- Email: [email protected]
Gait and attentional performance in freezers under methylphenidate
Gait & Posture 41 (2015) 384–388
Contents lists available at ScienceDirect
Gait & Posture journal homepage: www.elsevier.com/locate/gaitpost
Gait and attentional performance in freezers under methylphenidate A. Delval a,c,*, C. Moreau a,d, S. Bleuse a,c, D. Guehl b, E. Bestaven b, E. Guillaud b, K. Dujardin a,d, L. Defebvre a,d, D. Devos a,d,e a
Lille University, France Bordeaux 2 University, UMR 5293, Bordeaux, France c EA 1046, Department of Clinical Neurophysiology, Lille University Medical Center, France d EA 1046, Department of Neurology and Movement Disorders, Lille University Medical Center, France e EA 1046, Department of Pharmacology, Lille University Medical Center, France b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 February 2014 Received in revised form 14 October 2014 Accepted 20 October 2014
Background: Attentional resources appear to be involved in the occurrence of FoG. The Parkgait study recently reported that methylphenidate reduces gait hypokinesia and freezing of gait (FoG) in advanced PD patients receiving STN-DBS in the off-dopaminergic drug condition. Methylphenidate is considered to improve attention. The primary objective of the present ancillary study was to determine whether methylphenidate reduced the interference between a cognitive task and gait in patients with FoG. The study’s secondary objective was to compare attentional performance in methylphenidate-treated and placebo-treated patients. Methods: A total of 24 patients (from two centers) were included in the study. Patients were randomly assigned 1:1 to a three-month course of methylphenidate (1 mg/kg/day) or placebo. Patients were assessed after an acute L-dopa challenge. The primary outcome criterion was the stride length ratio ((dual-task stride length minus free gait stride length)/free gait stride length). Trials with FoG episodes were excluded from the analysis. Secondary outcomes included changes in reaction times for computerized attention tasks and FoG severity. Results: When comparing patients receiving methylphenidate with those receiving placebo, we did not observe any significant differences in the interaction between the dual task and gait or in attentional performance. Conclusion: As in the main Parkgait study, methylphenidate did not reduce gait hypokinesia in patients receiving dopaminergic treatment. Our present results suggest that the reduction in the number of FoG episodes previously observed in patients on methylphenidate was neither due to interaction between a dual-task and gait nor an increase in attentional performance. ß 2014 Elsevier B.V. All rights reserved.
Keywords: Parkinson’s disease Freezing of gait Cognition Gait Dopamine
1. Introduction Freezing of gait (FoG) in Parkinson’s disease (PD) is a major health concern because of its impact on quality of life and an increased risk of falls [1]. The circumstances that elicit FoG are well known and appear to be related to specific environmental triggers. The fact that external factors alleviate FoG suggests the presence of a (poorly understood) link between attentional processes and FoG [2]. Indeed, hypotheses concerning the
* Corresponding author at: Neurophysiologie Clinique, Hoˆpital Salengro, Centre Hospitalier Universitaire, F-59037 Lille cedex, France. Tel.: +33 320 446 751; fax: +33 320 446 680. E-mail address: [email protected] (A. Delval). http://dx.doi.org/10.1016/j.gaitpost.2014.10.022 0966-6362/ß 2014 Elsevier B.V. All rights reserved.
pathogenesis of FoG include impairments in attention [2–6] and executive functions [7,8]. These hypotheses are supported by the observation that (i) FoG occurs preferentially during attentional-costing tasks and (ii) patients with FoG are more impaired in executive function tasks. Two randomized clinical trials were recently performed, the first one in advanced nondemented patients without subthalamic nucleus deep brain stimulation (STN-DBS) [9,10]. Only a slight improvement in the gait composite score in the ‘off-levodopa’ condition was observed when patients were under methylphenidate but neither in the freezing severity nor the gait kinematic variables. In advanced PD patients receiving STN-DBS, methylphenidate was associated with a reduction in gait hypokinesia (in off l-dopa condition) and in the number of FoG episodes [10]. This particular population of PD patients was chosen because no alternative therapeutics
A. Delval et al. / Gait & Posture 41 (2015) 384–388
exists to treat FOG episodes at this advanced stage of the disease. Methylphenidate blocks dopamine and noradrenaline re-uptake by inhibiting the presynaptic dopamine transporter and the noradrenaline transporter – particularly in the striatum and prefrontal cortex [11,12] and is typically used to treat attention deficit hyperactivity disorder [13] This is particularly of interest in PD freezers since FoG seems to result of both dopaminergic and non-dopaminergic lesions and attentional disorders. [1]. Walking, especially under dual-task conditions, where the participants are asked to switch attention between gait and a concurrent cognitive task, is a complex procedure that requires higher executive control. Dual-task paradigms involve the combined use of working memory and executive functions. PD patients suffer from a lack of automaticity, as demonstrated by their poor performance in dual-task paradigms [14]. During dualtask paradigms, according to the nature and difficulty of the interferent task, some patients prioritize either the cognitive task or the motor task [15]. A decrement in performance in both the cognitive task and the motor task can be observed when the task is difficult [16]. FoG has been shown to be related to impairments in dual-task performance [17]. Automaticity refers to the ability to perform a task (such as walking) while devoting only minimal attention to it and allocating other attentional resources to a second task. Parkinson’s disease patients with FoG have been shown to be impaired when they have to divide attention between two tasks, which in turn suggests that attentional resources are being allocated to gait [15]. The various studies of methylphenidate and cognitive functions have yielded conflicting results. The slight impairment in attention tests (simple reaction time in fact) reported in several open-label studies has not been confirmed by randomized double-blind studies [18]. In the present study, we used a dual-task paradigm to investigate the interference effects of a cognitive task on gait in PD and to study methylphenidate’s influence on this interference. Indeed, it has been recently demonstrated that a single dose of 10 mg methylphenidate improved gait stability by reducing the number of step errors during the narrow base walking test in dual task condition in elderly patients [19]. This mechanism can explain the methylphenidate effect observed on walking, gait instability and executive functions in elderly subjects, effects that were not seen after treatment with the placebo [20]. Our main objective was to evidence a potential methylphenidate-associated reduction of the interaction between a cognitive task (counting backwards in steps of three) and a motor task (stabilized gait in the absence of FoG episodes) in a population of parkinsonian patients with FoG. We hypothesized that methylphenidate could reduce the cost of the interference task for gait performance by improving attentional resources. For this purpose, we tested attentional resources of the patients by studying different subcomponents of attention as proposed by Van Zomeren and Brouwer [21]: alertness, focused-attention (selectivity) and finally divided-attention (the ability to share attentional resources between two or more stimuli or two or more dimensions of a stimulus). 2. Patients and methods A total of 24 patients from two university medical centers (Lille and Bordeaux, France) were included in what was an ancillary part of a larger study (protocol ID: 2008-005801-20; clinicaltrials.gov reference: NCT00914095). The inclusion criteria were as follows: Parkinson’s disease (diagnosed according to Gibb’s criteria [22]), age under 80, receiving STN-DBS and the presence of mild to severe gait disorders (including FoG). Gait disorders were defined as gait hypokinesia (subscore 2 for
385
