| | Levodopa Improves Procedural Motor Learning in Chronic Stroke PatientsAbstract Rösser N, Heuschmann P, Wersching H, Breitenstein C, Knecht S, Flöel A. Levodopa improves procedural motor learning in chronic stroke patients. ObjectiveTo test the hypothesis that administration of dopamine precursor levodopa improves procedural motor learning (defined as the ability to acquire novel movement patterns gradually through practice) in patients with residual motor deficits in the chronic phase after stroke (≥1y after stroke). DesignA double-blind, placebo-controlled, randomized crossover design. SettingNeurology department in a German university. ParticipantsEighteen patients with chronic motor dysfunction because of stroke (13 men, 5 women; age range, 53–78y; mean time poststroke ± SD, 3.3±2.1y). InterventionPatients received 3 doses of levodopa (100mg of levodopa plus 25mg of carbidopa) or placebo before 1 session of procedural motor learning. Main Outcome MeasuresProcedural motor learning performed by using the paretic hand assessed by using a modified version of the serial reaction time task with a probabilistic sequence. The primary outcome measure was the difference in reaction times between random and sequential elements. ResultsLevodopa significantly improved our primary outcome measure, procedural motor learning, compared with placebo (P<.05). Reaction times to random elements, analysis of error rates, psychophysical assessments, and performance in a simple motor task were comparable between conditions, indicating that better learning under levodopa was not caused by differences in response styles, arousal, mood, or motor reaction times but that levodopa modulated learning. ConclusionsOur results show that levodopa may improve procedural motor learning in patients with chronic stroke, in line with our hypothesis. These findings suggest that this interventional strategy in combination with customary rehabilitative treatments could significantly improve the outcome of neurorehabilitation in the chronic stage after stroke. (Clinicaltrials.gov identifier NCT00126087.) List of Abbreviations: ADLs, activities of daily living, ANOVA, analysis of variance, LTP, long-term potentiation, MMSE, Mini-Mental State Examination, MRC, Medical Research Council, PANAS, Positive and Negative Affective Schedule, SRT, serial reaction time, TMT, Trail-Making Test, WMS, Wechsler Memory Scale STROKE IS THE LEADING cause of adult long-term disability in Western Europe and the United States, often resulting in deficits in motor function.1, 2, 3 The residual chronic deficits after initial spontaneous recovery demand training that invokes synaptic plasticity to remodel neuronal connections.3, 4, 5 Because the majority of stroke patients are older than 50 years,1, 2 this remodeling might be influenced by an age-related decline in memory formation and learning.6, 7, 8, 9 The brain dopamine system, crucial for motor learning,10, 11, 12, 13 experiences a parallel decline with aging.14, 15, 16 This age-dependent decline in dopamine receptors, transporters, and metabolism may contribute to the decreased learning ability in the elderly.16, 17, 18 Therefore, pharmacologic strategies that enhance dopaminergic neurotransmission represent a promising adjuvant therapy in motor rehabilitation of patients after stroke.9, 19 Prior studies in healthy humans already showed that premedication with levodopa20 or dopamine agonists21 improved the development of an elementary motor memory, an effect also substantiated in chronic stroke patients.9 However, the latter study was small in size and did not assess complex and ecologically valid motor outcome scores like motor learning or ADLs.9 A more complex form of motor memory acquisition is procedural motor learning. Procedural learning is defined as the ability to acquire motor skills or cognitive routines through regular exposure to a specific procedure constrained by invariant rules.22, 23 It is a form of nondeclarative or implicit memory without conscious recollection of the learning episode or the rules underlying the task. It is contrasted with declarative or explicit memory, which involves the acquisition of facts and events accompanied by conscious awareness of the learned information. Procedural motor learning most commonly entails acquiring novel movement patterns,24 which is also the main objective in rehabilitation of motor deficits after stroke. Deficient procedural motor learning could therefore be responsible for incomplete recovery of motor functions in the chronic poststroke phase. The most frequently used task to study procedural motor learning is the SRT task.25, 26 It incorporates the learning of complex successive finger movement by requiring participants to make key presses discretely to each of several visually presented cues. The order of key