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Deficit di controllo, mantenimento e apprendimento motorio nella malattia del Parkinson.
Motor Skill Learning, Retention, and Control Deficits inParkinson’s DiseaseLisa Katharina Pendt1*, Iris Reuter2, Hermann Muller1 ¨1 Department of Psychology and Sport Science, Justus-Liebig-University, Giessen, Germany, 2 Department of Neurology, Justus-Liebig-University, Giessen, Germany Abstract Parkinson’s disease, which affects the basal ganglia, is known to lead to various impairments of motor control. Since the basal ganglia have also been shown to be involved in learning processes, motor learning has frequently been investigated in this group of patients. However, results are still inconsistent, mainly due to skill levels and time scales of testing. To bridge across the time scale problem, the present study examined de novo skill learning over a long series of practice sessions that comprised early and late learning stages as well as retention. 19 non-demented, medicated, mild to moderate patients with Parkinson’s disease and 19 healthy age and gender matched participants practiced a novel throwing task over five days in a virtual environment where timing of release was a critical element. Six patients and seven control participants came to an additional long-term retention testing after seven to nine months. Changes in task performance were analyzed by a method that differentiates between three components of motor learning prominent in different stages of learning: Tolerance, Noise and Covariation. In addition, kinematic analysis related the influence of skill levels as affected by the specific motor control deficits in Parkinson patients to the process of learning. As a result, patients showed similar learning in early and late stages compared to the control subjects. Differences occurred in short-term retention tests; patients’ performance constantly decreased after breaks arising from poorer release timing. However, patients were able to overcome the initial timing problems within the course of each practice session and could further improve their throwing performance. Thus, results demonstrate the intact ability to learn a novel motor skill in non-demented, medicated patients with Parkinson’s disease and indicate confounding effects of motor control deficits on retention performance. ¨ Citation: Pendt LK, Reuter I, Muller H (2011) Motor Skill Learning, Retention, and Control Deficits in Parkinson’s Disease. PLoS ONE 6(7): e21669. doi:10.1371/ journal.pone.0021669 Editor: Efthimios M. C. Skoulakis, Alexander Flemming Biomedical Sciences Research Center, Greece Received February 10, 2011; Accepted June 5, 2011; Published July 8, 2011 Copyright: ß 2011 Pendt et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the German Research Foundation (DFG, http://www.dfg.de/en/index.jsp) [MU 1374/3-1] and the German National Academic Foundation (Studienstiftung des deutschen Volkes, http://www.studienstiftung.de/en/start.html) [to L.K.P.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: firstname.lastname@example.orgIntroduction learning tasks to investigate de novo motor learning and they suggest that in sequence learning tasks, the cerebellum is Parkinson’s disease (PD) is a neurodegenerative disease that predominant over the BG in early sequence learning. Thismostly affects the basal ganglia (BG). Drug therapy or surgical predominance decreases again with further practice [24–26,3]treatment can provide relief from the predominant motor symptoms and more BG activation is reported to occur later whensuch as rigor, tremor, bradykinesia, hypokinesia, and hypometria. performance reaches an asymptotic level [27,26,3,28]. Further-As there is currently no cure to the disease and the symptoms more, there is evidence from few studies that the BG are alsoworsen with the progression of the disease, movement therapy is important for the retention of learned motor skills . Thus, inimportant to delay the loss of motor function. In that sense, practice, patients with BG dysfunctions, de novo motor learning can bestabilization, and retention of movements, i.e. motor learning, play differently affected depending on the learning stage. To oura major role in preserving quality of life in PD patients as long as knowledge, there is no study specifically investigating motorpossible. Since several lines of research provided evidence of BG learning of PD patients as a function of the learning stage.involvement in motor learning [1–8], a considerable number of However, there are studies where, according to the study design,studies has tried to answer the question whether and how strong PD results suggest intact early learning for non-demented medicatedpatients are impaired in learning motor skills. Although most studies patients [9,20,29,10,13], as well as differences between patients andhave found impaired motor learning in PD patients [9–19], the control group in later stages [10,13]. There are only few studiesconclusions about characteristic learning deficits of PD patients investigating retention of performance in PD over at least 24 hours.are inconsistent; some find no impairments at all [20–23]. Besides Some suggest that retention might be impaired in PD patientsmethodological differences, operationalizations and specifics of the [30,12,31] but others report intact retention [32,13,14,23].patient populations, different foci on distinct learning stages can The inconsistencies in retention results can additionally beaccount for discrepancies between studies because the BG are explained by confounding effects of motor deficits. Observations ofvariably involved in the process of motor learning. such effects are frequently reported, although not systematically In de novo motor learning, one typically distinguishes early from investigated. For instance, Swinnen et al.  showed thatlate learning stages. Neuroimaging studies mostly use sequence retention performance of PD patients can be influenced by motor PLoS ONE | www.plosone.org 1 July 2011 | Volume 6 | Issue 7 | e21669