UPDRS-II item 15) and FoG (subscore 2 for UPDRS-II item 14) in the ‘‘on’’ condition, and score 2 for UPDRS-III item 30 on gait in the ‘‘on L-dopa’’ condition. Gait disorders had a moderate to severe impact on activities of daily living (i.e. score 2 for the third question in the FoG questionnaire [23]), despite optimized dopaminergic therapy and STN-DBS. Exclusion criteria included (i) gait disorders possibly induced by STN-DBS, (ii) any change in STN-DBS parameters or dopaminergic therapy three months prior to or during the study, (iii) inability to walk without continuous ambulatory assistance (walker or wheelchair) while on treatment, (iv) dementia (diagnosed according to the Movement Disorders Society criteria [24]), (v) patients with progressing axis I psychiatric disorders (psychosis, hallucinations, compulsive disorders, substance addiction, bipolar disorder, severe depression, etc.), as assessed in a semi-structured interview with a psychiatrist (according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, 2000), (vi) serious or unstable medical conditions and (vii) on-going treatment with sympathomimetics, monoamine oxidase inhibitors or opiates. All patients provided their written, informed consent to participation. 2.1. Randomization and masking Randomization was balanced by center. The 1:1 assignment sequence (based on a block size of four and the use of a computer random-number generator) was produced by the Statistics Department at Lille University Medical Center. Patients, caregivers, study staff and investigators were blinded to the assignment. 2.2. Procedures No patients had a history of previous use of methylphenidate. Patients received placebo or a dose of 1 mg/kg/day methylphenidate (i.e. four to eight 10 mg tablets per day) divided into three doses (at 8 am, noon and 4 pm). A four-week titration period was used, with a 0.25 mg/kg increment per week. In addition to main study’s inclusion criteria, patients had to be able to walk at least 10 m without FoG episodes in the ‘on- L-dopa’ condition. Patients were assessed under standardized conditions, after an acute Ldopa challenge. The L-dopa dose corresponded to 150% of the usual morning L-dopa equivalent dose taken by patients to relieve their symptoms (see [10] for further details). Evaluations were performed 30 min after L-dopa intake (best ‘on’ state). The last dose of study treatment was administered at 7 am on day 90 and Ldopa at 9 am. 2.3. The attention–gait interaction The primary outcome criterion measured at inclusion (day 0: before initiation of methylphenidate treatment) and at day 90 (after 3 months of methylphenidate treatment) was the stride length ratio ((stride length during the dual task minus stride length during free gait)/stride length during free gait). Space- and timedomain kinematic gait measurements (gait speed, stride length and stride time) were recorded by means of a video motion system (a VICON1 system for the 20 patients in Lille and an ELITE1 system for the 4 patients in Bordeaux; sampling rate: 50 Hz) and processed via a Matlab1 script using heel and toe markers. Subjects walked a distance of 10 meters indoors (constituting a trial). During free gait, the subject walked at his/her self-selected normal speed. Three trials were performed. Only gait cycles in FoG-free trials were taken into account. Indeed, we deliberately excluded trials with FoG episodes during free gait or dual task paradigms, since occurrence of FoG was one of the primary endpoints of the main study. For the cognitive dual-task paradigm, subjects were asked to
A. Delval et al. / Gait & Posture 41 (2015) 384–388
386
walk while counting backwards (in steps of three). Three trials were performed. Subjects were asked not to stop walking if and when they made a mistake. Subjects were not instructed to prioritize one task over the other. We took into account FoG severity evaluated by the number and duration of FoG episodes (short episodes of FoG < 10s were rated 1, medium episodes between 10 and 30 s were rated 2, episodes longer than 30 s were rated 3) during the FoG trajectory (patients performed the following trajectories: normal speed gait trajectory, walking through a narrow passage, stopping and starting again, 8 narrow turns (360 and 540) in different directions, at self-selected and rapid speeds, and walking while counting backward (subtracting serials of 3) [25].
3. Attention assessment Attention was assessed in terms of performance in a computercontrolled reaction time (RT) paradigm that included a simple RT task for measuring processing speed and four choice RT tasks for other attentional subcomponents (described in [26]). Briefly, participants were seated in front of a 15-inch color display screen and were told to fix a grey square in the center of the screen. They had to press the response key with their preferred hand as soon as the target stimulus appeared. The task comprised different levels: - Simple RT: at irregular intervals, the grey central square changed to green, blue or red. The subject was required to press the response key as quickly as possible when the color changed. - One-dimensional choice RT (‘‘focused attention’’): a single blue, red or yellow square appeared on the screen and was surrounded by a varying number of green rectangles. Subjects were instructed to ignore the green rectangles and to respond by pressing the response key as quickly as possible when the central square was blue, regardless of the number of distracters. - Two-dimensional choice RT (‘‘divided attention’’): the distracters became relevant, requiring the subject to pay attention to both the square’s color and the number of surrounding rectangles. Subjects were instructed to respond as quickly as possible when a blue square surrounded by only two green rectangles appeared. - A practice block preceded each level. The simple RT task was always administered first, as it constituted the basic task. However, the order of the other two levels was randomized. - An alternating choice RT task: the material was the same as in the focused-attention condition. In the first phase of the task, the instructions were the same as in the focused-attention condition. For the second phase, the instructions changed; the subjects were instructed to consider only the number of rectangles and to respond as quickly as possible when there were 2 rectangles (regardless of the square’ color). Four blocks of 30 trials were administered with alternate instructions in each block. This task condition was intended to measure the flexibility of attention. The mean RT for each condition was recorded. We then extracted the cognitive RT (referred to as the ‘‘attentional cost’’), which corresponds to the difference between the simple RT and the choice RT. The attentional cost reflects the cognitive processing
required for deciding whether the presented stimulus is a target or not. Misses and false alarms were recorded. The experimental program was written in E-prime Professional software (version 2.0). 3.1. Statistical analysis Patient’s characteristics in the 2 groups were compared with a t test (unpaired comparisons). We first evaluated the impact of the dual-task paradigm on gait parameters, we compared kinematics of gait in single-task and dual-task at baseline using a t test (paired comparisons). A two-factor repeated-measures analysis of variance was performed on gait and attention parameters, with time of assessment (at inclusion or at day 90) as a within-group factor and treatment (methylphenidate or placebo) as a between-group factor. The significance threshold was set to p = 0.05 for all analyses.
4. Results A total of 24 patients in the two centers met the inclusion criteria and all completed the study. The characteristics of the study population are summarized in Table 1. We observed no differences between both groups of patients in terms of age, disease duration, motor impairment, FoG characteristics or cognitive status. No patient had a score at the Mattis dementia rating scale lower than 130, showing preserved overall cognitive status. Gait kinematics differed between single and dual-tasks conditions at baseline: gait speed decreased in the dual-task condition (mean (SD)): 0.58 (0.38) m/s vs. 0.83 (0.38) m/s., p < 0.001, stride length decreased in the dual-task condition: 0.79 (0.36) m vs. 0.94 (0.33) m, p < 0.01. Stride time increased in the dual-task condition: 1.73 (1.20) sec. vs. 1.20 (0.46) s vs. sec., p < 0.001, Neither time (i.e. inclusion vs. day 90) (p = 0.156) nor the time treatment interaction (i.e. methylphenidate vs. placebo) (p = 0.062) had an effect on the stride length ratio. Descriptive statistics for the kinematic variables in both groups are shown in Table 2. No differences existed in gait kinematics between sessions and the treatment had no influence on these variables. Likewise, neither time nor the time treatment interaction had effects on any of the parameters measured in the attentional performance tests (simple RTs and cognitive RTs for focused attention, divided attention and alternating tasks), whatever the test condition. Median rate of false alarm or misses was below 1/30 in all attentional test conditions (no within, i.e. at inclusion vs 3 months evaluation, or between factor, placebo vs methylphenidate, differences). No reduction in FoG severity (assessed by the score during the freezing trajectory in ‘on’ state) was observed in the group of patients on methylphenidate compared with the patients on placebo (within subject effect (i.e. at inclusion vs 3 months evaluation): p = 0.173 and between effect (placebo vs methylphenidate), p = 0.107, interference, p = 0.379). However, median score on FoG trajectory performed after levodopa administration decreased from 12 to 7 after 3 months of treatment in the methylphenidate group vs. 5 to 4 in the placebo group.
