recurrent pathway in the cat (see Fig. 4.1) is based on a comprehensive review by Baldissera, Hultborn &Illert (1981), and emphasis is placed on data that can enlighten studies in human subjects. General features Morphology Renshaw cells are funicular cells located ventrally in lamina VII, medial to motoneurones (near their emergent axons), with axons that enter the spinal white matter to project over distances >12 mm ros- trally or caudally (Jankowska & Lindstr¨ om, 1971). The organisation of the disynaptic recurrent pathway Some relevant connections are sketched in Fig. 4.1: motor axons give off recurrent collaterals activating Renshaw cells, which have inhibitory projections to homonymous and synergistic motoneurones. Pharmacology Recurrent collaterals excite Renshaw cells using acetylcholine as the transmitter, much as do moto- neurone terminals at the neuromuscular junction (Eccles, Fatt & Koketsu, 1954). This characteristic provides the unique possibility in human studies of studying transmission through the pathway by altering it pharmacologically. 151 152 Recurrent inhibition Group II afferent MN extensor γ MN Extensor muscle Descending tracts Ach Ach Ia inhibitory interneurone Renshaw cell MN flexor Group Ia afferent Fig. 4.1. Wiring diagram of the connections of the recurrent inhibitory pathway in the cat. In this and subsequent figures, excitatory synapses are represented by Y-shape bars, inhibitory synapses by small filled circles, and inhibitory interneurones by larger filled circles. Renshaw cells, their axons and their inhibitory projections are in grey. An individual Renshaw cell activated by the recurrent collateral from an extensor motoneurone (MN) has inhibitory projections to motoneurones of this pool (and MNs of synergistic muscles, not represented), on ␥ MNs of the same muscle(s), on Ia inhibitory interneurones which are activated by Ia afferents from the extensor muscle and inhibit antagonistic flexor MNs, and on Renshaw cells activated from flexor MNs. Group II afferents inhibit Renshaw cells disynaptically. Descending tracts elicit both excitation and inhibition of Renshaw cells. There is the same transmitter, acetylcholine (Ach), at the neuromuscular junction and at the synapse between recurrent collaterals and Renshaw cells. From data in Baldissera, Hultborn & Illert (1981). Electrophysiology Asinglevolleyin␣motor axons produces arepetitive discharge of Renshawcells, due to a prolonged EPSP fromthe recurrent collaterals. Accordingly, the max- imal recurrent IPSP in motoneurones from a given heteronymous nerve (i.e. that elicited by antidromic stimulation of all motor axons in the nerve) has a central latency of slightly more than1 ms (disynaptic pathway), reaches its maximum 5 ms after its onset, and has a total duration of ∼40 ms (Eccles, Fatt & Koketsu, 1954). Strength of recurrent inhibition Conflicting results have been reported. Lindsay & Binder (1991) found a very low gain, which con- tradicted older results (Granit & Renkin, 1961). In reviewing the function of the recurrent pathway, Windhorst (1996) proposed that the gain of recur- rent inhibition: (i) may be low, albeit alterable; (ii) does not need to be high to have signifi- cant effects; (iii) depends on the relative location on the motoneurone dendritic tree of Renshaw cell synapses and of excitatory synapses that they 'oppose' (the depressive effect being greater in cases of extensive overlap; see Hultborn et al., 2003). Input–output relationship Inindividual Renshawcells therelationshipbetween the amount of injected current and the number of spikes produced by the cell is sigmoid (Hultborn & Pierrot-Deseilligny, 1979b). The output from the Renshaw cell pool caused by a phasic motor volley may be therefore facilitated when Renshaw cells receive a tonic excitatory input sufficient to move them to the steeply rising phase of the input-output relationship. Input to Renshawcells Input from␣ motoneurones In the cat hindlimb, recurrent collaterals are always given off by motoneurones innervating ankle and knee muscles but are absent from motoneurones of short plantar foot muscles (Cullheim & Kellerth, 1978). Similarly, recurrent collaterals areabsent from motoneurones of long digit extensors in the cat forelimb (H¨ orner, Illert & K¨ ummel, 1991). Motor axon collaterals spread a distance of less than 1 mm from their parent cell body, so that excitation of a given Renshaw cell can be obtained only from Background fromanimal experiments 153 motor nuclei located in the immediate neighbour- hood (Cullheim & Kellerth, 1978). Each individual Renshaw cell is excited by axon collaterals of many motoneurones, as evidenced both by their smoothly growing response to increasing intensity of stimu- lation of individual nerves and by their excitation from several nerves (Eccles, Fatt & Koketsu, 1954; Eccles et al., 1961b). Renshawcells areexcitedmainly by motoneurones of synergistic muscles and not by those of strict antagonists, and this indicates that convergence onto Renshaw cells is based, not only on proximity, but also on functional factors. This holds true also in the baboon hindlimb (Hultborn, Jankowska & Lindstr¨ om, unpublished data, cited by Baldissera, Hultborn & Illert, 1981). It has long been believed that Renshaw cells were preferentially acti- vated fromlarge motoneurones (fast-twitch fatigue- sensitivemotor units) (Eccles et al., 1961a). However, because of the small force contribution of the earli- est recruited units, the excitatory drive on Renshaw cells from motoneurones increases linearly with the developed force (Hultborn et al., 1988a). Segmental afferents Apart fromthe excitationproducedby motoneurone discharges, polysynaptic excitation of Renshawcells may occur after stimulation of cutaneous afferents (Ryall &Piercey, 1971) and ipsilateral group II and III muscle afferents (Piercey & Goldfarb, 1974). There arealsoinhibitoryinputs toRenshawcells fromcuta- neous and group II afferents (Wilson, Talbot & Kato, 1964; Fromm, Haase & Wolf, 1977). Descending inputs There is ample evidence that Renshaw cells may be facilitated or inhibited, independently of an alter- ation in motoneurone discharge by stimulation of various higher centres (cerebral cortex, internal cap- sule, red nucleus, cerebellum, reticular formation and thalamus; for references, see Baldissera, Hult- born & Illert, 1981). For instance, stimulation of the internal capsule increases the monosynaptic reflex discharge and decreases the resulting Renshaw cell activity, thus de-coupling Renshaw cells from their input motoneurones (Koehler et al., 1978). Projections of Renshawcells Projections to ␣ motoneurones Following activation of the motoneurones of a given muscle, recurrent inhibitionis evokedinanumber of motor nuclei. The largest recurrent IPSPs are found in homonymous motoneurones, but many other motoneurones are also strongly inhibited (Eccles, Fatt & Koketsu, 1954; Eccles et al., 1961b). This heteronymous recurrent inhibition is distributed to motoneurones of synergistic muscles acting at the same joint or even at another joint, and there is a striking overlap between the distribution of Ren- shaw inhibition and monosynaptic Ia excitation (Hultborn, Jankowska & Lindstr¨ om, 1971b). How- ever, there may be little or no recurrent inhibition to motor nuclei receiving strong Ia excitation (e.g. the distal forelimb muscles; Illert & Wietelmann, 1989) and recurrent inhibition may occur without Ia excitation (e.g. phrenic motoneurones; Lipski, Fyffe & Jodkowski, 1985). Thus, the 'rules' underly- ing the distribution of Ia excitation and recurrent inhibition are basically independent, even though they are often convergent (Hultborn, 1989). It has long been believed that small motoneurones (slow- twitch fatigue-resistant motor units) were subject to stronger recurrent inhibition than large motoneu- rones (Granit, Pascoe & Steg, 1957). However, the differences in the output from Renshaw cells, meas- ured as recurrent inhibitory current elicited in different motoneurone types close to their firing threshold, disappear (Hultborn, Katz & Mackel, 1988b). Projections to ␥ motoneurones Both␥ s and␥ d motoneurones receive recurrent inhi- bitionfrom␣motoneurones. Recurrent inhibitionis less potent and less evenly distributed in ␥ than in ␣ motoneurones of the same motor nucleus (Ellaway, 1971; Ellaway & Murphy, 1980). 154 Recurrent inhibition Ia inhibitory interneurones Renshaw cells inhibit the interneurones mediating disynaptic reciprocal Ia inhibition to ␣ motoneu- rones antagonistic to those giving off the recurrent collaterals that excite them (Hultborn, Jankowska & Lindstr¨ om, 1971a). ␣ motoneurones and 'corre- sponding' Ia interneurones (i.e. those with the same Ia excitatory input, see Fig. 4.1) receive recurrent inhibition in a strictly parallel fashion. This inhi- bition of Ia interneurones is responsible for recur- rent facilitation (i.e. the facilitation elicited in antag- onistic motoneurones by motor discharges), which was describedby Renshaw(1941), operates predom- inantly betweenantagonists, andis due toinhibition of tonically active Ia interneurones (Hultborn et al., 1971c). Other Renshawcells Renshawcells also inhibit other Renshawcells quite efficiently (Ryall, 1970). The principal pattern of mutual inhibition appears to be such that Ren- shawcells excitedby extensors strongly inhibit those excited by flexors (see Fig. 4.1) and vice versa (Ryall, 1981). Ventral spinocerebellar tract Finally, Renshawcells have inhibitory projections to the cells of origin of the ventral spinocerebellar tract (VSCT, cf. Baldissera, Hultborn & Illert, 1981). Conclusions Hypotheses about the role of the recurrent path- way have centred around four themes: '(i) con- trol of the spatial pattern of motoneuronal activ- ity (stretching from theories of a _sharpening¸of motor contrast to the hypothesis that the particu- lar distribution of recurrent inhibition may support specific _synergic¸ motor patterns; (ii) control of the temporal pattern(e.g. synchronisation, suppres- sion of oscillations, change of dynamic properties of motoneurones); (iii) control of the relative activity of slow and fast units; (iv) proposal that the Ren- shawsystemfunctions as a variable gainregulator at the output level' (Hultborn, 1989; cf. p. 179). So far, the functional role of recurrent inhibition remains unknown, and it is possible that it varies with motor tasks (see Windhorst, 1996). Methodology Using homonymous antidromic motor volleys is a flawed technique in humans Presumed recurrent effects Taking advantage of the fact that very brief (50 s) stimuli favour motor axons over Ia afferents (see Paillard, 1955; Chapter 1, p. 6), Veale & Rees (1973) conditioned the soleus H reflex by a brief stimu- lus evoking a pure M wave. This produced triphasic modulation of the test reflex with early inhibition at interstimulus intervals (ISIs) of 2–3 ms, facilitation peaking at 5–8 ms, followed by further inhibition. It was claimed that these changes were due to recur- rent effects elicited by the antidromic motor volley: recurrent inhibition on which a phase of recurrent facilitationduetomutual inhibitionof Renshawcells would be superimposed. This interpretation is erroneous (i) A similar curve can be obtained using a condi- tioning stimulus of 50 s durationsubthresholdfor a motor response, whether Hor M, due toexcitationof Ia afferents (Pierrot-Deseilligny & Morin, 1980). The afferentsinthetest volleywouldberefractoryat short ISIs of 2–3 ms andsupernormal at slightly longer ISIs of 5–8 ms (see Chapter 1, p. 11; Fig. 1.5(b)). In addi- tion, the conditioning Ia volley would create sublim- inal excitation in the motoneurone pool, explaining the phase of excitation. The absence of an H-reflex response does not indicate the absence of activation of Ia afferents: it takes only one motor axon to pro- duceadetectableMwave, but manyIaafferentsmust Methodology 155 be activated for there to be a reflex response. In this respect, the threshold for the H response elicited by such brief stimuli (50 s) may be higher than the thresholdfor theMwavebut it is closetoit (seeVeale, Rees & Mark, 1973, their Fig. 4.2(a )). (ii) In the cat, recurrent facilitation is observed betweenantagonisticmotoneurones, never between homonymous or synergistic motoneurones (Hult- born et al., 1971c). Other issues with stimuli >1 MT Using an antidromic motor discharge to activate Renshaw cells has been extensively used in exper- iments on animals with dorsal roots sectioned, but cannot be achieved in intact human subjects with- out extreme care (see p. 168). When the dorsal roots are intact, it is impossible to elicit an antidromic motor volley without producing two complicating factors: (i) an orthodromic group I volley, the effects of whichmay interfere withrecurrent inhibition(see above); and (ii) a complex afferent discharge evoked by the muscle twitch due to the orthodromic motor volley. The paired Hreflex technique to investigate homonymous recurrent inhibition Underlying principles The paired H reflex technique relies on a colli- sion in motor axons, and is an attempt to bypass the difficulties of studying homonymous recurrent inhibition when dorsal roots are intact (see below for details, and Pierrot-Deseilligny & Bussel, 1975; Bussel & Pierrot-Deseilligny, 1977). (i) Renshawcells are activated orthodromically by a conditioning monosynaptic reflex discharge, but a collision in motor axons prevents the conditioning reflex from reaching the muscle, and producing a twitch-induced afferent discharge. (ii) The test reflex cannot be an ordinary H reflex, because motoneurones that discharged in the con- ditioning reflex undergopost-spike afterhyperpolar- isation (AHP), while those that did not will be sub- liminally excited. Because of this, a second (test) H reflex will recruit predominantly the latter (Pierrot- Deseilligny et al., 1976). The larger the conditioning reflex, the smaller will be the test reflex, independent of recurrent inhibition. The particular technique of collision used to test recurrent inhibition creates a homogeneous population of motoneurones avail- able for assessment by the test reflex. Only those motoneurones that discharged in the conditioning reflex(andhaveundergonetheAHP) canbeinvolved in the test reflex (see below). (iii) Long conditioning-test intervals (≥10 ms) prevent Ib inhibition evoked by the conditioning volley from contaminating the recurrent inhibition (Pierrot-Deseilligny, Katz & Morin, 1979; Chapter 6, p. 255). Conditioning and test reflexes The method was originally described for soleus. The conditioningandtest stimuli aredeliveredtothepos- terior tibial nerve through the same unipolar elec- trode. As sketched inFig. 4.2(a ), the Ia volley elicited by the conditioning stimulus (S1) discharges a group of motoneurones (motoneurones 'X' and 'Y') to pro- duce the conditioning reflex (Fig. 4.2(e)), hereafter referred to as H1. This reflex volley activates Ren- shaw cells orthodromically via recurrent collaterals. The test stimulus (SM) is supramaximal for ␣-motor axons and, when given by itself, is not followed by a reflex response in the EMG (Fig. 4.2(f )), because of collision between the antidromic volley set up in motor axons and the reflex discharge (cf. Chapter 1, p. 7 and the sketch of Fig. 4.2(b)). Providing that the ISI is appropriate, the H1 conditioning reflex discharge will collide with this antidromic ␣ volley (Fig. 4.2(c )) and eliminate it in the corresponding motor axons (axons 'X' and 'Y') so that the H / test reflexduetothesupramaximal test stimulus cannow pass (cf. axon 'X' in Fig. 4.2(d )) and appear in the EMG(Fig. 4.2(g )). Thus, the populationof motoneu- rones responsible for the H / test reflex evoked by SM is homogeneous, because all of them have already discharged in the H1 conditioning reflex. As a result, 156 Recurrent inhibition (a) (e) (f ) (g) (i) (h) (b) (c) (d) M m a x ) M max M max ) M m a x ) M max H ' ' ' Fig. 4.2. The paired H reflex technique. (a)–(g ) Volleys in Ia afferents and motor axons ((a)–(d )), and corresponding EMG responses ((e)–(g )). Motoneurones (MNs) and muscle fibres activated in the H reflex are grey; muscle fibres activated in the M wave are speckled; orthodromic and antidromic volleys are indicated by vertical arrows. (a) Conditioning stimulation (S1) activates some Ia afferents (dashed line) and discharges MNs 'X' and 'Y', and the resulting H1 response is shown in (e). (b) Supramaximal (SM) stimulation recruits all Ia afferents (dashed and dotted lines) and all motor axons, producing the maximal M wave in (f ), which is not followed by a reflex response, because the antidromic motor volley collides with and eliminates any reflex volley in motor axons. (c) When S1 precedes SM by 10 ms, the EMG contains the M max response (g ). The antidromic volley evoked by SMcollides with the conditioning H1 reflex discharge elicited by S1 in MNs 'X' and 'Y', and eliminates it in the corresponding axons, so that the H1 discharge disappears from the EMG (the arrow in G indicates its predicted site). (d ) Because of the collision between the SM antidromic volley and the H1 reflex discharge, the axons of MNs 'X' and 'Y' are freed from antidromic impulses, and the reflex response due to SM (H') can appear in the EMG in (g ). However, due to recurrent inhibition brought about by the H1 reflex discharge, the strong Ia volley due to SM cannot fire MN 'Y' ((c), (d )), and H / is smaller than H1. Because MN 'Z' is not involved in the conditioning reflex, it cannot be assessed by the test reflex (see p. 161). (h) H1 (❍) and the corresponding M wave () elicited by S1, and H / (●, when SM is preceded by S1 by 10 ms), expressed as a percentage of M max , are plotted against the logarithm of the S1 intensity. (i) 'Bell-shaped' curve illustrating the variation of H / (as a percentage of M max ) when the size of H1 (as a percentage of M max ) is increased. The dotted oblique line represents the theoretical curve which would be obtained if H / equalled H1. Note that initial data points fall on or just below this line of identity. The horizontal line ('plateau') represents the maximal inhibition of H / due to the AHP of the MNs (see p. 159). Each symbol in (h), (i ) is the mean of five measurements. Modified from Pierrot-Deseilligny & Bussel (1975) ((e)–(h)) and Bussel & Pierrot-Deseilligny (1977) (i ), with permission. Methodology 157 (i) they all undergo the post-spike AHP, and (ii) the action potential has eliminated the underlying EPSP evoked in these motoneurones by the conditioning Ia volley (Coombs, Eccles & Fatt, 1955b). The H / test reflex can, at most, be equal to H1, and the ampli- tude of H1 can be considered the unconditioned value of the H / test reflex. Because of the collision, H1 does not appear in the EMG when followed by SM(arrowin Fig. 4.2(g )), and it is necessary to alter- nate the combined S1-SM stimulation and the S1 conditioning stimulus alone to measure it. Several characteristics of H / show that it is not an F wave: (i) very stable latency, (ii) large amplitude (up to 40% of M max ), which contrasts with the small size of F waves insoleus (Chapter 1, p. 23), (iii) strong depres- sionproducedbypost-activationdepressionat theIa afferent-motoneurone synapse when the frequency of stimulation is increased or the response condi- tioned by vibration (Pierrot-Deseilligny et al., 1976). Evidence for recurrent inhibition Inhibition of the test reflex after the conditioning discharge Initially the H / test reflex increases as the stimulus intensity for the H1 conditioning reflex increases. Thenincreasingthesizeof theH1conditioningreflex results in a decrease in the amplitude of the H / reflex (Fig. 4.2(h)). Accordingly, at low conditioning reflex amplitudes H / equals (or nearly equals) H1, i.e. the motoneurones recruitable into the test reflex are those in whose motor axons collision has elimi- natedthe antidromic impulses. As the H1 condition- ing reflex continues to increase, there is a gradual decrease in the amplitude of H / . Three factors could contribute to the decrease: (i) activation of a larger number of group I afferent fibres producing non- reciprocal groupI (Ib) inhibitionof soleus motoneu- rones and/or presynaptic inhibition of Ia terminals; (ii) post-spike AHPof motoneurones, preventing the less excitable motoneurones from being recruited by the test volley (Coombs, Eccles &Fatt, 1955a); and (iii) increasingrecurrent inhibitionbrought about by the increasingly large conditioning reflex discharge. Reflex inhibition is related to the size of the conditioning reflex discharge Non-reciprocal group I inhibition should have sub- sided by the 9-ms ISI and cannot account for the test reflex inhibition illustrated in Fig. 4.2(h), which was recorded at a 10 ms ISI (see Chapter 6, p. 255). In addition, the increase in the inhibition of the H / test reflex is not related to the intensity of S1, i.e. not to the number of afferent fibres per se, but to the H1 motor discharge they evoke. This was demonstrated by facilitating the conditioning reflex either by sti- mulation of a remote nerve (superficial radial) or by a soleus stretch (cf. Fig. 4.3(c)–(e ), and its legend). Whentheamplitudeof H / isplottedagainst theinten- sityof theS1conditioningstimulus, for agiveninten- sity of S1, activating a fixednumber of afferent fibres, the H / test reflex amplitude is smaller when the con- ditioning reflex is facilitated than in the control situ- ation (Fig. 4.3(d )). This indicates that the inhibition of H / is a function of the number of motoneurones involved in the H1 conditioning discharge. Accord- ingly, when the amplitude of H / is plotted against that of the corresponding conditioning reflex, for each given amplitude of H1, the test reflex ampli- tude is identical whether the conditioning reflex is facilitated or not (Fig. 4.3(e )). Possible role of AHP The above findings indicate that the amplitude of the H / test reflex is related only to the amplitude of the conditioning reflex discharge. The 'bell-shaped' curve in Fig. 4.2(i ) shows the variations of the H / test reflex expressed as a percentage of M max (hereafter referred to as the 'absolute' size of H / ) vs that of H1. The dotted oblique line represents the curve which would be obtained if H / equalled H1. Values below this theoretical curveindicateadepressionof H / with respect to H1. This depression could be explained in terms of differences in susceptibility to the Ia test volley of the different motoneurones (early and late recruited) undergoing the AHP. As long as the H1 conditioning reflex is small, motoneurones which are the most sensitive to the Ia input are recruited Fig. 4.3. Evidence for recurrent inhibition. (a) Sketch of the presumed pathways. The arrow (H1) represents the conditioning reflex discharge. (b) Time course of the supplementary recurrent inhibition due to facilitation of H1 by stretch of soleus: the amplitude of H / when H1 is facilitated, expressed as a percentage of its value when H1 is not facilitated (e.g. Y as a percentage of V in panel (d )), is plotted against the ISI between S1 and SM. (Ib inhibition may contribute to H / inhibition at short ISIs, but this factor may be neglected when considering the supplementary recurrent inhibition brought about by the facilitation of H1, since Y and V in (d ) were obtained with the same S1 intensity). Note that the need for collision limits the extent to which the ISI can be altered, so that the full time course cannot be explored. (c)–(e) Augmentation of the inhibition of H / due to stretch-induced enhancement of the H1 conditioning reflex. Stretch of triceps surae was produced by a twitch of intrinsic foot muscles due to tibial nerve stimulation at the ankle, while the nerve was blocked proximally with xyloca¨ıne; Bussel & Pierrot-Deseilligny, 1977, their Fig. 3). Control (▲) and responses obtained after H1 facilitation (❍) are compared at the 10-ms ISI. (c) Amplitude of H1 (as a percentage of M max ) is plotted against intensity of S1 (mA); an H1 reflex of a given amplitude (horizontal dashed line) was obtained with a S1 intensity larger in the control situation than when H1 was facilitated (dotted vertical lines). (d), (e) Amplitude of H / (as a percentage of H1) is plotted against the intensity of S1 (d ) and the amplitude of H1 (as a percentage of M max (e )). (f ), (g) Time course of the changes in the amplitudes of H / ((f ) conditioned by an H1 reflex of 45% of M max , H / being well in its decay phase, 10 ms ISI) and of a reference H reflex of similar amplitude (g ) during (thick horizontal bars) and after administration of L-acetylcarnitine (L-Ac). Each symbol is the mean of 10 (b), 5 ((d )–(e )) or 6 ((f ), (g)) measurements. Modified from Bussel & Pierrot-Deseilligny (1977) ((b)–(e)), and Mazzocchio & Rossi (1989) ((f ), (g)), with permission. Methodology 159 (seeChapter 1, pp. 3–4), andtheSMtest volley, which activates all Ia fibres, canovercome the AHPinthem. H / will then equal H1. Further increases in H1 will recruit motoneurones that are less sensitive to the Ia input. It is conceivable that, in these motoneurones, the AHP cannot be overcome by the test volley, and would therefore prevent them from firing in the test reflex. This is one reason why the test reflex does not followtheconditioningreflexat highamplitudes. However, if the AHPwere acting alone tosuppress H / (i.e. if therewas norecurrent inhibition), therewould be at most a fixed limit to the number of motoneu- rones available for the test reflex. As a result, increas- ing the conditioning reflex beyond a certain value (20% of M max in the case illustrated in Fig. 4.2(i )) would result in a fixed number of motoneurones that SM could discharge, and this would produce a 'plateau' in the absolute size of H / . However, this could not produce the characteristic 'bell-shaped' pattern seen in Fig. 4.2(i ), where the H / amplitude having reached its maximum gradually decreases as H1 increases. Decrease in the absolute size of H / The decrease