Motor Skill Learning in Parkinson’s Diseasecontrol deficits. They had PD patients practice a bimanual figure criteria for both groups were any other neurological disease,drawing task over two days and reported performance decreases of orthopedic issues, and global cognitive deterioration as indicatedthe patients at the beginning of new practice sessions that could be by performance below 24 points on the German version of theascribed to bradykinesia and hypometria. Similarly, Smiley-Oyen Minimal Mental State Examination (MMSE) (originally ). Allet al.  showed that PD patients had poorer performance in a participants had normal or corrected to normal vision and they allmovement scaling task (underscaling) at the beginning of practice were right-handed and used their right hand for the task. Patientsand at a 24 h-retention test which might be related to hypometria. had either bilateral or right unilateral symptoms.In agreement with this, other studies report a similar influence ofmotor control deficits on motor learning [10,34,19]. Task and Apparatus The purpose of this study is to analyze motor learning of a novel skill The experimental task was a semi-virtual throwing task calledin medicated, mild to moderate, non-demented PD patients with Skittles that has been used in other studies [37–39]. The idea ofrespect to different learning stages, as well as the influence of the task comes from a British pub game where a ball is suspendedsymptomatic control deficits on the motor learning measure. from a string attached to the tip of a vertical post. The player hasMoreover, since retention of a practiced task is not well investigated to throw the ball around the post in order to knock down a targetin PD, we put a special emphasis on short- and long-term retention of skittle on the other side (Fig. 1A). The movements of theperformance, which is scrutinized by retention tests after varying time participants in the experimental task were real, whereas the ballperiods. flight was virtual. Participants saw the work space of the task in With respect to learning stages, we conceptually distinguish early two dimensions from a bird’s eye view on the projection surfacefrom late learning in a novel motor skill as follows: Early learning is from which they sat approximately 2 m away. The post in thereferred to using the concept of sensorimotor transformation. That center of the work space was represented by a circle of 25 cmis, a mapping between sensory inputs and motor commands needs diameter at position x = 0, y = 0. A circular target of 5 cm radiusto be established in order to solve a particular motor task . This was presented with its center 35 cm to the right and 100 cm aboveprocess occurs early in practice and improvements evolve relatively the center of the post. The virtual arm was represented as a solidfast. With continued practice, the mapping is incrementally fine- bar of 40 cm length, fixed at one end (Fig. 1B). Sitting frontal totuned through constant comparison, selection and reinforcement of the projection screen, the participant rested his or her forearm onappropriate motor commands, as well as inhibition of unwanted, a metal arm (the manipulandum) with a plastic support paddedperturbing commands. We will call this fine-tuning stage. It is with foam rubber. The horizontal manipulandum was fixedimportant, however, to mention that those phases do not develop in to a vertical support adjusted to a comfortable height for eacha discrete manner but rather overlap. Hence, they cannot be exactly participant and pivoted around an axle centered directlytemporally determined. Usually, stages are approximated from the underneath the elbow joint. The elbow was fixed with a Velcroamount of practice , evoked by experimental conditions , or strap. Rotations of the arm were measured by a 5-turnspecifically the fine-tuning stage is represented by reduction of potentiometer with a rate of 1000 samples/s. By touching anvariability . We will use a method that exclusively andexhaustively identifies different components whose contribution to electrical switch at the free end of the metal arm, the virtual ballperformance improvement varies across different learning stages was attached to the virtual arm on the projection. Upon releasing(see Methods). Analysis of kinematic variables is used to highlight the contact, the electrical current was disrupted and this accountedthe influences of motor control deficits (see Methods). as trigger for releasing the virtual ball. Participants first closed the Thus, focusing on de novo learning over a long series of practice switch with their index finger, then rotated the forearm in ansessions and based on the neuroimaging and patient literature, we outward horizontal motion and simultaneously released the switch.can expect that mild to moderate, medicated, non-demented PD The ball traversed on a trajectory initialized by the angle andpatients show similar improvements in early learning stages velocity of the participant’s arm at the moment of release. Both thecompared to healthy people (1), and that differences occur movements of the arm and the simulated trajectory of the ballpreferentially in later phases of fine-tuning (2). Not many studiesinvestigated retention in PD, and results are inconsistent. Hence, Table 1. Demographic and clinical characteristics of PD andwe will not formulate an explicit expectation with respect to control group for the five-day practice sessions.retention, but in reference to Swinnen et al.  and Smiley-Oyenet al. , we scrutinize whether retention deficits might beinfluenced by the typical parkinsonian motor control deficits (3). PD (n = 19) CG (n = 19) Variable M SD Range M SD RangeMaterials and Methods Age 63.9 8.8 45–77 64.8 10.1 44–80Ethics Statement Duration of PD (years) 6.8 5.7 1–20 All subjects were informed about the purpose of the study and UPDRS motor score 26 9 11–41gave written informed consent. The protocol was approved by the H&Y 1.5–3Ethical Review Board of the Justus-Liebig University, Giessen. MMSE 27.6 2.3 22–30 28.6 1.3 26–30Participants Medication (mg): 459.5 192 187.5–900 Levodopa (n = 19) 19 patients with Parkinson’s disease (PD) and 19 age and gendermatched healthy subjects participated in the study. The PD Carbidopa (n = 19) 112 48 47–187.5patients were tested on medication and they all fulfilled the UK Entacapon (n = 8) 771.4 335.2 200–1200Brain Bank Criteria for the clinical diagnosis of PD. Six patients UPDRS = Unified Parkinson’s disease Rating Scale.and seven control participants agreed to come to an additional H&Y = Hoehn and Yahr rating scale.retention testing after 7–9 months. Demographic and clinical MMSE = Mini Mental State Examination.information of the participants is given in Table 1 and 2. Exclusion doi:10.1371/journal.pone.0021669.t001 PLoS ONE | www.plosone.org 2 July 2011 | Volume 6 | Issue 7 | e21669