Table 1 Demographic and clinical characteristics of the study population (median, 1st and 3rd quartiles). Groups were compared using t test (p values are indicated). Group
Age (median, Q1–Q3)
Disease duration
Sex ratio
Part III UPDRS ‘‘on L-dopa’’
Axial sub-score
Mattis rating scale
FoG questionnaire
Placebo Methylphenidate p value
61.5 (54–67) 66 (59.5–69.5) 0.36
14 (12–21.75) 17 (13.75–22.5) 0.36
4 M, 8 F 6 M, 6 F
26 (10.5–36) 24 (14.5–34.25) 0.34
7 (4.75–9.75) 8.5 (4.5–12.5) 0.23
139 (135.5–141) 138 (133–141.75) 0.37
14 (12.25–15) 15 (12.5–16) 0.22
A. Delval et al. / Gait & Posture 41 (2015) 384–388
387
Table 2 Kinematic characteristics of the study population (mean (SD)). Within subject factor (time) and between subject factor (group) and interaction group condition were indicated (p values). DT: dual task.
Gait speed (m/s) Stride Time (s) Stride length (m)
Gait speed (m/s) Stride Time (s) Stride length (m)
Baseline placebo free gait
3 months placebo free gait
Baseline methylphenidate free gait
3 months methylphenidate free gait
Time effect
Group effect
Interaction
0.87 (0.47) 1.26 (0.60) 0.99 (0.41)
0.85 (0.42) 1.18 (0.35) 0.98 (0.40)
0.80 (0.27) 1.14 (0.26) 0.89 (0.25)
0.79 (0.27) 1.14 (0.16) 0.93 (0.27)
0.75 0.55 0.50
0.63 0.60 0.58
0.83 0.51 0.40
0.52 0.44 0.80
0.57 0.47 0.49
0.28 0.97 0.37
Baseline placebo DT
3 months placebo DT
Baseline methylphenidate DT
3 months methylphenidate DT
0.60 (0.47) 1.92 (1.53) 0.83 (0.44)
0.62 (0.41) 1.99 (1.91) 0.85 (0.42)
0.56 (0.29) 1.54 (0.71) 0.75 (0.26)
0.49 (0.27) 1.60 (0.60) 0.72 (0.32)
Significance of p values are in italics.
5. Discussion When comparing patients receiving methylphenidate with those receiving placebo, we did not observe any significant differences in the interaction between the dual task and gait or in attentional performance. Moreau et al. have reported that methylphenidate reduces gait hypokinesia and the number of FoG episodes in STN-stimulated advanced PD patients in the offdrug condition [10]. Here (as in the main study), methylphenidate was not associated with a reduction in gait hypokinesia in patients receiving dopaminergic treatment. In the main study [10], although the effect of methylphenidate on FoG reduction was seen in both on and off-dopa medications conditions, the improvement of gait hypokinesia was seen only in the off-dopa condition. Gait hypokinesia was assessed by counting the number of steps required to perform as quick as possible a stand-walk-sit test [27]. This latter condition does not reflect ‘daily-life’ condition when patients on dopaminergic medications have to walk and deal with environmental constraints that require more attentional resources than a SWS test. This justifies this ancillary study that gave further insight into the effect of methylphenidate on other aspects of gait performance of parkinsonian freezers than those explored in the main study. One could legitimately have expected to see a smaller decrease in gait quality in the dual-task condition (relative to free gait) in patients on methylphenidate than in patients on placebo. Indeed, the simultaneous performance of two tasks may create a conflict and the need to determine which of the tasks should receive priority – especially when information processing is limited. Interestingly, PD patients apparently prioritize the cognitive task when they have not received explicit instructions to prioritize gait and thus inadvertently increase their risk of falling [15]. Here, we chose not to give any instructions concerning prioritization. Due to methylphenidate’s pharmacological proprieties, we could have expected to see an increase in the attentional resources that are required for concentration on both tasks in patients receiving methylphenidate, relative to patients receiving placebo. Methylphenidate did not improve dual-task performance in our patients and thus did not improve attentional resources. This fact was confirmed by the lack of differences between patients with or without methylphenidate, whatever the domain of attention tested. Methylphenidate’s stimulation of dopaminergic and noradrenergic neurotransmission did not improve gait parameters in these patients suggesting that other neurotransmitters (such as acetylcholine and serotonin, for example) could be involved in the associated gait disorders. A direct dopaminergic/ noradrenergic effect of methylphenidate could explain the reduction in the number of FoG episodes and may be unrelated to the drug’s action on attention although this remains
hypothetic. The fact that methylphenidate mainly reduces the number of FoG in patients without dopaminergic medications [10] is in favor of this hypothesis. It must be borne in mind that the patients included in this study were suffering from advanced PD. Although the patients had been receiving STN-DBS, their UPDRS III axial subscore remained high after levodopa intake reflecting non-dopaminergic signs (Table 1). In fact, FoG can be considered as the ultimate stage of akinesia. It can be attributed to dysfunction of the motor loops (encompassing the supplementary motor area (SMA)) that manage automatic, internally-driven motor actions. Freezing of gait can be overcome by triggering movement with visual or acoustic stimuli. This approach involves sensorimotor networks that encompass the premotor lateral cortex but not the SMA. Thus, one can hypothesize that by allowing cognitive flexibility [28], methylphenidate could facilitate the transition from an internallydriven motor action to an externally-driven motor action. Our study had several limitations. First, the sample size in this ancillary study was small (n = 12 in the placebo group and n = 12 in the active treatment group). We did not perform an a priori calculation of the required sample size, since the distribution and mean of the primary outcome data were not known. However, there was no apparent trend towards a reduction in the strength of the dual task/locomotion interaction in the methylphenidate group. Secondly, we chose to exclude episodes of FoG from the analysis because stride length (which decreases dramatically during FoG episodes) would have changed whatever the condition during FoG episodes. Although dual-task paradigms have already been used to trigger FoG in laboratory settings, they appear to be less effective in this respect than other specific tasks (such as turns, for example). Only one patient suffered worse FoG while dualtasking (relative to the free gait session) and these trials were excluded from our analysis. Another limit was that the analyses were made on dopaminergic medications since gait impairment was too severe in those patients in ‘off-dopaminergic drug’ condition to permit to analyse stabilized gait without FoG episodes. We should highlight that none of the patients presented significant cognitive impairment that would have been a confounding factor for attentional performance.