in the absolute size of H / implies increasing failure of motoneurone recruitment, as Renshawcell activationincreases withthe size of the conditioning reflex discharge. Under these conditions, the extent of inhibition of H / between the dotted oblique line and the plateau in Fig. 4.2(i ) represents the maximal inhibition pos- sible due to the AHP alone. Accordingly, in intrin- sic muscles of the hand and foot, where there is no homonymous recurrent inhibition, there is nodecay phase of the H / test reflex (see p. 169). Time course of recurrent inhibition Inorder toensurecollisionbetweentheconditioning reflex and the antidromic test volley, the ISI between S1 and SM must be adjusted so that the S1-induced reflex volley does not reach the site of peripheral stimulation before SM is delivered: thus, the maxi- mal ISI that canbe useddepends onthe lengthof the conduction paths, the extreme values found being 21 ms for a subject 1.56 m tall, and 33 ms for a sub- ject 1.98 m tall (Pierrot-Deseilligny et al., 1976). For each S1–SM ISI, the ratio of the test reflex ampli- tudes obtainedinthe two conditions, withandwith- out facilitation of H1 (e.g. Y as a percentage of V in Fig. 4.3(d )), can be used to estimate the supplemen- tary recurrent inhibition brought about by facilita- tion of the conditioning reflex: the smaller the ratio, the larger the supplementary recurrent inhibition. Supplementary recurrent inhibition is maximal at the shortest ISI explored (6 ms), and progressively decreases at longer ISIs (Fig. 4.3(b)), much as does recurrent inhibitionassessedbythesizeof amonosy- napticreflexinanimal experiments (Renshaw, 1941). Validation Animal experiments Some assumptions on which the method relies have been tested in animal experiments (Hultborn, Pierrot-Deseilligny & Wigstr¨ om, 1979b). (i) There is a linear increase in recurrent inhi- bition with increasing conditioning reflex size and even small monosynaptic reflexes are able to pro- duce measurable recurrent inhibition of motoneu- rones. (ii) Inthe spinal cat, maximal homonymous recur- rent inhibitionandAHPareof thesameorder of mag- nitude. This is one of the prerequisites for the paired H reflex method. If the depression due to recurrent inhibition was minor compared to that caused by AHP, the method would produce results that were difficult to interpret. Pharmacological validation Animportant finding validating the methodwas that of Mazzocchio &Rossi (1989) who showed inhuman experiments that recurrent inhibition, as assessedby the paired Hreflex technique, was selectively poten- tiated by intravenous injection of L-acetylcarnitine (L-Ac). L-Ac is a derivative of acetylcholine with a stereospecific facilitatory action on nicotine recep- tors, thereby affecting the synapses responsive to 160 Recurrent inhibition acetylcholine. It has few or no systemic side effects in human subjects (see Mazzocchio & Rossi, 1989). Intravenous injection of L-Ac decreases the ampli- tude of the H / test reflex, but does not change that of a 'reference' H reflex of similar amplitude (Fig. 4.3(f ), (g )). Nor does it change Ib inhibition or the AHP (Rossi & Mazzocchio, 1992). The L-Ac- induced increase in depression of the H / test reflex therefore indicates potentiation of recurrent inhibi- tion and confirms that the decrease in the size of H / expressed as a percentage of M max ('absolute size') results from greater Renshaw cell activation. The inhalation of tobacco smoke also results in a rapid and dramatic decrease in H / lasting for ∼50 min, without altering H1 reflex significantly (Shefner, Berman & Young, 1993). Given the potentiation of recurrent inhibitionby nicotine demonstratedinthe cat (Eccles, Fatt & Koketsu, 1954), this provides fur- ther pharmacological support for the view that the inhibition of H / by the H1 reflex discharge is due to activation of Renshaw cells. Critique: limitations, advantages, conclusions Assessing changes in recurrent inhibition requires attention to methodology Criteria are required for the valid use of the size of the H / test reflex to assess changes in recurrent inhibition (i) The size of the H1 conditioning reflex discharge must be identical in the two situations which are compared. (ii) The H1 conditioning reflex must be within the range where its increase results in a pro- gressive decrease in the absolute size of the H / test reflex. This is not always possible, particularly in motor nuclei other than the soleus. This problem can be overcome by facilitating H1 by a condition- ing stimulus subthresholdfor the Hreflex, preceding S1 by 3–5 ms so that S1 will recruit more motoneu- rones (Mazzocchio & Rossi, 1997a), but this intro- duces the additional complication of another affer- ent volley. (iii) The conditioning-test ISI must be > 9 ms so that Ib inhibition evoked by the condi- tioning stimulus has subsided. Then, the smaller the H / test reflex amplitude, the larger the recurrent inhibition elicited by a given H1 conditioning reflex discharge. Comparison with a reference H reflex The amplitude of the H / test reflex depends not only on the recurrent inhibition produced by H1, but also on experimentally produced changes in motoneurone excitability (e.g. enhanced motoneu- rone excitability during a voluntary contraction of soleus). Thus, the excitability of the motoneurones must also be evaluated by an ordinary H reflex (ref- erence H) of the same size as H / under control con- ditions (see Hultborn & Pierrot-Deseilligny, 1979a; Fig. 4.8(b )). Apart fromthe depression due to H1, H / and the reference H are subject to the same periph- eral andsupraspinal influences duringthetest. Adif- ferential net effect onthesetworeflexescantherefore be taken to reflect variations in the recurrent inhi- bition elicited by the constant conditioning reflex discharge (however, see below). Limitations A sizeable H / reflex can be obtained in only 65% of the normal subjects It has been shown that in those subjects without an H / response the threshold of the M wave in the soleus and/or gastrocnemius muscle(s) is belowthat of the soleus H reflex. This suggests that the addi- tional recurrent inhibition caused by the antidromic volley fromthe conditioning stimulus is responsible for the absence of the H / test reflex (Katz & Pierrot- Deseilligny, 1982). Ib contribution The timing of SM 10 ms after S1 ensures that Ib afferents in the S1 volley will not affect the H / reflex (cf. Chapter 6, p. 255). However, Ib afferents in a test volley can limit the size of the test H reflex (see Chapter 1, pp. 14–16), and Ib afferents in the strong SM volley could do so. This might account for the finding that initially H / is often slightly smaller than H1 (as evidenced by the data points below the beginning of the dotted oblique line in Fig. 4.2(i )). Methodology 161 However, such a contribution would not explain the subsequent divergence of H / from H1 at larger H1 amplitudes, and is unlikely to explain the differen- tial changes in H / and in a reference H reflex during voluntary activity or in pathology (see pp. 173–87). Underestimation of the extent of recurrent inhibition While recurrent inhibition can only be assessed for those motoneurones that produce a reflex EMG potential, the H1 discharge could have pro- duced recurrent inhibition in motoneurone 'Z' in Fig. 4.2(a)–(d ). Whether or not this occurs cannot be determined because this motoneurone cannot contribute to the reflex EMG potential, since it is not involved in the conditioning reflex. Owing to the orderly recruitment and de-recruitment of motoneurones in the monosynaptic reflex (see Chapter 1, pp. 3–4), the earliest changes in recurrent inhibition could occur in those motoneurones that cannot be assessed. Possible changes in the post-spike AHP Because the depression of the test reflex after the H1 conditioning reflex discharge depends on both the AHP of the motoneurones and the recurrent inhibition brought about by H1, the suppression of H / will not measure only recurrent inhibition. AHP is not a fixed parameter, as was thought when the method was developed, but can vary: (i) activation of descending monoaminergic pathways canreduce the AHP of target motoneurones inthe cat (see Hult- born et al., 2004); (ii) plateau potentials can prob- ably be triggered in motoneurones during volun- tary contractions in human subjects (see Chapter 1, p. 20), and it remains to be seen how this change in motoneurone behaviour would influence the AHP; (iii) AHP following a spike may also summate with that resulting from a preceding spike (Ito & Oshima, 1962), and this factor must be taken into account in situations, such as soleus contractions, where tem- poral summation of the AHP might occur. Lesser sensitivity of H / than of the reference H to PSPs Changes inmembrane conductance during the AHP reduce the sensitivity of motoneurones discharging in the H / test reflex to synaptic inputs. As a result, identical excitatory or inhibitory inputs tomotoneu- rones cause smaller changes in the H / test reflex than in a reference H reflex (Hultborn & Pierrot- Deseilligny, 1979a; Katz & Pierrot-Deseilligny, 1984). Thus, no conclusions concerning changes in recur- rent inhibition can be drawn if both reflexes vary in the same directionandthe variationof the test reflex is less thanthat of the reference Hreflex. Conversely, larger changes intheH / test reflexthanthat intheref- erence H reflex (and a fortiori in the opposite direc- tion) indicate a change in recurrent inhibition. Pro- vided that there is no change in the AHP (see above), greater facilitation reflects decreased recurrent inhi- bitionandgreater inhibitionreflectsincreasedrecur- rent inhibition. The weaker sensitivity to synaptic inputs of themotoneurones firedinH / maythenlead to an underestimation of the changes in recurrent inhibition. Conclusions Although the paired H reflex technique may seem complex, it is simple to use. It is the only available methodallowingassessment of homonymous recur- rent inhibitionat rest andduringvarious motor tasks innormal subjects and patients. However, interpret- ations concerning the changes in H / in physiological and pathological conditions must take into account the fact that the size of H / also depends on the AHP, and this is not a fixed parameter. Methods for investigating heteronymous recurrent inhibition Underlying principles A conditioning motor discharge, whether a reflex or antidromic motor volley, is used to activate Renshawcells and the resulting recurrent inhibition 162 Recurrent inhibition is assessed in a heteronymous muscle by one of the methods exploring the excitability of the moto- neurones: PSTHs of single units, H reflex, modula- tion of the on-going EMG or the MEP. The criteria by which the resulting inhibition can be attributed to recurrent inhibition are given below (pp. 166–7). Inhibition evoked by an orthodromic (reflex) discharge Inhibition may be produced by the tendon jerk In Fig. 4.4, the PSTHs of a tibialis anterior unit are conditioned by patellar tendon taps of increasing strength. The early increase in firing probability, due to heteronymous monosynaptic Ia excitation (see Chapter 2), was followed by a trough that appeared with the tendon jerk (e )–(g ) and increased with it in size and duration (h)–(m) (Meunier et al., 1990). Inhibition may be produced by an H reflex Thus, Fig. 4.6 shows inhibition evoked in tibialis anterior and soleus motoneurones by femoral nerve stimulation sufficient to produce a quadriceps H reflex discharge, as assessed using the H reflex (c), the PSTH of a single unit ((d ), (e )), on-going EMG ((f ), (g )) or the MEP ((h), (i )). In each case, there is an initial facilitation due to monosynaptic Ia exci- tation, followed by inhibition, which appears in the PSTHs with a short central delay of 2 ms and has a long duration (30–40 ms). Inhibition is related to the conditioning reflex discharge The above inhibition could result from the afferent volley per se or from the motor discharge it evoked. To distinguish between these two possibilities either the reflex discharge canbe changedwithout modify- ing the intensity of the conditioning stimulus, or the afferent volley can be altered without changing the reflex discharge. Thus, a constant stimulus to the femoral nerve, subthreshold for the quadriceps H reflex at rest and without inhibitory effect in the PSTH of a tibialis anterior unit, produced inhibi- tion in the PSTH after the early Ia excitation when a voluntary contraction of the quadriceps caused the H reflex to appear (Meunier et al., 1990; Fig. 4.5(d)–(g)). Similarly, the inhibition of the soleus H reflex elicited by a quadriceps H reflex discharge disappeared when a stimulus of the same intensity but eliciting no reflex discharge was applied to the branchof the femoral nerve supplying the vastus lat- eralis (Barbeauet al., 2000; Fig. 4.6(c ) andits legend). Conversely, it has been verified that quadriceps ten- don jerks and Hreflexes of the same size evoke simi- lar inhibitioninthe PSTHs of leg muscle single units (Meunier, Pierrot-Deseilligny & Simonetta-Moreau, 1994), even though there are differences in the com- position of the two afferent volleys (see Chapter 3, pp. 117–18). Conditioning-test combinations Such evidence for recurrent inhibition produced orthodromically by reflex discharges has been described: (i) in various heteronymous lower limb muscles with quadriceps and soleus H reflexes and tendon jerks (cf. Meunier, Pierrot-Deseilligny & Simonetta-Moreau, 1994; Table 4.1), and (ii) in prox- imal upper limbmuscles after Hreflexes andtendon jerks of forearmandarmmuscles (cf. Katzet al., 1993; Table 4.2). Inhibition elicited by an antidromic motor volley To compare the distribution of recurrent inhibition inhumans andcats requires conditioningdischarges from a number of motor nuclei. However, reflexes cannot be confined to selected muscles, and it is generally impossible to evoke a reflex involving only one head of a complex muscle: e.g. the gastrocne- mius medialis (triceps surae) or the vastus lateralis (quadriceps). In such cases, an antidromic motor volley can be used, but note that here heterony- mous recurrent inhibition is tested, unlike the situ- ation critiqued earlier, supposedly testing homony- mous recurrent inhibition (pp. 154–5). Qualitatively Methodology 163 (a) (b) (e) (h) (k) (c) (f ) (i ) (l ) (d) (g) ( j) (m) Fig. 4.4. Evidence for recurrent inhibition from quadriceps to tibialis anterior. (a) Sketch of the presumed pathways of heteronymous Ia excitation and recurrent inhibition from quadriceps (Q) to tibialis anterior (TA). The arrow represents the conditioning reflex discharge that activates Renshaw cells (RC). (b), (e), (h), (k) Changes in firing probability evoked in PSTHs (1 ms bin width) for a TA unit by a Q tendon tap () are compared with the control histograms (without stimulation, ). The number of counts as a percentage of number of triggers is plotted against the latency after the stimulation. (c), (f ), (i ), (l) Differences between conditioned and control histograms. (d), (g), (j), (m) The conditioning reflex response in the Q. The strength of the tendon tap was increased from top to bottom: 0.95 tendon jerk threshold (TT) ((b)–(d)), 1.05 TT ((e)–(g)), 1.10 TT ((h)–(i )), 1.15 TT ((k)–(m)), and the reflex response assessed as a percentage of M max increased accordingly (0% in (d ), 3% in (g ), 12% in (j), 20% in (m)). The tap evoked an early increase in firing probability, the latency of which (33 ms) reflects heteronymous monosynaptic Ia excitation (see Chapter 2), and this was followed by a trough when the tap produced a tendon jerk ((e)–(m)). Modified from Meunier et al. (1990), with permission. 164 Recurrent inhibition (a) (b) (c) (e) (g) (f ) (d) Fig. 4.5. Further evidence for recurrent inhibition from quadriceps to tibialis anterior. (a) Sketch of the presumed pathways of heteronymous Ia excitation and recurrent inhibition from quadriceps (Q) to tibialis anterior (TA). Conditioning motor discharges (reflex or antidromic motor volley) activate Renshaw cells (RC), as indicated by arrows. (b), (c), (e), (g) Changes in firing probability evoked in PSTHs for a tibialis anterior (TA) unit by femoral nerve (FN) volleys (after subtraction of the background firing, 1 ms bin width). The number of counts as a percentage of number of triggers is plotted against the latency after the stimulation. (b) Stimulation of the femoral nerve (FN, 1.5 MT). (c) Stimulation of its branch to the vastus lateralis (VL, 1.5 MT). The latency difference between the peaks in (b) and (c) is largely due to the supplementary conduction time for a volley arising more distally in the VL nerve, and this suggests that the excitation and inhibition elicited by stimulation of the FN and of its branch to the VL have the same origin. (d)–(g) Stimulation of the FN (0.6 MT) at rest ((d ), (e )) and during Q contraction ((f ), (g)). At rest, there was no H reflex (d ), and no inhibition followed the early excitation in the PSTH (e). During Q contraction, an H reflex appeared in the Q (f ), and the early excitation was followed by an inhibition in the PSTH (g ). Despite a similar amount of early Ia facilitation in (e) and (g ), the trough was only observed in (g ), where there was a conditioning reflex discharge. This indicates that the AHP following the peak of Ia excitation is insufficient by itself to explain the following suppression. Modified from Meunier et al. (1990), with permission. Methodology 165 (a) (b) (c) (e) (g) (d) (f ) (h) (i) Fig. 4.6. Recurrent inhibition from quadriceps to tibialis anterior and soleus demonstrated by different methods. (a) Sketch of the presumed pathways of heteronymous Ia excitation and recurrent inhibition from quadriceps (Q) to tibialis anterior (TA) and soleus (Sol) motoneurones (MN). Arrows indicate the conditioning reflex discharges that activate Renshaw cells (RC). (b) Conditioning Q H reflex elicited by femoral nerve (FN) stimulation (1.1 MT) producing the heteronymous recurrent inhibition shown in (d), (e). (c)–(i ) Heteronymous Ia excitation and recurrent inhibition elicited in Sol (c), (e), (g), (i ) and TA (d), (f ), (h) MNs, assessed using the H reflex (c), the PSTHs of single units (after subtraction of the background firing, 1 ms bin width (d), (e)), the modulation of voluntary on-going EMG ((f ), (g)), the initial excitation is truncated in (g )) or the MEP ((h), (i )). Conditioned responses (expressed as a percentage of control responses in (c) and (f )–(i ), while the difference between conditioned and control histograms expressed as a percentage of the number of triggers is shown in (d )–(e )), are plotted against the central latency (i.e. the zero of the abscissa corresponds to the expected time of arrival of the FNIa volley at the level of the MNtested). (c) Comparison of the modulation of the soleus H reflex by stimulation of the same intensity (0.95 MT) applied to the FN eliciting a Q H reflex (●, 24% of M max ) and the vastus lateralis (VL) nerve eliciting no motor or reflex response (❍, after allowance for the extra peripheral conduction time; note, however, that displacing the stimulating electrodes to activate only VL would have also changed the afferent volley). The finding that the conditioning stimulation evokes a similar inhibition of the MEP ((h), (i )) indicates that the inhibition of the H reflex (c), PSTH ((d), (e)) and on-going EMG ((f ), (g)) is not due to FN-induced presynaptic inhibition of Ia terminals mediating the afferent volley of the H reflex or contributing to the on-going EMG or the motor unit discharge required for PSTH experiments (see Chapter 8, pp. 343–4). Modified from Meunier et al. (1990) ((b), (d), (e)), and Barbeau et al. (2000) ((c), (f )–(i )), with permission. 166 Recurrent inhibition Table 4.1. Heteronymous recurrent inhibition and Ia excitation to human leg and thigh muscles Columns: nerve stimulated: Sol (inferior soleus), GM(nerve to the gastrocnemius medi- alis), SP (superficial peroneal), DP (deep peroneal), FN (femoral nerve), TN (tibial nerve at the ankle). Lines: motoneurone (MN) pools investigated with the PSTH method: Sol (soleus), GM(gastrocnemius medialis), Per Brev (peroneus brevis), TA (tibialis anterior), Q (quadriceps), Bi (biceps femoris). The number of asterisks indicates the strength of the inhibition(see p. 169). Grey cells: recurrent inhibitionand Ia excitation(crossed cells correspond to homonymous pathways). Horizontally hatched cells: recurrent inhibition without Ia excitation. Vertically hatched cells: Ia excitation without recurrent inhibition. 0 =absence of recurrent inhibition and Ia excitation. NE =not explored. From Meunier et al. (1990), Meunier, Pierrot-Deseilligny & Simonetta-Moreau (1994) and P. Marque, G. Nicolas &E. Pierrot-Deseilligny (unpublished data on projections fromthe tibial nerve). similar results, with initial heteronymous monosy- naptic Ia excitation immediately followed by a long- lasting inhibition, have thenbeenobtained, whether stimulating the nerve supplying the whole muscle or one of its branches (Meunier et al., 1990; Fig. 4.5(b ), (c ) and its legend). Inhibition that has a short cen- tral delay andparallels the size of the conditioning M response is likely to be due to the antidromic motor volley (see below). Insome cases, suchas the inferior soleus nerve, the conditioning stimulation evokes both direct (M) and reflex (H) discharges. To scale theinhibitionwithrespect totheconditioningmotor discharge, Iles &Pardoe (1999) then simply summed the two conditioning motor responses. Evidence for recurrent inhibition Arguments for recurrent inhibition The depressions illustrated in Figs. 4.4–4.6 have characteristics consistent with recurrent inhibition: (i) They appear and increase with the conditioning motor discharge, whether it be due to a reflex (Fig. 4.4) or M response. (ii) They are independent of the conditioning stimulus intensity per se (Fig. 4.5(d )– (g )). (iii) They have a short central delay, 1–2 ms longer than monosynaptic Ia excitation. (iv) They have a long duration, more than 15 ms. In addition, the suppressions are generally, though not always, preceded by a peak of monosynaptic Ia excitation, Methodology 167 Table 4.2. Heteronymous recurrent inhibition and Ia excitation in the human upper limb Columns: nervestimulated: MC(musculo-cutaneous), Tri (nerveof thetricepsbrachii), Med(median), Radial (radial at the elbow), Ulnar (ulnar), Median & Ulnar (wrist) median and ulnar at the wrist. Lines: motoneurone (MN) pools investigated with the PSTH method: Deltoid, Bi (biceps brachii), Tri (triceps brachii), FCR (flexor carpi radialis), ECR (extensor carpi radialis), FCU (flexor carpi ulnaris), ECU (Extensor carpi ulnaris), FDS (flexor digitorum superficialis), ED (extensor digitorum), Hand (intrinsic hand muscles). The number of asterisks indicates the strength of the inhibition (see pp. 169–71). Grey cells: recurrent inhibition and Ia excitation (crossed cells correspond to homony- mous pathways). Horizontally hatched cells: recurrent inhibition without Ia excitation. Vertically hatched cells: Ia excitation without recurrent inhibition. 0 = absence of recurrent inhibition and Ia excitation. NE =not explored. FromCr´ eange et al. (1992), Katz et al. (1993) and V. Marchand-Pauvert, C. Iglesias, G. Lourenc¸o &E. Pierrot-Deseilligny (unpublished data onprojections fromintrinsic hand muscles). and there is a striking overlap between the distri- bution of heteronymous Ia excitation and recurrent inhibitioninthelower limb(seep. 170). Noneof these arguments, by itself, provides unequivocal evidence for recurrent inhibition, but their conjunctionmakes it highly probable. Arguments against other mechanisms There are cogent arguments against a significant contribution of other mechanisms or pathways to the inhibitions brought about by conditioning reflex discharges. 