Archives of Physical Medicine and Rehabilitation
Volume 89, Issue 9 , Pages 1633-1641, September 2008

Levodopa Improves Procedural Motor Learning in Chronic Stroke Patients

  • Nina Rösser, MA

      Affiliations

    • Department of Neurology, University of Münster, Münster, Germany
    • ,
  • Peter Heuschmann, MD, MPH

      Affiliations

    • Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
    • ,
  • Heike Wersching, MD

      Affiliations

    • Department of Neurology, University of Münster, Münster, Germany
    • ,
  • Caterina Breitenstein, PhD

      Affiliations

    • Department of Neurology, University of Münster, Münster, Germany
    • IMF Münster, University of Münster, Münster, Germany
    • ,
  • Stefan Knecht, MD

      Affiliations

    • Department of Neurology, University of Münster, Münster, Germany
    • ,
  • Agnes Flöel, MD

      Affiliations

    • Department of Neurology, University of Münster, Münster, Germany
    • IMF Münster, University of Münster, Münster, Germany
    • Corresponding Author InformationReprint requests to Agnes Flöel, MD, Dept of Neurology, University of Münster, Albert-Schweitzer-Str 33, 48149 Münster, Germany

Article Outline

Abstract 

Rösser N, Heuschmann P, Wersching H, Breitenstein C, Knecht S, Flöel A. Levodopa improves procedural motor learning in chronic stroke patients.

Objective

To 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).

Design

A double-blind, placebo-controlled, randomized crossover design.

Setting

Neurology department in a German university.

Participants

Eighteen patients with chronic motor dysfunction because of stroke (13 men, 5 women; age range, 53–78y; mean time poststroke ± SD, 3.3±2.1y).

Intervention

Patients received 3 doses of levodopa (100mg of levodopa plus 25mg of carbidopa) or placebo before 1 session of procedural motor learning.

Main Outcome Measures

Procedural 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.

Results

Levodopa 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.

Conclusions

Our 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.)

Key Words: Levodopa, Motor skills disorders, Neurologic manifestations, Reaction time, Rehabilitation, Stroke

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.

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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).

Table 1. Patient Characteristics
Patient No.Age (y)SexEducation (y)Years After StrokeTaken Medication⁎Lesioned Hemisphere and LocationHandedness†Motor Function
MRC33MAS35RMA36
0162M13.06.31,2,7Right basal gangliaRH/1004.5112
0267M13.02.71,2,5,6,10Right insula, caudate nucleusRH/1004.5012
0375M18.02.61,2,6,7,11Right parietal cortexRH/1004.5012
0453F12.01.57,11Left frontal cortexRH/1004.5012
0562M14.01.57,2,4,6Left frontal cortexRH/805013
0661M13.55.46,7Left basal gangliaRH/1004.5112
0778F11.03.27Left basal ganglia, parietal-occipital cortexRH/1004.5014
0861M12.01.94,6,7,8Right basal ganglia, temporoparietal cortexRH/1004.5014
0965M18.01.71,2,3,6,7Left corona radiataRH/905015
1069M11.04.51,2,3,4,10Right basal gangliaRH/1004.5111
1170M11.01.31,2,6,8Left corona radiata, nucleus lentiformisLH/704.5110
1256F13.022,4,6,7Right corona radiataRH/804.5110
1369F11.01.81,2,4,8Left insula, parietalRH/1005111
1468M16.02.32,4,8Left frontal cortexRH/804.5012
1562F14.08.32,6,8Left frontoparietal cortexRH/1005014
1674M17.06.42,4,8Left posterolateral temporal lobeRH/1004.5010
1775M11.01.54,6,10Right thalamicRH/805013
1868M12.04.52,6,7Left basal gangliaRH/1004.5011
Mean66.4 13.43.3 93.34.60.312.1
SD6.8 2.42.1 10.30.20.51.5

Abbreviations: F, female; LH, left-handedness before stroke; M, male; MAS, Modified Ashworth Scale; RH, right-handedness before stroke; RMA, Rivermead Motor Assessment.

⁎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.

