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References | PMC10439640 |
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Background: | Parkinson’s disease, PD | These authors contributed equally to this work.Axial symptoms of Parkinson’s disease (PD) can be debilitating and are often refractory to conventional therapies such as dopamine replacement therapy and deep brain stimulation (DBS) of the subthalamic nuclei (STN). | PMC10357146 |
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Objective: | Evaluate the efficacy of bilateral DBS of the pedunculopontine nucleus area (PPNa) and investigate structural and physiological correlates of clinical response. | PMC10357146 |
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Methods: | A randomized, double-blind, cross-over clinical trial was employed to evaluate the efficacy of bilateral PPNa-DBS on axial symptoms. Lead positions and neuronal activity were evaluated with respect to clinical response. Connectomic cortical activation profiles were generated based on the volumes of tissue activated. | PMC10357146 |
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Results: | PPNa-DBS modestly improved ( | PMC10357146 |
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Conclusion: | PD | Bilateral PPNa-DBS influenced gait symptoms in patients with PD. Anatomical and physiological information may aid in localization of a favorable stimulation target. | PMC10357146 |
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INTRODUCTION | Parkinson’s disease, gait disturbances, PD, axial motor symptoms | DISEASE PROGRESSION | Parkinson’s disease (PD) is generally well-managed by dopamine replacement therapy and/or deep brain stimulation (DBS) of the subthalamic nucleus (STN); however, axial motor symptoms can emerge with disease progression, including postural instability and gait disturbances. These features can result in falls and diminished quality of life, and are often refractory to both dopamine replacement therapy and DBS [ | PMC10357146 |
METHODS AND MATERIALS | PMC10357146 |
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Patients | Seven patients were treated with bilateral PPNa-DBS within a controlled clinical trial. Patient information is available in Patient information | PMC10357146 |
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Surgical procedures | Bilateral electrode implantations (3389 Model, Medtronic, MN, USA) were performed under local anesthesia after overnight withdrawal from anti-parkinsonian medication. The PPNa was targeted via direct localization using a proton-density MRI protocol at 1.5T [ | PMC10357146 |
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Therapy and stimulation parameters | The optimal stimulation parameters ( | PMC10357146 |
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Complications and side effects | ischemia, bleeding, transient motor aphasia | ISCHEMIA, BLEEDING, POSTOPERATIVE COMPLICATIONS | MRI images acquired postoperatively showed no abnormalities related to asymptomatic bleeding or ischemia. The following postoperative complications were documented: transient motor aphasia without a morphological MRI correlate and without indications for seizure-typical activity in EEG ( | PMC10357146 |
Study design | micro-lesions | A prospective, randomized, double-blind, cross-over study design was applied with two 2-month treatment periods subsequent to a 2-month postoperative period (see Randomized double-blind cross-over study design. The patients were brought in for baseline evaluations preoperatively. The operation was followed by a two-month familiarization phase with stimulation OFF, and to account for possible micro-lesions effects. At two months postoperatively, the patients visited for a postoperative evaluation, randomization of stimulation settings, and titration of the stimulation settings. At four months postoperatively, the patients visited again for the first treatment evaluation, cross-over, and stimulation titration. The second treatment evaluation, marking the end of the study, was performed at six months postoperatively. | PMC10357146 |
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Outcome measures | Parkinson’s Disease Questionnaire (PDQ-39). | SECONDARY, COMPLICATIONS, MOS | Per the registered study protocol, the primary outcome was the “Axial-Score” (UPDRS items 13–15; falling unrelated to freezing, freezing when walking, walking; and 27–31; arising from chair, posture, gait, postural stability, body bradykinesia) comparison between Stim-ON and Stim-OFF, in the medication-OFF condition. Axial-Score subscores were also assessed, including Gait-Score (items 13, 14, 15, 29) and Posture-Score (items 27, 28, 30, 31) as posthoc variables (outside of protocol). Secondary outcome measures included UPDRS-I (Mentation, Behavior, and Mood), II (Activities of Daily Living), and IV (Complications of Therapy) in the medication-OFF condition, and UPDRS-III (Motor Examination) in medication-OFF and medication-ON. Additional secondary outcomes included Schwab & England activities of daily living, Hoehn & Yahr Scale, Freezing of Gait Questionnaire (FOGQ), BDI, MMST, Medical Outcomes Study (MOS) Sleep-Scale, and Parkinson’s Disease Questionnaire (PDQ-39). The Axial-Score (medication-ON), Gait-Score (medication-ON), Posture-Score (medication-ON), UPDRS-II (medication-ON), and Gait and Falls Questionnaire (GFQ) scores were acquired and analyzed as additional variables. The study protocol that specified the applied assessments was submitted in 2009. Therefore, an old UPDRS version was applied in subsequent years to remain consistent throughout the study period. Notably, assessments that are conducted by means of a rater or patient self-report only (and not with objective gait analysis measures) may limit the generalizability of the results. | PMC10357146 |
Structural and functional connectomic profiles | In additional to structural imaging analyses in stereotactic space, DBS lead localizations were performed in Lead-DBS, as previously described in detail [ | PMC10357146 |
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RESULTS | PMC10357146 |
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Trial outcomes | SECONDARY | Complete results including primary and secondary outcome measures and additional findings are available in | PMC10357146 |
