title: Blood Pressure and Clinical Outcomes in the International Stroke Trial Physiotherapy Coupled With Dextroamphetamine for Rehabilitation After Hemiparetic Stroke: A Randomized, Double-Blind, Placebo-Controlled Trial Motor response to amphetamine treatment, task-specific training, and limited motor experience in a postacute animal stroke model An fMRI Study of the Effect of Amphetamine on Brain Activity Cardiac Baroreceptor Sensitivity Predicts Long-Term Outcome After Acute Ischemic Stroke Amphetamine fails to facilitate motor performance and to enhance motor recovery among stroke patients with mild arm paresis: interim analysis and termination of a double blind, randomised, placebo-controlled trial. Safety of Dexamphetamine in Acute Ischemic Stroke: A Randomized, Double-Blind, Controlled Dose-Escalation Trial Modification of practice-dependent plasticity in human motor cortex by neuromodulators. Amphetamine increases blood pressure and heart rate but has no effect on motor recovery or cerebral haemodynamics in ischaemic stroke: a randomized controlled trial (ISRCTN 36285333) Modulation of use-dependent plasticity by d-amphetamine. Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers. No benefit from D-amphetamine when added to physiotherapy after stroke: a randomized, placebo-controlled study A Double-Blind, Placebo-Controlled Study of the Use of Amphetamine in the Treatment of Aphasia
abstract: Background and Purpose — Among patients with acute stroke , high blood pressure is often associated with poor outcome , although the reason is unclear . We analyzed data from the International Stroke Trial ( IST ) to explore the relationship between  systolic blood pressure ( SBP ) , subsequent clinical events over the next 2 weeks , and functional outcome at 6 months in patients with acute stroke . Methods — We included in the analysis 17 398 patients from IST with confirmed ischemic stroke . A single measurement of SBP was made immediately before r and omization . Clinical events within 14 days of r and omization were recorded : recurrent ischemic stroke , symptomatic intracranial hemorrhage , death result ing from presumed cerebral edema , fatal coronary heart disease , and death . Survival and dependency were assessed at 6 months . Outcomes were adjusted for age , sex , clinical stroke syndrome , time to r and omization , consciousness level , atrial fibrillation , and treatment allocation ( aspirin , unfractionated heparin , both , or neither ) . Results — A U-shaped relationship was found between baseline SBP and both early death and late death or dependency : early death increased by 17.9 % for every 10 mm Hg below 150 mm Hg ( P < 0.0001 ) and by 3.8 % for every 10 mm Hg above 150 mm Hg ( P = 0.016 ) . The rate of recurrent ischemic stroke within 14 days increased by 4.2 % for every 10–mm Hg increase in SBP ( P = 0.023 ) ; this association was present in both fatal and nonfatal recurrence . Death result ing from presumed cerebral edema was independently associated with high SBP ( P = 0.004 ) . No relationship between symptomatic intracranial hemorrhage and SBP was seen . Low SBP was associated with a severe clinical stroke ( total anterior circulation syndrome ) and an excess of deaths from coronary heart disease ( P = 0.002 ) . Conclusions — Both high blood pressure and low blood pressure were independent prognostic factors for poor outcome , relationships that appear to be mediated in part by increased rates of early recurrence and death result ing from presumed cerebral edema in patients with high blood pressure and increased coronary heart disease events in those with low blood pressure . The occurrence of symptomatic intracranial hemorrhage within 14 days was independent of SBP Background and Purpose — Hemiparesis is the commonest disabling deficit caused by stroke . In animals , dextroamphetamine ( AMPH ) paired with training enhances motor recovery , but its clinical efficacy is uncertain . Methods — In a r and omized , double-blind , placebo-controlled trial , 71 stroke patients were stratified by hemiparesis severity and r and omly assigned to 10 sessions of physiotherapy coupled with either 10 mg AMPH or placebo . Study treatments were administered by 1 physiotherapist , beginning 5 to 10 days after stroke and continuing twice per week for 5 weeks . Outcomes were assessed by 1 physiotherapist at baseline , after each treatment session , at 6 weeks , and at 3 months . The primary outcome was motor recovery ( impairment level ) on the Fugl-Meyer ( FM ) scale . Secondary outcomes assessed mobility , ambulation , arm/h and function , and independence in activities of daily living . Results — Baseline hemiparesis was severe overall ( mean FM score 27.7±20.0 ) . Motor scores improved during treatment in both groups ( mean change , baseline to 3 months 29.5±16.6 ) . Repeated- measures ANOVA revealed no significant