Inclusion criteria 

All patients fulfilled the following inclusion criteria: (1) subcortical or cortical stroke at least 1 year before inclusion in the study, (2) initial severe hemiparesis (MRC scale32 score <2) that had recovered to a degree so that they were able to perform the experimental tasks (MRC scale score ≥4.5, with low spasticity) (see table 1), (3) MMSE33 score of 27 or higher (table 2), and (4) age between 50 and 80 years.

Table 2. Neuropsychologic Testing
Patient No.WMS VerPA 1–3/RecallWMS VisPA 1–3/RecallWMS Digit Span Forward/Backward (% rank)TMT-A/TMT-B (% rank)RWT S-Words (% rank)Complex Figure Copy/RecallVLMT List A Learning/Delayed Free Recall (% rank)MMSE Score
0124/84/177/6710/207925.5/7.540/3530
0222/76/376/1310/108630.0/7.025/2528
0317/67/228/1310/202228.0/5.530/2529
0419/713/613/3410/20536.0/14.020/2029
0514/63/488/8030/304319.0/11.040/4529
0624/79/388/3810/407631.0/19.065/2029
0722/812/476/2780/306336.0/10.025/3529
0823/810/598/8810/303136.0/18.540/529
0924/815/698/9360/909834.0/17.080/9529
1016/86/228/1310/204815.0/3.020/2529
1114/613/55/5320/205232.0/16.020/4529
1221/714/620/1210/205033.0/18.040/2030
1320/814/528/2710/205233.0/13.025/3530
1419/74/488/5320/202236.0/15.050/2530
1519/814/62/3810/10436.0/19.070/9530
1618/614/628/2710/20234.0/15.05/530
1722/817/628/1390/609936.0/22.060/4530
1820/83/528/1310/202233.0/11.05/1030
Mean19.9/7.39.9/4.449.8/39.023.3/27.847.431.4/13.436.7/33.929.4
SD3.2/0.84.7/1.634.7/27.425.7/19.331.46.0/5.321.5/25.40.6

Abbreviations: Complex Figure Copy, Rey-Osterrieth complex figure copy (drawing of the draft); Complex Figure Recall, Rey-Osterrieth complex figure recall (delayed recall after 30 minutes); RWT, Regensburger Wortflüssigkeitstest (German version of the Controlled Oral Word Association Test); S Words, subtest s-words (phonematic word fluency); VerPA 1–3, verbal paired associates subtest (sum of blocks 1–3); VerPA recall, verbal paired associates subtest (delayed recall); VisPA 1–3, visual paired associates subtest (sum of blocks 1–3); VisPA recall, visual paired associates subtest (delayed recall); VLMT, Verbaler Lern- und Merkfähigkeitstest (German version of the Rey Auditory Verbal Learning Test) list A learning, sum of scores in block 1–5; Verbaler Lern- und Merkfähigkeitstest, delayed free recall, recall of list A after 30 minutes.

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.

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  • Fig 1. 

    Overview of the study design: (A) Prestudy day: examination and familiarization; (B) study day 1: dose 1 (left) and dose 2 (right); and (C) study day 2: dose 3 and motor tasks. Abbreviations: PA, psychophysical assessment, taken every 30 minutes, starting at time 0 after medication, including systolic and diastolic blood pressure, heart rate, PANAS, and side effects (fatigue, dizziness, nausea); post, posttraining.

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.

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  • Fig 2. 

    The procedural motor learning task. The left side of the figure shows a patient performing the procedural motor learning task. Patients sat in front of a monitor and were asked to press the key on a special keypad corresponding to a given asterisk on the screen as fast as possible. The right side of the figure shows the schematic setup of the task. Note that the correct button in the presented arrangement is highlighted in gray.

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.

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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).

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  • Fig 3. 

    Results for procedural motor learning (procedural motor learning task). Abbreviation: RT, reaction time. Note that conditions differed significantly in block 2, the primary outcome measure, with larger procedural motor learning in the levodopa condition. Error bars indicate the standard error of the mean. *P<.05.

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).

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  • Fig 4. 

    Reaction times to random elements (procedural motor learning task). Abbreviation: RT, reaction time. Note that the overall reaction time did not differ between conditions in block 2. Error bars indicate the standard error of the mean.

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).

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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.