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Lead placements | Based on MRI analyses in stereotactic space, more anterior lead placements appeared to be favorable (A) Lead placement correlates, and B) single-unit recordings. A) MRI results suggest that more anterior lead placements were favorable. B) Single-unit recordings show two clusters of neurons (cluster-1 being faster and more regular versus cluster-2 being slower and less regular). Neurons resembling cluster-2 were more prominent in recording trajectories of patients with more anterior electrode placements (who had better therapeutic responses). | PMC10357146 |
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Microelectrode recordings | A correlation fit with a power function ( | PMC10357146 |
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Structural and functional connectomic profiles | PPNa-DBS leads were localized in Lead-DBS (Lead locations and groupwise structural and functional connectomic profiles. A, B) Reconstructions of all electrodes, C, D) fibers traversing the groupwise VTA, and E) structural and F) functional connectivity profiles. | PMC10357146 |
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DISCUSSION | Bilateral PPNa-DBS modestly influenced axial features (particularly gait) in the medication-OFF condition. Only two other randomized clinical studies evaluated the efficacy of bilateral PPN-DBS without concurrent STN-DBS [The results of an open-label study (Other double-blind studies which applied different stimulation approaches have also reported mixed outcomes. Stefani and colleagues [ | PMC10357146 |
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Lead placements | The finding that more anterior electrode placements were favorable seemed contradictory to that of Goetz and colleagues [ | PMC10357146 |
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Single-neuron activity | Assessment of neuronal activity along surgical trajectories suggested that it may be more favorable to target a slower (22.5±6.37 Hz), less regular neuronal population. This observation is in line with a recent report on two cases where similar discharge rates have been detected (19.1±15.1 Hz) [ | PMC10357146 |
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Structural and functional connectomic profiles | multiple basal ganglia and limbic areas | CORTEX | The PPN has connections with the cerebral cortex, multiple basal ganglia and limbic areas, the thalamus, other brainstem regions, the spinal cord, and the cerebellum. These connections implicate the PPN in a variety of functions including movement, cognition, and sleep. With respect to cortical connectivity, dense projections exist between upper extremity regions of the motor cortex, followed by the lower extremity, trunk, and orofacial regions [In adult cats, skilled locomotor performance was disrupted by lesions to motor cortical areas, including M1, S1, and parietal cortices [ | PMC10357146 |
Limitations | PD | The medication-OFF Axial-Score and Gait-Score improvements of 7.7% and 16.3%, respectively, were modest; thus, the results should be interpreted with caution. However, a recent study demonstrated that axial symptom score worsening (the only predictor of mortality in patients with PD) was 27% over the course of 10 years [ | PMC10357146 |
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Conclusions | Bilateral PPNa-DBS modestly influenced axial symptoms, particularly with respect to gait, in the medication-OFF condition. Electrode placements near the 50% mark of the PMJ line, where slow irregular neurons were encountered along surgical trajectories, yielded better therapeutic responses. | PMC10357146 |
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Supplementary Material | PMC10357146 |
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Supplementary Material | Click here for additional data file. | PMC10357146 |
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ACKNOWLEDGMENTS | The authors thank the patients for participating in this study and Dr. Ramin Azodi-Avval for his contribution to an earlier version of | PMC10357146 |
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SUPPLEMENTARY MATERIAL | The supplementary material is available in the electronic version of this article: | PMC10357146 |
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CONFLICT OF INTEREST | D.W. | FOX | S.B. has ownership interest in Neurostar GmbH (not related to this work). A.G. was supported by research grants (not related to this work) from Medtronic, Boston Scientific, Abbott, the Baden-Wuerttemberg Foundation, and the German Federal Ministry of Education and Research. D.W. has received research support from the German Research Council and the Michael J. Fox Foundation (not related to this work). L.M. has received honoraria from Medtronic (nor related to this work). G.N., I.C. have no conflicts of interest to report. | PMC10357146 |
DATA AVAILABILITY | The data will be available upon request, as the ethics approval does not allow uploading the datasets to a publicly available repository. | PMC10357146 |
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REFERENCES | PMC10357146 |
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Background: | Alzheimer’s disease, AD, cognitive impairment | DISEASE PROGRESSION, DISEASE | Alzheimer’s disease (AD) is a chronic condition marked by progressive objective cognitive impairment (OCI). No monotherapy has substantially altered disease progression, suggesting the disease is multifactorial and may require a multimodal therapeutic approach. | PMC10473097 |
Objective: | infection, cognitive decline | INFECTION | We sought to determine if cognitive function in a sample with OCI would change in response to a multimodal, individualized care plan based on potential contributors to cognitive decline (e.g., nutritional status, infection, etc.). | PMC10473097 |
Methods: | Participants ( | PMC10473097 |
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Results: | At 6 months, mean MoCA scores improved from 19.6±3.1 to 21.7±6.2 ( | PMC10473097 |
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Conclusion: | Multiple measures of cognitive function improved after six months of intervention. Our results support the feasibility and impact of a multimodal, individualized treatment approach to OCI, warranting further research. | PMC10473097 |