Motor Skill Learning in Parkinson’s Disease Table 2. Demographic and clinical characteristics of PD and new, even for participants with extensive throwing experience. control group for the long-term retention session. The center post between arm and target impeded trivial solutions, i.e. releasing with zero velocity. PD (n = 6) CG (n = 7) Experimental Design and Procedure Participants were instructed to throw the ball in a counter- Variable M SD Range M SD Range clockwise direction around the center post in order to hit the target. Age 62 11.33 46–79 68 9.1 53–80 The movement direction was clockwise, similar to performing a Duration of PD in years 5 0.9 4–6 Frisbee backhand. After every 10 trials, a summed score, reflecting UPDRS motor score 24 6.7 16–44 their performance (see Dependent Variables), was displayed on the screen. Participants were encouraged to keep their score as high as H&Y 2–3 possible by achieving as many zero distance hits as possible and by MMSE 28.8 1.5 26–30 28 1.3 26–30 avoiding collisions with the center post. The relation between Medication (mg): execution variables, angle and velocity at the moment of release, Levodopa (n = 6) 439.6 247.8 187.5–900 and performance result is illustrated in Figure 1C. Carbidopa (n = 6) 105.8 61.5 47–225 After instruction and 30 test trials with a different target position Entacapon (n = 2) 900 424.3 600–1200 on the first day, participants performed 200 throws per day. After each 100 throws, participants were given a short break; however, doi:10.1371/journal.pone.0021669.t002 they could rest anytime in between if they wished. To assess short- term retention, participants performed five experimental sessionswere displayed on the screen in real time. The ball’s trajectory was on five separate days, resulting in a total of 1000 trials. The firstdetermined by the simulated physics of the task and described an four sessions were scheduled on subsequent days; the fifth day waselliptic path around the pole . The ball trajectory was not conducted after another five days. The subjects participating in theimmediately intuitive to participants, and they had to learn the long-term retention session performed 200 additional trials 7–9mapping between the real arm movements and the ball’s months after the practice period. Sessions were scheduled withintrajectories in the projected work space. Hence, the task was one hour about the same time each day for individual participants.Figure 1. Experimental task. A: Sketch of the real Skittles task. A ball is suspended on a string and swings around the center post with theobjective of knocking down the skittle at the opposite side. B: Experimental set-up. Participants operate a lever to throw the virtual ball on the screenin front of them with the goal to hit the target located behind the center post. The angular displacement of the participant’s forearm is measured bya potentiometer and recorded by the computer. C: Execution and result space of the Skittles task. For each combination of the execution variablesrelease angle and velocity the color codes the result variable, the minimal distance (d) of the resulting ball trajectory to the target (error). Whitedenotes the solution manifold with zero-error solutions. Superimposed in white is the trajectory of one throw with its moment of release (whitecircle) at 98u and 4 m/s.doi:10.1371/journal.pone.0021669.g001 PLoS ONE | www.plosone.org 3 July 2011 | Volume 6 | Issue 7 | e21669
Motor Skill Learning in Parkinson’s DiseaseDependent Variables with further practice. Hence, Tolerance is dominant in the early Assessing Performance Changes: the Score. The result learning stage. With continued practice, performers fine tune theirmeasure was defined as the minimal distance (d) between the movements by reducing motor variability or noise and bytrajectory of the ball and the center of the target (Fig. 1B). This covariation between execution variables (an error in one variabledistance was converted to a score from 0 to 100 points where is directly compensated in the other variable). The dominance of100 points were achieved with a distance equal to zero. The score these components called Noise Reduction (N) and Covariation (C)decreased linearly with increasing distance to the target and represents the fine-tuning stage.reached zero for a distance equal or higher than 50 cm (including In order to quantitatively determine the dominance of thecenter post hits). components, they need to be compared. Muller and Sternad  ¨ Decomposing Performance Changes: the TNC- developed a method that exclusively and exhaustively quantifiesMethod. Motor learning in a goal-oriented task involves the contributions of the three components TNC by decomposingimprovement in the accuracy of performance which can be performance improvement. There exist two different approachesbroken down into three different, although not independent, of the TNC method [37,39] related to the same concept butcomponents: exploitation of task tolerance, noise reduction, and addressing different aspects of it. Here, we apply the approach ofcovariation between the execution variables [37,40] (see Fig. 2). Muller and Sternad . In this approach, performance changes ¨These components prevail in different phases of the motor learning over a sequence of practice trials are extracted by comparingprocess. Since learning stages do not develop in a discrete manner subsequent sets of trials. Each set is formed by the executionbut rather overlap, the prevailing learning stage is preferentially variables (here release angle and velocity) and has a meandetermined by the dominance of one component