168 Recurrent inhibition (i) In the PSTH of a discharging motoneurone, the post-spike AHP following the discharge of the motoneurone in a heteronymous monosynaptic Ia peak could contribute to the suppression following the excitation. In fact, the AHP does not play a major roleinthesuppressionbecausethetroughappearsto be independent of the heteronymous monosynap- tic peak (Meunier et al., 1990; Fig. 4.5(d )–(g ) and its legend) and, in any case, the peak of monosynaptic excitation contains few discharges when compared with the subsequent trough (e.g. see Fig. 1.15(c )). (ii) Conditioning stimulation evokes a group I vol- ley able to produce non-reciprocal group I inhibi- tion. However, evidence for Ib inhibition is rarely seen in PSTHs, probably because transmission in Ib pathways to motoneurones responsible for the con- traction is depressed during the steady contractions required for PSTHs (see Chapter 6, p. 252). In addi- tion, a similar inhibition can be observed with a ten- don tap (Meunier et al., 1990; Fig. 4.4), which, in a 'conditioning' muscle at rest, is much less effective in eliciting Ib inhibition than electrical stimulation (cf. Chapter 6, pp. 252–3). (iii) The conditioning volley could evoke pre- synaptic inhibition of Ia terminals mediating the afferent volley of the test H reflex, or contributing to the on-going EMG or the motor unit discharge required for PSTH experiments. However, such a contributionis unlikely because the MEPis similarly suppressed (Barbeau et al., 2000; Fig. 4.6(h)–(i ), cf. Chapter 8, pp. 343–4). (iv) A contribution from group II afferents is also unlikely when the conditioning electrical stimula- tion is below 1 MT (Chapter 7, p. 303). (v) The twitch-induced afferent discharge follow- ing the reflex response can be discounted because it cannot produce spinal effects for several tens of milliseconds (see Meunier et al., 1990). Electrical stimuli above 1 MT When the inhibition is evoked by electrical stim- uli above 1 MT, its Renshaw origin may appear more debatable, because the afferent volley elicited by the conditioning shock is more complex. It may then include both group II afferents, the thresh- old for which is 1.2 MT (see Chapter 7, p. 303) and the twitch-induced afferent discharge evoked by the M response. However, the resulting effects appear later than the recurrent inhibition: a group II volley elicited at knee level produces effects in motoneurones ∼10 ms later than the monosynaptic Ia excitation (Chapter 7, pp. 293–7), and the twitch- induced Ib inhibition would start to manifest itself in motoneurones even later after the orthodromic monosynaptic Ia facilitation (because of the time to and from the muscle, plus the time between the onset of the twitch and the activation of Golgi ten- don organs; see Binder et al., 1977). Three addi- tional arguments support the Renshaworigin of this inhibition. (i) Inhibition evoked in motor nuclei by the reflex discharge of triceps surae or quadriceps motoneu- rones is in all likelihood of Renshaw origin (see above), and it is reasonable to assume that inhibi- tioninducedinthesamemotor nuclei, withthesame central delayandduration, bymotor dischargesfrom one head of these muscles (e.g. vastus lateralis in Fig. 4.5(c )) results from recurrent inhibition set up by the antidromic motor volley. (ii) Intravenous administration of L-Ac increases the long-lasting inhibition produced by antidromic volleys above 1 MT from gastrocnemius medialis to soleus and from wrist extensors to FCR (Rossi, Zalaffi&Decchi, 1994; Aymardet al., 1997), anddoes so without altering the early low-threshold group I inhibition. (iii) Similar resultshavebeenobtainedintheupper limbof adeafferentedpatient (V. Marchand-Pauvert, J. B. Nielsen, B. Conway, J. C. Lamy & H. Hultborn, unpublished data). Critique: limitations, conclusions Limitations GroupI EPSPs andIPSPs elicitedby the conditioning volley can overlap the onset of recurrent inhibition, and could affect the test response. This is important because the relative strengths of monosynaptic Ia Organisation and pattern of connections 169 excitationandrecurrent inhibitioninmotoneurones are similar (cf. p. 170). Recurrent inhibition should therefore be assessed at a long ISI where Ia EPSPs and group I IPSPs have subsided but recurrent IPSPs are still present. Conclusions Inroutine clinical studies, a simple methodis prefer- able, and the modulationof the on-going EMGis the simplest method to compare the amount of recur- rent inhibition elicited by a conditioning motor dis- charge in different motor tasks (Meunier et al., 1996; Barbeauet al., 2000). However, themodulationof the Hreflex shouldbeusedtoinvestigatechanges inhet- eronymous recurrent inhibition during motor tasks with respect to rest (Iles & Pardoe, 1999). Organisation and pattern of connections Homonymous recurrent projections to motoneurones Homonymous recurrent inhibition in proximal muscles With the paired H reflex technique, evidence for homonymous recurrent inhibition has been found not only in the soleus (Bussel & Pierrot-Deseilligny, 1977), but also in quadriceps and the peroneal mus- cles (Rossi & Mazzocchio, 1991), FCR and ECR (Katz et al., 1993). Inthese different motor nuclei, support- ive evidence for the Renshaw origin of the inhibi- tion came from its potentiation by L-Ac. Evidence for recurrent inhibition of soleus motoneurones fol- lowing an antidromic motor volley has also been found in PSTHs (Kudina & Pantseva, 1988; Miles, Le & T¨ urker, 1989). Similarly, in the deltoid, triceps brachii, FCU and ECU, an antidromic motor volley evoked by selective stimulation of the parent nerve just above 1 MT has been shown to produce long- lasting inhibition, probably due to recurrent inhibi- tion (Rossi & Mazzocchio, 1992; Katz et al., 1993). Recurrent inhibition of ECR motoneurones elicited by a pure antidromic volley has been documented in a deafferented patient (Mattei, Schmied & Vedel, 2003). Absence of homonymous recurrent inhibition in distal muscles The paired H reflex technique has also been used to look for homonymous recurrent inhibitioninintrin- sic muscles of the foot (abductor hallucis brevis; Rossi &Mazzocchio, 1991) andhandmuscles (oppo- nens pollicis and abductor digiti minimi; Katz et al., 1993). In these distal muscles, increasing the size of the H1 conditioning reflex discharge resulted in a plateau-like pattern, where H / reflex remained the same once it had reached its maximum. In addi- tion, H / was not altered by administration of L-Ac. There are no recurrent collaterals from the axons of motoneurones innervating distal limb muscles of the cat (see p. 152), and the absence of evidence for recurrent inhibition in the human studies probably reflects an absence of such collaterals in humans. Heteronymous recurrent projections to motoneurones in the lower limb Pattern of distribution Strength and distribution of heteronymous recurrent inhibition in the lower limb Table 4.1 shows the distribution of heteronymous recurrent inhibition to leg and thigh muscles, deter- mined using PSTHs (Meunier et al., 1990; Meunier, Pierrot-Deseilligny & Simonetta-Moreau, 1994; P. Marque, G. Nicolas & E. Pierrot-Deseilligny, unpub- lished data). An attempt has been made to estimate thestrengthof recurrent inhibition(number of aster- isks ineachcell), basedon(i) the frequency of occur- rence (i.e. the percentage of units in which there was a significant recurrent inhibition), and (ii) the mean durationof therecurrent inhibitionelicitedby acon- ditioning discharge ∼50% of M max . In the human lower limb, recurrent connections are much more 170 Recurrent inhibition widely distributed than in the cat hindlimb with, in particular, the appearance of transjoint connections that do not exist in the cat (apart from quadriceps to soleus) between quadriceps and all tested mus- cles operating at the ankle, and fromtriceps surae to quadriceps. Comparison with the pattern of monosynaptic Ia excitation Overlap between recurrent and Ia projections The grey cells in Table 4.1 indicate that in the humanlower limb, as inthe cat hindlimb (cf. p. 153), most of the recurrent connections, and in particular most transjoint connections, arematchedbyparallel monosynapticIaexcitatoryprojections. Comparison of Table 4.1withtheTable 2.1of Chapter 2shows that this parallel remains true in quantitative terms: the stronger theIaexcitation, themoremarkedtherecur- rent inhibition (e.g. both Ia excitation and recurrent inhibition from gastrocnemius medialis are strong on biceps and weak on quadriceps motoneurones). Recurrent inhibition without Ia excitation The overlap in the expression of Ia excitation and recurrent inhibition in different motoneurone pools is not total: recurrent connections from gastrocne- mius medialis to soleus and peroneus brevis are not paralleledby corresponding Ia projections (hori- zontallyhatchedcells). Additional recurrent connec- tions also exist in the cat, and this 'extended pat- tern' (Hultborn, Jankowska & Lindstr¨ om, 1971b) has been presumed to link muscles that act in func- tional synergismalthoughthey are not connectedby the Ia input. The functional synergism between two heads of the triceps surae (gastrocnemius medialis and soleus) is obvious. The absence of Ia input from gastrocnemius medialis to soleus may be related to a particular requirement of plantigrade gait (cf. Chapter 2, p. 93). Ia excitation without recurrent inhibition Ia excitatory connections without their recurrent counterpart (vertically hatched cells) also exist between some muscles acting on the ankle. Such Ia connections essentially link ankle muscles that are not synergists in flexion–extension movements (soleus and peroneus brevis, tibialis anterior and gastrocnemius medialis), but are believed to con- tribute to the stabilisation of the ankle during the stance phase of locomotion (cf. Chapter 11, p. 546). This finding is reminiscent of the Ia connections without recurrent inhibition found between flex- ors of the digits in the cat (Hamm, 1990), and sug- gests that the patternof recurrent inhibitionis deter- mined by function during locomotion rather than anatomical synergism. Thefindingthat theextensive Ia projections from intrinsic foot muscles to leg and thighmuscles inhumans (see Table 2.1 inChapter 2) are not paralleled by recurrent connections is most probably due to the absence of recurrent collater- als from motoneurones innervating distal muscles. The absence of recurrent inhibition in all combina- tions testedfromthe deepperoneal nerve (Table 4.1) raises the question of whether recurrent collaterals from pretibial flexors exist in man. Functional implications It has been assumed that, in the cat, the recurrent pathway has a focusing action, which helps limit the extent of Ia excitation (Hultborn, Jankowska & Lindstr¨ om, 1971b). Similarly, it will be suggested on pp. 183–4 that transjoint recurrent connections found in the human lower limb have probably evolvedtocontrol matchedIaexcitatoryconnections during postural co-contractions of bipedal stance (see Chapter 11, p. 538). Heteronymous recurrent projections to motoneurones in the upper limb Pattern of distribution The patternof heteronymous recurrent inhibitionin the cat forelimb differs from that in the hindlimb: more extended transjoint connections, and projec- tions from proximal to distal muscles (see Illert & K¨ ummel, 1999). In contrast, transjoint connections Organisation and pattern of connections 171 are more restricted in the upper than in the lower limb of human subjects (Cr´ eange et al., 1992; Katz et al., 1993). Table 4.2 is arranged as Table 4.1, and shows that, as for heteronymous Ia excitation (see Chapter 2, p. 84), therearenoproximal-to-distal pro- jections, if one ignores the weak projection from tri- ceps to ECU(which is not matched by an equivalent Ia connection). The deltoid motor nucleus, supply- ing the most proximal muscle investigated, receives the largest number of recurrent heteronymous pro- jections fromdistal muscles, but some of them(from muscles supplied by the median nerve) are not matched by equivalent Ia connections. An interest- ing finding, also described in the cat (Illert &Wietel- mann, 1989), is that ECR-coupled Renshaw cells inhibit FCR motoneurones and vice versa (Aymard et al., 1997). This is in keeping with the finding that Renshaw cells activated by FCR or ECR motor discharges do not inhibit reciprocal inhibition directed to the antagonistic motor nucleus (see below). As in the lower limb, Ia projections from intrinsic hand muscles are not matched by equiv- alent recurrent connections, presumably because the corresponding motor axons lack recurrent collaterals. Functional implications Thedistributionof recurrent inhibitioninthehuman upper limbismorerestrictedthaninthecat forelimb, adifferencethat is theoppositeof that for thehuman lower limb and the cat hindlimb. Heteronymous Ia projections fromdistal toproximal muscles presum- ably provide support to the hand during manipu- latory movements (see Chapter 2, p. 94). However, the motor repertoire of the upper limb is much moreversatile, andheteronymousrecurrent connec- tions from forearm to proximal muscles might be used (together with the corticospinal facilitation of presynaptic inhibitionof Ia terminals, see Chapter 8, p. 353) to counteract excitatory Ia connections and bias the motoneurones infavour of the transmission of the descending excitationinthose movements for which the assistance of Ia excitatory projections is not critical. Recurrent inhibition of interneurones mediating reciprocal Ia inhibition A characteristic feature of the recurrent pathway in thecat is theprojectionof Renshawcells tointerneu- rones mediating disynaptic reciprocal Ia inhibition (p. 154; Fig. 4.1). Evidence for recurrent inhibition of Ia inhibitory interneurones Reciprocal inhibition produced by an electrical vol- ley to the triceps brachii nerve and assessed with the biceps tendon jerk was conditioned by a pre- ceding tendon reflex discharge in the triceps (Katz, P´ enicaud & Rossi, 1991; Fig. 4.7(a ), (b )). The tri- ceps motor discharge strongly depressed recipro- cal Ia inhibition, with a short central delay and a long duration, i.e. a time course closely resem- bling that of recurrent inhibition of motoneurones (Fig. 4.7(b)). Figure 4.7(b ) also shows that the sup- pression of reciprocal inhibition was not seen when the conditioning tendon tap was just subthreshold for the tendon jerk and therefore did not activate Renshaw cells (D), although it would have produced similar post-activation depression at the synapse of the Ia fibre and the Ia interneurone. It is there- fore likely to be due to recurrent inhibition and not to the tap-induced afferent volley. A similar sup- pression was observed in the opposite direction, from biceps brachii to triceps, indicating that Ren- shaw cells coupled to elbow motor nuclei project to Ia interneurones mediating reciprocal Ia inhibi- tion between elbow muscles. Recurrent inhibition from soleus similarly depresses reciprocal Ia inhibi- tionfromsoleus totibialis anterior (Baret et al., 2003; Chapter 5, p. 206; Fig. 5.5(b )). Absence of recurrent inhibition of reciprocal inhibition at wrist level Different results have been obtained at the wrist (Aymard et al., 1995). Recurrent inhibition evoked by a flexor or extensor motor discharge has no effect on group I inhibition directed to the 'antagonistic' 172 Recurrent inhibition Fig. 4.7. Recurrent inhibition of reciprocal Ia inhibition and cortical depression of recurrent inhibition. (a), (c), (e) Sketches of the presumed pathways. Continuous arrows indicate the conditioning reflex discharges. (a) Renshawcells (RC) activated fromrecurrent collaterals of triceps brachii (Tri) motoneurones (MN) inhibit interneurones mediating reciprocal inhibition from Tri to biceps (Bi). The dashed arrow indicates the conditioning volley eliciting reciprocal Ia inhibition. (b) The test response is the reciprocal Ia inhibition of the Bi tendon jerk elicited by an electrical volley to the Tri nerve (0.95 MT) at the –3-ms ISI (cf. Fig. 5.3(b)). Reciprocal Ia inhibition was conditioned by a Tri tendon jerk, and the resulting amount of reciprocal inhibition (●, expressed as a percentage of the unconditioned value of reciprocal inhibition) is plotted against the ISI between this tendon tap and the test stimulus. , Results obtained with a tap just subthreshold for the Tri tendon jerk for a single subject. Each symbol, mean of 20 measurements; vertical bars ±1 SEM. (c) Sketch of the corticospinal inhibition of homonymous recurrent inhibition to FCR MNs. (d ) The onset of the cortical effect on the reference (_) and the H / (●) test reflexes in FCR. Reflexes (expressed as a percentage of their control value) are plotted against the ISI between cortical and test stimulation (TMS given at time zero). The intensity of TMS was set to produce no significant effect on the reference H reflex. Each point is the grand mean of results from four subjects. Vertical bars ±1 SEM. (e) Sketch of the pathway of corticospinal inhibition of heteronymous recurrent inhibition from quadriceps (Q) to tibialis anterior (TA) MNs. (f ) Rectified averaged (15 sweeps) MEP (TMS =38% of the maximal stimulator output) in the TA conditioned by a preceding Q H reflex discharge (thick line, ∼20% of M max , 5 ms ISI) and unconditioned (thin line), expressed as a percentage of M max , are plotted against the latency after femoral (FN) stimulation. Adapted from Katz, P´ enicaud & Rossi (1991) (b), Mazzocchio, Rossi & Rothwell (1994) (d ), Barbeau et al. (2000) (f ), with permission. Motor tasks – physiological implications 173 motor nucleus (cf. Chapter 5, pp. 207–8; Fig. 5.5(d )). This is in keeping with the mutual recurrent inhi- bition between 'antagonistic' ECR and FCR (see above) andraises the questionwhether the so-called 'reciprocal inhibition' between wrist muscles truly represents reciprocal Ia inhibition (see Chapter 5, pp. 211–14). Corticospinal suppression of recurrent inhibition Corticospinal depression of homonymous recurrent inhibition Changes in recurrent inhibition of FCR and soleus motoneurones, assessed with the paired H reflex technique, have been investigated after cortical sti- mulation(Mazzocchio, Rossi &Rothwell, 1994). TMS produced significant facilitation of the H / test reflex in the FCR at an intensity that produced no facil- itation of the reference H reflex (Fig. 4.7(c ), (d )). At soleus level, TMS elicited a similar facilitation of the H / test reflex, whereas the reference H reflex was inhibited. A change in the AHP was eliminated, and these findings presumably reflect corticospinal depression of Renshaw cells, as has been observed in the cat after stimulation of the pericruciate cortex (MacLean & Leffman, 1967) or the internal capsule (see Koehler et al., 1978, and p. 153). Because the corticospinal inhibitionof Renshawcells has a lower threshold than the cortical facilitation of motoneu- rones, Mazzocchio, Rossi & Rothwell (1994) argued that TMS might also act by corticospinal suppres- sion of a tonic excitatory drive from the reticular formation (specifically, the nucleus raphe magnus; there is also an indirect corticospinal inhibitory drive via the locus coeruleus; see the sketch in Fig. 4.11(a )). Regardless, thecortical effects onrecur- rent inhibition occur 3–4 ms later than the effects on motoneurones. Corticospinal depression of heteronymous recurrent inhibition Figure4.7(f ) shows that theMEPintibialis anterior is depressedby the heteronymous recurrent inhibition produced by a quadriceps H reflex discharge, and that this involves the initial part of the MEP but not its later part (Barbeau et al., 2000). The spar- ing of the later part can be explained because, in this experiment, the corticospinal volley produces two effects: activation of motoneurones responsible for the MEP (the test response), and depression of Renshawcells. However, as seen above, the suppres- sion of recurrent inhibition begins some millisec- onds later than the facilitation of the corresponding motoneurones. Thus, thefemoral-inducedrecurrent inhibition of the earliest motoneurones discharging intheMEPis not depressedbythecorticospinal inhi- bitionof Renshawcells, whereas recurrent inhibition of motoneurones discharged by later corticospinal volleys is depressed by the action of the fastest cortical volley on Renshaw cells. Motor tasks and physiological implications The picture that emerges fromthe changes in recur- rent inhibition during various motor tasks in human subjects suggests that recurrent inhibition might serve several functions, that are not exclusive. How- ever, functional interpretations must be made with care because: (i) it cannot be taken for granted that the response of Renshaw cells to a tonic input is the same as the response to the phasic inputs explored in the experiments below, and (ii) experiments deal- ingwithhomonymousrecurrent inhibitionwereper- formed using the paired H reflex technique, and would be affected by changes in the motoneuronal AHP (see p. 161). Recurrent inhibitionof motoneurones of a muscle involved in selective contractions Methodology These studies have focused on the changes in homonymous recurrent inhibition of soleus motoneurones, investigated with the paired Hreflex technique during various voluntary contractions of 174 Recurrent inhibition the gastrocnemius-soleus. The H / test reflex was comparedtoareferenceHreflex, andsamplerecords in Fig. 4.8(b ) show the different responses recorded intheEMGat rest andduringastrongtonicvoluntary contraction of the gastrocnemius-soleus. The inten- sity of the S1 conditioning stimulus (upper traces) was adjusted so that the H1 conditioning reflex was maximal at rest, thus ensuring that (i) its size was modified little by the contraction, and (ii) the corre- sponding H / reflex was well within its decay phase (cf. p. 160), whatever the strength of contraction(see the vertical dashedline inFig. 4.8(c )). S1 also evoked a small M wave, the stability of which was used to verify that stimulating conditions did not change during the contraction (Chapter 1, p. 8). The test stimulus (SM, second traces) can evoke a small late response, 'V1', at reflex latency during contraction, because: (i) the collision in a very few motor axons betweennatural impulses due tothe voluntary effort andthe antidromic motor volley frees themfromthe latter, and allows the reflex response due to SM to pass (Upton, McComas & Sica, 1971), and (ii) the contraction potentiates F waves (Chapter 1, p. 23). When present, this late response was subtracted from the H / test reflex. Combined S1 and SM (10 ms ISI, third traces) resulted in M max followed by the H / test reflex. Changes in H / during contraction were compared to those of a reference H reflex (bottom traces) of the same amplitude as H / at rest. To inves- tigate the period preceding the contraction, despite the silent period induced in the voluntary EMGby H and M waves, the subjects were trained to perform simultaneous contractions of soleus inbothlegs. The time interval between reflex responses in the ipsilat- eral limb and the onset of the on-going EMG in the contralateral soleus was then assessed. Changes in H / and reference Hreflexes during various soleus voluntary contractions Tonic contractions of gastrocnemius-soleus During tonic contractions of gastrocnemius-soleus at various force levels, the H / and reference H re- flexes undergo different changes (Hultborn & Pierrot-Deseilligny, 1979a; Fig. 4.8(d )). Thesizeof the reference H reflex increases with each level of con- traction, though the greatest increase occurs from rest to weak contraction. By contrast, the amplitude of the H / test reflex decreases during the weakest contractions. With greater contraction force, there is facilitation of H / , which then increases with contrac- tion force, and finally exceeds the reference H reflex in the strongest contractions. Effect of muscle fatigue During a prolonged contraction of soleus at 20% of MVC for 10 min, the amplitude of the H / test reflex is significantly greater at the end of the contraction, when there is evidence of muscle fatigue (L¨ oscher, Cresswell & Thorstensson, 1996). Ramp contractions During ramp contractions, the H / and reference H reflexes undergo almost reciprocal changes (Hult- born &Pierrot-Deseilligny, 1979a; Fig. 4.8(e )). At the earliest intervalsfollowingtheEMGonset, theampli- tude of H / was smaller than at rest, as occurs dur- ing weak tonic contractions, but it then increased progressively until the end of the ramp. By contrast, the reference H reflex was maximal at the onset of the ramp and then decreased throughout the ramp phase. Thus, thegreatest increaseinH / relativetothe reference H reflex was towards the end of the ramp. During the plateau, the H / test reflex decreasedwhile thereferenceHreflexremainedstable, sothat thetwo reflexes became more similar in amplitude, much as occurs during tonic contractions of mediumforce. A similar reciprocal time course for H / and reference H has been found for faster ramp contractions lasting 250 and 500 ms. Changes prior to contraction Throughout the 50 ms prior to a ramp contraction, the same changes have beenobservedas at the onset of contraction, i.e. an increase in the reference Hbut a decrease in the H / test reflex with respect to rest values (Katz, Pierrot-Deseilligny & Hultborn, 1982). Motor tasks – physiological implications 175 Fig. 4.8. Changes in homonymous recurrent inhibition to soleus motoneurones during voluntary contractions of gastrocnemius- soleus. (a) Sketch of the presumed pathways, with projections of Renshaw cells (RC) to both soleus (Sol) motoneurones (MN) and Ia inhibitory interneurones (INs) to tibialis anterior (TA) MNs, and mutual inhibition of 'opposite' Ia INs. Continuous arrow: conditioning reflex discharge (H1); dotted arrow: stretch of TA caused by Sol contraction. (b)–(e) Data from single subjects. (b) Sample records of EMG responses elicited at rest (left) and during strong tonic contraction of gastrocnemius-soleus (GS) (right). From top to bottom, responses elicited by S1 (6 mA, eliciting a maximal H reflex which did not increase during contraction), SM evoking a late response (V1, arrow) during contraction, S1 ÷SM (10 ms ISI), and a stimulus evoking a reference H reflex of the same size as H / at rest. (c) The H / test reflex (as a percentage of M max ) is plotted against H1 at rest () and during tonic GS contractions of 10% (▲), 40% () and 80% (●) of MVC (dotted oblique line, theoretical curve obtained if H / =H1). (d ) Reference (left group of histograms) and H / test (right group of histograms) reflexes (as a percentage of M max ) are compared at rest () and during tonic GS contractions of increasing force: 10% (pale grey), 40% (dark grey) and 80% () of MVC. H / was obtained with the H1 reflex at 60% of M max , i.e. within the range where increases in H1 resulted in a progressive decrease in the absolute size of H / (vertical dashed line in (c)). (e) Time course of the changes in H / (●) and reference H () reflexes (as a percentage of M max ) during a ramp-and-hold contraction of 1 s. Torque (continuous thin line) increased over 1 s (ramp phase) to reach 60%of MVC and was then held at that level for a further 1 s. Large symbols on the left and horizontal dashed line indicate rest values. Each column or symbol in (c)–(e) is the mean of 20 measurements. Vertical bars 1 SEM (d ), ±1 SEM (e ). Modified from Hultborn & Pierrot-Deseilligny (1979a), with permission. 