differences in recovery between the treatment groups for the entire cohort ( n=67 ) or for subgroups with a severe hemiparesis ( n=43 ) , moderate hemiparesis ( n=24 ) , or cortically based stroke ( n=26 ) . In the moderate subgroup , there was a significant drug × time interaction for upper extremity motor recovery ( F=5.14 ; P<0.001 ) , although there was a significant baseline imbalance in motor scores in this subgroup . Conclusion — In stroke patients with a severe motor deficit , 10 mg AMPH coupled with physiotherapy twice per week for 5 weeks in the early poststroke period provided no additional benefit in motor or functional recovery compared with physiotherapy alone . Patients with moderate severity hemiparesis deserve further investigation . Increased intensity and longer duration drug/therapy dosing regimens should be explored , targeting the upper and lower limbs separately Despite advances in acute treatment of ischemic cerebrovascular events , the most common clinical outcome is disabling neurological impairment . Despite experimental evidence that psychostimulant treatment can positively affect recovery rate after focal brain lesions , beyond rehabilitation therapies there are no currently accepted medical treatments indicated for diminishing neurological impairment after clinical ly established stroke . To test the effect of amphetamine , task-specific training , limiting motor experience , and their interaction on motor recovery in a postacute animal model of stroke , animals were nonaversively trained in beam walking before a unilateral photochemical sensorimotor cortex lesion and tested for 10 days after lesion . Animals were r and omized to groups receiving : a single session of motor training 24 h after lesion ; a single injection of amphetamine 2 mg/kg 24 h after lesion ; beam-walking experience limited to testing on days 1 and 10 after lesion ; and groups that received amphetamine treatment combined with training or combined with limited experience .  Motor recovery was maximally enhanced by training , delayed by amphetamine treatment , and most negatively affected by limiting beam-walking experience during the recovery period . These findings support physical training after stroke , indicating that limiting physical activity negatively affects motor recovery and raises questions about the role of stimulant treatment to enhance motor recovery in the postacute phase after stroke Functional magnetic resonance imaging was used to evaluate the effects of oral d-amphetamine on brain activation elicited by auditory and simple motor tasks in ten normal right-h and ed subjects . We measured the percent signal change and number of voxels activated by a tone discrimination task and a right h and finger-tapping task after 20 mg of d-amphetamine and after placebo . Compared to placebo , amphetamine significantly increased the number of activated voxels in the left and right primary auditory cortices during the tone discrimination task and increased the number of activated voxels in the ipsilateral primary sensorimotor cortex and right middle frontal area during the motor task . Although highly specific vascular effects of drug can not be ruled out as an explanation , these results could also mean that amphetamine increases the neuronal activity associated with each of these two tasks Background and Purpose — The baroreceptor reflex arc is important in the short-term regulation of the cardiovascular system , and small studies have reported impaired cardiac baroreceptor sensitivity ( BRS ) after acute stroke . However , the prognostic significance of impaired BRS is uncertain . Methods — One hundred twenty-four patients underwent simultaneous ECG and noninvasive beat-to-beat blood pressure ( BP ) monitoring within 72 hours of neuroradiologically confirmed acute ischemic stroke . Cardiac BRS was assessed from the combined & agr;-index by means of power spectral analysis techniques . Baseline data for acute stroke patients were compared with those of a control group matched for age , sex , and casual BP . Patients were followed up for a median of 1508 days ( range , 9 to 2656 days ) , and outcome was compared between patients with and without impaired BRS . Results — Median BRS values were significantly lower in stroke patients than in controls ( 5 [ interquartile range , 3.5 to 7.4 ] versus 6.2 [ interquartile range , 4.5 to 8.3 ] ms/mm Hg;P = 0.04 ) . Sixty-one ( 33 male ) patients ( mean age , 70.2 [ SD 10.5 ] years ) had impaired BRS ( ≤5.0 ms/mm Hg ) compared with 63 ( 35 male ) patients ( mean age , 70.6 [ SD 11.7 ] years ) without impaired BRS ( > 5.0 ms/mm Hg ) . Stroke patients with impaired BRS values had a significantly poorer prognosis ( 28 % versus 8 % mortality rate during the follow-up period ) although there were no differences in age , stroke severity , stroke type , or casual or 24-hour BP