over the others. performance result (here the score). The mean results of twoFor instance, healthy subjects first exploit different combinations of subsequent sets A and B are compared and differences areexecution variables when learning a goal-oriented task, i.e. they decomposed in the TNC components by a stepwise reproductionbecome familiar with the execution space and its mapping to results. of changes from set A to set B. Concretely, to analyze the dataAdditionally, they seek combinations that are tolerant to noise, i.e. here, we combined practice trials in sets or blocks of 50. Theallowing a certain amount of motor variability and still solving the contributions of the TNC components to changes in performancetask. In Skittles, like in most motor tasks, this is possible since the were quantified by calculating the difference in performancetask is redundant and hence offers an infinite set of solutions between two sequential blocks (DScore) and decomposing thatto achieve the same motor performance. This exploratory difference into individual components. The contributions are non-contribution to motor improvement is called exploitation of task overlapping and fully account for DScore: DScore = DT+DN+DC.tolerance, or Tolerance (T). Muller and Sternad  could show that ¨ The component with the highest contribution to a performancein over 70% of cases T had the highest contribution to performances change from one block to the next is the prevailing one. Detailschanges in the first trials of practicing Skittles that decreased again about the calculation steps can be found in Muller and Sternad ¨Figure 2. TNC components. Schematic Illustration of the three components contributing to performance change. A: A random set of 10 throws isplotted onto the execution and result space. The mean result of these trials, as indicated by the color coding, can be improved by shifting the cloudof trials to a more error tolerant area. That is, the mean performance of these 10 trials (with identical dispersion) would be better if execution variableswere on average 80u and 1.9 m/s (B). This improvement can be achieved through exploration of the task space, searching for error (noise) tolerantareas. Hence, we call this component Tolerance. C and D show two additional options for performance improvement. Having found a tolerantsolution (as in B), performance can be improved even further by co-varying the execution variables such that the trials align with the solutionmanifold (C). Note that the co-variated set of trials still has the same dispersion as the sets in A and B. Finally, reducing dispersion, or rather stochasticnoise, can improve performance as well (D).doi:10.1371/journal.pone.0021669.g002 PLoS ONE | www.plosone.org 4 July 2011 | Volume 6 | Issue 7 | e21669
Motor Skill Learning in Parkinson’s Disease. Note that when we speak of overlapping learning stages, we short-term retention (24 h–5 days) before examining the long-termmean an incremental shift in dominance throughout practice retention session after seven to nine months.between components, as indicated by different extents ofcontribution of the components to performance change, whereas Result Variable: Scorethe contributions themselves are non-overlapping. Figure 3 displays average performance in the outcome measure Release Timing: Timeshift Measure. When adjacent score over blocks of 50 trials for both groups. Across the fiveangle velocity combinations of the moved manipulandum of practice days, the score increased in both groups (day:several trials are plotted onto the execution and result space, they F(2.7,82.8) = 37.7, p,.001, gp2 = .55), but the overall performanceform a trajectory that performers produce preparing their throw of the patients stayed below that of control group (group:(e.g. Fig. 1C). The release will lie on this trajectory and hence, F(1,31) = 13.7, p,.01, gp2 = .31). Performance changes did notperformers seek to produce a movement trajectory that intersects differ across days (day6group: F(2.7,82.8) = 1.7, p = .17, gp2 = .05),the solution manifold (zero error solutions) in addition to optimally i.e. PD patients and controls improved similarly over the fivetime their release at the intersection so that the ball hits the target. practice days. However, groups differed within days (block6group:One can assume that after exploration of the task, performers find F(1.9,58.4) = 3.3, p,.05, gp2 = .10). This difference was due to aan adequate movement trajectory and keep it in a similar fashion consistent drop in performance of the PD patients at the beginningover continued practice (as long as the task does not change). of each new practice day: Initial performance of each day (asTiming of the release, on the other hand, is less stable. Due to its represented by the performance in the first block of every session)short time window, even subtle changes in neuronal processing was lower than the performance in the last block of the previouscan have essential consequences on the result. Hence, timing of the day. Since overall performance of the patients was lower thanrelease represents an additional kinematic variable to analyze performance of the control group, their performance increasecontrol processes in Skittles. within a day was steeper relative to controls. Although faster To analyze timing, the relative position of release points on the improvements on relatively low performance levels is typical inthrowing trajectories of several subsequent trials were computed motor learning processes, it shows that patients were able to regainby a numerical procedure (see File S1 for more details). As a result, their previous performance and even exceed it, until performancerelease timing of each trial is expressed with a measure in ms called leveled off on day four. An additional one way ANOVA withtimeshift, describing a relative time difference between release repeated measures did not reveal any significant differencespoints on similar trajectories. Timeshift of one trial is positive when between the performance drops, meaning the reduction was ofrelease of the trial is delayed relative to others and negative when similar size each day (F(2.1,27.1) = .27, p = .78, gp2 = .02). Even onrelease of the trial is early. day five (after five days of rest) the decrease in performance was not worse compared to the other days. To separately address initial improvement rate, an additional 2Statistical Analyses (group) 6 4 (block) ANOVA for only the first four blocks was For each subject, score was averaged over blocks of 50 trials. conducted. No significant interaction effect was found (block6group:Changes in score and TNC contributions across the 20 practice F(2.2,77.4) = 1.5, p = .22, gp2 = .04), indicating that the improvementblocks and differences between days and groups were determined rate on the first practice day was similar between groups.by a 2 (group)65 (day)64 (block) ANOVA with repeated With respect to the long-term retention session, performance ofmeasures. To address the influence of release control on retention the PD patients underwent, on average, a greater drop than theperformance, 50 trials before and 50 trials after a practice break control group (Fig. 3), but this was not significant (F(1,11) = 2.7,were passed to the timeshift algorithm, resulting in a timeshift value p = .13, gp2 = .20). Regarding the small group sizes in the long-for each of these 100 trials, expressing release timing of each trial term session, statistical power was too low to reach significance.relative to the others Thereafter, average timeshift of trials after rest Individual results showed a performance decrease only for two outwas compared to trials before rest. To get a sensitive measure of of six PD patients (Table 3). The two deviant patients did not showchange in timeshift after rest, five series of 10 post-rest trials eachwere averaged to create post-rest sets. Pre-rest sets consisted of theaverage of 50 pre-rest trials to provide a reliable reference for thecomparison with the post-rest trials. The mean timeshift of the pre-rest set was then subtracted from the mean timeshift of each of thepost-rest sets. These five resulting differences per break werecompared between groups and the four practice breaks using a 2(group)64 (rest)65 (series) ANOVA with repeated measures. Results of the long-term retention session were analyzed with a2 (group)62 (block) ANOVA with repeated measures between thelast practice block and the first long-term retention block. Besidesstatistical hypotheses testing, we used additional ANOVAs tovalidate data requirements or to exclude alternative explanations. All statistical analyses were carried out using SPSS version 17.0.The level of significance was set at p,.05. If variance homogeneitywas not given, the Greenhouse Geisser correction was applied toadjust the degrees of freedom and control for the violation. Figure 3. Performance scores over practice. Average performance over the course of five practice sessions and the retention session after 7–9 months for patients and the control group. Each session consistedResults of four blocks (50 trials). Note that there was a 24 hour break between the first four days and a five day break between the forth and the fifth We will illustrate the results in the following order: For all day. Error bars denote the standard error of the mean.dependent variables, we first report the five practice days including doi:10.1371/journal.pone.0021669.g003 PLoS ONE | www.plosone.org 5 July 2011 | Volume 6 | Issue 7 | e21669
Motor Skill Learning in Parkinson’s Disease Table 3. Mean and SD of performance score of the PD in early learning and Noise Reduction (N) and Covariation (C) in the patients (PD) and control subjects (C) for the long-term fine-tuning stage. Figure 4 depicts the contribution to performance retention session. changes over practice accounted for by each of the three components. Note that the measure is in score points and contributions are displayed in a cumulative fashion, i.e. contribu- Block 20 Block 21 tions in one block are added to or subtracted from the previous block. Contributions are positive if the score increases and Mean SD Mean SD negative if the score decreases. Therewith, an increase in the area PD 14 73.6 16.9 73.5 25.1 of a component represents an increase in its contribution to PD 15 83.9 11.3 80.7 15.1 performance improvement and vice versa. PD 16* 58.1* 24.7* 32.0* 24.7* Tolerance. Performance changes due to T are represented by the black area in Figure 4. Both groups used the component T to PD 24 84.6 18.0 85.7 9.0 improve their performance (day: F(1.9,57) = 4.2, p,.01, gp2 = .12; PD 25* 86.5* 10.6* 41.6* 30.9* block: F(2,60) = 15.3, p,.001, gp2 = .34). The contribution of T PD 26 87.4 16.0 68.6 22.9 was significantly higher in the PD group than in the control group C3 91.6 7.3 88.4 9.0 (group: F(1,30) = 7.1, p,.05, gp2 = .19) due to the generally lower C6 84.9 11.0 76.3 19.6 performance level of the patients. Patients started off in less C8 81.2 28.5 87.2 8.9 tolerant areas than the healthy participants (Fig. 5). The same group6block interaction as in the score measure was observed C9 87.4 9.3 79.7 14.7 (F(2.0,59.7) = 7.2, p,.01, gp2 = .20). That is, the performance of C 11 91.2 7.1 87.3 14.1 the patients decreased because the contribution of T became C 17 91.1 8.1 87.0 14.3 negative in each first block of each new practice session. In other C 22 94.0 5.4 89.1 9.5 words, the patients performed worse in the beginning of each new session because, compared to the previous day, they were throwing The last block of the fifth practice day and the first block of the long-term in less tolerant areas. However, throughout a session they were retention session are shown. Results of Patient 16 and 25, who showed performance decreases in long-term retention, are highlighted with an asterisk. able to find the better areas and hence increased their score again. doi:10.1371/journal.pone.0021669.t003 In the first long-term retention block, both groups showed a drop in T. Although this drop was larger in the PD group ondifferences in the general Parkinson motor rating scales. However, average, there was no significant interaction effect (block6group:in the cognitive examination, scores were 2.75 (patient 16) and F(1,11) = 1.6, p = .23, gp2 = .13) and the individual results revealed4.75 (patient 25) points