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INTRODUCTION | cognitive impairment, MCI, Alzheimer’s disease, debilitating disorder, cognitive decline, AD | Alzheimer’s disease (AD) is a debilitating disorder that affects approximately 6 million people in the United States and 50 million people worldwide [Mild cognitive impairment (MCI), a formal diagnosis that includes measures of both objective cognitive impairment (OCI) and subjective cognitive decline, is a known predictor for developing AD [The goals of the research presented here were to explore a multimodal, individualized medicine approach to OCI, extending participation to those with AD. The primary aims of the pragmatic interventional trial presented here were to: describe a model of multimodal, individualized medicine approach for the treatment of OCI; and, to collect preliminary data on before and after changes in validated cognitive function instruments. | PMC10473097 |
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METHODS | PMC10473097 |
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Design | infection, cognitive decline, traumatic brain injury | INFECTION, RECRUITMENT, SLEEP APNEA | A protocol-driven, uncontrolled, pragmatic trial was used in order to test feasibility and estimate effects in a real-world clinical setting. This research was approved by the Institutional Review Board (IRB) at the National University of Natural Medicine and was registered on ClinicalTrials.gov as NCT04284449. Participants attended a minimum of four clinical visits with additional clinical visits as needed. Recruitment began in February 2020, but was paused due to the SARS-CoV-2 pandemic and nation-wide quarantine measures. Recruitment resumed in August 2020 and concluded in March of 2022.Following a baseline assessment, a multimodal, individualized care plan was created, driven by the identification of contributors to cognitive decline (e.g., nutritional status, infection, toxicant burden, vascular health, sleep apnea, traumatic brain injury, etc.). Data collection took place at four study visits (baseline, one month, three months, and six months), and at the 12-month follow-up visit. The six-month study visit was specified a priori as the primary endpoint. Study participants received weekly phone calls for nutrition support from health coaches and/or clinical research staff throughout the six months of study participation and active data collection. Care plans were modified throughout study involvement based on individual participant response (i.e., the treating clinician took into account challenges to adherence, feasibility, etc., to tailor the care plan).Participants were allowed to have a Health Care Proxy with them at study visits, if they chose to, and having a proxy was a requirement for participants with a Montreal Cognitive Assessment (MoCA) score from 12–16 (indicating moderate impairment) upon screening [ | PMC10473097 |
Participants and inclusion/exclusion criteria | deafness, cognitive impairment, neurological impairment, MCI, visual impairment, somatic disease, dementia, word of mouth, cognitive decline, substance abuse, congenital cognitive impairment or disability | RECRUITMENT | Recruitment was conducted regionally via flyers, social media, email, physician referral, and word of mouth. Inclusion criteria included the following: age≥45 years; cognitive impairment, as demonstrated by a Montreal Cognitive Assessment (MoCA) of 12–23; ability to independently make decisions or have a legal Health Care Proxy; ability to safely travel to clinical site for Informed Consent and Formal Eligibility screening, Baseline study visit, then once per month for a duration of six months, and a twelve-month follow-up visit (nine trips to clinical site); ability to wear a wrist-worn activity tracker and keep it regularly charged; a high school diploma or equivalent; ability to communicate via email; ability to independently fill out a computer-administered questionnaire; willingness to adhere to a treatment plan, to complete computer based tests, to undergo brain wave testing by electroencephalogram, and to undergo a finger prick for a blood test at each study visit; and approved to be eligible for study participation at the discretion of the Clinical Investigator, after review of the Formal Eligibility Screen results.Exclusion criteria included the following: MoCA score > 23 or < 12; inability to read and write in English; a visual impairment that would prevent reading a computer screen; full deafness; congenital cognitive impairment or disability; alcohol or substance abuse; serious somatic disease, acute onset of cognitive decline, or rapid neurological impairment; inability to bring an affiliate to the informed consent consultation; current use of narcotics and/or marijuana, or use during the study period; and previous or ongoing treatment for MCI or dementia with the protocol used here or a very similar approach. Medications and supplements prescribed and taken outside of the study were tracked for the duration of study participation. | PMC10473097 |
Clinical visit content | A 90-min clinical initial intake visit was conducted for each participant, with subsequent visits lasting from 45–75 min. Clinical visits were usually conducted on the same day as study visits, though participants had the flexibility to schedule clinical visits on days separate from study visits. The baseline clinical visit included a thorough medical intake, including a complete review of systems, and review of medications, supplements, lifestyle, diet, and exercise; and a discussion of the foundational treatment plan that all participants received, including supplements, diet, and lifestyle counseling. The second clinical visit took place one month after baseline and consisted of a review of laboratory results, a clinical evaluation of the participant’s response to the initial treatment plan, and a discussion of the individualized portion of the treatment plan (based on laboratory results), given at the end of the visit. The remaining clinical visits (at months three and six) were similar to the second visit, with changes to the treatment plan made according to patient need and/or response to treatment. Participants were given the chance to ask questions and discuss concerns at each clinical visit. | PMC10473097 |
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Laboratory evaluation | blood sugar dysregulation | CHRONIC INFECTION, INFLAMMATION, CARDIOVASCULAR DISEASE | To support diagnosis and the development of an individual treatment plan, extensive analysis of blood, urine, hair, and stool samples were performed through commercial clinical laboratory services. These included biomarkers of environmental toxicant exposure, blood sugar dysregulation, gastrointestinal health, nutrient status, cardiovascular disease, systemic inflammation, chronic infection, and hormone dysregulation (see list in | PMC10473097 |