176 Recurrent inhibition Period following contraction H / test and reference H reflexes are suppressed to the same extent immediately after relaxation of a tonic voluntary contraction of soleus (Schieppati & Crenna, 1985). This suggests that increasedrecurrent inhibition does not contribute to the termination of a voluntary contraction. (The reflex suppression is thenprobably due to post-activationdepressionfol- lowing the activation of Ia afferents in the contrac- tion, cf. Chapter 1, pp. 13–14). Ballistic contractions Both reference H and H / test reflexes are facilitated at the onset of ballistic contractions with respect to their rest values, and this facilitation then progres- sively decreases, but the H / test reflex is much less facilitated than the reference H reflex (Katz, Pierrot- Deseilligny & Hultborn, 1982). Mechanisms underlying the changes in H / during homonymous voluntary contractions A number of mechanisms may contribute to the finding that H / test and reference H reflexes are dif- ferentially changed during homonymous contrac- tions. They include (i) the lesser sensitivity of H / to excitatory inputs (p. 161), (ii) changes in the AHP (p. 178), (iii) changes in transmission in the recur- rent pathway following its activation by the motor discharge, and (iv) changes in the descending con- trol of Renshaw cells. Mechanisms other than changes in recurrent inhibition Both the lesser sensitivity of H / to excitatory inputs and the summation of AHP following the H1 con- ditioning discharge with that resulting from a pre- ceding voluntary spike could explain why H / is less facilitated than the reference H during soleus con- tractions. However, the summationof the AHPs does not apply prior to ramp contractions, and the lesser sensitivity of H / to excitatory inputs cannot explain the depression of H / with respect to rest values dur- ing weak contractions. Nor can such mechanisms account for the opposite result (the greater facilita- tionof H / thanof referenceH) observedduringstrong contractions andtowards the endof ramps. The pos- sible effects of a decrease in the AHP during strong contractions are considered below. Effects of the voluntary motor discharge Activation of Renshaw cells by the voluntary motor discharge via recurrent collaterals is the most obvi- ous change in the input to Renshaw cells during homonymous contractions. The greater drive on Renshaw cells could facilitate their discharge or, paradoxically have the opposite effect, i.e. a reduced Renshawcell output. The latter could occur through different 'occlusive' mechanisms between natural motor and conditioning reflex discharges: occlusion at Renshaw cell level (Eccles, Fatt & Koketsu, 1954), mutual inhibition of Renshaw cells (Ryall, 1970), and post-activation depression at the recurrent col- lateral terminals (Hultborn, Pierrot-Deseilligny & Wigstr¨ om, 1979a). However, there are several argu- ments why occlusive mechanisms are unlikely to be responsible for the greater facilitation of H / dur- ing strong contractions (an unexpected result, given the greater natural motor drive to Renshaw cells). (i) Incat experiments, the output fromRenshawcells and the resulting recurrent inhibition of motoneu- rones caused by a phasic motor volley is increased when Renshaw cells receive a tonic excitatory input (see p. 152; Hultborn & Pierrot-Deseilligny, 1979b). (ii) In human subjects, the same results were obtained with H1 conditioning reflexes of different size, but occlusion should be reduced with smaller conditioning reflex discharges (Hultborn & Pierrot- Deseilligny, 1979a,b). (iii) During ballistic contrac- tions, H / is less facilitated than reference H despite the strong voluntary drive (see above). (iv) H / is pro- foundly inhibited towards the end of co-contraction of soleus and tibialis anterior with the same level of soleus EMGactivityas duringisolatedplantar flexion (see pp. 180–1; Fig. 4.9(d ), (e )). Motor tasks – physiological implications 177 Fig. 4.9. Changes in homonymous recurrent inhibition to soleus motoneurones during contractions of tibialis anterior and soleus, separately and together. (a) Sketch of the presumed pathways, with projections of Renshaw cells (RC) to both soleus (Sol) motoneurones (MNs) and Ia inhibitory interneurones (INs) directed to tibialis anterior (TA) MNs, and mutual inhibition of 'opposite' Ia INs. The arrow (H1) indicates the conditioning reflex discharge. (b)–(e) show data from different subjects (same subject in (d), (e)). (b) Reference H (left group of histograms) and H / test reflexes (right group of histograms) (as a percentage of M max ) are compared at rest () and during TA tonic contractions of increasing forces: 8% (pale grey), 30% (dark grey) and 45% () of MVC. (c) H / (●) and reference H () reflexes (expressed as a percentage of their value at rest) are plotted against the time after onset of EMG activity during ramp dorsiflexion over 250 ms (torque, continuous thin line). (d), (e) H / (●) and reference H() reflexes (expressed as a percentage of M max ) are plotted against the time after onset of EMG activity during a ramp-and-hold plantar flexion (d ) and co-contraction of Sol and TA (e). The EMG activity progressively increased over 700 ms. Horizontal dashed lines indicate the rest value of the reflexes. Sample records at the top of (d), (e) show the integrated EMG traces (time constant 120 ms) from Sol and TA. Each column or symbol in (b)–(e) is the mean of 20 measurements. Vertical bars 1 SEM (b), ±1 SEM ((c)–(e)). Adapted from Katz & Pierrot-Deseilligny (1984) ((b), (c)) and Nielsen & Pierrot-Deseilligny (1996) ((d), (e)), with permission. 178 Recurrent inhibition Decreased recurrent inhibition or reduction of the AHP? During strong tonic contractions and towards the end of ramp contractions, H / is more facilitated than the reference H, despite (i) its lesser sensi- tivity to excitatory inputs, (ii) the summation of the AHPs, and (iii) the facilitation of Renshaw cells by the strong motor discharge via recurrent collaterals. This cannot be attributed to occlusion in the recurrent pathway (see above). Inhibition of Renshaw cells therefore appears probable. Indeed, the degree of H / inhibition is likely to be underesti- mated in these studies, because of the factors dis- cussed above that would produce less facilitation of H / than of the reference H. An alternative possibil- ity would be a differential change in the AHP dur- ing weak and strong contractions. It might there- fore be prudent to retain a reservation about the cause of the changes in H / during contractions of different strengths until it is clarified (i) whether these contractions are accompanied by descend- ing monoaminergic excitation depressing the AHP, (ii) whether they produce plateau potentials, and (iii) whether plateau potentials alter the AHP (and therefore H / ) (see p. 161). Regardless of this unre- solvedissue, similar changes inheteronymous recur- rent inhibition to voluntarily activated motoneu- rones have been observed using a method in which the test reflex did not undergo the AHP following the conditioning reflex discharge (Iles & Pardoe, 1999; see below). Because this finding was observed witha method independent of changes in AHP, it confirms that recurrent inhibition is decreased during strong contractions. Origin of Renshaw cell inhibition Thepossibilityof Renshawcell inhibitionduetoacti- vationof cutaneous receptors bypressureonthesole of thefoot hasbeenexcludedinspecificexperiments, in which similar pressure by itself did not modify recurrent inhibition(Hultborn&Pierrot-Deseilligny, 1979a). By exclusion, the inhibition of Renshawcells is likely to be of supraspinal origin, and this con- clusion is supported by direct evidence: stimulation of the motor cortex depresses transmission in the recurrent pathway (see p. 173). Descending facilitation of Renshaw cells The increase in recurrent inhibition observed dur- ing weak tonic contractions in normal subjects has not been observed in spastic patients, despite the same on-going motor activity and a normal level of recurrent inhibition at rest (see pp. 186–7). This sug- gests that the increase is not due to Renshaw cell activation by the natural motor discharge. Further support comes fromthefindingthat theH / test reflex is inhibited prior to a ramp contraction while refer- ence H is facilitated, changes that occur in advance of any motoneurone discharge or afferent activation related to the contraction. This suggests supraspinal facilitationof Renshawcells during moderate volun- tary tonic contractions, as has beendescribedinani- mal experiments after stimulationof different higher centres (p. 153). Changes in heteronymous recurrent inhibition during voluntary contractions Heteronymous recurrent inhibition of quadriceps motoneurones due to a soleus motor discharge has been assessed with the quadriceps H reflex during tonic voluntary contractions of the quadriceps (Iles & Pardoe, 1999). Recurrent inhibition progressively declined with the strength of the contraction, and fell to zero at ∼35%of MVC. This resembles the inhi- bition of soleus-coupled Renshaw cells described during strong soleus contraction, but differs in two points: (i) absence of increased recurrent inhibi- tion for the lowest levels of forces (which has been observed for homonymous recurrent inhibition at quadriceps level using the paired H reflex tech- nique, Rossi & Mazzocchio, 1991), and (ii) the find- ing that recurrent inhibition was completely inhib- ited with a much lower level of force than during homonymous soleus contraction. Tworeasons could account for the lesser decrease in homonymous than in heteronymous recurrent inhibition of the Motor tasks – physiological implications 179 motoneurones involved in voluntary contractions: (i) as discussed above, the decrease in homony- mous recurrent inhibition is underestimated with the paired Hreflex technique, given the lesser sensi- tivity of H / to excitatory inputs, and the summation of the AHPs; (ii) if homonymous and heteronymous inhibitions operate through different pathways, the summation in Renshaw cells of the natural motor activity and the conditioning discharge would facil- itate homonymous recurrent inhibition (see above), but not heteronymous recurrent inhibition. Conclusions and functional implications The main finding is that, during a strong contrac- tion or towards the end of ramp contractions, recur- rent inhibition directed to active motoneurones is depressed despite the activation of Renshawcells by the natural motor discharge via recurrent collater- als. Asimilar result was obtainedwithheteronymous recurrent inhibition, i.e. witha methodindependent of possiblechanges inthemotoneuronal AHPduring contraction. Descending inhibition of Renshaw cells The decreased recurrent inhibition occurs because Renshaw cells receive potent descending inhibition whichislikelytobecorticospinal inorigin. Thisinter- pretationis consistent withthe decrease inrecurrent inhibition observed after stimulation of the motor cortex (cf. p. 173). The reduction of recurrent inhi- bition of motoneurones during strong contractions ensures a high input–output gain for the motoneu- rone pool, and this would favour large tension out- put. During sustained long-lasting contractions, the absence of recurrent inhibition of silent homony- mous motoneurones would facilitate their recruit- ment, thus helping overcome fatigue. Inhibition of Renshaw cells favours reciprocal Ia inhibition It has been a general feature that, for a given level of force reached towards the end of phasic ramp contractions, Renshawcells are more inhibited than when the same force is developed in a tonic con- traction (Fig. 4.8(e )). This particular control prob- ably occurs because effective reciprocal Ia inhibition of the antagonistic muscle is required during phasic contractions (Pierrot-Deseilligny, Katz & Hultborn, 1983). Indeed, agonist contractions (e.g. soleus) pro- duce a stretch-induced Ia discharge from the antag- onistic muscle (here tibialis anterior, Fig. 4.8(a )), and this is greater during a ramp contraction than during a tonic contraction, because the stretch is then both dynamic and static. This Ia discharge tends to produce two undesirable effects: excitation of antagonistic motoneurones (tibialis anterior) and of 'corresponding' Ia interneurones inhibiting ago- nist motoneurones (soleus). These effects may be opposed by the reciprocal Ia inhibition from soleus to tibialis anterior motoneurones and of 'opposite' Ia interneurones, provided that soleus-coupled Ia interneurones are not inhibited by recurrent inhibi- tion. Thus, Renshaw cell inhibition during flexion– extension movements allows reciprocal Ia interneu- rones to exert their necessary inhibitory action (Fig. 4.8(a ); Chapter 5, p. 222; Chapter 11, p. 519). The gain hypothesis The facilitation of Renshaw cells during weak con- tractions would be explained if recurrent inhibi- tion served as 'a variable gain control' on the 'final common path' (Hultborn, Lindstr¨ om & Wigstr¨ om, 1979a): if the recurrent pathway is active, it will reduce the slope (the gain) of the input–output relation for the motoneurone pool. This reduction will be maximal when Renshaw cells are facilitated, as occurs during weak contractions. The resulting low gain for the motoneurone pool would allow supraspinal centres to operate over a large part of their working range and cause only small changes in muscle force. As a result, a facilitatedrecurrent path- waywouldimproveresolutioninthecontrol of motor output. In contrast, an inhibited recurrent pathway wouldgiverisetoahighoutput gainallowingthecen- tral command to generate larger forces for a given drive, despite the strong motor discharge reaching Renshaw cells via recurrent collaterals. 180 Recurrent inhibition Recurrent inhibition during contraction of the antagonistic muscle The paired H reflex technique has been used to investigate changes in homonymous recurrent inhi- bition directed to soleus motoneurones during vol- untary contraction of the antagonistic pretibial flex- ors (Katz & Pierrot-Deseilligny, 1984). With contrac- tions of the antagonist, it is likely that there would be no change in the AHP of the agonist to compli- cate the interpretation of the changes in H / . Because of the AHP, the H / test reflex is less sensitive than the reference Hreflex tothe inhibitory inputs related to the antagonistic contraction (see p. 161), and greater inhibition of H / than of the reference H may be attributed to increased homonymous recurrent inhibition. Changes during various contractions Whatever the force of tonic voluntary ankle dorsi- flexion, the H / test reflex in the antagonistic soleus was more inhibited than the reference Hreflex, indi- cating an increase in recurrent inhibition, as com- pared to rest (Fig. 4.9(b )). During the ramp phase of a ramp-and-hold voluntary dorsiflexion, the H / test reflex continuously decreases, whereas thereference H reflex, which is inhibited at the onset of volun- tary dorsiflexion, undergoes a later 'relative facilita- tion' due to the stretch-induced Ia discharge from the antagonistic muscle (Fig. 4.9(c ); see Morin & Pierrot-Deseilligny, 1977). The stronger inhibition of H / when there is relative facilitation of the ref- erence H reflex indicates an increase in recurrent inhibition. Origin and significance of the changes in recurrent inhibition It was suggested that the increased recurrent inhibi- tion of soleus motoneurones during voluntary con- traction of antagonistic pretibial flexors was due to a descending facilitation of soleus-coupled Renshaw cells (Katz &Pierrot-Deseilligny, 1984). This couldbe one of the mechanisms that prevent a stretch reflex in soleus (see Chapter 11, p. 520). Any discharging motoneurones would inhibit other motoneurones and thus curtail the stretch reflex. In this respect, it is of interest that the maximal Renshaw cell facil- itation is observed when the stretch-induced Ia dis- chargefromtheantagonisticmuscleelicits a'relative facilitation' of the reference H reflex. Recurrent inhibition of antagonistic muscles involved in co-contraction Recurrent inhibition during voluntary co-contraction of antagonistic muscles Homonymous recurrent inhibition of soleus moto- neurones, assessed with the paired H reflex tech- nique, has been measured during co-contraction of antagonistic ankle plantar and dorsiflexors and during plantar flexion alone, at matched levels of background activity in the soleus muscle (Nielsen & Pierrot-Deseilligny, 1996). Depression of the H / test reflex In soleus, the H / reflex is depressed during weak and facilitated during strong plantar flexion (cf. p. 174), but it is always strongly depressed during tonic co-contractions, regardless of their force level. This finding suggests differential control of recur- rent inhibition during the two types of contraction (see below). Interestingly, heteronymous recurrent inhibition to quadriceps motoneurones, assessed with a method independent of possible changes in the motoneuronal AHP during contraction, is also differentially controlled during tonic contrac- tions of quadriceps (decreased) and co-contraction of quadriceps and hamstrings (unchanged) (Iles & Pardoe, 1999). During a ramp contraction, the refer- ence H reflex was facilitated with respect to its rest value inbothtypes of contraction, but H / underwent different changes: continuous increase throughout the ramp plantar flexion with complete suppression at theendof therampco-contraction(Fig. 4.9(d),(e)). Motor tasks – physiological implications 181 Specific control during co-contraction It is unlikely that the control of soleus-coupled Ren- shaw cells during co-contraction is the sum of the opposite effects observed during isolated voluntary plantar and dorsiflexions. (i) The inhibition observed during strong co- contraction is greater than the sum of the strong facilitation during strong plantar flexion and the moderate inhibition during strong dorsiflexion. (ii) The strong inhibition of H / observed during the first 100 ms of voluntary dorsiflexion(Fig. 4.9(c )) does not fit the finding that during co-contraction the H / test reflex is inhibited towards the end of the ramp (Fig. 4.9(e )). This implies a specific con- trol of recurrent inhibition during co-contraction, and would be in line with previous studies which have suggestedthat the descending control of spinal segmental pathways is conveyed by different des- cending pathways during co-contraction and dur- ing flexion–extension movements (see Chapter 11, p. 533). Which control? During strong contraction of the target muscle, the decreased recurrent inhibition to active motoneu- rones probably results fromcorticospinal inhibition of Renshaw cells (see above). The strong recurrent inhibitionduring co-contractioncould be explained simply by suppression of this descending control, leaving the motor discharge-induced excitation of Renshawcells unopposed by descending inhibition. If this were so, recurrent inhibition should paral- lel the on-going motor discharge. However, during ramp co-contractions, the inhibition of the H / test reflex increases abruptly at the end of the ramp, and this suggests the existence of a supplementary descending facilitation of Renshaw cells. Homonymous recurrent inhibition during active standing Because contraction of either of the antagonistic ankle muscles may be required in postural tasks such as the maintenance of upright stance, recur- rent inhibition of soleus motoneurones has been compared when standing with and without support (Pierrot-Deseilligny et al., 1977). The H / test reflex was significantly smaller during active stance than when standing with support (Fig. 4.10(b ), (c )). The size of the reference H reflex was the same in the two situations, and increased recurrent inhibition of soleus motoneurones during active standing is therefore likely. The increased recurrent inhibition was not directly related to muscle contraction in the explored leg, because the same result has been observedintheabsenceof musclecontraction, when the subject placed most of the body weight on the unexplored leg. Neither was it due to the cutaneous afferent discharge from the sole of the foot because this discharge would be the same whether stance was supported or unsupported. The main differ- ence between the two positions is that when equi- librium is unsteady, contractions may be required in either of the antagonistic muscles operating at the ankle, and this creates a situation where an increase in recurrent inhibition may be helpful in controlling body sway. The reinforcement of recur- rent inhibition in active standing is probably due to a supraspinal mechanism, possibly vestibular. In this connection, homonymous recurrent inhibition of soleus motoneurones is enhanced during static backward tilt from 80 ◦ to 40 ◦ of a subject fixed to a tilting chair (Rossi, Mazzocchio & Scarpini, 1987). Functional implications Renshaw cells are facilitated during co-contractions of antagonistic muscles, contractions which, in the lower limbs, may be necessary inpostural tasks. This is of functional interest, because: (i) transmission in the Iainhibitory pathway must be depressedtoallow the parallel activation of the two antagonistic mus- cles (see Chapter 5, p. 227), and Renshaw cell out- put contributes significantly to this depression; and (ii) it ensures that the gain of the stretch reflex is diminishedat theoutput stagetoprevent oscillations and clonus from developing during co-contractions (cf. Chapter 11, p. 534). 182 Recurrent inhibition (a) (b) (c) (e) (f ) (d) Fig. 4.10. Changes in recurrent inhibition during postural tasks. (a) and (d ) Sketches of the presumed pathways of homonymous recurrent inhibition of soleus (Sol) motoneurones (MNs) (a), and heteronymous recurrent inhibition from quadriceps (Q) to Sol and tibialis anterior (TA) MNs (d ). The arrows indicate the conditioning reflex discharges that activate Renshaw cells (RC). (b), (c) Homonymous recurrent inhibition to Sol MNs, assessed with the paired H reflex technique, in the sitting position () and in standing (●) with (b) and without (c) support of a wall. The size of the H / test reflex of Sol (expressed as a percentage of the H1 conditioning reflex) is plotted against the size of H1 (expressed as a percentage of M max ). (e), (f ) Heteronymous recurrent inhibition elicited by a Q Hreflex discharge in the TA (e) and the Sol (f ), assessed as the modulation on the on-going EMG of TA or Sol, during a voluntary co-contraction in sitting position on a high stool (thin lines) and postural co-contractions (thick lines) of Q and TA ((e), leaning backwards) or of Qand Sol ((f ), preparation for hopping). The sketches on the right of each trace represent the postural task. Modified from Pierrot-Deseilligny et al. (1977) ((b), (c)), and Barbeau et al. (2000) ((e), (f )), with permission. Motor tasks – physiological implications 183 Heteronymous recurrent inhibition and heteronymous Ia excitation The hypothesis that a function of heteronymous recurrent inhibition may be to limit the extent of Ia excitation has been examined by studying the changes in heteronymous recurrent inhibition during postural tasks requiring co-contraction of lower-limb muscles linked in Ia synergism. Methodology Recurrent inhibition of tibialis anterior and soleus motoneurones produced by a quadriceps H reflex discharge has been measured using three test responses: (i) the rectified and averaged ongoing EMG activity of tibialis anterior or soleus; (ii) the MEPelicitedinthesemusclesbycortical stimulation; (iii) the soleus H reflex (Barbeau et al., 2000). Recur- rent inhibition from quadriceps was compared at matched levels of background EMG activity dur- ing voluntary co-contraction of quadriceps and of the relevant ankle muscle while sitting (control situ- ation) and in different postural tasks. In the reverse paradigm(soleus toquadriceps), Renshawcells were activatedby a soleus Hreflex andthe resulting recur- rent inhibition assessed with a quadriceps H reflex (Iles, Ali & Pardoe, 2000). Decreased recurrent inhibition to motoneurones of the muscle involved in postural co-contraction During postural co-contractions of quadriceps and tibialis anterior, as occur when standing and lean- ing backwards, heteronymous recurrent inhibition from quadriceps to tibialis anterior was reduced with respect to sitting, whether assessed with the on-going EMG activity (Fig. 4.10(e )) or the MEP. In the same situation, recurrent inhibition from quadriceps to soleus assessed with the H reflex was unchanged or increased. During postural co- contractions of quadriceps and soleus, as occur in preparation for hopping, recurrent inhibition from quadriceps tosoleus was reducedwithrespect tosit- ting, whether assessedwiththe on-going EMGactiv- ity (Fig. 4.10(f )), the H reflex or the MEP, and recur- rent inhibitionto tibialis anterior was unchanged. In situations in which the soleus contraction was not associated with a quadriceps contraction (standing on tip of toes or leaning forwards during stance), heteronymous recurrent inhibitionfromquadriceps to soleus was unchanged. Similarly, heteronymous recurrent inhibition from soleus to quadriceps was reduced during postural stance involving quadri- ceps andsoleus co-contractionwhencomparedwith similar voluntary muscle contractions when sitting (Iles, Ali & Pardoe, 2000). Origin of the posture-related changes in recurrent inhibition The decreased recurrent inhibition directed to mus- cles associated with the quadriceps in postural co- contractions is probably due to descending control becausetheon-goingmotor dischargereachingRen- shaw cells via recurrent collaterals and the cuta- neous activation due to the pressure of the foot sole wouldhavebeenthesameinthecontrol andpostural situations. Functional implications The above results support the view that the facilita- tionof heteronymous recurrent inhibitionfunctions to limit the extent of heteronymous Ia excitation. As discussed in Chapter 2, prewired Ia connections link the quadriceps to both tibialis anterior and soleus operating at the ankle (and, similarly, the gastrocnemius-soleustobothquadricepsandbiceps femoris). In functional terms this may be explained by the versatile synergisms required for various tasks (see Chapter 2, p. 94). These connections could become functionally inconvenient because any increase in activity of quadriceps Ia afferents might result inthe simultaneous activationof antag- onistic ankle flexor and extensor motoneurones. The Ia excitatory connection that is not appropri- ate for a