parameters between the 2 groups . Conclusions — Impaired cardiac BRS is associated with increased long-term mortality after acute ischemic stroke , irrespective of age , sex , stroke type , and BP . This may reflect cardiac arrhythmias , but the mechanisms underlying this association are unknown , although therapies that improve cardiac BRS after stroke warrant further investigation PURPOSE To assess the effects of d-amphetamine on motor facilitation and recovery in stroke patients with mild arm paresis receiving the Arm Ability training . METHODS Thirty-one stroke patients with mild arm paresis were r and omly assigned to either ( a. ) receiving placebo or ( b. ) d-amphetamine twice a week 2 hours before Arm Ability training sessions for three weeks . MAIN OUTCOME MEASURE time needed to perform TEMPA tasks , a measure of upper extremity performance reflecting everyday life tasks . Secondary measures : aim ed movements , tapping , and a 10 m walkway as well as motor performance during training sessions . RESULTS The interim efficacy analysis of 26 stroke patients who completed the study intervention showed overall arm motor recovery both from pre to post test after 3 weeks of training and from pre test to follow-up 1 year later . No superior effect of d-amphetamine over placebo could be substantiated for either motor facilitation during training or motor recovery ( post training or long-term ) . D-amphetamine exerted mild effects on blood pressure . Serious adverse events were not observed . CONCLUSIONS d-Amphetamine failed to facilitate motor performance during training sessions , to promote skill acquisition with training tasks , and most importantly to enhance motor recovery among patients with mild arm paresis after stroke Background and Purpose — Amphetamine is reported to enhance recovery after experimental stroke , but results from the first few trials in humans are inconclusive . Limited information is available on treatment safety . This study intended to investigate the safety and tolerability of dexamphetamine in patients with acute cerebral ischemia . Methods — Forty-five patients with cerebral ischemia were enrolled within 72 hours after onset of symptoms . Patients were r and omized to 1 of 3 dose levels ( 2.5 , 5 , or 10 mg orally twice daily ) or placebo for 5 consecutive days . Adverse events , blood pressure , heart rate , body temperature , consciousness level , and functional outcome measures were followed up daily during treatment . Follow-ups were made at day 7 and 1 and 3 months after stroke . Results — Mean systolic and diastolic blood pressures and heart rate increased 14 mm Hg , 8 mm Hg , and 9 bpm , respectively , with dexamphetamine treatment compared with placebo ( P ≤0.01 ) . There was no difference between dexamphetamine and placebo  regarding adverse events , body temperature , or consciousness level . During treatment , there was a benefit of dexamphetamine in neurological and functional outcome ( P < 0.05 ) , but differences were not maintained at follow-up . Conclusions — Overall , dexamphetamine was safe and well tolerated by patients with acute cerebral ischemia , but blood pressure and heart rate increased during treatment in comparison to placebo . These observations may be important in the future planning of amphetamine trials because changes in these variables have been observed to interfere with clinical outcome . The suggestions of improvement in outcome must be confirmed in further studies Practice -dependent plasticity underlies motor learning in everyday life and motor relearning after lesions of the nervous system . Previous studies showed that practice -dependent plasticity is modifiable by neuromodulating transmitters such as norepinephrine ( NE ) , dopamine ( DA ) or acetylcholine ( ACh ) . Here we explored , for the first time comprehensively and systematic ally , the modifying effects of an agonist versus antagonist in each of these neuromodulating transmitter systems on practice -dependent plasticity in healthy subjects in a  placebo-controlled , r and omized , double-blind crossover design . We found that the agonists in all three neuromodulating transmitter systems ( NE : methylpheni date ; DA : cabergoline ; ACh : tacrine ) enhanced practice -dependent plasticity , whereas the antagonists decreased it ( NE : prazosin ; DA : haloperidol ; ACh : biperiden ) . Enhancement of plasticity under methylpheni date and tacrine was associated with an increase in corticomotoneuronal excitability of the prime mover of the practice , as measured by the motor evoked potential amplitude , but with a decrease under cabergoline . Our findings demonstrate that agonists and antagonists in various neuromodulating transmitter systems produce significant and oppositely directed modifications of practice -dependent plasticity in human motor cortex . Enhancement of plasticity occurred through