Conclusion Methylphenidate’s effects on gait in parkinsonian freezers appear to be complex. Although the drug may improve gait performance and reduce FoG slightly in these patients, the mechanism remains unclear. Our study results do not argue in favor of a direct improvement of attentional resources by methylphenidate, since no reduction in the cost of the dual-task
A. Delval et al. / Gait & Posture 41 (2015) 384–388
388
for gait was observed when patients received dopaminergic medications. Conflicts of interest We declare that we have no conflicts of interest. Funding source for study French Ministry of Health and Novartis Pharma. Acknowledgments We thank Dr David Fraser (Biotech Communication, Damery, France) for helpful comments on the manuscript’s English. References [1] Nutt JG, Bloem BR, Giladi N, Hallett M, Horak FB, Nieuwboer A. Freezing of gait: moving forward on a mysterious clinical phenomenon. Lancet Neurol 2011;10:734–44. http://dx.doi.org/10.1016/S1474-4422(11)70143-0. [2] Giladi N, Hausdorff JM. The role of mental function in the pathogenesis of freezing of gait in Parkinson’s disease. J Neurol Sci 2006;248:173–6. http:// dx.doi.org/10.1016/j.jns.2006.05.015. [3] Naismith SL, Shine JM, Lewis SJG. The specific contributions of set-shifting to freezing of gait in Parkinson’s disease. Mov Disord 2010;25:1000–4. http:// dx.doi.org/10.1002/mds.23005. [4] Shine JM, Naismith SL, Palavra NC, Lewis SJG, Moore ST, Dilda V, et al. Attentional set-shifting deficits correlate with the severity of freezing of gait in Parkinson’s disease. Parkinsonism Relat Disord 2012. http://dx.doi.org/ 10.1016/j.parkreldis.2012.07.015. [5] Shine JM, Matar E, Ward PB, Frank MJ, Moustafa AA, Pearson M, et al. Freezing of gait in Parkinson’s disease is associated with functional decoupling between the cognitive control network and the basal ganglia. Brain 2013;136:3671–81. http://dx.doi.org/10.1093/brain/awt272. [6] Tard C, Dujardin K, Bourriez J-L, Deste´e A, Derambure P, Defebvre L, et al. Attention modulates step initiation postural adjustments in Parkinson freezers. Parkinsonism Relat Disord 2014;20:284–9. http://dx.doi.org/10.1016/ j.parkreldis.2013.11.016. [7] Amboni M, Cozzolino A, Longo K, Picillo M, Barone P. Freezing of gait and executive functions in patients with Parkinson’s disease. Mov Disord 2008;23:395–400. http://dx.doi.org/10.1002/mds.21850. [8] Yogev-Seligmann G, Hausdorff JM, Giladi N. The role of executive function and attention in gait. Mov Disord 2008;23:329–42. http://dx.doi.org/10.1002/ mds.21720. quiz 472.. [9] Espay AJ, Dwivedi AK, Payne M, Gaines L, Vaughan JE, Maddux BN, et al. Methylphenidate for gait impairment in Parkinson disease: a randomized clinical trial. Neurology 2011;76:1256–62. http://dx.doi.org/10.1212/WNL. 0b013e3182143537. [10] Moreau C, Delval A, Defebvre L, Dujardin K, Duhamel A, Petyt G, et al. Methylphenidate for gait hypokinesia and freezing in patients with Parkinson’s disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial. Lancet Neurol 2012. http://dx.doi.org/ 10.1016/S1474-4422(12)70106-0.
[11] Madras BK, Miller GM, Fischman AJ. The dopamine transporter and attentiondeficit/hyperactivity disorder. Biol Psychiatry 2005;57:1397–409. http:// dx.doi.org/10.1016/j.biopsych.2004.10.011. [12] Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Logan J, Ding YS, et al. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 1998;155:1325–31. [13] Swanson J, Baler RD, Volkow ND. Understanding the effects of stimulant medications on cognition in individuals with attention-deficit hyperactivity disorder: a decade of progress. Neuropsychopharmacology 2011;36:207–26. http://dx.doi.org/10.1038/npp.2010.160. [14] Hallett M. The intrinsic and extrinsic aspects of freezing of gait. Mov Disord 2008;23(Suppl 2):S439–43. http://dx.doi.org/10.1002/mds.21836. [15] Bloem BR, Grimbergen YAM, van Dijk JG, Munneke M. The posture second strategy: a review of wrong priorities in Parkinson’s disease. J Neurol Sci 2006;248:196–204. http://dx.doi.org/10.1016/j.jns.2006.05.010. [16] Fuller RL, Van Winkle EP, Anderson KE, Gruber-Baldini AL, Hill T, Zampieri C, et al. Dual task performance in Parkinson’s disease: A sensitive predictor of impairment and disability. Parkinsonism Relat Disord 2013;19:325–8. http:// dx.doi.org/10.1016/j.parkreldis.2012.11.011. [17] Spildooren J, Vercruysse S, Desloovere K, Vandenberghe W, Kerckhofs E, Nieuwboer A. Freezing of gait in Parkinson’s disease: the impact of dualtasking and turning. Mov Disord 2010;25:2563–70. http://dx.doi.org/10.1002/ mds.23327. [18] Devos D, Moreau C, Delval A, Dujardin K, Defebvre L, Bordet R. Methylphenidate: a treatment for Parkinson’s disease? CNS Drugs 2013;27:1–14. http:// dx.doi.org/10.1007/s40263-012-0017-y. [19] Shorer Z, Bachner Y, Guy T, Melzer I. Effect of single dose methylphenidate on walking and postural stability under single- and dual-task conditions in older adults—a double-blind randomized control trial. J Gerontol A Biol Sci Med Sci 2013;68:1271–80. http://dx.doi.org/10.1093/gerona/glt035. [20] Ben-Itzhak R, Giladi N, Gruendlinger L, Hausdorff JM. Can methylphenidate reduce fall risk in community-living older adults? a double-blind, single-dose cross-over study. J Am Geriatr Soc 2008;56:695–700. http://dx.doi.org/ 10.1111/j. 1532-5415.2007.01623.x. [21] Van Zomeren AH, Brouwer WH. Clinical Neuropsychology of Attention. Oxford: Oxford University Press; 1994. [22] Gibb WR, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatr 1988;51: 745–52. [23] Giladi N, Tal J, Azulay T, Rascol O, Brooks DJ, Melamed E, et al. Validation of the freezing of gait questionnaire in patients with Parkinson’s disease. Mov Disord 2009;24:655–61. http://dx.doi.org/10.1002/mds.21745. [24] Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, et al. Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 2007;22:1689–707. http://dx.doi.org/10.1002/mds. 21507. quiz 1837. [25] Snijders AH, Haaxma CA, Hagen YJ, Munneke M, Bloem BR. Freezer or nonfreezer: clinical assessment of freezing of gait. Parkinsonism Relat Disord 2012;18:149–54. http://dx.doi.org/10.1016/j.parkreldis.2011.09.006. [26] Dujardin K, Tard C, Duhamel A, Delval A, Moreau C, Devos D, et al. The pattern of attentional deficits in Parkinson’s disease. Parkinsonism Relat Disord 2013;19:300–5. http://dx.doi.org/10.1016/j.parkreldis.2012.11.001. [27] Langston JW, Widner H, Goetz CG, Brooks D, Fahn S, Freeman T, et al. Core assessment program for intracerebral transplantations (CAPIT). Mov Disord 1992;7:2–13. http://dx.doi.org/10.1002/mds.870070103. [28] Pietrzak RH, Mollica CM, Maruff P, Snyder PJ. Cognitive effects of immediaterelease methylphenidate in children with attention-deficit/hyperactivity disorder. Neurosci Biobehav Rev 2006;30:1225–45. http://dx.doi.org/10.1016/j. neubiorev.2006.10.002.