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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.

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References 

  1. Dennis 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
  2. Ferrucci L, Bandinelli S, Guralnik JM, et al. Recovery of functional status after stroke (A postrehabilitation follow-up study). Stroke. 1993;24:200–205
  3. Rossini PM, Calautti C, Pauri F, Baron JC. Post-stroke plastic reorganisation in the adult brain. Lancet Neurol. 2003;2:493–502
  4. Chen R, Cohen LG, Hallett M. Nervous system reorganization following injury. Neuroscience. 2002;111:761–773
  5. Taub E, Uswatte G, Elbert T. New treatments in neurorehabilitation founded on basic research. Nat Rev Neurosci. 2002;3:228–236
  6. Cabeza R. Cognitive neuroscience of aging: contributions of functional neuroimaging. Scand J Psychol. 2001;42:277–286
  7. Li SC, Sikstrom S. Integrative neurocomputational perspectives on cognitive aging, neuromodulation, and representation. Neurosci Biobehav Rev. 2002;26:795–808
  8. Hedden T, Gabrieli JD. Insights into the ageing mind: a view from cognitive neuroscience. Nat Rev Neurosci. 2004;5:87–96
  9. Floel A, Hummel F, Breitenstein C, Knecht S, Cohen LG. Dopaminergic effects on encoding of a motor memory in chronic stroke. Neurology. 2005;65:472–474
  10. Bao S, Chan VT, Merzenich MM. Cortical remodelling induced by activity of ventral tegmental dopamine neurons. Nature. 2001;412:79–83
  11. Goerendt IK, Messa C, Lawrence AD, Grasby PM, Piccini P, Brooks DJ. Dopamine release during sequential finger movements in health and Parkinson's disease: a PET study. Brain. 2003;126(Pt 2):312–325
  12. Roelfsema PR, Engel AK, König P, Singer W. Visuomotor integration is associated with zero time-lag synchronization among cortical areas. Nature. 1997;385:157–161
  13. Stelmach GE, Worringham CJ, Strand EA. The programming and execution of movement sequences in Parkinson's disease. Int J Neurosci. 1987;36:55–65
  14. Carlsson A. Age-dependent changes in central dopaminergic and other monoaminergic systems. Adv Exp Med Biol. 1978;113:1–13
  15. Fearnley JM, Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain. 1991;114(Pt 5):2283–2301
  16. Volkow ND, Gur RC, Wang GJ, et al. Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals. Am J Psychiatry. 1998;155:344–349
  17. Jay TM. Dopamine: a potential substrate for synaptic plasticity and memory mechanisms. Prog Neurobiol. 2003;69:375–390
  18. Wise RA. Dopamine, learning and motivation. Nat Rev Neurosci. 2004;5:483–494
  19. Scheidtmann K, Fries W, Müller F, Koenig E. Effect of levodopa in combination with physiotherapy on functional motor recovery after stroke: a prospective, randomised, double-blind study. Lancet. 2001;358:787–790
  20. Floel A, Breitenstein C, Hummel F, et al. Dopaminergic influences on formation of a motor memory. Ann Neurol. 2005;58:121–130
  21. Meintzschel F, Ziemann U. Modification of practice-dependent plasticity in human motor cortex by neuromodulators. Cereb Cortex. 2006;16:1106–1115
  22. Rosenbaum DA, Carlson RA, Gilmore RO. Acquisition of intellectual and perceptual-motor skills. Annu Rev Psychol. 2001;52:453–470
  23. Cohen NJ, Squire LR. Preserved learning and retention of pattern-analyzing skill in amnesia: dissociation of knowing how and knowing that. Science. 1980;210:207–210
  24. Sanes JN. Neocortical mechanisms in motor learning. Curr Opin Neurobiol. 2003;13:225–231
  25. Nissen MJ. Attentional requirements of learning: evidence from performance measures. Cogn Psychol. 1987;19:1–32