different strategies that either favoured extrinsic ( NE , ACh ) or intrinsic ( DA ) modulating influence on the motor cortical output network Amphetamine enhances recovery after experimental ischaemia and has shown promise in small clinical trials when combined with motor or sensory stimulation . Amphetamine , a sympathomimetic , might have haemodynamic effects in stroke patients , although limited data have been published . Subjects were recruited 3–30 days post-ischaemic stroke into a phase II r and omized ( 1:1 ) , double-blind , placebo-controlled trial . Subjects received dexamphetamine ( 5 mg initially , then 10 mg for 10 subsequent doses with 3- or 4-day separations ) or placebo in addition to inpatient physiotherapy . Recovery was assessed by motor scales ( Fugl – Meyer ( FM ) ) , and functional scales ( Barthel index ( BI ) and modified Rankin score ( mRS ) ) . Peripheral blood pressure ( BP ) , central haemodynamics and middle cerebral artery blood flow velocity were assessed before , and 90 min after , the first two doses . Thirty-three subjects were recruited , aged 33–88 ( mean 71 ) years , males 52 % , 4–30 ( median 15 ) days post stroke to inclusion . Sixteen patients were r and omized to placebo and seventeen to amphetamine . Amphetamine did not improve motor function at 90 days ; mean ( s.d . ) FM 37.6 ( 27.6 ) vs control 35.2 ( 27.8 ) ( P=0.81 ) . Functional outcome ( BI , mRS ) did not differ between treatment groups . Peripheral and central systolic BP , and heart rate ( HR ) , were 11.2 mm Hg ( P=0.03 ) , 9.5 mm Hg ( P=0.04 ) and 7 beats per minute ( P=0.02 ) higher , respectively , with amphetamine , compared with control . A nonsignificant reduction in myocardial perfusion ( BUI ) was seen with amphetamine . Other cardiac and cerebral haemodynamics were unaffected . Amphetamine did not improve motor impairment or function after ischaemic stroke but did significantly increase BP and HR without altering cerebral haemodynamics Use-dependent plasticity , thought to contribute to functional recovery after brain injury , is elicited by motor training . The purpose of this study was to determine if administration of d-amphetamine facilitates the effects of motor training on use-dependent plasticity . Healthy human volunteers underwent a training period of voluntary thumb movements under the effects of placebo or d-amphetamine in different sessions in a r and omized double-blind , counterbalanced design . Previous work in a drug-naive condition showed that such training causes changes in the direction of thumb movements evoked by transcranial magnetic stimulation and in transcranial magnetic stimulation-evoked electromyographic responses . The endpoint measure of the study was the magnitude of training-induced changes in transcranial magnetic stimulation-evoked kinematic and electromyographic responses in the d-amphetamine and in the placebo conditions . Motor training result ed in increased magnitude , faster development and longer lasting duration of use-dependent plasticity under d-amphetamine compared to the placebo session . These results document a facilitatory effect of d-amphetamine on use-dependent plasticity , a possible mechanism mediating the beneficial effect of this drug on functional recovery after cortical lesions UNLABELLED Functional brain imaging is a powerful tool for examining the central nervous system ( CNS ) response to pharmacologic challenges . Amphetamine is of interest both because of its role as a stimulant of the dopaminergic system and because of its use to alter mood in mood-disordered patients , particularly in patients suffering from depression . In this study , we report the effects of oral D-amphetamine relative to placebo on regional cerebral blood flow ( rCBF ) measured by SPECT in healthy volunteers to characterize the normal CNS response to this primarily dopaminergic stimulant . METHODS SPECT was used to assess changes in rCBF induced by amphetamine in 16 healthy volunteers . Subjects received placebo and then 0.4 mg/kg oral amphetamine in a fixed-order single-blind design and were imaged on a triple-head tomograph . Another six healthy volunteers received placebo at both times to assess normal rCBF variability . rCBF changes were assessed with a three-dimensional voxel-based analysis integrated into an automated co registration system . Data were automatically normalized to whole-brain counts and coregistered . Result ant rCBF changes were evaluated parametrically through the formation of an image whose voxel values were based on the paired t statistic . RESULTS Amphetamine increased rCBF in two mesial prefrontal zones ( Brodmann 's areas 8 and 10 ) , inferior orbital frontal lobe ( area 11 ) , brain stem ( ventral tegmentum ) , anteromesial temporal lobe ( amygdala ) , and anterior thalamus . Amphetamine decreased rCBF to motor cortex , visual cortex , fusiform