Contents lists available at ScienceDirect
Gait & Posture journal homepage: www.elsevier.com/locate/gaitpost
Gait and attentional performance in freezers under methylphenidate A. Delval a,c,*, C. Moreau a,d, S. Bleuse a,c, D. Guehl b, E. Bestaven b, E. Guillaud b, K. Dujardin a,d, L. Defebvre a,d, D. Devos a,d,e a
Lille University, France Bordeaux 2 University, UMR 5293, Bordeaux, France c EA 1046, Department of Clinical Neurophysiology, Lille University Medical Center, France d EA 1046, Department of Neurology and Movement Disorders, Lille University Medical Center, France e EA 1046, Department of Pharmacology, Lille University Medical Center, France b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 6 February 2014 Received in revised form 14 October 2014 Accepted 20 October 2014
Background: Attentional resources appear to be involved in the occurrence of FoG. The Parkgait study recently reported that methylphenidate reduces gait hypokinesia and freezing of gait (FoG) in advanced PD patients receiving STN-DBS in the off-dopaminergic drug condition. Methylphenidate is considered to improve attention. The primary objective of the present ancillary study was to determine whether methylphenidate reduced the interference between a cognitive task and gait in patients with FoG. The study’s secondary objective was to compare attentional performance in methylphenidate-treated and placebo-treated patients. Methods: A total of 24 patients (from two centers) were included in the study. Patients were randomly assigned 1:1 to a three-month course of methylphenidate (1 mg/kg/day) or placebo. Patients were assessed after an acute L-dopa challenge. The primary outcome criterion was the stride length ratio ((dual-task stride length minus free gait stride length)/free gait stride length). Trials with FoG episodes were excluded from the analysis. Secondary outcomes included changes in reaction times for computerized attention tasks and FoG severity. Results: When comparing patients receiving methylphenidate with those receiving placebo, we did not observe any significant differences in the interaction between the dual task and gait or in attentional performance. Conclusion: As in the main Parkgait study, methylphenidate did not reduce gait hypokinesia in patients receiving dopaminergic treatment. Our present results suggest that the reduction in the number of FoG episodes previously observed in patients on methylphenidate was neither due to interaction between a dual-task and gait nor an increase in attentional performance. ß 2014 Elsevier B.V. All rights reserved.
Keywords: Parkinson’s disease Freezing of gait Cognition Gait Dopamine
1. Introduction Freezing of gait (FoG) in Parkinson’s disease (PD) is a major health concern because of its impact on quality of life and an increased risk of falls [1]. The circumstances that elicit FoG are well known and appear to be related to specific environmental triggers. The fact that external factors alleviate FoG suggests the presence of a (poorly understood) link between attentional processes and FoG [2]. Indeed, hypotheses concerning the
* Corresponding author at: Neurophysiologie Clinique, Hoˆpital Salengro, Centre Hospitalier Universitaire, F-59037 Lille cedex, France. Tel.: +33 320 446 751; fax: +33 320 446 680. E-mail address: [email protected] (A. Delval). http://dx.doi.org/10.1016/j.gaitpost.2014.10.022 0966-6362/ß 2014 Elsevier B.V. All rights reserved.
pathogenesis of FoG include impairments in attention [2–6] and executive functions [7,8]. These hypotheses are supported by the observation that (i) FoG occurs preferentially during attentional-costing tasks and (ii) patients with FoG are more impaired in executive function tasks. Two randomized clinical trials were recently performed, the first one in advanced nondemented patients without subthalamic nucleus deep brain stimulation (STN-DBS) [9,10]. Only a slight improvement in the gait composite score in the ‘off-levodopa’ condition was observed when patients were under methylphenidate but neither in the freezing severity nor the gait kinematic variables. In advanced PD patients receiving STN-DBS, methylphenidate was associated with a reduction in gait hypokinesia (in off l-dopa condition) and in the number of FoG episodes [10]. This particular population of PD patients was chosen because no alternative therapeutics
A. Delval et al. / Gait & Posture 41 (2015) 384–388
exists to treat FOG episodes at this advanced stage of the disease. Methylphenidate blocks dopamine and noradrenaline re-uptake by inhibiting the presynaptic dopamine transporter and the noradrenaline transporter – particularly in the striatum and prefrontal cortex [11,12] and is typically used to treat attention deficit hyperactivity disorder [13] This is particularly of interest in PD freezers since FoG seems to result of both dopaminergic and non-dopaminergic lesions and attentional disorders. [1]. Walking, especially under dual-task conditions, where the participants are asked to switch attention between gait and a concurrent cognitive task, is a complex procedure that requires higher executive control. Dual-task paradigms involve the combined use of working memory and executive functions. PD patients suffer from a lack of automaticity, as demonstrated by their poor performance in dual-task paradigms [14]. During dualtask paradigms, according to the nature and difficulty of the interferent task, some patients prioritize either the cognitive task or the motor task [15]. A decrement in performance in both the cognitive task and the motor task can be observed when the task is difficult [16]. FoG has been shown to be related to impairments in dual-task performance [17]. Automaticity refers to the ability to perform a task (such as walking) while devoting only minimal attention to it and allocating other attentional resources to a second task. Parkinson’s disease patients with FoG have been shown to be impaired when they have to divide attention between two tasks, which in turn suggests that attentional resources are being allocated to gait [15]. The various studies of methylphenidate and cognitive functions have yielded conflicting results. The slight impairment in attention tests (simple reaction time in fact) reported in several open-label studies has not been confirmed by randomized double-blind studies [18]. In the present study, we used a dual-task paradigm to investigate the interference effects of a cognitive task on gait in PD and to study methylphenidate’s influence on this interference. Indeed, it has been recently demonstrated that a single dose of 10 mg methylphenidate improved gait stability by reducing the number of step errors during the narrow base walking test in dual task condition in elderly patients [19]. This mechanism can explain the methylphenidate effect observed on walking, gait instability and executive functions in elderly subjects, effects that were not seen after treatment with the placebo [20]. Our main objective was to evidence a potential methylphenidate-associated reduction of the interaction between a cognitive task (counting backwards in steps of three) and a motor task (stabilized gait in the absence of FoG episodes) in a population of parkinsonian patients with FoG. We hypothesized that methylphenidate could reduce the cost of the interference task for gait performance by improving attentional resources. For this purpose, we tested attentional resources of the patients by studying different subcomponents of attention as proposed by Van Zomeren and Brouwer [21]: alertness, focused-attention (selectivity) and finally divided-attention (the ability to share attentional resources between two or more stimuli or two or more dimensions of a stimulus). 2. Patients and methods A total of 24 patients from two university medical centers (Lille and Bordeaux, France) were included in what was an ancillary part of a larger study (protocol ID: 2008-005801-20; clinicaltrials.gov reference: NCT00914095). The inclusion criteria were as follows: Parkinson’s disease (diagnosed according to Gibb’s criteria [22]), age under 80, receiving STN-DBS and the presence of mild to severe gait disorders (including FoG). Gait disorders were defined as gait hypokinesia (subscore 2 for
385