Intervention | PMC10473097 |
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Individualized treatment | cognitive decline | The intervention consisted of a multimodal, individualized medicine treatment plan (i.e., an approach characteristic of the integrative medical care model), as would happen in a real-world setting. Participants were treated for six months with a treatment plan based on individualized evaluations for the presence or absence of probable contributors to OCI (see Demographics of study participantsIdentifying and addressing potential contributors to cognitive decline with a multimodal, individualized medicine therapeutic approach is supportive of cognitive health. Shown in the figure are the baseline strategies and treatment plans for reversal of OCI and optimizing brain health, prior to testing and individualized treatment. | PMC10473097 |
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Lifestyle treatments | Participants were encouraged to increase exercise and adopt novel exercise routines with the goal of getting regular aerobic and strength training exercise. Exercise recommendations were given after assessment of risk, accessibility, and possible maximal impact to the participant. Depending on participant activity level at baseline, these recommendations varied (e.g., if a participant was already doing strength training, aerobic exercise was added, etc.). If participants were doing no exercise at the time of study enrollment, then a recommendation to walk each day was recommended as a starting point (the timing component dependent upon the above-mentioned assessments). The foci of exercise recommendations were novelty to the participant and increases in movement. Self-reported exercise diaries were collected monthly.Participants were encouraged to increase social interaction with peers, including in church groups and/or through hobbies and activities, with COVID-19 risk mitigation in mind. All participants were encouraged to engage in mindfulness practices, including daily meditation or prayer depending on participant preference. Twelve minutes daily of Kirtan Kriya meditation was recommended to all participants [ | PMC10473097 |
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Dietary treatments | To optimize metabolism, a ketogenic diet was encouraged for all participants [All participants received a commercially available nootropic blend including herbs and nutrients, omega-3 s, and vitamin D (see | PMC10473097 |
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Environmental exposures treatments | low mercury seafood | Strategies to mitigate environmental exposures included: avoidance (e.g., low mercury seafood, mold avoidance or remediation, changes in cleaning or personal care products), support for hepatic detoxification (e.g., herbs, supplemental nutrients, glutathione), binding agents (e.g., cholestyramine, chlorella, charcoal, zeolite, clay), chelating agents (e.g., EDTA, thiol-functionalized silica), sauna, and lymphatic mobilization (e.g., vibration, massage, movement). Choice of therapies was driven by lab values plus participant access, ability, and tolerance. | PMC10473097 |
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Gastrointestinal health treatments | When indicated, improvement in digestion and assimilation of macro- and micronutrients was encouraged through the use of digestive enzymes, probiotics, herb-based and supplemental anti-inflammatories (curcumin, pro-resolvins), gut healing nutrients (e.g., aloe, deglycyrrhizinated licorice, glutamine), gut immune support (colostrum, vitamin A, vitamin D, probiotics), pharmaceutical and/or herbal antimicrobials (e.g., nitazoxanide, oregano oil, etc.), as indicated by symptoms and comprehensive stool analysis. | PMC10473097 |
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Systemic inflammation treatments | inflammation, infections | INFLAMMATION, INFECTIONS | Systemic inflammation was treated by reducing causes of inflammation, including toxin reduction, treatment of infections, dietary changes, exercise, omega-3 s, and additional dietary supplementation (e.g., curcumin, glutathione, B-vitamins, vitamin C, alpha-lipoic acid). | PMC10473097 |
Sleep treatments | SLEEP APNEA | Sleep hygiene was supported and tracked using a Garmin Vivo Smart 4 to measure hours and quality of sleep per night, plus oxygen saturation. All participants with O2 saturation levels falling below 85% during sleep were referred to sleep medicine for further evaluation and treatment of potential sleep apnea. Supplements to support sleep (e.g., melatonin, theanine, magnesium threonate, inositol, progesterone) were provided based on individual need and response. | PMC10473097 |
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Traumatic brain injury (TBI) treatments | stroke, traumatic brain injuries | STROKE | Those with a history of traumatic brain injuries or stroke were provided oral supplemental phosphatidylcholine, phosphatidylserine, omega-3’s, methyl-B12, and intravenous nicotinamide adenine dinucleotide (i.e., NAD+). | PMC10473097 |
Hormone treatments | Bio-identical hormone replacement and/or herbal hormonal support was initiated for participants with laboratory confirmed reduction in hormone levels [ | PMC10473097 |
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Chronic infection treatments | P., cognitive decline, Herpetic, tick-borne infections | CHRONIC INFECTIONS, POSITIVE | Participants with recurrent or chronic infections associated with cognitive decline were treated. Herpetic outbreaks were prevented with lysine supplementation and Valacyclovir or Acyclovir, to be used at the first sign of prodrome. Positive tick-borne infections were treated with herbal antimicrobials (e.g., berberines, oregano oil, garlic, grapeseed extract, black walnut, etc.) and immune support. Participants with evidence of P. gingivalis were referred to a dentist for deep cleaning and received coaching on oral hygiene. | PMC10473097 |
Outcome measures | The primary outcome of the study was changes in cognitive scores. Feasibility was qualitatively assessed. Study visits at baseline, month one, month 3, month 6, and month 12 included the following assessments, conducted by clinical research staff: | PMC10473097 |