gyrus , posterolateral temporal lobe , and right lateral temporal lobe . CONCLUSION Our data suggest that amphetamine induces focal increases and decreases in rCBF in healthy volunteers in areas primarily innervated by dopamine pathways and in areas with secondary ( primarily limbic ) affiliations . These data are consistent with glucose metabolic data from autoradiographic studies in animals , in which the largest increases are seen in brain stem , followed by striatum , thalamus , and frontal and sensory cortices . Frontopolar and temporal increases observed in our study appear to be unique to humans Objective : To assess the effect of D-amphetamine on the recovery of activities of daily living and motor functions after stroke , Design : R and omized , placebo-controlled study , Setting : Inpatient rehabilitation centre , Subjects : Twenty-four stroke survivors after a first ischaemic supratentorial stroke within six weeks before study onset , severely to moderately affected , with a Barthel Index ( 0–100 ) ranging from 25 to 50 , no severe concomitant internal , neurological or psychiatric diseases , and participating in a comprehensive rehabilitation programme of 10–12 weeks , Interventions : Ten sessions with 10 mg D-amphetamine ( or placebo ) every fourth day totalling 100 mg in a time period of 36 days combined with physical therapy according to the neurodevelopmental concept within 60 minutes after drug intake . Main outcome measures : Barthel Index ( 0–100 ) served as the primary outcome measure and the Rivermead Motor Assessment Score with its three sections ( gross function , leg and trunk , and arm ) as the secondary outcome measure , assessed at days 0 , 20 , 36 , 90 , 180 and 360 . Results : The two groups did not differ with respect to clinical data and outcome measures at study onset . All patients improved significantly except for arm function over the intervention period and up to day 90 after study onset . The comparison between groups did not reveal any difference at any time ; amphetamine-treated patients did not show any increase in motor function or ADL compared with the control group . Conclusions : The placebo-controlled study failed to show any effect of D-amphetamine on stroke recovery compared with control . The small number of patients , the timing and content of physical therapy were limiting factors of the present study . Further trials are warranted Background and Purpose — A number of studies suggest that drugs which increase the release of norepinephrine promote recovery when administered late ( days to weeks ) after brain injury in animals . A small number of clinical studies have investigated the effects of the noradrenergic agonist dextroamphetamine in patients recovering from motor deficits following stroke . To determine whether these findings extend to communication deficits subsequent to stroke , we administered dextroamphetamine , paired with speech/ language therapy , to patients with aphasia . Methods — In a prospect i ve , double-blind study , 21 aphasic patients with an acute nonhemorrhagic infa rct ion were r and omly assigned to receive either 10 mg dextroamphetamine or a placebo .  Patients were entered between days 16 and 45 after onset and were treated on a 3-day/4-day schedule for 10 sessions . Thirty minutes after drug/placebo administration , subjects received a 1-hour session of speech/ language therapy . The Porch Index of Communicative Ability was used at baseline , at 1 week off the drug , and at 6 months after onset as the dependent language measure . Results — Although there were no differences between the drug and placebo groups before treatment ( P = 0.807 ) , by 1 week after the 10 drug treatments ended there was a significant difference in gain scores between the groups ( P = 0.0153 ) , with the greater gain in the dextroamphetamine group . The difference was still significant when corrected for initial aphasia severity and age . At the 6-month follow-up , the difference in gain scores between the groups had increased ; however , the difference was not significant ( P = 0.0482 ) after correction for multiple comparisons . Conclusions — Administration of dextroamphetamine paired with 10 1-hour sessions of speech/ language therapy facilitated recovery from aphasia in a small group of patients in the subacute period after stroke . Neuromodulation with dextroamphetamine , and perhaps other drugs that increase central nervous system noradrenaline levels , may facilitate recovery when paired with focused behavioral treatment
target: No evidence exists at present to support the use of amphetamine after stroke .
background: INTRODUCTION The use of drugs to enhance recovery ( " rehabilitation pharmacology " ) has been assessed .
  Amphetamine can improve outcome in experimental models of stroke , and several small clinical trials have assessed its use in stroke .