presses underlies a structure or sequence not known to the participant. Although participants are unaware of this underlying sequence, it is learned implicitly (without consciousness) shown in a decrease in reaction times. The amount of procedural motor learning is measured as the difference in reaction times between the learned sequential and intermixed random elements (for further information on classical deterministic SRT tasks, please refer to Howard and Howard27). A modified version of the SRT task uses probabilistic sequences,28, 29, 30 mixing shorter and longer sequential segments with random ones. Thus, no single element can entirely be predicted based only on the knowledge of pairwise associations or on memory for entire sequences.31 To best prepare their response to successive stimuli during the probabilistic SRT task, subjects need to encode the temporal context in which stimuli occur so as to reduce the uncertainty associated with the next element.30, 31 The amount of procedural motor learning is again measured as the difference in reaction times between the learned sequential and intermixed random elements. The advantage of the method is that participants are not able to develop explicit knowledge about the sequences even after several trials. Furthermore, an unlimited amount of possible sequence combinations can be generated.30 The main purpose of the present study was to examine if procedural motor learning, assessed by the difference in reaction times between random and sequential elements in the probabilistic version of the SRT task, can be improved by the administration of levodopa in patients in the chronic phase after stroke. Methods  Participants Patients were recruited from the inpatient and outpatient clinic at the Neurological Department of the University of Muenster, local stroke clubs, and local rehabilitation hospitals. Recruitment took a period of nearly 1 year, from April 2006 to March 2007, during which approximately 50 patients were screened. In total, 18 chronic (≥1y after the acute event) stroke patients (13 men, 5 women; mean age ± SD, 66.4±6.8y; age range, 53–78y) with remaining chronic motor deficits in their arm and hand who met the entry criteria (see Inclusion Criteria below) gave written informed consent and participated in this double-blind, placebo-controlled, randomized crossover study. Patients were tested at least 1 year after stroke (mean ± SD, 3.3±2.1y poststroke; range, 1.5–8.3y) (table 1). Formal years of education ranged from 11 to 18 years (mean ± SD, 13.4±2.4y) (see table 1). | | |  | Patient No. | Age (y) | Sex | Education (y) | Years After Stroke | Taken Medication⁎ | Lesioned Hemisphere and Location | Handedness† | Motor Function | |
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| MRC33 | MAS35 | RMA36 | |
|---|
| 01 | 62 | M | 13.0 | 6.3 | 1, 2,7 | Right basal ganglia | RH/100 | 4.5 | 1 | 12 | | | 02 | 67 | M | 13.0 | 2.7 | 1,2,5,6,10 | Right insula, caudate nucleus | RH/100 | 4.5 | 0 | 12 | | | 03 | 75 | M | 18.0 | 2.6 | 1,2,6,7,11 | Right parietal cortex | RH/100 | 4.5 | 0 | 12 | | | 04 | 53 | F | 12.0 | 1.5 | 7,11 | Left frontal cortex | RH/100 | 4.5 | 0 | 12 | | | 05 | 62 | M | 14.0 | 1.5 | 7,2,4,6 | Left frontal cortex | RH/80 | 5 | 0 | 13 | | | 06 | 61 | M | 13.5 | 5.4 | 6,7 | Left basal ganglia | RH/100 | 4.5 | 1 | 12 | | | 07 | 78 | F | 11.0 | 3.2 | 7 | Left basal ganglia, parietal-occipital cortex | RH/100 | 4.5 | 0 | 14 | | | 08 | 61 | M | 12.0 | 1.9 | 4,6,7,8 | Right basal ganglia, temporoparietal cortex | RH/100 | 4.5 | 0 | 14 | | | 09 | 65 | M | 18.0 | 1.7 | 1,2,3,6,7 | Left corona radiata | RH/90 | 5 | 0 | 15 | | | 10 | 69 | M | 11.0 | 4.5 | 1,2,3,4,10 | Right basal ganglia | RH/100 | 4.5 | 1 | 11 | | | 11 | 70 | M | 11.0 | 1.3 | 1,2,6,8 | Left corona radiata, nucleus lentiformis | LH/70 | 4.5 | 1 | 10 | | | 12 | 56 | F | 13.0 | 2 | 2,4,6,7 | Right corona radiata | RH/80 | 4.5 | 1 | 10 | | | 13 | 69 | F | 11.0 | 1.8 | 1,2,4,8 | Left insula, parietal | RH/100 | 5 | 1 | 11 | | | 14 | 68 | M | 16.0 | 2.3 | 2,4,8 | Left frontal cortex | RH/80 | 4.5 | 0 | 12 | | | 15 | 62 | F | 14.0 | 8.3 | 2,6,8 | Left frontoparietal cortex | RH/100 | 5 | 0 | 14 | | | 16 | 74 | M | 17.0 | 6.4 | 2,4,8 | Left posterolateral temporal lobe | RH/100 | 4.5 | 0 | 10 | | | 17 | 75 | M | 11.0 | 1.5 | 4,6,10 | Right thalamic | RH/80 | 5 | 0 | 13 | | | 18 | 68 | M | 12.0 | 4.5 | 2,6,7 | Left basal ganglia | RH/100 | 4.5 | 0 | 11 | | | Mean | 66.4 | | 13.4 | 3.3 | | | 93.3 | 4.6 | 0.3 | 12.1 | | | SD | 6.8 | | 2.4 | 2.1 | | | 10.3 | 0.2 | 0.5 | 1.5 | | | | |
| ⁎ Legend: 1, antihypertensive and cardiac drugs including calcium channel blockers; 2, angiotensin-converting enzyme inhibitors; 3, nitrates; 4, β-blockers; 5, antidiabetic drugs; 6, cholesterol-lowering agents; 7, aspirin; 8, clopidogrel; 9, antidiuretics; 10, coumarine; 11, thyroid hormone replacement. †Assessed by the Edinburgh Handedness Inventory.72 |