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Cognitive function testing (primary outcome) | cognitive domains— | BRAIN | The Cambridge Brain Sciences (CBS) assessments were used as the primary measure of cognition throughout the study. The CBS cognitive battery is a validated suite of 12 individual assessments designed to measure function in four cognitive domains— Memory, Reasoning, Verbal Ability, and Concentration. Each domain is assessed with multiple tasks that the participant completes on a computer, with a composite score for the domain calculated from the individual tasks [ | PMC10473097 |
Montreal Cognitive Assessment (MoCA) | The MoCA is a brief, single page, valid and reliable 30-point screening test widely used clinically to assess and screen cognitive status [ | PMC10473097 |
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Adverse events | ADVERSE EVENTS, ADVERSE EVENT, ADVERSE EVENT, ADVERSE EVENT | Adverse events were collected via a standardized adverse events questionnaire at each study and clinical visit, and participants were encouraged to contact study staff between study visits if adverse events occurred. These were tracked in an Adverse Events Log, and any unanticipated and/or severe adverse events were reported to the Institutional Review Board (IRB) at the time of the adverse event. All adverse events were reported to the IRB annually as part of the continuing review process. | PMC10473097 |
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Statistical analysis | In this uncontrolled study, before and after differences between baseline and endpoint values were calculated. The six-month endpoint was the primary endpoint of the study. An alpha threshold of Standardized individual scores from each CBS test (12 individual tests total) were transformed into four domain scores (Concentration, Memory, Reasoning, and Verbal Ability, where each domain represents the composite score of several domain-specific tests from the battery of 12), as well as a single, overall/composite cognition score. These scores were then compared between baseline and the primary endpoint (month six) using paired We then compared our baseline CBS values to the normative means calculated from the CBS data repository (consisting of test results from eight million tests completed globally by more than 75,000 cognitively healthy adults), represented as percentiles [ | PMC10473097 |
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DISCUSSION | Alzheimer’s disease, cognitive decline, dementia, cognitive impairment | As a proof-of-concept trial aimed at implementing a complex, multimodal, individualized medicine care plan in a sample of people with cognitive decline, the intervention demonstrated success in feasibility, thus supporting a larger, controlled, multi-site clinical trial. Additionally, results reported here corroborate the current literature, thus providing rationale for progress in the field of multimodal, individualized medicine in the treatment of cognitive decline. For example, recently published research from Toups et al reported improvements in cognition in 25 participants with cognitive decline who underwent a similar individualized medicine-based intervention for nine months [The improvements in MoCA were reinforced by the use of objective measures of cognition via the CBS Battery, administered online and independent of the study clinicians. The CBS battery of neurocognitive tests demonstrated significant improvements in overall cognition, as well as significant improvements in memory. Overall cognition in our population at baseline was at the 24th percentile compared to age- and gender-matched scores from a large CBS data set of healthy individuals (i.e., We recruited a participant population relatively reflective of those affected by dementia in the normal population. The gender distribution of participants included 74% women, reflective of dementia statistics, which show that 65% of dementia sufferers are female. Four of seventeen women included were women of color, including three African American and one Asian American. Five male participants were Caucasian and one was Hispanic.Despite the overall significance of the clinical findings reported here, we acknowledge there are several limitations. First, our sample size was small, and the research design was uncontrolled, non-randomized, and limited to a single clinical site. Yet the results demonstrate feasibility and proof-of-concept of medium effect sizes, which warrant further research. Future studies will be strengthened by randomization, adding a control group, and including multiple study sites. Secondly, this research did not assess the impact of the intervention on participants with advanced AD. Trial participants with MoCA scores below 12 were excluded from participation. Third, the research was done within a clinical care setting. Although we consider this feature to be pragmatic, and potentially a strength, we recognize this feature does not prove generalizability and therefore needs to be considered a limitation. Finally, the 32% (11/34) withdrawal rate is high; however, it is lower than the 36% withdrawal rate found in the study of Swanson et al, which assessed lecanemab-treated participants [We would like to acknowledge the care model used as the intervention for our study may present significant financial costs for individuals, and the time burden for adherence is high. Additionally, this kind of individualized, integrative care approach requires advanced and specialized training of the clinicians administering the care. Thus, we acknowledge that questions remain as to the accessibility of this intervention on a broad scale. Even so, this study presents a proof-of-concept for a model of care in patients with cognitive impairment. Future research will model whether or not this type of care is effective, scalable, and further generalizable. As further research will inform target-optimizing the approach, including improvements in access, the potential benefits will become more accessible to more of the population affected by cognitive decline.Results reported herein have the potential to advance the field by demonstrating a clinically delivered multimodal, individualized medicine intervention that has the potential to stabilize, if not improve, the cognitive function of patients with cognitive impairment. The