UPDRS-II item 15) and FoG (subscore 2 for UPDRS-II item 14) in the ‘‘on’’ condition, and score 2 for UPDRS-III item 30 on gait in the ‘‘on L-dopa’’ condition. Gait disorders had a moderate to severe impact on activities of daily living (i.e. score 2 for the third question in the FoG questionnaire [23]), despite optimized dopaminergic therapy and STN-DBS. Exclusion criteria included (i) gait disorders possibly induced by STN-DBS, (ii) any change in STN-DBS parameters or dopaminergic therapy three months prior to or during the study, (iii) inability to walk without continuous ambulatory assistance (walker or wheelchair) while on treatment, (iv) dementia (diagnosed according to the Movement Disorders Society criteria [24]), (v) patients with progressing axis I psychiatric disorders (psychosis, hallucinations, compulsive disorders, substance addiction, bipolar disorder, severe depression, etc.), as assessed in a semi-structured interview with a psychiatrist (according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, 2000), (vi) serious or unstable medical conditions and (vii) on-going treatment with sympathomimetics, monoamine oxidase inhibitors or opiates. All patients provided their written, informed consent to participation. 2.1. Randomization and masking Randomization was balanced by center. The 1:1 assignment sequence (based on a block size of four and the use of a computer random-number generator) was produced by the Statistics Department at Lille University Medical Center. Patients, caregivers, study staff and investigators were blinded to the assignment. 2.2. Procedures No patients had a history of previous use of methylphenidate. Patients received placebo or a dose of 1 mg/kg/day methylphenidate (i.e. four to eight 10 mg tablets per day) divided into three doses (at 8 am, noon and 4 pm). A four-week titration period was used, with a 0.25 mg/kg increment per week. In addition to main study’s inclusion criteria, patients had to be able to walk at least 10 m without FoG episodes in the ‘on- L-dopa’ condition. Patients were assessed under standardized conditions, after an acute Ldopa challenge. The L-dopa dose corresponded to 150% of the usual morning L-dopa equivalent dose taken by patients to relieve their symptoms (see [10] for further details). Evaluations were performed 30 min after L-dopa intake (best ‘on’ state). The last dose of study treatment was administered at 7 am on day 90 and Ldopa at 9 am. 2.3. The attention–gait interaction The primary outcome criterion measured at inclusion (day 0: before initiation of methylphenidate treatment) and at day 90 (after 3 months of methylphenidate treatment) was the stride length ratio ((stride length during the dual task minus stride length during free gait)/stride length during free gait). Space- and timedomain kinematic gait measurements (gait speed, stride length and stride time) were recorded by means of a video motion system (a VICON1 system for the 20 patients in Lille and an ELITE1 system for the 4 patients in Bordeaux; sampling rate: 50 Hz) and processed via a Matlab1 script using heel and toe markers. Subjects walked a distance of 10 meters indoors (constituting a trial). During free gait, the subject walked at his/her self-selected normal speed. Three trials were performed. Only gait cycles in FoG-free trials were taken into account. Indeed, we deliberately excluded trials with FoG episodes during free gait or dual task paradigms, since occurrence of FoG was one of the primary endpoints of the main study. For the cognitive dual-task paradigm, subjects were asked to
A. Delval et al. / Gait & Posture 41 (2015) 384–388
386
walk while counting backwards (in steps of three). Three trials were performed. Subjects were asked not to stop walking if and when they made a mistake. Subjects were not instructed to prioritize one task over the other. We took into account FoG severity evaluated by the number and duration of FoG episodes (short episodes of FoG < 10s were rated 1, medium episodes between 10 and 30 s were rated 2, episodes longer than 30 s were rated 3) during the FoG trajectory (patients performed the following trajectories: normal speed gait trajectory, walking through a narrow passage, stopping and starting again, 8 narrow turns (360 and 540) in different directions, at self-selected and rapid speeds, and walking while counting backward (subtracting serials of 3) [25].
3. Attention assessment Attention was assessed in terms of performance in a computercontrolled reaction time (RT) paradigm that included a simple RT task for measuring processing speed and four choice RT tasks for other attentional subcomponents (described in [26]). Briefly, participants were seated in front of a 15-inch color display screen and were told to fix a grey square in the center of the screen. They had to press the response key with their preferred hand as soon as the target stimulus appeared. The task comprised different levels: - Simple RT: at irregular intervals, the grey central square changed to green, blue or red. The subject was required to press the response key as quickly as possible when the color changed. - One-dimensional choice RT (‘‘focused attention’’): a single blue, red or yellow square appeared on the screen and was surrounded by a varying number of green rectangles. Subjects were instructed to ignore the green rectangles and to respond by pressing the response key as quickly as possible when the central square was blue, regardless of the number of distracters. - Two-dimensional choice RT (‘‘divided attention’’): the distracters became relevant, requiring the subject to pay attention to both the square’s color and the number of surrounding rectangles. Subjects were instructed to respond as quickly as possible when a blue square surrounded by only two green rectangles appeared. - A practice block preceded each level. The simple RT task was always administered first, as it constituted the basic task. However, the order of the other two levels was randomized. - An alternating choice RT task: the material was the same as in the focused-attention condition. In the first phase of the task, the instructions were the same as in the focused-attention condition. For the second phase, the instructions changed; the subjects were instructed to consider only the number of rectangles and to respond as quickly as possible when there were 2 rectangles (regardless of the square’ color). Four blocks of 30 trials were administered with alternate instructions in each block. This task condition was intended to measure the flexibility of attention. The mean RT for each condition was recorded. We then extracted the cognitive RT (referred to as the ‘‘attentional cost’’), which corresponds to the difference between the simple RT and the choice RT. The attentional cost reflects the cognitive processing
required for deciding whether the presented stimulus is a target or not. Misses and false alarms were recorded. The experimental program was written in E-prime Professional software (version 2.0). 3.1. Statistical analysis Patient’s characteristics in the 2 groups were compared with a t test (unpaired comparisons). We first evaluated the impact of the dual-task paradigm on gait parameters, we compared kinematics of gait in single-task and dual-task at baseline using a t test (paired comparisons). A two-factor repeated-measures analysis of variance was performed on gait and attention parameters, with time of assessment (at inclusion or at day 90) as a within-group factor and treatment (methylphenidate or placebo) as a between-group factor. The significance threshold was set to p = 0.05 for all analyses.
4. Results A total of 24 patients in the two centers met the inclusion criteria and all completed the study. The characteristics of the study population are summarized in Table 1. We observed no differences between both groups of patients in terms of age, disease duration, motor impairment, FoG characteristics or cognitive status. No patient had a score at the Mattis dementia rating scale lower than 130, showing preserved overall cognitive status. Gait kinematics differed between single and dual-tasks conditions at baseline: gait speed decreased in the dual-task condition (mean (SD)): 0.58 (0.38) m/s vs. 0.83 (0.38) m/s., p < 0.001, stride length decreased in the dual-task condition: 0.79 (0.36) m vs. 0.94 (0.33) m, p < 0.01. Stride time increased in the dual-task condition: 1.73 (1.20) sec. vs. 1.20 (0.46) s vs. sec., p < 0.001, Neither time (i.e. inclusion vs. day 90) (p = 0.156) nor the time treatment interaction (i.e. methylphenidate vs. placebo) (p = 0.062) had an effect on the stride length ratio. Descriptive statistics for the kinematic variables in both groups are shown in Table 2. No differences existed in gait kinematics between sessions and the treatment had no influence on these variables. Likewise, neither time nor the time treatment interaction had effects on any of the parameters measured in the attentional performance tests (simple RTs and cognitive RTs for focused attention, divided attention and alternating tasks), whatever the test condition. Median rate of false alarm or misses was below 1/30 in all attentional test conditions (no within, i.e. at inclusion vs 3 months evaluation, or between factor, placebo vs methylphenidate, differences). No reduction in FoG severity (assessed by the score during the freezing trajectory in ‘on’ state) was observed in the group of patients on methylphenidate compared with the patients on placebo (within subject effect (i.e. at inclusion vs 3 months evaluation): p = 0.173 and between effect (placebo vs methylphenidate), p = 0.107, interference, p = 0.379). However, median score on FoG trajectory performed after levodopa administration decreased from 12 to 7 after 3 months of treatment in the methylphenidate group vs. 5 to 4 in the placebo group.