lower relative to the other four patients. a significant negative contribution of T, similar to the score, only In summary, PD patients improved similarly well over five for patients 16 and 25 (Table 4).practice days compared to control subjects, whereas preservation Reduction of Noise. The contribution to performanceof performance across breaks was lower. Long-term retention was changes of N is illustrated by the light gray area in Figure 4.not different from control subjects in four out of six patients. Both groups managed to enhance their score over the five practice days by reducing noise, i.e. the area of the N component increasedTNC Components (day: F(1.6, 48.1) = 27.2, p,.001, gp2 = .48; block: F(2.1, We ascribed performance changes to the three different 63.4) = 17.3, p,.001, gp2 = .37). No significant group effect wascomponents with different time scales. Tolerance (T) is prominent found (F(1, 30) = 1.6, p = .22, gp2 = .05). Furthermore, there was noFigure 4. TNC-Contributions to performance changes over practice. Contributions of T, N, and C to performance changes over the course ofthe five practice sessions and the retention session for the control group (A) and PD patients (B).doi:10.1371/journal.pone.0021669.g004 PLoS ONE | www.plosone.org 6 July 2011 | Volume 6 | Issue 7 | e21669
Motor Skill Learning in Parkinson’s DiseaseFigure 5. Initial execution areas and their influence on performance. Release and distance to target in execution space for a PD patient(white circles) and a control subject (gray circles) for the first 50 trials of practice.doi:10.1371/journal.pone.0021669.g005significant interaction effect block 6 group (F(2.1, 63.4) = 1.2, Release is clearly delayed after the break, resulting in poorerp = .30, gp2 = .04), indicating that the contribution of N was similar performance (darker areas on the solution manifold). Group resultsin both groups across all practice blocks. of the timeshift analysis are illustrated in Figure 7. Average timeshift For the long-term retention session, there was no significant values of the first 10 trials of each new session increased in bothblock6group effect either (F(1, 11) = .47, p = .51, gp2 = .04). Both groups with respect to the reference of 50 trials before rest,groups showed a slight decrease in N contribution. meaning that release was delayed in both groups (PD: Covariation. C did not play a role in performance M = 38.1 ms, SD = 30.9 ms; Control: M = 31.2 ms, SD = 29.5 ms).improvement for neither of the groups (Fig. 4 dark gray area). Within each first five series after rest, timeshift values in both groupsNeither group showed significant improvements due to C, and decreased again, i.e. timing became better. This was supported bythere were no significant differences between groups. a significant effect for series in the 2 (group)64 (rest)65 (series) In summary, PD patients and control subjects used Tolerance to ANOVA with repeated measures (F(1.8,53.9) = 10.9, p,.001,improve in Skittles. But in the patient group, Tolerance was also the gp2 = .27). In addition, we found a significant rest6seriescomponent responsible for the performance decreases after rest. interaction (F(5.3,159.4) = 2.4, p,.05, gp2 = .08), which was dueContribution of Noise Reduction increased throughout practice in both to the different change in timeshift between the first post-rest sessiongroups. Covariation did not contribute to performance changes in neither and the other three. There were no significant group orgroup. rest6group interaction effects (group: F(1,30) = 2.0, p = .17, gp2 = .06; rest6group: F(2.6,77.5) = .5, p = .66, gp2 = .02), indicat-Timing of Release: Timeshift ing that both groups released later at the beginning of each new Figure 6 shows sample data of throwing trajectories and release practice session compared to the end of the previous sessions.points of a PD patient before and after the last break of 24 h. However, leaving out the first post-rest session because of its discrepancy from the other sessions, an additional 2 (group)63 (rest)65 (series) ANOVA indicated a tendency for a group Table 4. Contribution of Tolerance (T) to performance difference in timing (F(1,30) = 3.7, p = .06, gp2 = .11). change from the last block of practice to the first block of the Similarly, timeshift increased, on average, from the last practice long-term retention session of patients (PD) and control block to the first long-term retention session block in both groups, subjects (C). with a greater mean increase in PD patients. However, no significant main or interaction effects were found. Looking more Block 21 Block 21 closely at the two patients with performance decreases in long- term retention, revealed a delayed release for patient 16 T Contribution T Contribution (M = 42.29 ms, SD = 16.4 ms). Throwing trajectories of patient PD 14 12.8 C3 20.1 25 did not satisfy the conditions for analysis. PD 15 22.9 C6 27.2 In summary, after rest, timing of release was delayed in both groups. There was a tendency that the delay was greater in PD 16* 224.2* C8 2.2 patients relative to controls from the second post-rest session on. PD 24 21.0 C9 20.3 PD 25* 245.2* C 11 0.4 Discussion PD 26 25.7 C 17 23.2 The goal of this study was to examine the specific problems of C 22 0.3 PD patients in different stages of motor skill learning and the Results of Patient 16 and 25 are highlighted with an asterisk. Note that patient 14 influence of typical parkinsonian control deficits on the learning considerably improved his performance through component T (by 12.8 points). outcome. In reference to studies about the role of BG in motor doi:10.1371/journal.pone.0021669.t004 learning and patient studies, it can be expected for de novo motor PLoS ONE | www.plosone.org 7 July 2011 | Volume 6 | Issue 7 | e21669