trial provides additional data that begins to address gaps in the literature regarding therapeutic options for cognitive decline. Namely, that a multimodal, individualized medicine therapeutic approach is feasible clinically in a cognitively declined population, and that such an approach has the potential to reverse domains of cognitive decline and overall cognition. Given the progressive nature of cognitive decline and dementia, our results also indicate the need for longer intervention and follow-up periods within a randomized trial, in order to determine the possible maximum effects (i.e., how much reversal is possible in cognitive decline with this therapeutic approach?), and how long those effects may be expected to last. This research is part of a broadening body of work that is beginning to reveal the possible positive impact of multimodal, individualized medicine. Given the context of decades of failed efforts to develop effective therapeutics for Alzheimer’s disease and cognitive decline, the findings provide an exciting and hopeful direction for research, medicine, and most importantly, patients. | PMC10473097 |
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Supplementary Material | PMC10473097 |
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Supplementary Table 1 | Click here for additional data file. | PMC10473097 |
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Supplementary Table 2 | Click here for additional data file. | PMC10473097 |
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Supplementary Table 3 | Click here for additional data file. | PMC10473097 |
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Supplementary Table 4 | Click here for additional data file. | PMC10473097 |
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ACKNOWLEDGMENTS | We are grateful to Nova Biomedical Corp, Quicksilver Scientific, Diagnostic Solutions Laboratory, DHA Labs, Xymogen, ReadiSorb, Pure Encapsulations, Douglas Labs, and Neurohacker Collective and Integrative Therapeutics for discounts and donations of labs and supplements. | PMC10473097 |
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SUPPLEMENTARY MATERIAL | The supplementary material is available in the electronic version of this article: | PMC10473097 |
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FUNDING | Funding was provided by an anonymous philanthropic donor.Mentorship on this research was supported by grant # K24AT011568 from the National Center for Complementary and Integrative Health of the National Institutes of Health. | PMC10473097 |
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CONFLICT OF INTEREST | This manuscript is not under consideration by another journal, nor has it been published. Dr. Heather Sandison is the owner of a medical clinic and senior living facility. All the other authors have no conflict of interest to report. | PMC10473097 |
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DATA AVAILABILITY | All data generated by our experiments will be shared in the form of publications, abstracts, and presentations. In the case of complex datasets, they will be available as supplementary data in publications or upon request by academic researchers. Where possible, primary data will be securely held for a period of ten years in electronic format in community resources (databases) after completion of the research project. We will ensure that we retain a local copy of any data submitted to third party resources. | PMC10473097 |
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REFERENCES | PMC10473097 |
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Background: | CM, pain | MECHANICAL LOW BACK PAIN | The study aimed to compare the effects of connective tissue massage (CTM) and classical massage (CM) in patients with chronic mechanical low back pain on pain and autonomic responses and to determine the most effective manual therapy method. | PMC10101266 |
Methods: | Oswestry disability, CM, pain | MECHANICAL LOW BACK PAIN, HEART | Seventy individuals with chronic mechanical low back pain were randomly divided into CTM (n = 35) and CM (n = 35) groups. The participants were given a 4-week treatment protocol consisting of a hot pack, exercise, and CTM or CM for 20 sessions. A visual analog scale was used to measure pain intensity. Heart rate, blood pressure, and skin temperature were measured for the evaluation of autonomic responses. In addition, disability (Oswestry disability index), quality of life (short form 36), and sleep quality (Pittsburgh sleep quality index) were evaluated. Participants were assessed before and after the 4-week treatment period as well as at the end of the 6-week follow-up period. In addition, visual analog index measurements were repeated at the end of each treatment week. | PMC10101266 |
Results: | Pain | Pain intensity was decreased in both groups ( | PMC10101266 |
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Conclusion: | CM, pain | The results of this study showed that massages were similar effect. The fact that CM is a frequently used technique in pain management and is as effective as CTM in autonomic responses will make it more preferred in the clinic. | PMC10101266 |
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1. Introduction | tumor, low back pain, headaches, fracture, muscle soreness, pain, infection, chronic neck pain, CM, drug abuse, Disability, disability | TUMOR, AUTONOMIC NERVOUS SYSTEM IMBALANCE, CHRONIC LOW BACK PAIN, FIBROMYALGIA, MECHANICAL LOW BACK PAIN, INFECTION, ADVERSE EFFECTS, INCREASED SLEEP, MECHANICAL LOW BACK PAIN, OSTEOPOROSIS | Mechanical low back pain is defined as a condition that causes tension, pain, or stiffness in the lumbar region without any specific cause (e.g., infection, tumor, osteoporosis, fracture, etc).Chronic low back pain negatively affects daily life and causes other problems in addition to pain. Disability due to pain can severely limit participation in work, social, and family life.Another common finding of low back pain are neurophysiological changes caused by autonomic nervous system imbalance.Pharmacotherapy is widely used for chronic low back pain and other accompanying problems. However, the possibility of drug abuse and adverse effects has led researchers to focus on non-pharmacological approaches.However, massage is a safe treatment option with few side effects in patients with low back pain. It is an effective therapy in some types of headaches, muscle soreness, and mechanical neck pain.Connective tissue massage (CTM) has local and reflex effects that reshape the tissue through manipulation. Influences of the CTM stimuli in the skin and subcutaneous fascial layers result in reflex effects on the autonomic nervous system.Previous studies have stated that CM and CTM reduced pain and disability and increased sleep quality and quality of life in patients with fibromyalgia, chronic neck pain, and chronic low back pain.Based on the information discussed above, the primary aim of the study was to determine the most effective manual therapy by comparing the effects of CM and CTM on pain in patients with chronic mechanical low back pain (CMLBP). The second aim was to compare the effects of massage methods on autonomic responses, disability, quality of life, and sleep quality. | PMC10101266 |