The sample size was determined by power analysis (NQuery) based on a previous study of our group.9 The study was approved by the local ethics committee of the University of Muenster and the German Federal Institute for Drugs and Medical Products. Exclusion criteria Patients were excluded if they met one of the following criteria: (1) severe untreated cardiac, metabolic, or psychiatric diseases; (2) abuse of drugs or alcohol; (3) consumption of more than 50g of alcohol, more than 10 cigarettes, or more than 6 cups of caffeine-containing drinks per day; (4) use of recreational drugs, as verified by questioning subjects and by a urine test for recreational drugsa; (5) current intake of medication that affects the central nervous system (eg, antipsychotics, antidepressants, or drugs affecting the dopaminergic system); and (6) known hypersensitivity for levodopa and/or carbidopa. Assessment of motor function The degree of spasticity was assessed with the Modified Ashworth Scale for grading spasticity34 (see table 1). To assess arm motor function, the upper-extremity section of the Rivermead Motor Assessment35 was used (range, 0–15) (see table 1). Cognitive screening Patients were screened with a comprehensive neuropsychologic test battery before participation to ensure normal cognitive functioning. This battery comprised tests of working memory (subtest digit spans forward and backward of the German version of the WMS), executive functions (TMT part B [TMT-B]; subtests verbal and semantic fluency of the Regensburger Wortflüssigkeitstest, German version of the Controlled Oral Word Association Test; Farb-Wortinterferenz-Test, German version of the Stroop test), verbal learning and memory (Verbaler Lern- und Merkfähigkeitstest, German version of the Rey Auditory Verbal Learning Test), visuospatial learning and memory (Rey-Osterrieth complex figure), attention (TMT part A [TMT-A]), verbal and visual paired associates learning (subtests of the German version of the WMS), and dementia (MMSE). Low scores indicate poorer function in the respective cognitive domain. For further information on neuropsychologic testing, see table 2. Experimental Procedures General outline To ascertain that inclusion criteria were met, prospective patients participated in a prestudy day to evaluate their medical history, their neurologic status, and their degree of motor impairment. Additionally, we assessed handedness and conducted a detailed neuropsychologic screening (as described previously). On the prestudy day, patients were also familiarized with the motor tasks they would later perform in the intervention sessions. Each patient who met the inclusion criteria was studied in 2 separate sessions to determine the effects of levodopa (orally) or a placebo (identical capsule, orally) on procedural motor learning (see Procedural Motor Learning Paradigm section later). The capsules were randomized by the hospital pharmacy, packed in identical boxes with numbers encoding the content. The order of sessions (levodopa, placebo) was randomized between patients with at least 2 weeks between sessions to prevent drug carryover effects. Each session comprised 2 days of treatment. Motor tasks were only administered on the second day of each session. We chose to use dosages that had been shown to be effective in improving learning and memory formation in previous studies in both the motor and the language system.20, 36 On the first day, patients received 1 dose of levodopa (100mg of levodopa plus 25mg carbidopa) or placebo in the morning (between 8:00 and 10:00 am) and 1 dose in the afternoon (between 3:00 and 5:00 pm) with an interval of at least 6 hours. On the second day, patients received 1 dose of levodopa or placebo in the morning (between 8:00 and 10:00 am) and started performing the motor tasks (finger-tapping task and procedural motor learning task) 90 minutes later (fig 1). The order of the motor tasks and instructions were the same in both sessions (levodopa and placebo). First, patients performed the finger-tapping task 3 times, 10 seconds each with 1-minute rest intervals between trials. After a break of 5 minutes, 2 blocks of 500 keypresses, of the procedural motor learning task, were assessed. Each of these blocks was split up in 250 keypresses with 3-minute resting intervals between blocks to avoid fatigue. Procedural motor learning paradigm A standard paradigm to test procedural motor learning in humans is the SRT task.25, 26 In this task, patients performed finger movements repeatedly without being aware of the sequential order underlying most of the presented stimuli. We used a modified version of the SRT task with a probabilistic instead of a deterministic sequence to ensure the procedural task nature (for further information on probabilistic SRT tasks and their validity and reliability, see Jimenez30 or Cleeremans and McClelland31), mixing shorter and longer sequential segments with random ones (15% random and 85% sequential elements in each block). The sequential structure of the 85% was generated by a so-called finite-state grammar (for further information on the finite-state grammar used, see Jimenez30 or Cleeremans and McClelland31) that instantiated a set of rules that described the permissible transitions between successive stimuli. This program was written in Matlab and then implemented in Presentation software.b The advantage of a probabilistic sequence is that participants show no explicit knowledge of the learned sequences, even after several trials, and that an almost unlimited number of different sequences of equal complexity can be produced.31 Although improved performance during the whole task was because of procedural motor learning and increasing task routine, differences in reaction times between random and sequential elements represented a measure of procedural motor learning only, the main outcome measure of our study. For the SRT task, patients sat in front of a 14-inch monitor. Their paretic hand was placed on a special keypad with 5 different keys, one for each finger (fig 2). Following the rules of the finite-state grammar described earlier, one of the black squares on the screen was replaced by an asterisk. The patients had to press the key corresponding to the given asterisk as fast as possible. The task consisted of 2 blocks of 500 keypresses, respectively. To prevent stroke patients from becoming fatigued, the blocks were further divided into sets of 250 keypresses each with 3-minute resting intervals between blocks. A new asterisk was presented 500ms after every keypress. Data were saved as a .log-file by the Presentation software. At the end of the study, patients were queried if they had noticed regularities in the task to determine the degree of explicit learning. Psychophysical Assessments Blood pressure and heart rate To monitor possible effects of levodopa on cardiovascular parameters,37, 38 blood pressure and heart rate were recorded digitallyc every 30 minutes, starting with patients' arrival on the respective study day (see fig 1). Mood To assess effects on motivation and mood, patients rated their subjective positive and negative feelings by using the PANAS39 (German version40) every 30 minutes (see fig 1). The PANAS consists of two 10-item mood scales, which measure the dimensions positive affect (high score: a state of high energy; low score: sadness and lethargy) and negative affect (high score: state of distress; low score: state of calmness). Side effects and blinding Patients were also interviewed for the presence of the most common side effects of levodopa, including fatigue, dizziness, and nausea caused by slight decreases in blood pressure41 every 30 minutes. After the completion of the study, patients were asked to identify in which session they had received levodopa. On study day 1, psychophysical assessments were taken 3 times (0, 30, 60min) after each of the 2 drug administrations. On study day 2, all parameters were collected at 5 time points (0, 30, 60, 90min after medication and after the motor tasks). Finger-Tapping Task To assess simple motor reaction time, patients also performed a fast finger-tapping task in both sessions.42, 43 Patients were instructed to press a key with the paretic index finger as quickly as possible for a total of 10 seconds. The task was repeated 3 times, with 1-minute resting intervals between trials. The keypad was connected to a laboratory computer that recorded the frequency of tappings. Outcome Measures The primary outcome measure was the difference in reaction times between randomly and sequentially presented elements in the second block. The second block was defined as the primary outcome measure because sequential elements first have to be learned implicitly before an improvement in reaction times compared with the nonsequential (random) elements can be observed. As secondary outcome measures, we assessed reaction times to random elements, errors to random and errors to sequential elements, and correlations of procedural motor learning with neuropsychologic background measures. Additionally, we collected psychophysical parameters, information on side effects and blinding, and performance in a simple motor reaction task. Statistical Analysis Data analysis was performed by an investigator blind to the intervention type. No significant deviations from normal distribution could be determined for any of the dependent measures by using the Kolmogorov-Smirnov test of normality (set at P<.05) before data analysis. Primary outcome measure: procedural motor learning Procedural motor