Motor Skill Learning in Parkinson’s DiseaseFigure 6. Sample data of release control of a PD patient. Throwing trajectories and moments of ball release of a PD patient before (A) andafter (B) a break. Movement direction is from left to right. Note that although there is no time dimension in this figure, when comparing A to B, therelease points in B (with higher release angles) could only be achieved by releasing later relative to A (see File S1).doi:10.1371/journal.pone.0021669.g006learning that non-demented, mild to moderate PD patients on PD patients compared to the healthy subjects. Improvements atmedication should have no problems in early learning stages but that early stage resulted from an exploration of the task solutionsshould show deficits in fine-tuning of a newly practiced skill. In and tolerant areas, as represented by the component Tolerance (T ).addition, there are indications that motor control deficits might With reference to findings documenting that it is primarily theinfluence retention performance of PD patients. We will discuss cerebellum that is involved in early learning stages of a novelour results with respect to consistencies and inconsistencies with motor task [24–26,3], our results confirm the expectation that PDthese expectations. patients are not impaired in this phase. Reasons could be that they compensate the BG failure with activation of other brainExpectation 1: Early learning is intact in PD patients structures, like the cerebellum [41,42]. We showed that the PD patients were able to improve in a novel Consistent with expectation: We found intact learning of a new motor skillvirtual throwing task. Under the assumption that motor learning is at an early stage in PD patients.represented by performance changes as a function of the amountof practice, patients improved similar to healthy subjects over the Expectation 2: Fine-tuning is impaired in PD patientscourse of five practice days. However, performance of the Expectation 2 originates from the findings of few studiespatients remained below that of the control group. The rate of addressing late learning in PD where late learning can beperformance improvement on the first day was equally high for the determined by the amount of practice [10,13]. However, theFigure 7. Group averaged timeshift measure quantifying release control. Average timeshift for the last block of a session and the first blockof the subsequent session for patients and the control group. Note that timeshift values after breaks are displayed in five series of ten trials toillustrate change with continued practice. Error bars denote standard error of the mean.doi:10.1371/journal.pone.0021669.g007 PLoS ONE | www.plosone.org 8 July 2011 | Volume 6 | Issue 7 | e21669
Motor Skill Learning in Parkinson’s Diseaseidentification of the fine-tuning stage simply by the amount of decrease was due to the component Tolerance, i.e. patients startedpractice is oftentimes difficult. In our data this becomes especially off throwing in less tolerant regions and hence achieved fewerevident regarding the constant performance decrements at the points. This could indicate that they failed to properly store thebeginning of new sessions in the patient group. Analyzing the task model and had to reacquire it each day. However, especiallyperformance score, we found that patients overcame these initial release timing is, due to its relatively short time window, sensitivedeficits and even exceeded their previous performance level. to random changes in neuronal processing. Control deficits likeHence, they learned more each day instead of only regaining what movement initiation problems in PD can be a cause of suchthey had already achieved in the first day. To be able to determine changes. The timing analysis demonstrated that both experimentalto what extent, however, this learning can be ascribed to fine- groups constantly released later after rest compared to before rest,tuning and to what extent early learning components, because of as represented by the higher timeshift values. Aside from the firstthe break, might be involved, we need an additional approach to post-rest session, the delay was generally higher in patients than inparse the behavioral results from the internal mechanisms that controls and it had a negative effect on their performance. This isunderlie them. because, according to Figures 1C and 6, if participants release Earlier, we defined fine-tuning as selection and reinforcement of later, they land in less error tolerant areas.appropriate motor commands, as well as inhibition of unwanted Since poorer retention of release timing would be expected toperturbing commands, i.e. an improvement of the signal-to-noise- cause later as well as earlier release times after rest compared toratio. There are studies reporting higher movement variability in before rest, the constant release delay indicates that the post-restPD patients [43,44] which they cannot reduce as well as healthy performance decrements in the patient group were not due topeople , i.e. fine-tuning seems to be poorer in PD patients. retention deficits.However, variability is not only caused by higher motor noise but Performance of the control group decreased in the first block ofalso through task exploration and the utilization of covariation the first post-rest session (see Fig. 3, session 2, block 5) where theybetween execution variables. To be more precise, what people also showed the greatest increase in timeshift, i.e. poorest timing (seeseek in order to enhance task accuracy is the reduction of motor Fig. 7). In contrast to the patients, however, their performance didnoise, not variability per se. Therefore, SD of execution variables not continue to decrease after rest in the following sessions, due tois not appropriate to detect motor noise and reduction of it. In the an improved timing. Apparently, healthy elderly present similarTNC-method Noise Reduction (N) is determined after having timing problems as PD patients but they can control them better ineliminated the influence of Covariation (C) and Tolerance (T ) . the course of practice. Considering the symptomatic problems ofHence, N can ascribe performance improvements solely to a hypokinesia and related movement initiation deficits in PD, poorerreduction of motor noise, and a better attuning of execution timing and hence lower performance after rest could have arisenvariables is quantified by C. Thus, the contribution of N and C to from constant impairment of initiation of ball release at theperformance change over practice indicates to what