particular movement (e.g. the quadriceps projections to soleus motoneurones when leaning 184 Recurrent inhibition backwards) must thereforebecontrolled. This canbe done through appropriate control of Renshaw cells: recurrent inhibition directed to motoneurones of the ankle muscle not involved in the co-contraction opposes Ia excitation, whereas Renshaw cells pro- jecting onto motoneurones involved in the postu- ral co-contraction are depressed (cf. Chapter 11, p. 538). Studies in patients and clinical implications In patients, only homonymous recurrent inhibition of soleus motoneurones has been studied using the paired Hreflex technique. These investigations have involved mainly spastic patients. Spasticity On theoretical grounds, decreased recurrent inhi- bition could contribute to the stretch reflex exag- geration that characterises spasticity: activity of the motoneurone pool would then be less effectively opposedbyrecurrent inhibition, andsoagreater dis- charge would ensue. Changes in recurrent inhibition at rest Three abnormal patterns have been observed in some patients (Katz & Pierrot-Deseilligny, 1982; 1998; Mazzocchio et al., 1990): (i) absence of H / test reflex, (ii) a plateau-like pattern, where the H / reflex having attained its maximum remains unchanged (Fig. 4.11(e )), and (iii) a 'straight-line' pattern, in which H / keeps increasing in parallel with H1 (Fig. 4.11(f )). The amplitude of H / depends on the excitability of the monosynaptic reflex arc, which is enhanced in the lower limbs of spastic patients (as evidenced by an increased H max /M max ratio, see Chapter 12, p. 562). The greater excitability of motoneurones could protect them from the inhi- bition following the H1 discharge. Hence, an abnor- mally large H / test reflex might reflect an increase in excitability of the monosynaptic reflex arc and/or a decrease in recurrent inhibition. The latter pos- sibility can be explored by measuring the extent to which the H / test reflex is modified by the acute injection or the chronic intake of L-Acetylcarnitine (L-Ac; pp. 159–60; Mazzocchio et al., 1990; Maz- zocchio & Rossi, 1997b). Abnormal patterns of H / are unlikely to reflect a change in the AHP of the motoneurones because, in the cat, the AHP is not modified after chronic spinal transsection (Gustafs- son, Katz & Malmsten, 1982). Stroke patients The absence of H / is the most frequent finding onthe affected side of stroke patients whatever the ampli- tude of H1. The H / response cannot be elicited in ∼30% of normal subjects and this is more frequent instrokepatients (53%, of 85patients, Katz &Pierrot- Deseilligny, 1982). Whenpresent, H / following a con- ditioning reflex discharge of 50%of M max (i.e. within the range producing a decrease in the H / test reflex in normal subjects) was of the same size as in nor- mal subjects, andof equal or smaller amplitude than on their unaffected side (Katz & Pierrot-Deseilligny, 1982; Chacoet al., 1984). Giventhat H max is increased in soleus on the affected side of stroke patients (see Chapter 12, p. 576), theabsenceof H / inmost patients andlackof increaseinits amplitudeinothers suggest enhanced recurrent inhibition in these patients. Patients with spinal cord injury There is evidence for anincrease inrecurrent inhibi- tion in patients with complete or partial spinal cord injury at the cervical and thoracic levels. The soleus H / reflex was absent in 13 of 18 patients and, when present, its amplitude was significantly smaller than in normal subjects (Shefner et al., 1992). Patients with amyotrophic lateral sclerosis While H max is not greater than in normal subjects, the amplitude of the H / response was increased, sug- gesting a decrease in recurrent inhibition (Raynor & Shefner, 1994). Studies in patients 185 0 10 20 30 40 Strong Weak Rest Normal subject Stroke patient (b) (c) Reference H H' Reference H H' H ' how often can i take 20mg cialis cialis generico en madrid t r i g g e r s ) 16 Fig. 7.8. Corticospinal projections to interneurones mediating peroneal group I–group II excitation to quadriceps motoneurones. (a) Sketch of the presumed pathways with corticospinal projections to quadriceps (Q) motoneurones (MN), excitatory interneurones (IN or PN) fed by group I and II afferents in the common peroneal nerve (CPN), and inhibitory INs (Inhib. IN) inhibiting them (group II projections onto Inhib. INs have been omitted). FN, femoral nerve. (b) The motor evoked potential (MEP, ●) and the H reflex (❍) of the Q (as a percentage of the control responses) during a weak Q voluntary contraction (∼2 % MVC) conditioned by a CPN volley (2 MT) plotted against the interstimulus interval (ISI) CPN-TMS (upper abscissa) and CPN-FN (lower abscissa, in italics), the two abscissae being aligned to start at the simultaneous arrival of conditioning and test volleys at the Q MN pool. Each symbol, mean of 20 measurements; vertical bars ±1 SEM. Because convergence of peroneal and corticospinal volleys onto MNs should have modified the H and MEP responses to the same extent, the differential effect (larger late group II excitation) observed on the two responses indicates a convergence onto INs. (c), (d) PSTHs of a vastus lateralis (VL) unit (after subtraction of the background firing, 0.2 ms bin width). (c) The algebraic sum () of effects elicited by separate CPN (2 MT) and cortical stimuli is compared to the effect on combined stimulation (9 ms ISI, ). (d ) Extra facilitation on combined stimulation, i.e. the difference (– ) in (c). Dashed and dotted lines in (c), (d ) highlight the onset of the corticospinal peak and of the extra facilitation on combined stimulation, respectively. (e) The amount of extra facilitation on combined stimulation (calculated as in (d ), same unit as in (c), (d ) plotted against the ISI. Extra facilitation peaked at 14 and 10 ms ISIs corresponding to the synchronous arrival of the group II volley with successive corticospinal (D and I waves) volleys at relevant interneurones. Modified from Marchand-Pauvert, Simonetta-Moreau & Pierrot-Deseilligny (1999), with permission. peak (Fig. 7.8(c), (d )). Sparing of the initial 0.8 ms corresponds to the delay required for transmission across one interneurone in human pathways, and this sparing is what wouldbe expectedif the twovol- leys converged onto common interneurones rather than directly onto the motoneurone (see Chapter 1, pp. 46–7). Overall, these findings suggest that part of the corticospinal volley is transmitted to motoneu- rones by lumbar propriospinal neurones (cf. the sketch in Fig. 7.8(a) and Chapter 10, pp. 498–500). 310 Group II pathways Corticospinal control of interneurones inhibiting lumbar propriospinal neurones Inhibition from low-threshold afferents Corticospinal and peripheral group I (and pos- sibly cutaneous) volleys converge onto inhibitory interneurones projecting to lumbar propriospinal neurones (see Chapter 10, p. 500). This conver- gence accounts for the early GM-induced inhibi- tion of the semitendinosus MEP at the 4 ms ISI (Fig. 7.7(d )), observedinall subjects. It alsoaccounts for (i) the finding that, in the quadriceps, common peroneal stimulation elicits a smaller early facilita- tion of the MEP than of the H reflex (Fig. 7.8(b)), and (ii) the early peroneal-induced inhibition of the corticospinal peak in the PSTHs of quadriceps units (4 ms ISI in Fig. 7.8(e)). Convergence of corticospinal and group II volleys onto inhibitory interneurones When increasing the gastrocnemius medialis stimu- lus intensity above 1.5 MT, there is complete sup- pression of the group II facilitation of the semitendi- nosus MEP (Fig. 7.7(c)). This contrasts with the weak decrease in the group II facilitation of the H reflex in this muscle in the absence of cortical stimulation (Fig. 7.3(d )). Thus, group II volleys, which cannot activate the inhibitory interneurones in the absence of TMS, become very effective when their synaptic actionsarecombinedwithcorticospinal volleys. This suggests that inhibitory interneurones also receive corticospinal excitation. GroupII volleys inthe com- mon peroneal nerve also suppress the corticospinal peakinquadriceps units, andthegroupII facilitation is consistently followed by an inhibition (as at the 16 ms ISI in Fig. 7.8(e)). Conclusions Corticospinal volleys facilitate lumbar propriospinal neurones co-activated by group I and group II afferents. However, they also facilitate inhibitory interneurones mediating feedback inhibition to lumbar propriospinal neurones. Overall the domi- nant effect of corticospinal volleys on the lumbar propriospinal systemseems to be excitation of feed- back inhibition, particularly in the pathway of pro- priospinal excitation to semitendinosus motoneu- rones. Motor tasks and physiological implications There is no evidence for post-activation depression of group I inputs to human lumbar propriospinal neurones co-activated by group I and group II affer- ents (Lamy et al., 2005). This finding is in keeping with the absence of post-activation depression in feline interneurones of the intermediate zone fed by group I and group II afferents (see pp. 292–3). Thus, contrary to Ia inputs at the Ia-motoneurone synapse (cf. Chapter 2, pp. 96–9), the synaptic efficacy of groupI andgroupII excitatory inputs tolumbar pro- priospinal neurones would not be held at a lowlevel during motor tasks by post-activation depression. Voluntary contractions Voluntary contraction of the quadriceps Modulation of the H reflex appears a priori to be the best method to investigate how transmission in spinal pathways is changed by motor tasks, because it enables a comparison of the results obtained at rest and during movement. The biphasic facilita- tion of the quadriceps H reflex produced by com- mon peroneal stimulation at 2 MT is unchanged with respect to rest during weak tonic quadriceps contractions (Marchand-Pauvert et al., 2002, their Fig. 7.1(a)). However, during relatively strong con- tractions of quadriceps at ∼10% of MVC, the early peroneal group I facilitation of the quadriceps H reflex is truncated by a suppression that also abol- ishes the late group II facilitation (Figs 1.12(c) and Fig. 7.9(g)). This suppression is due to the con- vergence of joint and/or cutaneous inputs in the conditioning peroneal volley and group I input in Motor tasks – physiological implications 311 Fig. 7.9. Changes in group II excitation during postural tasks. (a) and (e) Sketches of the presumed pathways of homonymous group I–group II excitation to soleus (Sol) and flexor digitorum brevis (FDB) motoneurones (MN) (a), and heteronymous group I– group II excitation from tibialis anterior (TA) to quadriceps (Q) MNs (e). Noradrenergic descending gating of group II excitation is represented. Sketches of the posture on the right of (b), (c), (g). (a) Monosynaptic projections on MNs of Ia afferents, and convergence of Ia and group II afferents onto group II excitatory interneurones (IN or PN). (b), (c) Short-latency (SLR) and medium-latency (MLR) responses (average of 10 trials) elicited in the Sol by upward tilt during free stance (b) and while holding onto a stable frame (c). The MLR (black area) is suppressed, but the SLR is not influenced by the 'postural set'. (d ) Average area (mV ms, 6 subjects) of the FDB MLR during free stance () and while holding onto a stable frame (dashed column). (e) Sketch with the convergence of Ia and group II afferents from TA onto INs (PN) exciting Q MNs, and the convergence of joint afferents in the deep peroneal (DPN) conditioning volley and Ib afferents in the femoral (FN) test volley on Ib INs projecting to Q MNs. (f ), (g) DPN (2 MT) modulation of the on-going EMG ((f ), 200 sweeps, as a percentage of control EMG) and of the H reflex ((g), as a percentage of its unconditioned value, mean of 20 measurements, vertical bars ±1 SEM) of the Q when leaning backwards (●) and during voluntary co-contraction of TA and Q (❍) at equivalent levels of EMG activity (21% MVC). Vertical arrows indicate the expected time of arrival of the peroneal Ia volley at Q MN level ((f ), 26 ms; (g), 6 ms interstimulus interval [ISI]). Early group I and late group II facilitations measured within the windows 29–34, and 35–38 ms for the on-going EMG, and at the 8–10, and 17–21 ms ISIs for the H reflex, respectively. Modified from Schieppati & Nardone (1991) (b), (c), Schieppati & Nardone (1999) (d ), and Marchand-Pauvert et al. (2005) ((f ), (g)), with permission. 312 Group II pathways the test femoral volley onto interneurones medi- ating the autogenetic 'Ib inhibition' to quadri- ceps motoneurones (see the sketch in Fig. 7.9(e); Marchand-Pauvert et al., 2002; Chapter 1, pp. 14–16). It complicates the use of the H reflex to assess the changes in peroneal-induced group II excita- tion during voluntary movement, whether the vol- untary contraction involves quadriceps only or both tibialis anterior and quadriceps. Common pero- neal group II facilitation of the on-going quadriceps EMG is larger during a strong voluntary contraction at 20% of MVC than during a weak contraction at 5% of MVC (Fig. 1.12(b); Marchand-Pauvert et al., 2002). Facilitation of the transmission of heterony- mous peroneal group II volleys during a selective contractionof thequadriceps is not surprising, given the convergence of peroneal and femoral volleys onto common propriospinal neurones projecting to quadriceps motoneurones (Forget et al., 1989; Chap- ter 10, p. 496). Because the greater peroneal-induced facilitation of the on-going EMG during strong con- tractions involves both early group I and late group II excitations, an increase in the excitability of pro- priospinal neurones co-activated by the two types of afferents is plausible. This increased excitability might be simply due to the g-driven Ia and group II inflow from the contracting quadriceps and/or increased corticospinal excitation. Voluntary contraction of the semitendinosus The gastrocnemius medialis-induced facilitation of the semitendinosus H reflex observed at rest (cf. Fig. 7.3(d), (e)) is suppressed during voluntary con- traction of the semitendinosus at ∼20% of MVC (Marchand-Pauvert et al., 2005). Presumably, this suppression also reflects convergence of afferents in the conditioning volley and group I afferents in the test volley onto interneurones mediating auto- genetic 'Ib inhibition' to the semitendinosus motoneurones (convergenceof Ibafferents fromdif- ferent muscles onto common Ib interneurones has been demonstrated, cf. Chapter 6, pp. 257–8). Only a weak facilitation of the on-going semitendinosus EMG by group II volleys from the gastrocnemius medialis was observed, whether the voluntary con- traction was weak, and involved only hamstrings, or was strong and involved both the triceps surae and hamstrings (Marchand-Pauvert et al., 2005). Despite the strong heteronymous excitatory group II pro- jections from gastrocnemius medialis to semitendi- nosus neurones (see Table 7.3), there is no evidence that heteronymous group II pathways are signifi- cantly implicated in the excitation of motoneurones involved in voluntary co-contractions of these two muscles. Conclusions Differences in the changes in transmission of het- eronymous group II excitation to quadriceps and semitendinosus motoneurones during contraction of the target muscle could reflect the dominant cor- ticospinal excitation of feedback inhibition in the pathway of propriospinal excitation to semitendi- nosusmotoneurones(seeabove). Inaddition, aspro- posed by Jankowska (1992), group II pathways in the cat maybeinvolvedparticularlyinthecontrol of pos- ture andgait, andthis alsoappears tobe soinhuman subjects (see below). Postural tasks Role of homonymous group II pathways in transient perturbations of stance A sudden displacement of the platform upon which subjects stand produces ankle rotation and stretch- induced responses in triceps surae after toe-up tilt and in tibialis anterior after toe-down tilt (Figs. 7.2, 7.9(b), (c); Schieppati et al., 1995). These responses help the subject counteract the displacement as it shifts the projection of the centre of mass from its normal positiononthefoot support base. Note, how- ever, that excessively large responses could desta- bilise posture (cf. Chapter 11, pp. 540–1). Stretch responses in triceps surae are accompanied and Motor tasks – physiological implications 313 completed by analogous activities in the flexor digitorum brevis. These latter responses create a background torque anchoring the foot to the plat- form (Schieppati & Nardone, 1999; Schieppati et al., 2001). Role of the 'postural set' Medium-latencystretchresponses elicitedbytoe-up tilt in soleus and flexor digitorum brevis during nor- mal upright stance are considerably reduced when subjects hold onto a stable frame, but the short- latency responses are not altered (Fig. 7.9(b)–(d ); Nardone, Corr` a & Schieppati, 1990; Nardone et al., 1990b). This differential effect indicates descend- ing control focused ontransmissioninthe pathways of group II excitation. Similarly, stabilisation of the upright posture considerably reduces the medium- latencyresponseelicitedintibialis anterior bydown- ward tilt (Schieppati &Nardone, 1991). The suppres- sionof themedium-latency responseis not triggered by arm motion or contact with the frame. Indeed, it begins about 200ms beforesubjects touchtheframe, andthis suggests that it is relatedtothetransitiontoa new stabilised 'postural set' (Schieppati & Nardone, 1995). Bilateral medium-latency responses Bilateral responses elicited by unilateral perturba- tions are functionally required, because even a uni- lateral displacement shifts thecentreof mass fromits normal position on the foot support base. However, the contralateral responses are then weaker (see p. 305), presumably because when one leg is on firm ground the perturbation is less destabilising, and this could have tuned down the excitability of the pathway in the same way as holding onto a stable frame. Conclusions Two lines of evidence indicate that stretch-induced group II-mediated medium-latency responses play a crucial role in compensating for perturbations to upright stance: (i) the responses are consider- ably reduced if they are not required to ensure equilibrium, such as when the subjects support themselves by holding onto a stable frame; and (ii) patients with Charcot–Marie–Tooth type 1A dis- ease, in whom medium-latency responses are pre- served (even if distorted, see Fig. 7.13(b)), do not have balance problems, despite the lack of short- latency Ia responses (see p. 320). The role of short-latency Ia-mediated reflex responses in cor- recting for rapid perturbations to the stance is questionable (see Chapter 11, p. 541). However, because of the convergence of Ia afferents onto pro- priospinal neurones mediating group II effects, a Ia discharge would contribute to medium-latency responses by depolarising these interneurones. Role of heteronymous group II pathways in postural tasks It has been investigated whether heteronymous group II excitation from pretibial flexors to quad- riceps and from gastrocnemius medialis to semi- tendinosus is involvedinthemaintenanceof bipedal stance in postural tasks requiring co-contraction of leg and thigh muscles (Pierrot-Deseilligny, 1999; Marchand-Pauvert et al., 2005). Peroneal group II facilitation of quadriceps The modulation of the on-going EMG of quadri- ceps by deep peroneal stimulation (2 MT) has been recorded during postural co-contractions of quadriceps and tibialis anterior produced by stand- ingandleaningbackwards, andduringvoluntary co- contraction of these two muscles, at matched levels of EMG activity. While the early group I facilitation was of the same magnitude inthe two situations, the late facilitation of the EMG was greater when lean- ingbackwards(Fig. 7.9(f )). Duringthestrongquadri- ceps contraction, the early group I facilitation of the quadriceps Hreflex was truncatedandthelategroup II facilitation completely suppressed, because of the 314 Group II pathways gating effect on the test H reflex of Ib afferents in the test volley (see above). Whenleaning backwards, the early group I facilitation was similarly trun- cated but, contrary to voluntary contraction, there was a late excitation attributable to II afferents (Fig. 7.9(g)). The finding that the early peak of reflex facilitation was truncated to the same extent with respect to rest in the two situations suggests that, while leaning backwards, there was facilitation of the peroneal-induced group II excitation, superim- posed on a suppression of equal magnitude as dur- ing voluntary contraction. In the postural task, the group II excitation was greater in the ongoing EMG than in the H reflex, because the former was not affected by changes in transmission of the affer- ent volley for the test H reflex. The early group I and late group II excitations are probably mediated through common interneurones (see p. 306). The similar magnitude of the early group I excitation in the two tasks therefore suggests that the enhanced group II excitation during the postural task was not due to increased excitability of these interneu- rones (e.g. due to vestibulospinal facilitation), but to a specific mechanism acting on transmission of group II effects. A good candidate would be a decrease in the monoaminergic gating of transmis- sioningroupII pathways exertedfromthebrainstem (see below). Gastrocnemius medialis group II facilitation of semitendinosus During postural co-contractions of triceps surae and hamstrings, as occurs when standing and lean- ing forwards, gastrocnemius medialis volleys at 1.3– 1.5 MT facilitate the on-going EMG of semitendi- nosus at central delays compatible with group II excitation. Becausethereis noequivalent facilitation during voluntary co-contractions of these muscles, here again, the postural task is presumably accom- panied by increased group II excitation. Functional implications A perturbation to stance produces postural responses in the tibialis anterior and triceps surae due to activation of homonymous group II afferents by stretch (see Schieppati et al., 1995; Fig. 7.2). In the cat, transmission of group II exci- tation is gated by monoaminergic control from the locus coeruleus/subcoeruleus and from raphe nuclei in the brainstem (cf. p. 292). A descending projection from the locus coeruleus/subcoeruleus probably also exists in human subjects, as shown by the suppression of group II excitation pro- duced by tizanidine (see p. 299). Thus, Nardone, Corna & Schieppati (2001) suggested that, when the medium-latency responses are nolonger requiredto ensure the control of upright quiet stance, there is a reductionina descending inhibitory control exerted on the locus coeruleus, leading to increased activity from the locus, and thereby to increased gating of group II volleys (see the sketch in Fig. 7.15(a)). In contrast, when balance is unstable, transmission in group II pathways would be tuned up by decreased activity in this monoaminergic control system. On the other hand, potent heteronymous group II exci- tation also exists fromtibialis anterior to quadriceps and from gastrocnemius medialis to semitendi- nosus, i.e. linking leg and thigh muscles involved in the maintenance of posture when leaning backwards and forwards, respectively. Transmission of group II discharges from stretched leg muscles, tuned up by the monoaminergic control system, might also contribute to the co-contraction of leg and thigh muscles required in each postural task. In concluding this section, it should be noted that these findings may shed more light on the corrective mechanisms for destabilising perturbations than they tell us about the control of quiet stance (see Chapter 11, pp. 539–41). Changes in group II excitation during gait Group II afferent activity has two actions in the con- trol of human walking: (i) contribution to the acti- vation of the muscles during normal unperturbed walking, and (ii) mediation of some of the reactions to sudden external perturbations. Motor tasks – physiological implications 315 Fig. 7.10. Changes in group II excitation elicited by unloading of ankle extensors during gait. (a) Sketch of the presumed pathways of homonymous group I–group II excitation through PNs to soleus (Sol) motoneurones (MN). Reciprocal Ia inhibition from tibialis anterior (TA) to Sol MNs is represented. Ischaemic block of group I afferents in the posterior tibial nerve (PTN) and lidocaine block of the common peroneal nerve (CPN) are sketched. Noradrenergic descending inhibition of the transmission of group II excitation is represented. (b) Sketch of the experimental paradigm for unloading gastrocnemius-soleus (GS). (c)–(f ) Effect of unexpected unloading of GS on Sol EMG activity. Unloading: 6 ◦ at a velocity of 330 ◦ s −1 , followed by a hold phase of 210 ms, onset indicated by the zero of the abscissa and the vertical dashed line, triggered 200 ms after heel contact. Upper traces: ankle angle position (0 ◦ equals standing position, positive values plantar movement direction). Lower traces: averaged rectified and filtered Sol EMG. Control steps, thick lines; steps with an unloading, thin lines. Sol EMG prior to the unloading matched the Sol EMG activity in the control steps until ∼60 ms after perturbation onset. A marked decrease in EMG (black area) was present at this time until ∼180 ms after unloading onset. When the unloading was terminated, a peak occurred with a 40 ms latency, reflecting the short-latency Ia stretch reflex. The EMG suppression produced by unloading is compared before (c) and 20 min after ischaemia of the thigh blocking group I afferents ((d ), as shown by the disappearance of the Achilles tendon jerk, while M max was unchanged), and before (e) and after (f ) a total block of transmission in the CPN using lidocaine. Modified from Sinkjær et al. (2000) ((c)–(f )), with permission. Contribution of homonymous group II afferents to soleus activation Methodology Removal of the afferent feedback generated by the movement by suddenly unloading of the active