Table 1 Demographic and clinical characteristics of the study population (median, 1st and 3rd quartiles). Groups were compared using t test (p values are indicated). Group
Age (median, Q1–Q3)
Disease duration
Sex ratio
Part III UPDRS ‘‘on L-dopa’’
Axial sub-score
Mattis rating scale
FoG questionnaire
Placebo Methylphenidate p value
61.5 (54–67) 66 (59.5–69.5) 0.36
14 (12–21.75) 17 (13.75–22.5) 0.36
4 M, 8 F 6 M, 6 F
26 (10.5–36) 24 (14.5–34.25) 0.34
7 (4.75–9.75) 8.5 (4.5–12.5) 0.23
139 (135.5–141) 138 (133–141.75) 0.37
14 (12.25–15) 15 (12.5–16) 0.22
A. Delval et al. / Gait & Posture 41 (2015) 384–388
387
Table 2 Kinematic characteristics of the study population (mean (SD)). Within subject factor (time) and between subject factor (group) and interaction group condition were indicated (p values). DT: dual task.
Gait speed (m/s) Stride Time (s) Stride length (m)
Gait speed (m/s) Stride Time (s) Stride length (m)
Baseline placebo free gait
3 months placebo free gait
Baseline methylphenidate free gait
3 months methylphenidate free gait
Time effect
Group effect
Interaction
0.87 (0.47) 1.26 (0.60) 0.99 (0.41)
0.85 (0.42) 1.18 (0.35) 0.98 (0.40)
0.80 (0.27) 1.14 (0.26) 0.89 (0.25)
0.79 (0.27) 1.14 (0.16) 0.93 (0.27)
0.75 0.55 0.50
0.63 0.60 0.58
0.83 0.51 0.40
0.52 0.44 0.80
0.57 0.47 0.49
0.28 0.97 0.37
Baseline placebo DT
3 months placebo DT
Baseline methylphenidate DT
3 months methylphenidate DT
0.60 (0.47) 1.92 (1.53) 0.83 (0.44)
0.62 (0.41) 1.99 (1.91) 0.85 (0.42)
0.56 (0.29) 1.54 (0.71) 0.75 (0.26)
0.49 (0.27) 1.60 (0.60) 0.72 (0.32)
Significance of p values are in italics.
5. Discussion When comparing patients receiving methylphenidate with those receiving placebo, we did not observe any significant differences in the interaction between the dual task and gait or in attentional performance. Moreau et al. have reported that methylphenidate reduces gait hypokinesia and the number of FoG episodes in STN-stimulated advanced PD patients in the offdrug condition [10]. Here (as in the main study), methylphenidate was not associated with a reduction in gait hypokinesia in patients receiving dopaminergic treatment. In the main study [10], although the effect of methylphenidate on FoG reduction was seen in both on and off-dopa medications conditions, the improvement of gait hypokinesia was seen only in the off-dopa condition. Gait hypokinesia was assessed by counting the number of steps required to perform as quick as possible a stand-walk-sit test [27]. This latter condition does not reflect ‘daily-life’ condition when patients on dopaminergic medications have to walk and deal with environmental constraints that require more attentional resources than a SWS test. This justifies this ancillary study that gave further insight into the effect of methylphenidate on other aspects of gait performance of parkinsonian freezers than those explored in the main study. One could legitimately have expected to see a smaller decrease in gait quality in the dual-task condition (relative to free gait) in patients on methylphenidate than in patients on placebo. Indeed, the simultaneous performance of two tasks may create a conflict and the need to determine which of the tasks should receive priority – especially when information processing is limited. Interestingly, PD patients apparently prioritize the cognitive task when they have not received explicit instructions to prioritize gait and thus inadvertently increase their risk of falling [15]. Here, we chose not to give any instructions concerning prioritization. Due to methylphenidate’s pharmacological proprieties, we could have expected to see an increase in the attentional resources that are required for concentration on both tasks in patients receiving methylphenidate, relative to patients receiving placebo. Methylphenidate did not improve dual-task performance in our patients and thus did not improve attentional resources. This fact was confirmed by the lack of differences between patients with or without methylphenidate, whatever the domain of attention tested. Methylphenidate’s stimulation of dopaminergic and noradrenergic neurotransmission did not improve gait parameters in these patients suggesting that other neurotransmitters (such as acetylcholine and serotonin, for example) could be involved in the associated gait disorders. A direct dopaminergic/ noradrenergic effect of methylphenidate could explain the reduction in the number of FoG episodes and may be unrelated to the drug’s action on attention although this remains
hypothetic. The fact that methylphenidate mainly reduces the number of FoG in patients without dopaminergic medications [10] is in favor of this hypothesis. It must be borne in mind that the patients included in this study were suffering from advanced PD. Although the patients had been receiving STN-DBS, their UPDRS III axial subscore remained high after levodopa intake reflecting non-dopaminergic signs (Table 1). In fact, FoG can be considered as the ultimate stage of akinesia. It can be attributed to dysfunction of the motor loops (encompassing the supplementary motor area (SMA)) that manage automatic, internally-driven motor actions. Freezing of gait can be overcome by triggering movement with visual or acoustic stimuli. This approach involves sensorimotor networks that encompass the premotor lateral cortex but not the SMA. Thus, one can hypothesize that by allowing cognitive flexibility [28], methylphenidate could facilitate the transition from an internallydriven motor action to an externally-driven motor action. Our study had several limitations. First, the sample size in this ancillary study was small (n = 12 in the placebo group and n = 12 in the active treatment group). We did not perform an a priori calculation of the required sample size, since the distribution and mean of the primary outcome data were not known. However, there was no apparent trend towards a reduction in the strength of the dual task/locomotion interaction in the methylphenidate group. Secondly, we chose to exclude episodes of FoG from the analysis because stride length (which decreases dramatically during FoG episodes) would have changed whatever the condition during FoG episodes. Although dual-task paradigms have already been used to trigger FoG in laboratory settings, they appear to be less effective in this respect than other specific tasks (such as turns, for example). Only one patient suffered worse FoG while dualtasking (relative to the free gait session) and these trials were excluded from our analysis. Another limit was that the analyses were made on dopaminergic medications since gait impairment was too severe in those patients in ‘off-dopaminergic drug’ condition to permit to analyse stabilized gait without FoG episodes. We should highlight that none of the patients presented significant cognitive impairment that would have been a confounding factor for attentional performance.