extent the beginning of practice as opposed to retention deficits.change is accomplished through fine-tuning. In our results, N did The results of the long-term retention session further supportnot show any significant differences between PD patients and that impaired release initiation might have diminished post-restcontrol subjects. Furthermore, the contribution of N to perfor- performance in PD. Four out of six PD patients were able to retainmance changes increased continuously throughout practice in their performance in the Skittles task equally well as the controlboth groups, meaning that both groups were similarly good at group over seven to nine months. Examining the timeshift for thereducing motor noise to enhance their performance. Importantly, two patients with less good post-rest performance revealed delayedthis also implies that the patients did not decrease in performance release timing for one patient. The performance of the otherafter rest due to higher motor noise nor did the overcoming of this patient did not satisfy the conditions for the timeshift analysis. Hisdecrement within a practice session arise from an enhanced trajectories in the retention session differed severely from the lastreduction of motor noise. block of the five practice days, indicating either a progression in The component Covariation had no effect in neither of the disease and cognitive problems, respectively. Even though thegroups. This was not unexpected since the contribution of C is results of only four PD patients are not representative, it is strikinghighly dependent on the task and the position of the target, in that those patients could retain the Skittles task over a period of upother words on the shape of the solution manifold that changes to nine months equally well as the control subjects.with different target locations . For target positions that result Furthermore, all patients improved after the initial post-restin a more vertical solution manifold C seems to contribute less to decrements in the five practice sessions and they even exceededperformance changes even in healthy young participants [37,38]. their pre-rest level. This was also related to release timing. Inconsistent with expectation: We could not find impairments in the fine- Concretely, timing improved in the first 50 trials of each sessiontuning process in the PD patients. The inconsistency might be due to different (timeshift approached zero in Fig. 7) and according to the results ofnoise measures (execution level vs. result level). Moreover, studies that find the T component, patients therewith threw in more tolerant areasimpairment in fine-tuning, find it only for advanced disease stages , for again (Fig. 4B). This indicates that impaired release initiation is notpatients ‘‘off’’ medication, or motor control symptoms might have influenced the an irreversible symptom. Other studies also find that PD patientsresult . can improve their control deficits with practice [29,33]. Consistent with expectation: Poorer performance in short- and long-termExpectation 3: Retention performance in PD patients is retention tests might be due to problems in movement initiation at the beginninginfluenced by motor control deficits of a new session rather than due to poorer retention. In the motor learning context, retention usually stands for the The interpretation about influences of movement initiation inpreservation of a movement specific skill over a period of rest. In PD on motor learning is still speculative at this point. Often, noSkittles, this would include adequate generation of the movement significant correlations are found between motor function andtrajectory and timing of the release. The constant performance learning ability. However, these correlations are usually done withdecrease in the patient group in each first block of a new session the UPDRS motor score that combines all motor symptomsmight suggest that PD patients had problems retaining this related with PD. Given that some deviant results between studiespreviously acquired skill for at least 24 hours. The performance can possibly be explained by influences of very specific control PLoS ONE | www.plosone.org 9 July 2011 | Volume 6 | Issue 7 | e21669
Motor Skill Learning in Parkinson’s Diseaseproblems [33,12,10,19], a more systematic examination of important for therapeutic implications. Knowledge about theseconvolutions between learning and control needs to be considered. problems will be very helpful in motivating patients to keepOur timeshift analysis is in that sense more specific, connecting practicing despite initial difficulties and to prevent frustration.performance changes only to one symptom, namely impairedmovement initiation. But, further experiments are necessary to Supporting Informationspecifically scrutinize this matter. File S1 Quantification of release timing using a numer-Conclusion and Implications ical procedure. In conclusion, our results confirm that non-demented, medicated (PDF)patients with mild to moderate PD can improve their performancein a novel motor task and that they show no impairments at an early Author Contributionslearning stage. However, we did not find impairments in fine-tuning Conceived and designed the experiments: LKP HM IR. Performed thenor in retention. Performance decreases after a break or stagnations experiments: LKP IR. Analyzed the data: LKP HM. Wrote the paper:during practice might rather be confounded with motor control LKP HM IR.deficits which can recover in the course of practice. This isReferences 1. Graybiel AM (1995) Building action repertoires: memory and learning functions 24. Jenkins IH, Brooks DJ, Nixon PD, Frackowiak RS, Passingham RE (1994) of the basal ganglia. Curr Opin Neurol 5(6): 733–741. Motor sequence learning: a study with positron emission tomography. J Neurosci 2. Rauch SL, Whalen PJ, Savage CR, Curran T, Kendrick A, et al. (1997) Striatal 14(6): 3775–3790. recruitment during an implicit sequence learning task as measured by functional 25. Seitz RJ, Canavan AGM, Yaguez L, Herzog H, Teilmann L, et al. (1994) ¨ magnetic resonance imaging. Hum Brain Mapp 5(2): 124–132. 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