mus- cle may be a valid approach to the contribution of this feedback to locomotion. To that end, Sinkjær et al. (2000) haveusedaportablestretchdevicecapable of suddenly rotating the ankle joint during walking. Suppression of the EMG activity by unloading During the stance phase of walking, the unload- ing of gastrocnemius-soleus produced by passive ankle plantar flexion decreases soleus EMG activ- ity on average ∼64 ms after the onset of the unloading (Fig. 7.10(c)). The extent of EMG sup- pression was generally similar, though sometimes delayed, after an ischaemic block of group I affer- ents (Fig. 7.10(d )), and it is therefore unlikely that an 316 Group II pathways unloading-related withdrawal of the group I dis- chargefromthegastrocnemius-soleus was themajor cause of the suppression. Reciprocal inhibition elicited by the stretch-induced Ia discharge from ankle dorsiflexors was also ruled out, because the amount of suppression was the same before and after complete block of the common peroneal nerve using local anaesthetic (Fig. 7.10(e), (f )). Withdrawal of groupII excitationfromgastrocnemius-soleuswas the favoured explanation for the EMG suppression. There are other data in favour of or consistent with a group II origin of the unloading response: (i) its onset latency is within the range of the medium- latency response to stretch seen during walking, and this has been demonstrated to be mediated by stretch-sensitive group II afferents (see below); (ii) contractionof the triceps surae during the stance phase of gait is weight-bearing and eccentric, cir- cumstances under which the co-activated g drive can powerfully excite muscle spindle endings and elicit a potent group II discharge (cf. Chapter 3, p. 135). Because of the convergence of Ia afferents ontointerneurones mediatinggroupII effects, Iadis- charges mayalsocontributetotheexcitationof these interneurones: this wouldexplainwhyblockadeof Ia afferents may delay the unloading response in some subjects. Conclusions Unloadingreduces byhalf theon-goingEMGactivity of soleus, largely due to withdrawal of group II exci- tation. This does not imply that the group II feed- back provides 50% of the excitatory drive to soleus motoneurones. The motoneurone discharge is pro- duced by spatial and temporal summation of com- bined peripheral and central inputs, and the abrupt removal of either could have a large effect. Contribution of group II afferents to an unexpected stretch-induced response Initial findings Dietz and colleagues first described group II- mediated responses in triceps surae during walk- ing on a treadmill (Berger, Dietz & Quintern, 1984; Dietz, Quintern & Sillem, 1987). Abrupt accelera- tion of the treadmill stretched triceps surae and produced a large medium-latency response in the gastrocnemius medialis at a latency (∼80 ms) con- sistent withgroupII mediation. Further evidence for the group II origin of this medium-latency response was provided by the finding that ischaemic block- ade of group I afferents did not modify the response (Fig. 7.11(c)). Interestingly, this large homonymous response in the triceps surae was accompanied by a small response in hamstrings, in keeping with the strong heteronymous group II projections from gastrocnemius medialis to semitendinosus motoneurones (seeTable7.3). Conversely, stretching the pretibial flexors by abrupt deceleration elicited a medium-latency response inthe ipsilateral andcon- tralateral tibialis anterior (Fig. 7.11(d )) and in the quadriceps. Here again, the pattern of the response corresponded to that of the heteronymous projec- tions of group II afferents from tibialis anterior: bilateral projections and activation of quadriceps motoneurones (see pp. 304–5). (The reasons for the absence of a monosynaptic Ia response [M1] in this experimental paradigm are discussed in Chapter 2, p. 89). Further evidence for group II excitation Further evidence for a group II origin of the stretch- induced responses in soleus has been provided by Grey et al. (2001). The same portable device used to unload the triceps surae was used to produce an unexpected dorsiflexion perturbation. Rapid stretch of the ankle extensors evokedbothanearly (M1) and a later (M2) response at latencies compatible with Ia and group II-mediated responses, respectively (Fig. 7.11(e), andits legend). There is strong evidence sug- gesting that M2 is mediated by group II pathways. (i) The medium-latency response was not velocity sensitive, contrary to the short-latency response, a finding consistent with the low dynamic sensitivity of muscle spindle secondary endings (cf. p. 289). (ii) Nervecoolingincreasedmorethelatencyof the M2 peak than that of the M1 peak (Fig. 7.11(e)). Fig. 7.11. Changes in group II excitation produced by passive stretch of ankle muscles during gait. (a) Sketch of the presumed pathways of homonymous group I–group II excitation through propriospinal neurones (PN) to soleus (Sol) motoneurones (MN). Group I–group II pathways to tibialis anterior (TA) MNs have been omitted. Ischaemic block and cooling of afferents in the posterior tibial nerve (PTN), and lidocaine block of cutaneous afferents from the foot are sketched. (b) Sketch of the experimental paradigm producing passive stretch of the plantar or dorsiflexors of the ankle during early stance phase of gait, due to either horizontal displacement of the body (horizontal arrows) or ankle rotation (vertical arrows). (c), (d ) A brisk acceleration, stretching the gastrocnemius medialis (GM, (c)), or deceleration, stretching the TA (d ), of the treadmill is triggered 80 ms after heel strike (first row, abscissa is time after heel contact). (c) The averaged rectified EMG of the GM is compared in the control situation (third row, conditioned EMG continuous line; unconditioned EMG, dotted line) and after 22 min of ischaemia (second row). (d ) Results in the ipsilateral (second row) and contralateral TA (third row, conditioned EMGcontinuous line; unconditioned EMG, dotted line). (e)–(h) Short-latency (M1) and medium-latency (M2) responses produced in averaged rectified Sol EMG activity, by unexpected ankle dorsiflexion: 8 ◦ , at a velocity of 263 ◦ s −1 , followed by a hold phase of ∼200 ms, onset (zero of the abscissa), triggered 200 ms after heel contact. Ankle angle position (0 ◦ standing position, negative values =dorsiflexion) is shown in (e) (lower trace). Mean latency of M1, 39 ms, and of the peaks for M1 and M2 55 and 78 ms, i.e. compatible with monosynaptic Ia and group II-mediated responses, respectively. EMG responses are compared in the control situation (thin line) and after (thick lines): (e) cooling of the nerve (dashed and dotted vertical lines highlight cooling-induced differences in latencies for the M1 and M2 responses, respectively); (f ) ischaemic blockade of group I afferents; (g) oral intake of tizanidine 150 g kg −1 ; (h) Lidocaine block of cutaneous afferents from the foot. Grey areas in (e)–(h) highlight the differences between the situations. Modified from Berger, Dietz & Quintern (1984) ((c), (d )), and Grey et al. (2001) with permission ((e)–(h)), with permission. 318 Group II pathways (iii) Ischaemic blockade of Ia afferents completely suppressed the Ia-mediated short-latency response, but had much less effect on the medium-latency response (Fig. 7.11(f )). (iv) Tizanidine suppressed M2, without affecting M1 (Fig. 7.11(g)). (v) Blocking cutaneous afferents with local anaes- thetic did not modify the amplitude of M2 (Fig 7.11(h)). Functional implications Stretch-induced responses insoleus (whether medi- atedby Iaor groupII afferents) appear particularly in theearlystancephaseof gait. Thissuggeststhat these responses contribute to the stabilisation of the sup- porting limb during walking rather than to propul- sion (see Chapter 11, p. 549). When the tibialis anterior is active during the swing phase of gait, medium-latency stretch-induced M2 responses are delayed and reduced with respect to tonic voluntary contraction, suggesting depres- sion of transmission in group II pathways. Dur- ing the stance phase, there was no evidence that vertical displacements of the ankle evoked M2 responses in the tibialis anterior (Christensen et al., 2001). This finding contrasts with the large responses produced by horizontal displacements due to brisk deceleration of the treadmill (see above), and the reasons for this discrepancy are discussed in Chapter 11 (p. 548). Changes in the peroneal-induced group II excitation of quadriceps motoneurones Methodology The averaged, rectified on-going EMG activity of quadriceps was conditioned by stimulation of the deep peroneal nerve (Marchand-Pauvert & Nielsen, 2002a). Results obtained during the early stance phase of walking, where there is a co-contraction of the quadriceps and tibialis anterior, were com- pared to those found during a tonic voluntary co- contraction of the two muscles when standing, at equivalent levels of EMG activity. Enhanced peroneal group II excitation of quadriceps During walking, deep peroneal stimulation pro- duced biphasic facilitation of the on-going EMG of quadriceps, with a large late peak following a weak early peak while, during voluntary contrac- tion, only the early facilitation was present (Fig. 7.12(b), (c)). Several arguments indicate that the late excitation was due to the activation of mus- cle group II afferents: (i) the mean latencies of the early and late excitations were 4 and 9 ms in excess of the expected time of arrival of the condition- ing Ia volley at motoneuronal level, much as the non-monosynaptic peroneal-induced group I and group II excitations of quadriceps motoneurones, respectively (see pp. 293–7); (ii) the threshold for the early peak was ∼1 MT, and that for the late excitation was > 1.3 MT, much as for peroneal- inducedexcitationof groupII afferents; and(iii) cool- ing the deep peroneal nerve delayed the latency of the late peak more than that of the early peak. How- ever, ischaemic blockade of group I afferents caused boththe early andlate peaks todisappear. This latter finding might argue against group II excitation, but it could also reflect the transmission of the group I and group II excitations through the same interneu- ronal pathway(seep. 306), andthat depolarisationof lumbar propriospinal neurones by the group I affer- ent volley was required for the group II excitation to manifest itself. Possible underlying mechanisms and functional implications The similar magnitude of the early groupI excitation in the two tasks suggests that the enhanced group II excitation during walking was not due to increased excitability of lumbar propriospinal neurones, but Motor tasks – physiological implications 319 85 10 25 30 35 40 50 Standing R e c t i f i e d cialis complications t h e lower back pain cialis r e f l e x d Miscellaneo cheap generic cialis free shipping 2. Compare a newly encountered drug with a prototype when possible. Relating the unknown to the known aids learning and retention of knowledge. 3. Try to understand how the drug acts in the body. This allows you to predict therapeutic effects and to predict, prevent, or minimize adverse effects by early detection and treatment. 5. Concentrate your study efforts on major characteristics. These include the main indications for use, common and potentially serious adverse effects, conditions in which the drug is contraindicated or must be used cautiously, and related nursing care needs. 6. Keep an authoritative, up-to-date drug reference readily available, preferably at work and home. This is a much more reliable source of drug information than memory, especially for dosage ranges. Use the reference freely whenever you encounter an unfamiliar drug or when a question arises about a familiar one. 7. Use your own words when taking notes or writing drug information cards. Also, write notes, answers to review questions, definitions of new terms, and trade names of drugs encountered in clinical practice settings directly into your pharmacology textbook. The mental processing required for these activities helps in both initial learning and later retention of knowledge. 8. Mentally rehearse applying drug knowledge in nursing care by asking yourself, "What if I have a client who is receiving this drug? What must I do to safely administer the drug? For what must I assess the client before giving the drug and for what must I observe the client after drug administration? What if my client is an elderly person or a child?" real cialis no prescription cialis and sperm count Expected responses to drugs are largely based on those occurring when a particular drug is given to healthy adult men (18 to 65 years of age) of average weight (150 lb [70 kg]). However, other groups of people (eg, women, children, older adults, different ethnic or racial groups, and clients with diseases or symptoms that the drugs are designed to treat) receive drugs and respond differently than healthy adult men. Therefore, current clinical trials are including more representatives of these groups. In any client, however, responses may be altered by both drug- and client-related variables, some of which are described in the following sections. cialis 100mg price Analgesic–Antipyretic–Anti-inflammatory and Related Drugs cialis generika nachnahme vision, dry mouth, constipation, urinary retention), and weight gain. They are well absorbed after oral administration, but first-pass metabolism by the liver results in blood level variations of 10- to 30-fold among people given identical doses. Once absorbed, these drugs are widely distributed in body tissues and metabolized by the liver to active and inactive metabolites. Because of adverse effects on the heart, especially in overdose, baseline and follow-up electrocardiograms (ECGs) are recommended for all clients. Amitriptyline (Elavil) is a commonly used TCA. Nortriptyline (Aventyl, Pamelor) Protriptyline (Vivactil) Trimipramine maleate (Surmontil) does cialis affect blood pressure Selective Serotonin Reuptake Inhibitors (SSRIs) Depression Citalopram (Celexa) cialis cure ed cialis aus indien bestellen 7. cialis stomach upset Manufacturer's recommendation new cialis rx index Answer: Prozac has a long half-life (24 to 72 hours), so it takes longer than a week to reach steady state. The dosage is usually not increased for 3 to 4 weeks. It is important to teach all clients beginning therapy with antidepressants that they may not see significant improvement in their depression for a number of weeks. Ms. Jordan's sleeping difficulty could be a symptom of her depression or a side effect of the Prozac. If it is a drug side effect, it might help to take the drug in the morning. Partial seizures, with other AEDs generic alternatives to cialis RATIONALE/EXPLANATION May occur with carbamazepine and oxcarbazepine, especially if taken concurrently with sodium-losing diuretics (eg, furosemide, hydrochlorothiazide). Usually transient and levels return to normal with fluid restriction or dose reduction. This reaction has occurred with several antiseizure drugs, most often with phenytoin. Life-threatening pancreatitis has occurred after short- and longterm therapy with valproic acid. Patients should be monitored for the development of acute abdominal pain, nausea, and vomiting. May occur with topiramate and zonisamide. Inadequate fluid intake or concurrent administration of triamterene may increase risk. cialis ajanta pharma General Intravenous Anesthetics Opioid analgesic–anesthetic related to fentanyl and Alfentanil (Alfenta) sufentanil. Rapid acting. A nonanalgesic hypnotic used for induction and Etomidate (Amidate) maintenance of general anesthesia buy cialis online in south africa like cialis i go hard Remifentanil (Ultiva) Sufentanil (Sufenta) Procaine (Novocain) buy cialis daily use online safe place buy cialis online 233 CHAPTER 15 SUBSTANCE ABUSE DISORDERS cialis langzeit and achieved a drug-free state for prolonged periods are apt to resume their drug-taking behavior when released from the institution. So far, voluntary self-help groups, such as Alcoholics Anonymous and Narcotics Anonymous, have been more successful than health professionals in dealing with drug abuse. Health professionals are more likely to be involved in acute situations, such as intoxication or overdose, withdrawal syndromes, or various medical-surgical conditions. As a general rule, treatment depends on the type, extent, and duration of drug-taking behavior and the particular situation for which treatment is needed. Some general management principles include the following: 1. Psychological rehabilitation efforts should be part of any treatment program for a drug-dependent person. Several approaches may be useful, including psychotherapy, voluntary groups, and other types of emotional support and counseling. 2. Drug therapy is limited in treating drug dependence for several reasons. First, specific antidotes are available only for benzodiazepines (flumazenil) and opioid narcotics (naloxone). Second, there is a high risk of substituting one abused drug for another. Third, there are significant drawbacks to giving CNS stimulants to reverse effects of CNS depressants, and vice versa. Fourth, there is often inadequate information about the types and amounts of drugs taken. 3. Despite these drawbacks, however, there are some clinical indications for drug therapy, including treatment of overdose or withdrawal syndromes. Even when drug therapy is indicated, there are few guidelines for optimal use. Doses, for example, must often be estimated initially and then titrated according to response. 4. General care of clients with drug overdose is primarily symptomatic and supportive. The aim of treatment is usually to support vital functions, such as respiration and circulation, until the drug is metabolized and eliminated from the body. For example, respiratory depression from an overdose of a CNS depressant drug may be treated by inserting an artificial airway and me- cialis upset stomach comprar cialis diario Central nervous system stimulants cause cardiac stimulation and thus are contraindicated in clients with cardiovascular disorders (eg, angina, dysrhythmias, hypertension) that are likely to be aggravated by the drugs. They also are contraindicated in clients with anxiety or agitation, glaucoma, or hyperthyroidism. They are usually contraindicated in clients with a history of drug abuse. the truth about cialis TABLE 17–1 cialis rxlist Hypotension/shock cialis commercial 2011 song of antiadrenergic drug therapy is to suppress pathologic stimulation, not the normal, physiologic response to activity, stress, and other stimuli. can you buy cialis online no prescription 288 • Deficient Knowledge: Drug administration and effects Planning/Goals cheap generic cialis uk online cialis emea PO 100–200 mg tid–qid. Reduce when symptoms improve. PO 5 mg bid or tid. Maximum dose 5 mg qid. Extended-release 5 mg PO qd up to 30 mg/d. PO 2 mg bid. May decrease to 1 mg when symptoms improve. Reduce doses to 1 mg PO bid in presence of hepatic impairment. 4 cialis sperm count daily cialis results THERAPEUTIC LIMITATIONS The client will: • Experience relief of symptoms without serious adverse effects • Take or receive the drug accurately • Comply with procedures for monitoring and follow-up naion cialis 347 cialis wirkungsweise Calcium and Phosphorus cialis alpha blockers cialis headphones commercial • Avoid preventable adverse effects of treatment for acute • cialis hepatitis CHAPTER 27 ANTIDIABETIC DRUGS cialis msds effets secondaires cialis 20 • Renal function should be assessed before starting metformin and at least annually during long-term therapy. The drug should not be given initially if renal impairment is present; it should be stopped if renal impairment occurs during treatment. • As with other antidiabetic drugs, clients taking metformin should continue their diet, exercise, and blood glucose testing regimens. • Parenteral radiographic contrast media containing iodine (eg, Cholografin, Hypaque) may cause renal failure, and they have been associated with lactic acidosis in clients receiving metformin. Metformin should be discontinued at least 48 hours before diagnostic tests are performed with these materials and should not be resumed for at least 48 hours after the tests are done and tests indicate renal function is normal. Glitazones cialis generico en farmacias similares these drugs should continue their diet, exercise, and blood glucose testing regimens. • Dosage is flexible, depending on food intake, but clients should eat within a few minutes after taking a dose, to avoid hypoglycemia. buy once a day cialis impairment. One important consideration with IV insulin therapy is that 30% or more of a dose may adsorb into containers of IV fluid or infusion sets. In addition, many critically ill clients are unable to take oral drugs. Overall, critically ill clients are at risk for serious hypoglycemia, especially if they are debilitated, sedated, or unable to recognize and communicate symptoms. Vigilant monitoring is essential for any client who has diabetes and a critical illness. cialis covered by medicare Norethindrone 1 mg Norgestimate 0.09 mg Tri-Norinyl instructions for using cialis How Can You Avoid This Medication Error? how long does cialis last 10mg cialis time peak effect Clinical indications, routes, and dosage ranges are listed in Drugs at a Glance: Androgens. cialis c'est quoi 438 health shop cialis TABLE 30–5 related to inadequate intake or impaired ability to digest nutrients Imbalanced Nutrition: More Than Body Requirements related to excessive intake Deficient Fluid Volume related to inadequate intake Excess Fluid Volume related to excessive intake Diarrhea related to enteral nutrition Feeding Self Care Deficit Disturbed Body Image related to excessive weight loss or weight gain Deficient Knowledge: Nutritional needs and weight management cialis components cialis schweiz rezeptfrei • • cialis healthy men GI tract. The injections must be continued for life. Vitamin B12 is also given to prevent pernicious anemia in clients who are strict vegetarians, who have had a gastrectomy, or who have chronic small bowel disease. Although folic acid relieves hematologic disorders of nombre generico de cialis Severity of manifestations depends largely on dose and duration of excess vitamin A intake. Very severe states produce additional clinical signs, including enlargement of liver and spleen, altered liver function, increased intracranial pressure, and other neurologic manifestations. Vitamin K rarely produces adverse reactions. Giving intravenous phytonadione slowly may prevent adverse reactions. Adverse reactions are generally rare. They are unlikely with B-complex multivitamin preparations. They are most likely to occur with large intravenous doses and rapid administration. Adverse reactions are rare with usual doses and methods of administration. cialis buying guide BUN, blood urea nitrogen; GI, gastrointestinal. (continued ) female cialis canada cialis and naion (5) Monilial vaginitis—rash in perineal area, itching, vaginal discharge c. Phlebitis at IV sites; pain at IM sites d. Nausea and vomiting e. Diarrhea SECTION 6 DRUGS USED TO TREAT INFECTIONS cialis la gi Fourth Generation Cefepime (Maxipime) cialis official site comprar cialis 10 Nursing Process recommendations on adjusting aminoglycoside doses for renal impairment. 