2. Methods | PMC10101266 |
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2.1. Study design | This study was designed as a randomized, comparative, and mono-center study. The study was conducted in the Orthopedic Rehabilitation Unit of the Health Sciences Faculty of Eastern Mediterranean University between March 2019 and August 2021. The study was approved by the Health Ethics Committee (ETK00-2019-0177) and registered into the Clinical Trials (NCT04211701). This study was conducted in accordance with the rules of the Declaration of Helsinki.All assessments and treatments were conducted by the same physiotherapist (GE) to standardize the study. The physiotherapist had 7 years of experience with the subject. | PMC10101266 |
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2.2. Participants | MECHANICAL LOW BACK PAIN | Patients diagnosed with chronic mechanical low back pain by orthopedics and traumatology doctors in local state hospital were included in the study. The G*Power software program (version 3.0; Kiel, Germany) was used to determine the required sample size for the study. Thus, a sample consisting of 54 participants (27 per group) was needed to obtain 80% power with Cohen effect size of d = .80 (for 80% power), α = .05, and β = .20. It was predicted that some participants would not be able to fulfill the treatment protocols for various reasons, and the sample sizes of each group were increased by 30%.Before the enrollment process, the participants were informed about the study and signed informed consent forms were obtained. Thus, 76 interviewed participants who complied with the inclusion and exclusion criteria. | PMC10101266 |
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1.2.2. Inclusion and exclusion criteria | congenital malalignment, lower extremity inequality, numbness, pain, malignity | MECHANICAL LOW BACK PAIN, AXIAL SPONDYLOARTHROPATHY | The inclusion criteria were as follows: aged between 20 and 60 years, referred to a physiotherapy clinic, the presence of mechanical low back pain for more than 12 weeks, the absence of neurological problems originating from the lumbar region, and not participating in any physiotherapy and rehabilitation program in the last 6 months.The exclusion criteria were as follows: the presence of axial spondyloarthropathy, pain and numbness radiating to the hip and lower extremities, congenital malalignment in columna vertebralis, malignity, lower extremity inequality greater than 1 cm, a difference in blood pressure measurements of more than 10 mm Hg between the 2 arms, and/or pregnancy. | PMC10101266 |
2.3. Randomization | CM | The patients were randomly assigned to one of the following 2 groups: CTM group (n = 35) and CM group (n = 35). Using the minimization method, the groups were made similar in terms of gender, age, and occupation. The participant flow chart is displayed in Figure The participant flow chart according to CONSORT is displayed in Figure 1. | PMC10101266 |
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2.4. Interventions | CM | Patients were treated with CM or CTM after a hot pack application (20 minutes) to the lumbar region. In addition, all the participants were given lumbar strengthening and stretching exercises (Table Exercise program. | PMC10101266 |
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1.2.4. Connective tissue massage | hyperemia, strokes | HYPEREMIA, STROKES | The participant was seated on a stool with the entire back and sacral region open, hip and knee flexed at 90°, and feet on the ground during the treatment. While sitting, it was ensured that the back of the individual was straight and their hands supported the thighs for slight loosening of the connective tissue. CTM was applied by the physiotherapist in the form of short and long pulling strokes in a hooking style with the third finger flexed at 45° to 60° from the distal phalanx. CTM was applied to the basic region during the first 3 sessions and then progressed to the lower thoracic region, scapular region, and interscapular region, for the following sessions respectively. CTM pulls were performed 3 to 4 times for each area. Decreased tension, the appearance of lines of hyperemia, and appropriate vascular response were identified as the criteria for progression to other regions. CTM application initially lasted for 5 minutes and reached 20 to 25 minutes with the progression of the massage to the upper segments. | PMC10101266 |
2.2.4. Classical massage | CM | CM was applied to the lower and upper back regions in the prone position. Massage oil was used as an intermediate. After general stroking to the entire back, stroking and kneading were applied to the erector spine, latissimus dorsi, and gluteus maximus muscles in the lower back. An upper back massage was performed after the lower back massage and stroking and kneading were applied to the erector spine and trapezius muscles. The back massage ended with a general stroking application. The duration of the massage was approximately 15 to 20 minutes. | PMC10101266 |
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2.5. Outcome measures | pain | All the outcomes were measured by the same physiotherapist the day before the first treatment session, the day after the completion of all treatments, and at the end of the 6-week follow-up. In addition, pain intensity was measured at the end of the 5 | PMC10101266 |
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1.2.5. Primary outcome measure | PMC10101266 |
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1.2.5.1. Pain intensity | pain | A visual analog scale (VAS) was used to measure pain intensity. | PMC10101266 |