  26. Steinberg GK, Bell TE, Yenari MA. Dose escalation safety and tolerance study of the N-methyl-d-aspartate antagonist dextromethorphan in neurosurgery patients. J Neurosurg. 1996;84:860–866
  27. Howard JH, Howard DV. Age differences in implicit learning of higher order dependencies in serial patterns. Psychol Aging. 1997;12:634–656
  28. Berns GS, Cohen JD, Mintun MA. Brain regions responsive to novelty in the absence of awareness. Science. 1997;276:1272–1275
  29. Maquet P. Sleep on it!. Nat Neurosci. 2000;3:1235–1236
  30. Jimenez L, Mendez C, Cleeremans A. Comparing direct and indirect measures of sequence learning. J Exp Psychol Learn Mem Cogn. 1996;22:948–969
  31. Cleeremans A, McClelland JL. Learning the structure of event sequences. J Exp Psychol Gen. 1991;120:235–253
  32. Medical Research Council. Aids to examination of the peripheral nervous system. London: HMSO; 1976.
  33. Folstein MF, Robins LN, Helzer JE. The Mini-Mental State Examination. Arch Gen Psychiatry. 1983;40:812
  34. Bohannon RW, Smith MB. Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther. 1987;67:206–207
  35. Lincoln N, Leadbitter D. Assessment of motor function in stroke patients. Physiotherapy. 1979;65:48–51
  36. Knecht S, Breitenstein C, Bushuven S, et al. Levodopa: faster and better word learning in normal humans. Ann Neurol. 2004;56:20–26
  37. Goldberg LI. Dopamine-receptors and hypertension (Physiologic and pharmacologic implications). Am J Med. 1984;77:37–44
  38. Murphy MB, Elliott WJ. Dopamine and dopamine receptor agonists in cardiovascular therapy. Crit Care Med. 1990;18(1 Pt 2):S14–S18
  39. Watson D, Clark LA, Tellegen A. Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol. 1988;54:1063–1070
  40. Krohne HW, Egloff B, Kohlmann CW, Tausch A. Investigations with a German version of the positive and negative affect schedule (PANAS). Diagnostica. 1996;42:139–156
  41. Rascol O, Brefel-Courbon C, Payoux P, Ferreira J. The management of patients with early Parkinson's disease. Adv Neurol. 2003;91:203–211
  42. Werhahn KJ, Conforto AB, Kadom N, Hallett M, Cohen LG. Contribution of the ipsilateral motor cortex to recovery after chronic stroke. Ann Neurol. 2003;54:464–472
  43. Floel A, Nagorsen U, Werhahn KJ, et al. Influence of somatosensory input on motor function in patients with chronic stroke. Ann Neurol. 2004;56:206–212
  44. Baumer T, Dammann E, Bock F, Klöppel S, Siebner HR, Münchau A. Laterality of interhemispheric inhibition depends on handedness. Exp Brain Res. 2007;180:195–203
  45. Zemke AC, Heagerty PJ, Lee C, Cramer SC. Motor cortex organization after stroke is related to side of stroke and level of recovery. Stroke. 2003;34:e23–e28
  46. Karni A, Meyer G, Jezzard P, Adams MM, Turner R, Ungerleider LG. Functional MRI evidence for adult motor cortex plasticity during motor skill learning. Nature. 1995;377:155–158
  47. Muellbacher W, Ziemann U, Wissel J, et al. Early consolidation in human primary motor cortex. Nature. 2002;415:640–644
  48. Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361:31–39
  49. Hess G, Aizenman CD, Donoghue JP. Conditions for the induction of long-term potentiation in layer II/III horizontal connections of the rat motor cortex. J Neurophysiol. 1996;75:1765–1778
  50. Rioult-Pedotti MS, Friedman D, Hess G, Donoghue JP. Strengthening of horizontal cortical connections following skill learning. Nat Neurosci. 1998;1:230–234
  51. Rioult-Pedotti MS, Friedman D, Donoghue JP. Learning-induced LTP in neocortex. Science. 2000;290:533–536
  52. Bailey CH, Giustetto M, Huang YY, Hawkins RD, Kandel ER. Is heterosynaptic modulation essential for stabilizing Hebbian plasticity and memory?. Nat Rev Neurosci. 2000;1:11–20