Conclusion Methylphenidate’s effects on gait in parkinsonian freezers appear to be complex. Although the drug may improve gait performance and reduce FoG slightly in these patients, the mechanism remains unclear. Our study results do not argue in favor of a direct improvement of attentional resources by methylphenidate, since no reduction in the cost of the dual-task
A. Delval et al. / Gait & Posture 41 (2015) 384–388
388
for gait was observed when patients received dopaminergic medications. Conflicts of interest We declare that we have no conflicts of interest. Funding source for study French Ministry of Health and Novartis Pharma. Acknowledgments We thank Dr David Fraser (Biotech Communication, Damery, France) for helpful comments on the manuscript’s English. References [1] Nutt JG, Bloem BR, Giladi N, Hallett M, Horak FB, Nieuwboer A. Freezing of gait: moving forward on a mysterious clinical phenomenon. Lancet Neurol 2011;10:734–44. http://dx.doi.org/10.1016/S1474-4422(11)70143-0. [2] Giladi N, Hausdorff JM. The role of mental function in the pathogenesis of freezing of gait in Parkinson’s disease. J Neurol Sci 2006;248:173–6. http:// dx.doi.org/10.1016/j.jns.2006.05.015. [3] Naismith SL, Shine JM, Lewis SJG. The specific contributions of set-shifting to freezing of gait in Parkinson’s disease. Mov Disord 2010;25:1000–4. http:// dx.doi.org/10.1002/mds.23005. [4] Shine JM, Naismith SL, Palavra NC, Lewis SJG, Moore ST, Dilda V, et al. Attentional set-shifting deficits correlate with the severity of freezing of gait in Parkinson’s disease. Parkinsonism Relat Disord 2012. http://dx.doi.org/ 10.1016/j.parkreldis.2012.07.015. [5] Shine JM, Matar E, Ward PB, Frank MJ, Moustafa AA, Pearson M, et al. Freezing of gait in Parkinson’s disease is associated with functional decoupling between the cognitive control network and the basal ganglia. Brain 2013;136:3671–81. http://dx.doi.org/10.1093/brain/awt272. [6] Tard C, Dujardin K, Bourriez J-L, Deste´e A, Derambure P, Defebvre L, et al. Attention modulates step initiation postural adjustments in Parkinson freezers. Parkinsonism Relat Disord 2014;20:284–9. http://dx.doi.org/10.1016/ j.parkreldis.2013.11.016. [7] Amboni M, Cozzolino A, Longo K, Picillo M, Barone P. Freezing of gait and executive functions in patients with Parkinson’s disease. Mov Disord 2008;23:395–400. http://dx.doi.org/10.1002/mds.21850. [8] Yogev-Seligmann G, Hausdorff JM, Giladi N. The role of executive function and attention in gait. Mov Disord 2008;23:329–42. http://dx.doi.org/10.1002/ mds.21720. quiz 472.. [9] Espay AJ, Dwivedi AK, Payne M, Gaines L, Vaughan JE, Maddux BN, et al. Methylphenidate for gait impairment in Parkinson disease: a randomized clinical trial. Neurology 2011;76:1256–62. http://dx.doi.org/10.1212/WNL. 0b013e3182143537. [10] Moreau C, Delval A, Defebvre L, Dujardin K, Duhamel A, Petyt G, et al. Methylphenidate for gait hypokinesia and freezing in patients with Parkinson’s disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial. Lancet Neurol 2012. http://dx.doi.org/ 10.1016/S1474-4422(12)70106-0.
[11] Madras BK, Miller GM, Fischman AJ. The dopamine transporter and attentiondeficit/hyperactivity disorder. Biol Psychiatry 2005;57:1397–409. http:// dx.doi.org/10.1016/j.biopsych.2004.10.011. [12] Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Logan J, Ding YS, et al. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 1998;155:1325–31. [13] Swanson J, Baler RD, Volkow ND. Understanding the effects of stimulant medications on cognition in individuals with attention-deficit hyperactivity disorder: a decade of progress. Neuropsychopharmacology 2011;36:207–26. http://dx.doi.org/10.1038/npp.2010.160. [14] Hallett M. The intrinsic and extrinsic aspects of freezing of gait. Mov Disord 2008;23(Suppl 2):S439–43. http://dx.doi.org/10.1002/mds.21836. [15] Bloem BR, Grimbergen YAM, van Dijk JG, Munneke M. The posture second strategy: a review of wrong priorities in Parkinson’s disease. J Neurol Sci 2006;248:196–204. http://dx.doi.org/10.1016/j.jns.2006.05.010. [16] Fuller RL, Van Winkle EP, Anderson KE, Gruber-Baldini AL, Hill T, Zampieri C, et al. Dual task performance in Parkinson’s disease: A sensitive predictor of impairment and disability. Parkinsonism Relat Disord 2013;19:325–8. http:// dx.doi.org/10.1016/j.parkreldis.2012.11.011. [17] Spildooren J, Vercruysse S, Desloovere K, Vandenberghe W, Kerckhofs E, Nieuwboer A. Freezing of gait in Parkinson’s disease: the impact of dualtasking and turning. Mov Disord 2010;25:2563–70. http://dx.doi.org/10.1002/ mds.23327. [18] Devos D, Moreau C, Delval A, Dujardin K, Defebvre L, Bordet R. Methylphenidate: a treatment for Parkinson’s disease? CNS Drugs 2013;27:1–14. http:// dx.doi.org/10.1007/s40263-012-0017-y. [19] Shorer Z, Bachner Y, Guy T, Melzer I. Effect of single dose methylphenidate on walking and postural stability under single- and dual-task conditions in older adults—a double-blind randomized control trial. J Gerontol A Biol Sci Med Sci 2013;68:1271–80. http://dx.doi.org/10.1093/gerona/glt035. [20] Ben-Itzhak R, Giladi N, Gruendlinger L, Hausdorff JM. Can methylphenidate reduce fall risk in community-living older adults? a double-blind, single-dose cross-over study. J Am Geriatr Soc 2008;56:695–700. http://dx.doi.org/ 10.1111/j. 1532-5415.2007.01623.x. [21] Van Zomeren AH, Brouwer WH. Clinical Neuropsychology of Attention. Oxford: Oxford University Press; 1994. [22] Gibb WR, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatr 1988;51: 745–52. [23] Giladi N, Tal J, Azulay T, Rascol O, Brooks DJ, Melamed E, et al. Validation of the freezing of gait questionnaire in patients with Parkinson’s disease. Mov Disord 2009;24:655–61. http://dx.doi.org/10.1002/mds.21745. [24] Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, et al. Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 2007;22:1689–707. http://dx.doi.org/10.1002/mds. 21507. quiz 1837. [25] Snijders AH, Haaxma CA, Hagen YJ, Munneke M, Bloem BR. Freezer or nonfreezer: clinical assessment of freezing of gait. Parkinsonism Relat Disord 2012;18:149–54. http://dx.doi.org/10.1016/j.parkreldis.2011.09.006. [26] Dujardin K, Tard C, Duhamel A, Delval A, Moreau C, Devos D, et al. The pattern of attentional deficits in Parkinson’s disease. Parkinsonism Relat Disord 2013;19:300–5. http://dx.doi.org/10.1016/j.parkreldis.2012.11.001. [27] Langston JW, Widner H, Goetz CG, Brooks D, Fahn S, Freeman T, et al. Core assessment program for intracerebral transplantations (CAPIT). Mov Disord 1992;7:2–13. http://dx.doi.org/10.1002/mds.870070103. [28] Pietrzak RH, Mollica CM, Maruff P, Snyder PJ. Cognitive effects of immediaterelease methylphenidate in children with attention-deficit/hyperactivity disorder. Neurosci Biobehav Rev 2006;30:1225–45. http://dx.doi.org/10.1016/j. neubiorev.2006.10.002.