learning was defined as the difference in reaction times (in milliseconds) between random and sequential elements. Repeated-measures ANOVA was used to test the influence of the repeated factors block (1, 2) and condition (levodopa, placebo) on procedural motor learning. Because hand dominance may influence recovery,44, 45 a subgroup analysis was performed by dividing the study population into patients in whom the dominant hand was paretic and those in whom the nondominant hand was paretic. Secondary outcome measures related to the procedural motor learning task For reaction times to random elements, repeated-measures ANOVA was used to test the influence of the repeated factors block (1, 2) and condition (levodopa, placebo) on the reaction times (in milliseconds) subjects needed to respond to random elements. With this approach, drug effects on general motor arousal were assessed. For errors to random and sequential elements, repeated-measures ANOVA was used to test the influence of the repeated factors block (1, 2) and condition (levodopa, placebo) on the number of errors in response to random or sequential patterns. For neuropsychologic measures and procedural motor learning, correlations of neuropsychologic parameters with procedural motor learning in the levodopa condition were examined by using Pearson correlation coefficients with Bonferroni-adjusted significance levels. Secondary outcome measures not related to the procedural motor learning task For blood pressure, heart rate, and mood, repeated-measures ANOVA with a polynomial contrast analysis on the factor time was used to test the influence of the repeated factors time (day 2: 0, 30, 60, 90min; post) and condition (levodopa, placebo) on systolic blood pressure, diastolic blood pressure, heart rate, and mood ratings (positive and negative PANAS scores) over the course of the study on the second day of each session. For side effects and blinding, to determine if the occurrence of side effects differed between conditions (placebo, levodopa), statistical comparisons of frequency distributions (chi-square tests) were conducted for the second study day. A chi-square test was also used to test if blinding was successful. For the finger-tapping task, repeated-measures ANOVA was used to test the influence of the repeated factors trial (1, 2, 3) and condition (levodopa, placebo) on the number of taps a patient generated. Condition (levodopa, placebo) differences were analyzed post hoc by using paired t tests as appropriate. Data were considered significant at a level of P less than .05. All data are expressed as mean ± standard error of the mean unless stated otherwise. For clarity of presentation, only results involving the factor condition are reported. Results Primary Outcome Measure Procedural motor learning Repeated-measures ANOVA showed a significant interaction of condition by block (F1,17=5.19, P<.05). Post hoc analysis revealed that this was caused by a significant reaction time difference in the levodopa condition compared with the placebo condition in block 2 (paired t test, t17=−2.09; P<.05), the primary outcome measure, but not in block 1 (paired t test, t17=0.81; P=.43) (fig 3). Because recovery may be influenced by hand dominance,44, 45 we compared improvement in procedural motor learning under levodopa in patients in whom the dominant hand was paretic (n=10) with improvement in patients in whom the nondominant hand was paretic (n=8). We found a more pronounced improvement in patients with dominant hand paresis (unpaired t test, t16=2.63; P<.05). Secondary Outcome Measures Related to the Procedural Motor Learning Task Reaction times to random elements Reaction times to random elements were comparable between conditions. Repeated-measures ANOVA revealed no significant interaction of condition and block (F1,17=2.14, P=.16) or a significant main effect of condition (F1,17=0.46, P=.51), indicating that levodopa did not lead to an unspecific increase in motor arousal (fig 4). Errors to random and sequential elements Repeated-measures ANOVA showed no significant interaction of condition and block (F1,17=2.36, P=.14) for errors in response to sequential elements or a significant main effect of condition (F1,17=4.28, P=.06). For errors in response to random elements, repeated-measures ANOVA revealed a significant interaction of condition by block (F1,17=12.01, P<.01) caused by a significant lower error rate in the placebo condition for block 1 (paired t test, t17=–3.00; P<.01) but not for block 2 (paired t test, t17=0.93; P=.37), the primary outcome measure, indicating that levodopa did not lead to a change in response styles. During the placebo condition, subjects responded nonsignificantly slower to random elements in block 1 compared with levodopa. This more careful response strategy may have led to fewer