  53. Wickens J, Kotter R. Cellular models of reinforcement. In:  Houk J editors. Models of information processing in the basal ganglia. Cambridge: MIT Pr; 1995;p. 187–214
  54. Bütefisch CM, Davis BC, Wise SP, et al. Mechanisms of use-dependent plasticity in the human motor cortex. Proc Natl Acad Sci U S A. 2000;97:3661–3665
  55. Bütefisch CM, Davis BC, Sawaki L, et al. Modulation of use-dependent plasticity by d-amphetamine. Ann Neurol. 2002;51:59–68
  56. Sawaki L, Cohen LG, Classen J, Davis BC, Bütefisch CM. Enhancement of use-dependent plasticity by D-amphetamine. Neurology. 2002;59:1262–1264
  57. Sawaki L, Werhahn KJ, Barco R, Kopylev L, Cohen LG. Effect of an alpha(1)-adrenergic blocker on plasticity elicited by motor training. Exp Brain Res. 2003;148:504–508
  58. Garris PA, Wightman RM. Different kinetics govern dopaminergic transmission in the amygdala, prefrontal cortex, and striatum: an in vivo voltammetric study. J Neurosci. 1994;14:442–450
  59. Otani S, Blond O, Desce JM, Crépel F. Dopamine facilitates long-term depression of glutamatergic transmission in rat prefrontal cortex. Neuroscience. 1998;85:669–676
  60. Smith R, Musleh W, Akopian G, Buckwalter G, Walsh JP. Regional differences in the expression of corticostriatal synaptic plasticity. Neuroscience. 2001;106:95–101
  61. Floel A, Garraux G, Xu B, et al. Levodopa increases memory encoding and dopamine release in the striatum in the elderly. Neurobiol Aging. 2008;29:267–279
  62. Murase N, Duque J, Mazzocchio R, Cohen LG. Influence of interhemispheric interactions on motor function in chronic stroke. Ann Neurol. 2004;55:400–409
  63. Mansur CG, Fregni F, Boggio PS, et al. A sham stimulation-controlled trial of rTMS of the unaffected hemisphere in stroke patients. Neurology. 2005;64:1802–1804
  64. Takeuchi N, Chuma T, Matsuo Y, Watanabe I, Ikoma K. Repetitive transcranial magnetic stimulation of contralesional primary motor cortex improves hand function after stroke. Stroke. 2005;36:2681–2686
  65. Grondin R, Zhang Z, Gerhardt GA, Gash DM. Dopaminergic therapy improves upper limb motor performance in aged rhesus monkeys. Ann Neurol. 2000;48:250–253
  66. Corwin JV, Kanter S, Watson RT, Heilman KM, Valenstein E, Hashimoto A. Apomorphine has a therapeutic effect on neglect produced by unilateral dorsomedial prefrontal cortex lesions in rats. Exp Neurol. 1986;94:683–698
  67. Sonde L, Lokk J. Effects of amphetamine and/or L-dopa and physiotherapy after stroke—a blinded randomized study. Acta Neurol Scand. 2007;115:55–59
  68. Hendricks HT, van Limbeek J, Geurts AC, Zwarts MJ. Motor recovery after stroke: a systematic review of the literature. Arch Phys Med Rehabil. 2002;83:1629–1637
  69. Kreisel SH, Bazner H, Hennerici MG. Pathophysiology of stroke rehabilitation: temporal aspects of neurofunctional recovery. Cerebrovasc Dis. 2006;21:6–17
  70. Scheidtmann K. Advances in adjuvant pharmacotherapy for motor rehabilitation: effects of levodopa. Restor Neurol Neurosci. 2004;22:393–398
  71. Martinsson L, Hardemark HG, Wahlgren NG. Amphetamines for improving stroke recovery: a systematic Cochrane review. Stroke. 2003;34:2766
  72. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia. 1971;9:97–113
  • a Acon Laboratories, 4108 Sorrento Valley Blvd, San Diego, CA 92121.
  • b Version 9.70; Neurobehavioral Systems Inc, 828 San Pablo Ave, Ste 216, Albany, CA 94706-1564.
  • c Bose medicus memory; Bosch, Bahnhofsstr 64, 72417 Jungingen, 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

Archives of Physical Medicine and Rehabilitation
Volume 89, Issue 9 , Pages 1633-1641, September 2008

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