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2.2.5. Secondary outcome measures | PMC10101266 |
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2.1.2.5. Autonomic functions | CM | BLOOD | Blood pressure, heart rate, and peripheral and local skin temperature changes were measured to evaluate the possible effects of CM and CTM on the autonomic responses.The blood pressure measurements were taken using a Erka Switch model manual sphygmomanometer. For the measurement, the participants were seated in a chair with back and arm support with their feet on the ground. After resting in this position for 5 minutes, the forearm was fixed on a flat table and the arm was brought to the level of the right atrium. If the individual smoked, drank coffee, or exercised, measurements were performed 30 minutes later.Peripheral skin temperature was measured from the medial longitudinal arch, which was reported to be the hottest point of the foot.Local skin temperatures were evaluated in the same laboratory conditions prepared for the peripheral skin temperature. Temperature measurements were performed bilaterally from the following anatomical points stated by Holey et al | PMC10101266 |
2.6. Disability | Oswestry disability, disability | The Oswestry disability index (ODI) was used to evaluate the disability of the individuals. | PMC10101266 |
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2.7. Health-related quality of life | The short form 36 (SF-36) was used to assess health-related quality of life. | PMC10101266 |
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2.8. Sleep quality | The Pittsburgh sleep quality index (PSQI) was used to determine sleep quality. PSQI is the preferred index in clinical and research studies. | PMC10101266 |
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2.9. Statistical analysis | The obtained data were evaluated with the SPSS Version 22.0 program (SPSS Inc., Chicago, IL). The level of significance was accepted as | PMC10101266 |
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3. Results | CM | The demographic information’s of the groups were similar (Table Comparisons of demographic information of individuals.BMI = body mass index, CM = classical massage, CTM = connective tissue massage. Mann–Whitney Chi-square test. | PMC10101266 |
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3.1. Pain intensity | CM, pain | When the time-dependent changes in the intensity of pain were analyzed, it was found that both treatments provided significant improvements (Table Comparison of pain intensity of the groups.Bold indicates significant values.CM = classical massage, CTM = connective tissue massage, VAS = visual analog scale. Mann–Whitney Friedman test.Change of pain intensity of the groups according to time.Bold indicates significant values.CM = classical massage, CTM = connective tissue massage, VAS = visual analog scale. Post hoc Dunn test.When the pretreatment, 1 | PMC10101266 |
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3.2. Autonomic functions | CM | When the time-dependent changes in the autonomic functions were analyzed, it was found that both treatments provided significant increases in right peripheral temperatures. Besides, it was found that there was a significant increase in left peripheral temperature in the CTM group (Table Comparisons of autonomic functions of groups.Bold indicates significant values.CM = classical massage, CTM = connective tissue massage. Mann–Whitney Friedman test.Change of autonomic functions of groups according to time.Bold indicates significant values.CM = classical massage, CTM = connective tissue massage. Post hoc Dunn Test.When the heart rate, blood pressure, and temperature measurements were compared between the 2 groups, no difference was found ( | PMC10101266 |
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3.3. Disability | disability, CM | When the time-dependent changes in the disability were analyzed, it was found that both treatments provided significant improvements (Table Comparisons of disability, sleep quality, and health-related quality of life.Bold indicates significant values.CM = classical massage, CTM = connective tissue massage, NT = not tested, PSQI = pittsburgh sleep quality index, SF-36 = short form 36. Mann–Whitney Friedman test.Change of disability, sleep quality, and quality of life of the groups according to time.Bold indicates significant values.CM = classical massage, CTM = connective tissue massage, PSQI = pittsburgh sleep quality index, SF-36 = short form 36. Post hoc Dunn test.When the pretreatment, posttreatment, and at the end of the 6-week follow-up ODI scores were compared between the groups, no difference was found ( | PMC10101266 |
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3.4. Sleep quality | daytime sleep dysfunction, sleep disturbance, CM | When the time-dependent changes in the PSQI were analyzed, it was found that all subcategories (without the sleep medication) provided significant improvements in the CTM group (Table In the CM group, it was found that the sleep duration, sleep disturbance, and daytime sleep dysfunction subcategories provided significant improvements (Table In the global score, there was a statistically significant decrease in both groups for posttreatment and at the end of the 6-week follow-up compared to the pretreatment (posttreatment When the pretreatment, posttreatment and at the end of the 6-week follow-up PSQI scores were compared between the groups, no difference was found ( | PMC10101266 |
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3.5. Health-related quality of life | CM | When the time-dependent changes in the SF-36 results were analyzed, it was found that all categories provided significant improvements in the CTM group (Table There were statistically significant improvements in the CTM group for posttreatment and at the end of the 6-week follow-up physical functioning (posttreatment There were statistically significant improvements in the CM group for posttreatment and at the end of the 6-week follow-up physical functioning (posttreatment When the pretreatment, posttreatment, and at the end of the 6-week follow-up SF-36 scores were compared between the groups, the emotional well-being at the end of the 6-week follow-up score for the CTM group was significantly higher than the score for the CM group ( | PMC10101266 |
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