4. In urinary tract infections, smaller doses can be used than in systemic infections because the aminoglycosides reach high concentrations in the urine. Single Daily Dosing The use of once-daily (or extended interval) aminoglycoside dosing is increasing. This dosing method uses high doses (eg, gentamicin, 7 mg/kg) to produce high initial drug concentrations, but a repeat dose is not administered until the serum concentration is quite low. Most clients can be successfully managed with one daily dose using this approach. However, certain populations require more than one daily dose, but still require fewer daily doses than are necessary in multiple dosing strategies (thus extended interval). This practice evolved from increased knowledge about the concentration-dependent bactericidal effects and postantibiotic effects of aminoglycosides. Concentration-dependent bactericidal effects mean that the drugs kill more microorganisms with a large dose and high peak serum concentrations. Postantibiotic effects mean that aminoglycosides continue killing microorganisms even with low serum concentrations. These characteristics allow administration of high doses to achieve high peak serum concentrations and optimal killing of microorganisms. The longer interval until the next dose allows the cheap cialis new zealand go hard like cialis You try to call Mr. Howles' physician with the abnormal laboratory results. The gentamicin peak level is normal but the trough level is high (4 mcg/mL rather than less than 2 mcg/mL) and both his blood urea nitrogen and creatinine are elevated. It is now time to give the next dose of gentamicin. You decide to give one half the ordered dose because his trough level was twice the normal value. how long does cialis 10mg last 536 difference between cialis and cialis professional NURSING ACTIONS b. With sulfonamides, observe for decreased symptoms of urinary tract infection (UTI), decreased diarrhea when given for ulcerative colitis or bacillary dysentery, lack of fever and wound drainage and evidence of healing in burn wounds. c. With urinary antiseptics, observe for decreased symptoms of UTI. 3. Observe for adverse effects a. Nausea, vomiting, diarrhea Use in Older Adults cialis bph dose best place to get generic cialis and linezolid are often used in critically ill clients because infections with resistant pathogens commonly occur in this population. cialis 5 mg no prescription 559 treatment cialis 48 hours buy cialis otc Routes and Dosage Ranges Generic/Trade Name Characteristics Adults Children non prescription cialis canada recurrence of viral infection. chapter 40 Antifungal Drugs cialis pill image environment and are either saprophytic (ie, obtain food from dead organic matter) or parasitic (ie, obtain nourishment from living organisms). Molds are multicellular organisms comprised of colonies of tangled strands. They form a fuzzy coating on various surfaces (eg, the mold that forms on spoiled food and the mildew that forms on clothing in damp environments). Yeasts are unicellular organisms. Some fungi, called dermatophytes, can grow only at the cooler temperatures of body surfaces. Other fungi, called dimorphic, can grow as molds outside the body and as yeasts in the warm temperatures of the body. As molds, these fungi produce spores that can persist indefinitely in the environment and be carried by the wind to distant locations. When these mold spores enter the body, most often by inhalation, they rapidly become yeasts that can invade body tissues. Dimorphic fungi include a number of human pathogens such as those that cause blastomycosis, histoplasmosis, and coccidioidomycosis. cialis 20 mg para que sirve 609 grapefruit cialis interaction Stromal cells of bone marrow generic cialis canada shipping cialis beer Memory cells Chapter 42. Many antigens that activate the immune response are microorganisms that cause infectious diseases. Early scientists observed that people who contracted certain diseases were thereafter protected despite repeated exposure to the disease. As knowledge evolved, it was discovered that protection stemmed from body substances called antibodies, and that antibodies could also be induced by deliberate, controlled exposure to the antigen. Subsequently, immunization techniques were developed. Although immunizations against some diseases have long been used, the development of immunizing agents and recommendations for their use continue. Some recommendations and changes of recent years are summarized as follows: • The American Academy of Pediatrics (www.aap.org) recommends that only the inactivated polio vaccine (IPV) be used in the United States. The oral vaccine cialis requiere receta medica 20 y and older: Engerix, IM, 20 mcg (1 mL) initially and 1 mo and 6 mo later (3 doses) Predialysis and dialysis clients, IM, 40 mcg (2 mL) initially and 1, 2, and 6 mo later (4 doses) Recombivax, IM, 10 mcg (1 mL) initially and 1 mo and 6 mo later (3 doses) Predialysis and dialysis clients, IM, 40 mcg (1 mL) initially and 1 mo and 6 mo later (3 doses) cialis 20 g Storage of Vaccines cialis 5g NURSING ACTIONS h. Have aqueous epinephrine 1:1000 readily available before administering any vaccine. k. After administration of an immunizing agent in a clinic or office setting, have the client stay in the area for at least 30 min. 2. Observe for therapeutic effects a. Absence of diseases for which immunized b. Decreased incidence and severity of symptoms when given to modify disease processes 3. Observe for adverse effects how long for cialis daily to work established. Filgrastim and sargramostim have been used in children with therapeutic and adverse effects similar to those in adults. In clinical trials, filgrastim produced a greater incidence of subclinical spleen enlargement in children than in adults, but whether this affects growth and development or has other long-term consequences is unknown. Oprelvekin has been given to a few children with adverse effects similar to those observed in adults. Reports indicate that tachycardia occurs more often in children and that larger doses are needed (eg, a dose of 75 to 100 mcg/kg in children produces similar plasma levels to a dose of 50 mcg/kg in adults). Long-term effects on growth and development are unknown. Little information is available about the use of interferons in children. Interferon alfacon-1 (Infergen) is not recommended for use in children. pharmacie en ligne france cialis ing complement, or targeting molecules on the cell surface that are necessary for growth or differentiation of that cell. Note that the generic names of monoclonal antibodies used as drugs end in mab and thus identify their origin. Polyclonal Antibody Lymphocyte Immune Globulin, Antithymocyte Globulin Lymphocyte immune globulin, antithymocyte globulin (LIG, ATG [or Atgam]) is a nonspecific antibody with activity against all blood cells, although it acts mainly against T lymphocytes. LIG, ATG is obtained from the serum of horses immunized with human thymus tissue or T lymphocytes. It contains antibodies that destroy lymphoid tissues and decrease the number of circulating T cells, thereby suppressing cellular and humoral immune responses. In addition to its high concentration of antibodies against T lymphocytes, the preparation contains low concentrations of antibodies against other blood cells. A skin test is recommended before administration to determine whether the client is allergic to horse serum. Because there is a high risk of anaphylactic reactions in recipients previously sensitized to horse serum, clients with positive skin tests should be desensitized before drug therapy is begun. LIG, ATG may be given for a few weeks to treat rejection reactions after solid organ transplantation, and it may be used to treat aplastic anemia. Monoclonal Antibodies Basiliximab (Simulect) and daclizumab (Zenapax) are similar drugs. They are humanized IgE (ie, a combination of human and murine antibodies). They are called IL-2 receptor antagonists because they bind to IL-2 receptors on the surface of activated lymphocytes. This action inhibits the ability of IL-2 to stimulate proliferation and cytokine production of lymphocytes, a critical component of the cellular immune response involved in allograft rejection. The drugs are used to prevent organ rejection in clients receiving renal transplants and are given in combination with cyclosporine and a corticosteroid. In clinical trials, adverse effects were consistent with those of transplant status, underlying disease, and concomitant immunosuppressive and other drug therapy. They were also similar to those reported with placebo (ie, basiliximab or daclizumab + cyclosporine and a corticosteroid vs. placebo + cyclosporine and a corticosteroid). Infliximab (Remicade) is a humanized IgG monoclonal antibody used to treat rheumatoid arthritis and Crohn's disease. It inhibits a cytokine, TNF-alpha, from binding to its receptors and thus neutralizes its actions. Biologic activities attributed to TNF-alpha include induction of other proinflammatory cytokines (eg, IL-1 and IL-6), increasing leukocyte migration into sites of injury or inflammation and stimulating neutrophil and eosinophil activity. Infliximab's ability to neutralize TNF-alpha accounts for its anti-inflammatory effects. (It does not neutralize TNF-beta, a related cytokine that uses the same receptors.) lyrica and cialis Nursing Notes: Apply Your Knowledge price of cialis in philippines 700 the weekend pill cialis Terbutaline (Brethine) cheap cialis online canadian pharmacy cialis legal uk Answer: Only short-acting beta-adrenergic bronchodilators should be used for acute dyspnea. Alupent, not Atrovent, is indicated. When patients have more than one inhaler, they should be taught which inhaler to use in emergency situations. The canister should be a different color (many manufacturers consider this) or clearly marked with tape, so that quick identification can occur in an emergency. Additional teaching may be indicated for the nurse and the patient regarding the action of each inhaler. cialis treatment for erectile dysfunction 1. Administer accurately a. Give most oral antihistamines with food; give loratadine on an empty stomach; give cetirizine with or without food. b. Give intramuscular antihistamines deeply into a large muscle mass. c. Inject intravenous (IV) antihistamines slowly, over a few minutes. d. When a drug is used to prevent motion sickness, give it 30–60 min before travel. 2. Observe for therapeutic effects a. A verbal statement of therapeutic effect (relief of symptoms) b. Decreased nausea and vomiting when given for antiemetic effects c. Decreased dizziness and nausea when taken for motion sickness d. Drowsiness or sleep when given for sedation 3. Observe for adverse effects a. First-generation drugs (1) Sedation Drowsiness due to central nervous system (CNS) depression is the most common adverse effect. (continued ) Therapeutic effects depend on the reason for use. To decrease gastrointestinal (GI) effects of the drugs To decrease tissue irritation Severe hypotension may result from rapid IV injection. Review and Application Exercises what does cialis do to you cialis 20mg erfahrung Causes of Heart Failure >10 y: Same as adult. 2–10 y: Digitalizing dose, PO 0.02–0.04 mg/kg in 4 divided doses over 24 h. Maintenance dose, PO, IV approximately 20–35% of the digitalizing dose or a maximum dose of 100–150 mcg/d 1 mo–2 y: Digitalizing dose, PO 0.035–0.06 mg/kg in 4 divided doses over 24 h; IV, 0.035–0.05 mg/kg in 4 divided doses over 24 h. Maintenance dose, PO, IV, approximately 20–35% of the digitalizing dose Newborns: Digitalizing dose, PO 0.025–0.035 mg/kg in 4 divided doses over 24 h. Maintenance dose, PO, IV, approximately 20–35% of the digitalizing dose. 1y and older: Same as adult. Infant: IV injection (loading dose), 3–4.5 mcg/kg, in divided doses. IV Infusion (maintenance dose), 10 mcg/kg/min Neonate: IV injection (loading dose), 3–4.5 mcg/kg, in divided doses. IV infusion (maintenance dose), 3–5 mcg/kg/min Not established cialis and alcohol mix Digoxin should be used cautiously, in reduced dosages, because renal impairment delays its excretion. Both loading and maintenance doses should be reduced. Clients with advanced renal impairment can achieve therapeutic serum concentrations with a dosage of 0.125 mg three to five times per week. In addition, in clients with reduced blood flow to the kidneys (eg, fluid volume depletion or acute HF), digoxin may be reabsorbed in renal tubules. As a result, less digoxin is excreted through the kidneys and maintenance doses may need even greater decreases than those calculated according to creatinine clearance. Thus, digoxin toxicity develops more often and lasts longer in renal impairment. Clients with renal impairment who are receiving digoxin, even in small doses, should be monitored closely for adverse effects, and serum digoxin levels should be monitored periodically. There is no information available about the use of inamrinone in renal impairment. However, pharmacokinetic data in- erectile dysfunction treatment cialis Quinidine (Cardioquin, Quinaglute) cialis hives Class I: Ordinary physical activity (eg, walking, climbing stairs) does not cause angina. Angina occurs with strenuous, rapid, or prolonged exertion at work or recreation. Class II: Slight limitation of ordinary activity. Angina occurs on walking or climbing stairs rapidly, walking uphill, walking or stair climbing after meals, or in cold, in wind, or under emotional stress. Walking more than two blocks on the level and climbing more than one flight of ordinary stairs at a normal pace and in normal conditions can elicit angina. Class III: Marked limitations of ordinary physical activity. Angina occurs on walking one or two blocks on the level and climbing one flight of stairs in normal conditions and at a normal pace. Class IV: Inability to carry on any physical activity without discomfort—anginal symptoms may be present at rest. cialis manufacturer in india Antianginal drugs have multiple cardiovascular effects and may be used alone or in combination with other cardiovascular drugs in clients with critical illness. They are probably used most often to manage severe angina, severe hypertension, or serious cardiac dysrhythmias. For example, IV nitroglycerin may be used for angina and hypertension; an IV beta blocker or calcium channel blocker may be used to improve cardiovascular function with angina, hypertension, or supraventricular tachydysrhythmias. With any of these drugs, dosage must be carefully titrated and clients must be closely monitored for hypotension and other drug effects. In addition, absorption of oral drugs or topical forms of nitroglycerin may be impaired in clients with extensive edema, heart failure, hypotension, or other conditions that impair blood flow to the gastrointestinal tract or skin. genuine cialis canada Carvedilol (Coreg) cialis in bangladesh D canadian pharmacy cialis daily Most clients with renal impairment require diuretics as part of their drug therapy regimens. In these clients, the diuretic taking cialis daily cialis enalapril SELECTED UPPER GASTROINTESTINAL DISORDERS Ranitidine (Zantac) buy cialis once a day what is cialis used to treat Safety and effectiveness not established for children <12 y cialis questions and answers Most antiemetic drugs cause drowsiness, especially in older adults, and therefore should be used cautiously. Efforts should be made to prevent nausea and vomiting when possible. Older adults are at risk of fluid volume depletion and electrolyte imbalances with vomiting. generic cialis alternatives NURSING ACTIONS (10) With ophthalmic nonsteroidal antiinflammatory drugs—potential for increased bleeding (11) With prostaglandin analogs—headache, cold/flu/upper respiratory infection, bronchitis, sinusitis, muscle and joint pain, chest pain 4. Observe for drug interactions a. Drugs that increase effects of antiglaucoma drugs: (1) Other antiglaucoma drugs b. Drugs that increase effects of adrenergic (sympathomimetic) ophthalmic drugs: (1) Anticholinergic ophthalmic drugs (2) Systemic adrenergic drugs c. Drugs that decrease effects of adrenergic ophthalmic preparations: (1) Cholinergic and anticholinesterase ophthalmic drugs d. Drugs that increase effects of antiadrenergic ophthalmic preparations: (1) Systemic antiadrenergics (eg, propranolol, atenolol, metoprolol, nadolol, timolol) e. Drugs that increase effects of anticholinergic ophthalmic drugs: (1) Adrenergic ophthalmic agents (2) Systemic anticholinergic drugs (eg, atropine) and other drugs with anticholinergic effects (eg, some antihistamines, antipsychotic agents, and tricyclic antidepressants) f. Drugs that decrease effects of cholinergic and anticholinesterase ophthalmic drugs: (1) Anticholinergics and drugs with anticholinergic effects (eg, atropine, antipsychotic agents, tricyclic antidepressants, some antihistamines) (2) Corticosteroids Abortion usually occurs within 24 h after a prostaglandin is given and approximately 5 d after mifepristone administration. The goal of drug therapy is to stop the labor process. cialis for bph dosage how long does cialis take to start working EXPERIMENTAL CASE STUDIES 1–4: Sensory Map Plasticity Using a mapping technique with an array of microelectrodes over the cortical surface of monkeys, Merzenich and colleagues conducted a series of experiments that demonstrate the mutability of somatosensory representations.388 Following the amputation of a digit in adult monkeys, the sensory representation of adjacent digits in cortical areas 3b and 1 enlarged topographically by approximately 1 mm to occupy the territory that had been filled by the sensory neurons associated with the lost digit.389 The change evolved over several weeks. Also, the details of the animal's touch maps improved in neighboring fingers. In another experiment, monkeys were rewarded for touching a rotating disk that had an uneven surface with the tip of a digit for approximately 1.5 hours a day.388 Compared to controls and to touching a static disk, reorganization of receptive fields in BA 3a and 3b evolved rapidly. The cortical representation of the stimulated phalanx enlarged immediately after stimulation and returned to the prestimulation size within 30 days. In other paradigms, stimulation of a small skin surface during a behavioral task leads to the emergence of a greatly expanded cortical zone of a coherent response that correlates with the improvement in the animal's ability to make relevant discriminations about the applied stimuli.91 A focal brain lesion model in the monkey is of special interest to rehabilitationists. A cortical lesion in area 3b was made where stimulation of one of the fingers had produced neuronal activation. The investigators induced the primate to use the same skin area of the hand in a reinforcing behavioral task by having it manipulate food pellets to eat. By the time the monkey was able to do so efficiently, the cortical region that represented the lesioned finger had shrunk, the map of surrounding finger areas enlarged, and a separate representation of the lesioned finger's skin arose in area 3a.390 The investigators suggested that behaviorally important stimulation at a constant skin location led to an increase in the synaptic effectiveness for the related thalamocortical inputs, which produced a larger thalamic receptive field. In addition, changes in synaptic effectiveness within the local intracortical somatosensory neural network seemed to account for some of the variations in representations they observed. Horizontal connections that link cortical neurons over 6 to 8 mm have been found in the visual system. Axons of primary sensorimotor cortex pyramidal cells have as many as five intracortical collateral axons that form synapses over distances of 6 mm.391 This increase in synaptic efficacy is equivalent to the neuroplasticity mechanism of unmasking synaptic connections after an injury. Subcortical representational maps are also mutable. Local anesthetic injected into dorsal column nuclei resulted in the emergence of a new receptive field for each affected neuron within minutes, which suggests that new fields arise from unmasking previously ineffective inputs.392 In another model of tactile learning, neurons of different cortical layers responded rapidly to changes in sensory experience within the whisker's receptive fields in rats.269 Unmasking of latent synapses appeared less important than strengthening specific synapses in the thalamus and cortex. These two mechanisms are related and account for much of the modulation of sensory representational plasticity in humans. cialis and flomax interactions TERMS FOR IMPROVEMENT AFTER INJURY Compensation Restitution and Substitution Impairment and Disability INTRINSIC BIOLOGIC ADAPTATIONS Spontaneous Gains Activity in Spared Pathways Sensorimotor Representational Plasticity Spasticity and the Upper Motor Neuron Syndrome Synaptogenesis Denervation Hypersensitivity Axon Regeneration and Sprouting Axon Conduction Growth Factors Neurogenesis POTENTIAL MANIPULATIONS FOR NEURAL REPAIR Activity-Dependent Changes at Synapses Stimulate Axonal Regeneration Deploy Neurotrophins Cell Replacement Pharmacologic Potentiation MUSCLE PLASTICITY Exercise Atrophy Regeneration Combined Approaches EXPERIMENTAL INTERVENTIONS FOR REPAIR OF SPINAL CORD INJURY Prevent Cell Death Increase Axonal Regeneration Remyelination Other Transplantation Strategies Retraining the Spinal Motor Pools 76 cialis for sale in the philippines how does cialis affect blood pressure Table 2–2.— continued cialis 20 mg contraindicaciones perhaps most important in this phase after onset of paresis and bedrest. For a muscle fiber to maintain or increase its usual size, it had to produce some minimum level of force for some minimum time each day. In rats whose hindlimbs were suspended so they bore no load, a modest isometric training program, amounting to 150 contractions per week, attenuated atrophy by 25% and decelerated the bias from slow to fast MHCs.188 Mechanical loading was better than electrical stimulation of muscle, perhaps because the protocol for stimulation did not allow the development of enough tension. HORMONES AND DRUGS Receptors for hormones are present on the muscle membrane and contribute to plasticity. Fiber features are altered by thyroid and growth hormones, testosterone, and other anabolic steroids,206 and beta-2 agonists.207 Each may stimulate muscle fiber growth or prevent disuse atrophy. For example, experimental animal models show that hypothyroidism can prevent the loss of slow MHC mRNA in the nonweight bearing soleus, whereas hyperthyroidism prevented the switch of fast MHC protein types.208 Growth hormone with exercise may have a synergistic effect on limiting muscle atrophy and increasing muscle mass and strength in the elderly subject,209 but can cause adverse side effects. Indeed, all hormone replacement strategies include some risk for medical complications (see Chapter 12). The beta-2 adrenergic agonists metaproterenol and clenbuterol have increased muscle mass and strength in patients with atrophy from a chronic SCI.210 Albuterol had modest effects in patients with a muscular dystrophy.211 These drugs probably exert an anabolic effect on protein structures in muscle,212 but may have to be combined with exercise. An observational study suggested that older, somewhat disabled women who took an angiotensin-converting enzyme (ACE) inhibitor for hypertension walked faster and had greater quadriceps strength than women who did not use these agents.212a The ACE inhibitors shift the MHC of skeletal muscle toward slow, aerobic, more fatigue-resistant isoforms and increase insulin sensitivity, among other factors. If shown to be valid in a clinical trial, the ACE inhibitors may lessen the decline of muscle loss in older persons and enhance recovery of buy cialis in calgary 162. 288. benign prostatic hyperplasia cialis cialis dose for bph TELETHERAPY 291 cialis temperature The Karnofsky Performance Status Scale was developed in the 1950s for oncology clinical trials and has been used occasionally in studies of patients with TBI or brain tumor. The scale ranges from normal without disease, to symptoms and signs of disease, to levels of required assistance, to death. The Rankin Scale (Table 7–20) has a special niche in stroke trials. The high interrater reliability of these 5step scales makes them especially useful for multicenter studies. For example, the National Institutes of Health trial of tissue plasminogen activator in acute stroke revealed that use of tPA within 3 hours of onset of stroke in selected patients led to a greater percentage of patients to have a Rankin score of 0 and 1 and an almost impairment-free NIHSS. In addition, the study suggested that a score of Ͼ17 on the NIHSS at 24 hours poststroke plus atrial fibrillation or a score Ͼ16 at 7–10 days predicts a Rankin score at 3 months of 4 or 5 or death.155 Impairment and disability were related especially at the extremes of no impairment and great impairment. The Karnofsky and Rankin Scales mix impairment, disability, and handicap. The measures are too insensitive to detect clinically important outcomes in individuals during their course of rehabilitation. The measures may be combined with the BI, but tend to correlate with BI scores in population studies and large interventional trials for acute stroke and TBI. cialis preise deutschland Describe protocol and deviations Provide summary data including means, standard deviations, and effect size State results in relative and absolute numbers, not just in percentages State estimated effect on each outcome measure, including confidence intervals Interpret findings in terms of internal validity and generalizability Put study into the context of all available evidence onde comprar cialis generico no brasil what happens if a woman takes cialis Oral sensory stimulation Thermal Vibration Resistance and placement exercises of tongue and jaw Chewing Oral manipulation of bolus Laryngeal adduction Biofeedback cialis no prescription fast delivery 248. 249. the nonneglect group, had a high response to rehabilitation, such that patients could walk independently on uneven ground and pick up an item from the floor while standing, even with the 40 hours of behavioral training. At discharge, 20% of the neglect group and 4% of the control (nonneglect) group were incontinent. Thus, the efficacy and efficiency of rehabilitation is significantly lower in the presence of hemispatial neglect in the 4 months following an acute stroke. An even more focused attempt at remediation for attention is needed. A therapy program starting 8 months after a stroke improved visuospatial attention, visuoconstruction, and ADLs, but not visual memory, using tasks related to ADLs, instead of only paper-and-pencil and reading activities.427 The patient had suffered a posterior cerebral artery occlusion and thalamo-occipital infarction, shown on the MRI scan in Figure 9–6. The patient ignored the left side of his meal and dangled his left arm in ways that could injure it. He made no attempt to search his left environs when walking, so he required hands-on assis- cialis order online india Complication Pressure ulcer Autonomic dysreflexia Abnormal renal tests Atelectasis/pneumonia Renal calculi Deep vein thrombosis Leg long bone fracture Pulmonary embolus Percentage 18 11 8 4 2 1 1 0.2 cialis australian price sta je cialis 84. 211. acquistare cialis in svizzera is it illegal to order cialis online to moderate TBI charges were approximately $57,000. Traumatic brain injury accounted for 19% of all hospital trauma discharges, but it contributed 26% to total charges. Based on a national study of estimated charges for all head-injured persons admitted to a hospital in 1 year,9 the average direct and indirect lifetime cost in 1991 dollars for survivors was $111,600, whereas those with fatal outcomes cost $454,700.10 The total national cost was $48.25 billion; $31.7 billion supported the survivors. Inpatient rehabilitation accounted for $1.15 billion, nursing home care for $350 million, home modifications for $62 million, and vocational rehabilitation for $4 million. By the year 2002, these costs likely increased by 30%. Other pathologic processes contribute to the effects of severe TBI. Systemic hypoxia and hypotension at onset of TBI add to the insult up to the point of causing cortical laminar necrosis or damaging especially vulnerable neuronal cialis daily effectiveness lloyds pharmacy cialis Traumatic Brain Injury how long does it take for cialis to start working Cognitive Impairments 29. cialis informazioni cialis generico online italia 218. 