errors. Neuropsychologic measures and procedural motor learning Procedural motor learning in the levodopa condition showed no significant association with neuropsychologic tests after correction for multiple comparisons. It was also noted that neuropsychologic tests that rely on fine motor control, like the TMT-A, did not show any correlation. Secondary Outcome Measures Not Related to the Procedural Motor Learning Task Blood pressure and heart rate Changes in blood pressure and heart rate on the second day of each session were comparable across conditions (levodopa: mean blood pressure, 126/74mmHg; mean heart rate, 64 beats/min; placebo: mean blood pressure, 126/75mmHg; mean heart rate, 65 beats/min). No significant interaction of time and condition or a significant main effect of condition emerged for systolic blood pressure, diastolic blood pressure, or heart rate. Mood For the PANAS, there were no significant interactions of time and condition for positive or negative feelings. The main effect of condition was significant for negative feelings only (linear trend: F1,17=7.39, P<.05) because of a significantly lower score (corresponding to better mood) in the levodopa condition compared with the placebo (paired t test, t17=2.72; P<.05). No significant correlation emerged between “the magnitude of negative PANAS scores” and “procedural motor learning” in the levodopa condition (r=–.36, P=.15), indicating that better learning in the levodopa condition was not mediated by differences in mood. Side effects In the levodopa condition, 1 patient reported dizziness, 2 fatigue, and 2 nausea. In the placebo condition, 2 patients reported fatigue and 1 patient nausea. Statistical comparisons of frequency distributions between conditions were not significant for dizziness (P=.31), fatigue (P=1.00), or nausea (P=.55). Blinding Participants were unable to distinguish between levodopa and placebo sessions (P=.10). Finger-tapping task The number of taps was comparable between conditions (levodopa, placebo). Repeated-measures ANOVA revealed no significant interaction of condition and trial (linear trend: F2,34=.18, P=.84) or a significant main effect of condition (linear trend: F1,17=.39, P=.56), indicating that levodopa did not lead to an enhanced performance in a simple motor reaction time task (fig 5). Discussion The main finding of this study was that 3 oral doses of levodopa, administered over the course of 2 days, significantly improved procedural motor learning in patients with chronic stroke compared with placebo. This finding suggests that dopaminergic neuromodulation, if combined with training, may enhance the acquisition of motor skills in the chronic stage of stroke when physical or occupational therapy alone often lack success. The difference between the levodopa and placebo conditions was not mediated by differences in mood. The positive effects of levodopa on motor learning were thus direct effects on procedural motor learning. Mechanisms for Dopamine-Enhanced Learning The formation of new memories or the acquisition of new skills is accompanied by changes in neuronal activity and excitability46, 47 (eg, N-methyl-d-aspartate receptor-dependent LTP).48, 49, 50, 51 One of the major mechanisms to promote LTP is dopaminergic neuromodulation.17, 18, 52 The proposed effect of dopamine release is to increase the signal-to-noise ratio by strengthening task-relevant synapses while suppressing neighboring (task irrelevant) ones.53 For the motor system, basic science studies have shown that formation of motor memories, which involves LTP-like processes,54, 55, 56, 57 is enhanced by dopamine,17, 18, 52 not only in the hippocampus but also in the cortex58, 59, 60 and the striatum.53 A previous study of our group, using molecular imaging, showed that levodopa administration compared with placebo leads to incremental release of dopamine in the striatum during training for motor memories.61 In the present study, patients in whom the dominant hemisphere was affected were able to benefit to a larger degree from the levodopa intervention compared with patients in whom the nondominant hemisphere was affected. Interhemispheric inhibition from the dominant hemisphere is stronger onto the nondominant hemisphere,44 and previous studies62 have indicated that inhibition from the noninjured onto the injured hemisphere may impair recovery. Stroke patients in whom the nondominant hemisphere is affected may suffer from a larger inhibition onto the affected hemisphere. Thus, they may only receive little improvement from an intervention aimed at improving dopaminergic neurotransmission but would rather benefit from interventions aimed at reducing interhemispheric inhibition, like cutaneous anesthesia43 or transcranial magnetic stimulation.63, 64 This hypothesis could be tested in future studies that directly compared interventions modulating interhemispheric inhibition with those modulating neurotransmitter levels in different patient groups. Previous Studies on Dopaminergic Neuromodulation and Motor Learning In several animal studies, a positive effect of dopamine or dopamine agonists on synaptic plasticity, learning,10, 17 and recovery after brain lesions65 was found, whereas haloperidol, a dopamine antagonist, impaired recovery.66 Experimental studies in healthy humans showed that premedication with levodopa20 and cabergoline, a D2-receptor dopamine agonist,21 improved the formation of elementary motor memories, whereas haloperidol had an inhibiting effect.21 Clinical trials on the effect of levodopa on motor learning are scarce. Only 2 trials with clinical endpoints (motor function, ADLs) so far have assessed the impact of levodopa on stroke recovery. Scheidtmann et al19 showed that overall motor function was significantly better for patients in the subacute state after stroke who received physical therapy and levodopa compared with those who received physical therapy only. A more recent study67 could only show a trend toward better recovery. However, both trials assessed patients in the subacute stage with intervals between stroke onset and treatment ranging from 3 weeks to 6 months. In this phase, spontaneous recovery still occurs.68, 69 Thus, it is difficult to differentiate spontaneous from therapy-induced recovery, especially because the authors did not use a crossover design. Additionally, the subgroup sample size in the trial by Sonde and Lokk67 was small, and treatment groups were heterogeneous with respect to their initial impairment. Only 1 study so far examined the impact of levodopa premedication in chronic stroke patients (≥1y poststroke).9 This period is clinically crucial given the enormous long-term disabilities in the chronic poststroke phase, which cannot be improved by training alone. However, the number of patients in this study was small (n=9), and only elementary motor memory formation was assessed. With regard to the reacquisition of ADLs, more complex motor behavior should be the target for investigation (ie, procedural motor learning). This type of learning is crucial for the (re-)acquisition of motor skills, like tying one's shoes, and the acquisition of novel associations between environmental events and motor actions, like learning to manipulate a tool.24 Motor learning is therefore essential to regain lost function and thus personal independence in patients with chronic motor deficits. Study Limitations The study design did not involve a retention trial. Therefore, we do not know how long the effects of levodopa on procedural motor learning lasted. Future studies should include follow-up assessments to determine if the beneficial effects of levodopa extend beyond the training session. Additionally, training plus levodopa sessions must be extended to several weeks to maximize the rehabilitative gain. Conclusions The present study shows that levodopa boosts behaviorally relevant procedural motor learning in the chronic stage after stroke. Because medication with levodopa carries no serious cardiovascular risks compared with amphetamines,19, 70, 71 it may represent a useful adjuvant during a period of extensive exercise in neurorehabilitation. Thus, our results lay the foundation for further clinical trials investigating the effects of intense training combined with dopaminergic neuromodulation in patients suffering from chronic motor deficits after stroke. Suppliers References 1. 1Dennis MS, Burn JP, Sandercock PA, Bamford JM, Wade DT, Warlow CP. Long-term survival after first-ever stroke: the Oxfordshire Community Stroke Project. Stroke. 1993;24:796–800. MEDLINE 2. 2Ferrucci L, Bandinelli S, Guralnik JM, et al. Recovery of functional status after stroke (A postrehabilitation follow-up study). Stroke. 1993;24:200–205. MEDLINE 3. 3Rossini PM, Calautti C, Pauri F, Baron JC. 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a Department of Neurology, University of Münster, Münster, Germany b Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany c IMF Münster, University of Münster, Münster, Germany  Reprint requests to Agnes Flöel, MD, Dept of Neurology, University of Münster, Albert-Schweitzer-Str 33, 48149 Münster, Germany
Supported by the Deutsche Forschungsgemeinschaft (grant no. FL 379-4/1), the Bundesministerium für Forschung und Bildung (grant no. 01GW0520), the Innovative Medizinische Forschung Münster (grant nos. FL110605, KN520301), and the Volkswagen Stiftung (grant no. Az I/80 708). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. PII: S0003-9993(08)00434-6 doi:10.1016/j.apmr.2008.02.030 © 2008 American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved. | |
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