219. 220. 221. 222. cialis 5 mg diario precio Symptom Fatigue Imbalance Paresis Sensory Bladder Spasticity Bowel Memory Depression Pain Lability Visual Tremor Speech No Difficulty in ADLs (%) 21 24 18 39 25 23 19 21 18 15 24 14 14 12 Interferes With ADLs (%) 56 50 45 24 34 26 20 16 18 21 8 16 13 11 can i get a prescription for cialis online Results in stretch of cervix Stimulus anafranil cialis FIGURE There are many ways to view the human body. Each view gives a different perspective on how the makeup of the body and how the body works. It is similar to viewing a flower. We can look at a flower's colors, with its green calyces and colorful petals, or we can view it's shape (the shape of it's petals or how they are arranged) or we can consider the flower's smell. We can pull the flower apart and view the individual parts. To go further, we can put the flower under a magnifying glass and scrutinize the pollen. If we are really curious, we can take it to a laboratory and analyze the flower's chemical makeup. So many differ- cialis marketing case Cytoplasm canadian pharmacy discount cialis cialis commercial headphones Multiple Choice 1. A; 2. E; 3. E; 4. D; 5. B Completion 1. systems; organs; tissues; cells; chemicals 2. a. O; b. I; c. N 3. a. protons, neutrons; b. neutrons; c. covalent; d. hydrogen bond; e. 2:1; f. nitrogen; g. hypertrophy 4. a. posterior or lateral; b. proximal or superior; c. anterior; d. superficial 5. a. a and c; b. a and b; c. a; d. c; e. b; f. a 6. a. d; b. a; c. b; d. c 7. a. fluid connective tissue; b. supporting connective tissue; c. dense connective tissue; d. lymph True–False 1. 2. 3. 4. 5. 6. 7. 7. 8. 9. 10. true false, it is a phospholipid bilayer false, glucose is organic false, there are about 20 significant amino acids in the body false, it is a positive feedback mechanism true False, it is the receptors, effectors produce the effect true true false, it is 7.35–7.45 false, pH below 7.0 would be acidic cialis heart failure and identify the anatomic structure of skin affected by each of these skin lesions. In the condition jaundice, the skin has a yellowish tinge, resulting from the accumulation of bilirubin in body fluids. Bilirubin is a breakdown product of hemoglobin. Its levels increase above the normal range if there is rapid and abnormal breakdown of hemoglobin, liver dysfunction, or blockage of the bile duct (see page XX). is cialis legal in uk Nails protect the tips of the fingers and toes and limit the distortion when exposed to excess stress. Nails are formed at the nail root, an epithelial fold deeply located near the periosteum of the bone. The body of the nail is composed of dead cells that are packed with keratin. Nail growth can be altered by body metabolism. Changes in structure, thickness, and shape can indicate different systemic conditions. what is the right dosage of cialis This chapter on the integumentary system would not be complete without considering the invisible layer of microorganisms that inhabit the surface of the skin. This huge colony of organisms is the "normal microbial flora." Similar to residents and tourists in a city, there are resident microorganisms (resident flora) that are regularly found in a specific area at a specific age and transient flora that inhabit the skin for hours, days, or weeks. The resident flora play an important part in maintaining health and normal function. cialis daily tablet cialis stuffy nose Chapter 3—Skeletal System and Joints para que serve o medicamento cialis Pterygoid fovea Head Neck Posterior border of ramus Ramus cialis 5mg france Interosseous space Ischial tuberosity Ischiopubic ramus how good does cialis work Calcaneus daily cialis effectiveness generic cialis next day delivery uk Base JOINT CLASSIFICATIONS cialis for erectile dysfunction treatment The temporomandibular joint (see Figure 3.35) is affected by dysfunction and disease in more than 20% of the population at sometime in their life. It is a complex joint; its function is affected by multiple structures such as the bones of the skull; mandible; maxilla; hyoid; clavicle; sternum; the joint between the teeth and the alveolar cavities; muscle and soft tissue of the head and neck; and muscles of the cheeks, lips, and tongue. It is affected by the posture of the head and neck and cervical curvature. The joint is used almost continuously for chewing, swallowing, respiration, and speech. Imbalance relating to any of the associated structures can affect this joint. Conversely, problems relating to the joint can reflect as dysfunction of any of the associated structures. Hence, dysfunction of this joint is difficult to diagnose and manage. cialis propiedades JOINTS OF THE WRIST AND HAND my experience with cialis cialis coupon walgreens B cialis 2.5 mg reviews 3.44. Pelvic Joints and Ligaments. A, Anterior View; B, Posterior View View cialis 5mg daily price Range of Motion how to pronounce cialis cialis efectos en mujeres Lower end of femur cialis super active generico Muscles that flex the knee: Hamstrings: semimembranosus, semitendinosus, biceps femoris Muscle that extends the knee: Primary extensor Quadriceps Muscles that rotate the knee medially: Semitendinosus Semimembranosus Muscle that rotates the knee laterally: Biceps femoris Lateral malleolus cialis 50mg pills cialis 20 prospecto Short-Answer Questions 1. Describe the effects of aging on the joints. Case Studies 1. One problem that Kate faced every day was to gauge the amount of pressure that could be safely used when treating older clients. She had heard a rumor of one therapist breaking the ribs of an elderly client while trying to help the client off the table! She was not sure if that was true, but could it happen? She had heard of osteoporosis—a bone problem. But what really happens to the bones? Who is more prone to osteoporosis? Does calcium help in any way? A. How is bone formed? B. What is the structure of bone? C. What are the factors that affect the density of bone? D. How is calcium regulated in the body? E. What are the effects of aging on bone and joints? 2. Mr. Hamilton was a regular client. One week ago, he fell off a ladder trying to clean ice off his roof. He fractured the neck of the humerus and was now in a plaster cast. He was coming to the clinic later that day for his monthly, scheduled massage. A. Is it safe to massage over the limb? B. How long does the bone take to heal? C. How does it heal? D. What are the factors that affect the healing of bone? E. What is the "neck" of the humerus? F. What are the muscles related to the proximal part of the humerus? 3. Mrs. Dixon is an elderly lady who loves to be massaged. She was diagnosed with rheumatoid arthritis 5 years ago. When the therapist first met her, the joints of both hands were red and swollen, and Mrs. Dixon was in pain. Now, 5 years later, despite taking medicine, her hands are disfigured, and Mrs. Dixon has difficulty holding a cup, writing, and doing many other activities with her hands that one takes for granted. Her doctor had explained that the cartilage in her joints had been affected by the condition. A. Is cartilage different from bone? B. Does it heal the same way as bone? C. What is the structure of a synovial joint? 4. June was a 19-year-old girl who had been referred to the therapist by a friend. June had been suffering from temporomandibular joint syndrome for over 6 months and was willing to During surgery, muscles are made to relax by administering drugs (muscle relaxants) that block ACh receptors at the myoneural junction. These drugs are similar to curare, a plant poison originally used by native Indians on arrowheads. In certain cases of food poisoning, such as botulism, the toxin produced by the microorganism blocks the release of ACh at the myoneural junction, resulting in respiratory paralysis and death. Small quantities of toxin (Botox) are used in medicine to reduce muscle spasms. Botox is also used in cosmetic surgery to reduce wrinkles. Myasthenia gravis is a chronic autoimmune disease characterized by muscle weakness (especially in the face and throat), in which the immune system attacks muscle cells at the neuromuscular junction. Drugs that reduce the activity of cholinesterase (anticholinesterase agents) are used to prolong the effects of ACh in patients with this disease. Many pesticides work by affecting the myoneural junction. To prevent complications, proper precautions should be taken when handling these pesticides. cialis once a day buy cialis prices in pakistan cid ic a cialis erfaringer is repaid, the individual continues to breathe at a much faster rate and depth than normal. The tissue involved in oxygen consumption during the recovery period are the skeletal muscles that must restore ATP, glycogen, and creatine phosphate to former levels. The liver uses ATP to convert lactic acid to glucose. ATP is also used by sweat glands to increase sweat secretion to dissipate heat by evaporation and bring the body temperature back to normal. Skeletal muscle fibers are classified into three types, according to the speed at which they respond to stimulus. The three types are fast fibers, slow fibers, and intermediate fibers. Cell body of motor neuron Motor neuron axon does medicare pay for cialis cialis reimport Ventricular compliance Internal ventricular dimensions Venous return End diastolic volume Ejection fraction cialis generika aus eu Subclavius venta de cialis en argentina Erector Spinae and Spinal Movement cialis in toronto canada Sternum Aorta cialis belgique vente libre held in place by the numerous muscles that originate from the axial skeleton. Teres major where can i buy cialis in australia with paypal one a day cialis cost Radius A cialis benign prostatic hyperplasia how often can i take cialis 20mg 1. Kenney RA. Physiology of Aging: A Synopsis. 2 Ed. Chicago: Year Book Medical, 1989. 2. Chamberlain GJ. Cyriax's friction massage: A review. J Orthoped Sports Physic Ther 1982;4:16–22. 3. Clews W. Effects of massage in athletes with rotator cuff tendinitis. Excel 1988;4(4):12–15. 4. Goats GC. Massage and arthritis—modern applications of an ancient art. Arthritis Today 1992;2:3–4. 5. Hammer WI. The use of transverse friction massage in the management of chronic bursitis of the hip or shoulder. J Manipulative Physiol Ther 1993;16(2):107–111. 6. Peng J. 16 cases of scalenus syndrome treated by massage and acupoint-injection. J Trad Chin Med 1999;19(3):218–220. 7. Andrade CK, Clifford P. Outcome-Based Massage. Baltimore: Lippincott Williams & Wilkins, 2001. 8. Hemmings B, Smith M, Graydon J, Dyson R. Effects of massage on physiological restoration, perceived recovery, and repeated sports performance. Br J Sports Med 2000;34(2):109–115. 9. Hemmings BJ. Massage effects on regeneration, recovery and performance in sport: recent research and implications for the management of athletes. Physiother Sport 1999;22(2):7–11. 10. Newman S. Canadian athletes and massage. Coaching Rev 1986;May/June:16–20. 11. Newman S. Canada's case for sports massage. Coaching Review 1986;May/June:20–25. 12. Mein EA, Richards DG, McMillin DL, McPartland JM. Physiological regulation through manual therapy. Phys Med Rehabil: A State of the Art Review 2000;14(1):27–42. 13. Gulick DT, Kimura IF. Delayed onset muscle soreness: What is it and how do we treat it? J Sport Rehabil 1996;5:234–243. 14. Stoll ST, Simmons SL. Inpatient rehabilitation and manual medicine. Phys Med Rehabil: A State of the Art Review 2000;14(1):85–106. 15. Kinalski R. The comparison of the results of manual therapy versus physiotherapy methods used in treatment of patients with low back pain syndromes. J Manual Med 1989;4(2):44–46. 16. Hernandez-Reif M, Field T, Krasnegor J, Theakston H, Burman I. Chronic lower back pain is reduced and range of motion improved with massage therapy. Intern J Neurosci 2000; 99:1–15. 17. Ernst, E. Massage therapy for low back pain: A systematic review [In Process Citation]. J Pain Symptom Manage 1999;17:65–69. 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Nerves from here innervate muscles of the neck, shoulder, and the diaphragm (phrenic nerves C3–5). The sensory component of this plexus can be visualized in Figure 2.6, page ••, showing the dermatomal pattern. It supplies the skin of the ear, neck, and upper chest. Major Nerves of Brachial Plexus and Their Distribution cialis vs cialis for daily use cialis generico postepay Extensor digitorum brevis m. cialis when you don't need it 1 cialis generique 5mg Dorsal column 349 how to tell counterfeit cialis cialis 5 mg for sale Concussion cialis dosage for bph Signs and Symptoms of Basal Nuclei Lesions (Basal Ganglia) Babinski's Sign how to write a prescription for cialis pillole cialis generico Spinal Cord Lesions cialis 5mg generique 372 cialis fever To Ponder: took too much cialis Gigantism (see left of figure) and dwarfism (see right of figure); two men of normal stature appear in between. Reproduced with permission from Thibodeau. Anatomy and Physiology. 3rd Ed. Mosby, 1996; p. 16. Thibodeau GA & Patton KT. Mosby-Yearbook Inc. St. Louis, MO. Posterior pituitary is cialis daily effective cialis 300 mg Problems related to the thyroid may be a result of various causes. Problems with the feedback control of thyroid secretion can play a role. Thyroid abnormalities may develop as a result of hypothalamus malfunctioning (TRH secretion), pituitary secretion (TSH), or changes in the availability of iodine. Thyroid problems can be a result of autoimmune reactions. Antibodies may be formed against the thyroid and either hyperthyroidism or hypothyroidism may result. Hyperthyroidism In hyperthyroidism, if food intake is not increased as the metabolic rate is increased, the body's protein and fat stores are used up and the person loses weight. There is associated muscle weakness, partly the result of the breakdown of muscle protein. However, the muscles react more vigorously with increased hormones. Hyperthyroidism is associated with a fine muscle tremor caused by the increased sensitivity of the nerves that control muscle tone. As a result of the increase in metabolic rate, more heat is produced and there is a rise in body temperature. This triggers the body mechanisms that regulate heat. The blood vessels in the periphery dilate to dissipate heat, there is increased sweating, and the person becomes intolerant to heat—all typical signs of hyperthyroidism. There is also a rise in heart rate and cardiac output, partly as a result of its effect on increasing the sensitivity of the heart to adrenaline and noradrenaline. The effect on metabolism raises the vitamin requirements; vitamin deficiency is often associated with hyperthyroidism. Although thyroid hormones do not increase the metabolism of the uterus, they are required for normal functioning of the reproductive system. Menstrual irregularities are associated with thyroid abnormalities. Excessive thyroid hormones make the person irritable and restless. In short, the signs and symptoms of hyperthyroidism or thyrotoxicosis are that of overactivity of the sympathetic nervous system—anxiety, nervousness, rapid heart rate, sweating, tremor, and diarrhea. Sometimes the metabolic rate of the hyperthyroid individual accelerates out of control and the person has a rapid heart rate, high fever, and other symptoms of high metabolism. This situation is termed thyrotoxic crisis or thyroid storm and requires immediate medical intervention. Graves' Disease Graves' disease is a thyroid gland disorder in which excessive thyroid hormones are produced. Its cause is believed to be a result of autoimmunity. All hyperthyroidism symptoms, together with protrusion of the eyes (exophthalmos) (see Figure) are observed. Exophthalmos may be caused by swelling of the eye muscles within the bony orbit or inflammatory reactions caused by accumulation of immune complexes connective tissue and fluid behind the eye. 20mg cialis daily Terms cialis porto alegre 450 Because of inheritance, the amino acid sequence in some hemoglobin peptide chains may be different in some people. These small sequence differences can alter the affinity of hemoglobin to oxygen or alter its properties. For example, in sickle cell anemia, the hemoglobin becomes insoluble when the oxygen levels in blood drop. The red cells become sickle-shaped (like a quarter moon) when the hemoglobin becomes insoluble. The cells are recognized as abnormal by the spleen and hemolyzed (broken down), resulting in anemia. cialis nopirkt cialis 20 mg half Heart pronounce cialis The Massage Connection: Anatomy and Physiology grapefruit cialis side effect B. vendita cialis generico in italia 507 prezzo cialis 10 mg farmacia Endothelium of lymphatic capillary order cialis online india Memory cells FIGURE cialis too expensive cialis rezeptfrei schweiz The primary function of the respiratory system is to provide the required oxygen and remove carbon dioxide from the body. By the removal of carbon dioxide, this system helps maintain the pH of the blood at 7.4. Another important respiratory system function is to help with the production of sound (e.g., speaking, singing). The upper part of the respiratory system houses the sensory receptors for smell, which are stimulated by chemicals present in the air the body breaths. The respiratory system helps eliminate some water and heat as air is breathed in and out. The movement of the respiratory muscles and the resultant changes in volume and pressure inside the thoracic cavity help increase venous return and lymphatic drainage. In addition to these functions, certain cells in the respiratory system help activate angiotensin I, a hormone involved in regulating blood pressure and volume (see page ••). secretion. The olfactory nerves penetrate the tiny openings in the cribriform plate and carry the sense of smell to the brain. To get a better sense of a smell, we sniff forcefully to draw air in and reach the portion of the nasal cavity that houses the olfactory epithelium (also see page ••). what is the difference between cialis and cialis professional The resistance to air flow is largely determined by the caliber of the bronchi. By contracting and relaxing the smooth muscle of the bronchi (see page •• for factors affecting the bronchi caliber), the resistance to airflow can be modified. When the sympathetic nerves are stimulated, the muscle wall relaxes, increasing the diameter of the bronchi and reducing resistance. In conditions such as asthma or obstructive pulmonary disease, the airway resistance is increased, making it harder to breathe. Normally, the airways increase in width during inspiration and reduce during expiration. Presence of mucus and edema in the airways can also affect resistance. In cystic fibrosis, as a result of the presence of a defective gene that carries instructions for a transmembrane protein responsible for the active transport of chloride ions, the transport of salts and water is inefficient. Thick and viscous secretions result, with mucous plug formation, inflammation, predisposition to infection, and an increase in airway resistance. spiration is the diaphragm. The diaphragm is a domeshaped, skeletal muscle, projecting into the thoracic cavity. Its origin is along the walls of the thorax and insertion is into a centrally placed tendon. The diaphragm is innervated by the phrenic nerve that arises from cervical segments 3, 4, and 5. When the diaphragm contracts, the central tendon is pulled downward into the abdominal cavity, increasing the diameter of the thoracic cavity in the superior-inferior direction. The diaphragm is responsible for 75% of air movement into the lungs. The external intercostal muscles that originate in the upper rib, with insertion in the lower rib, with the fibers running anteriorly and inferiorly, help elevate the ribs. They are innervated by nerves arising from thoracic segments 1 to 12. The ribs articulate with the vertebrae and sternum in a way that the anteroposterior and transverse diameters are increased when they are lifted up by this muscle. The activity of the external intercostals is responsible for bringing approximately 25% of the volume of air into the lungs. In addition to the diaphragm and external intercostals, other accessory muscles assist inspiration, including the sternocleidomastoid, scalenes, serratus anterior, pectoralis minor, pectoralis major, and upper trapezius. The sternocleidomastoid muscles help elevate the sternum, and the scalene muscles elevate the opinioni su cialis 1. Salvo SG. Massage Therapy. Principles & Practice. Philadelphia: W.B. Saunders, 1999. 2. Wade JF. Respiratory Nursing Care. 2nd Ed. St. Louis: C.V. Mosby, 1977. 3. Hernandez-Reif M, Field T, Krasnegor J, Martinez E. Cystic fibrosis symptoms are reduced with massage therapy intervention. J Pediatr Psychol 1999:24,183–189. 4. Miller, Frank B. Encyclopedia Dictionary of Medicine, Nursing & Allied Health. 6 Ed. W.B. Saunders, 1997. 5. Lawless J. The Complete Illustrated Guide to Aromatherapy. Shaftesbury: Element Books, 1997. 6. Premkumar K. Pathology A to Z. A Handbook for Massage Therapists. 2nd Ed. Calgary: VanPub books, 1999. 7. Field T, Henteleff T, Hernandez-Reif M, et al. Children with asthma have improved pulmonary functions after massage therapy. J Pediatr 1998:132,854–858. cialis song 2011 first time cialis use Fill–In Complete the following: 1. Cathleen is breathing at the rate of 12/minute. Her tidal volume is 450 mL. Her minute ventilation is . If the dead space air is 150 mL, her alveolar ventilation per minute is . 2. The volume of air taken in with each inspiration during normal breathing is called 3. The volume of air remaining in the lungs at the end of forced expiration is called 4. The volume of air breathed out completely after maximal inspiration is called . 5. The amount of vital capacity that can be forced out in one second is known as . 6. Carbon dioxide is transported in the blood as , , and . 7. The main chemical changes in the blood that stimulate respiration are an increase in , an increase in and a decrease in levels. 8. The respiratory centers are located in the and the . 9. The volume of air present in the conducting part of the respiratory system is known as . . . The Tongue cheap cialis next day delivery buy cialis one a day Digestion: Enzymes, Regions Secreting the Enzymes, and Actions cialis prescription only Colon REFERENCES cialis side effects grapefruit co to jest cialis Bladder Urethra acheter cialis quebec FIGURE cialis shape Medulla best website for generic cialis FIGURE 12.4. The Structure of a Cortical Nephron and a Juxtamedullary Nephron Shown in Relation to the Cortex and Medulla Principles of dialysis Ending Dialysis Blood Dialysis who ships cialis to canada Pain originating in the abdominal organs is often referred to areas on the surface of the body, not necessarily over the anatomic location of the organ. Often, pain originating in the kidney is felt in the lumbar region (upper back) or radiating to the right or left upper quadrant of the abdomen. Bladder infections (cystitis) may present as pain just above the pubis or in the upper inner aspect of the thigh. The pain produced by cystitis and urethritis (inflammation of the urethra) may be abated by swabbing the urethral opening with a cotton pad soaked in a dilute solution (10–12 drops in 100 mL water, or 6.1 in3 water) of tea tree oil after urination.4 Note that essential oils are very concentrated and must be diluted before application. Addition of 8–10 drops of bactericidal oils (e.g., bergamot, lavender, chamomile, tea tree, sandalwood, juniper, frankincense, parsley seed, celery seed, thyme, and yarrow) to bath water can be used as a general disinfectant or as a preventive measure in such conditions. Oil made of 3–10 drops each of tea tree, sandalwood, bergamot (or lavender) in 25 mL (1.5 in3) of a carrier oil (such as sweet almond or grape seed) may be used to massage over the lower abdomen and back to provide relief from pain originating from the urinary tract. do you need a prescription for cialis in canada
Welcome to Soham On-Line Community Website, the official website for the town of Soham in Cambridgeshire. The small market town is situated in the extreme South-East of Cambridgeshire, adjoining the County of Suffolk and is only a few miles away from the cathedral city of Ely and the horseracing town of Newmarket.
Soham On-Line has been actively and successfully promoting the town of Soham in many areas such as heritage, tourism, leisure and business since November 1999. In June/July 2012, the website was completely overhauled and redesigned to help bring the site right up-to-date with regards to the latest in website design and technology. There are lots of new features including a calendar of events, integration with social networking sites such as Facebook, Google+, LinkedIn and Twitter, a full Soham directory of businesses, amenities, clubs and organisations including Google Map locations.
There has been evidence of a settlement existing in Soham since the Stone Age but the documented history goes back to the year 630 AD when St. Felix 'The Apostle of the East Angles' is said to have founded an Abbey here. St. Felix's Abbey pre-dates the building of Eltheldreda's Convent/Monastery at Ely by 43 years and was the first centre of Latin Christianity in the whole of Cambridgeshire.
For many centuries the route to Ely was by boat across Soham Mere and over the Fens until windmills were introduced to drain them. With the arrival of the steam pumping engines in the late 19th century, the Mere was finally drained completely and the reclaimed land used for farming.
The present day small town is the centre of a prosperous farming and urban community. It has all the modern services and amenities and a very active and progressive urban life. Although it stands in a low-lying countryside, devoid of the scenic contrasts of hills and valleys, its far horizons and vast sky-scape of ever changing patterns and tints endow this fenland with distinctive charm.