A smartphone-based tapping task as a marker of medication response in Parkinson's disease: a proof of concept study.

Tapping tasks have the potential to distinguish between ON-OFF fluctuations in Parkinson's disease (PD) possibly aiding assessment of medication status in e-diaries and research. This proof of concept study aims to assess the feasibility and accuracy of a smartphone-based tapping task (developed as part of the cloudUPDRS-project) to discriminate between ON-OFF used in the home setting without supervision. 32 PD patients performed the task before their first medication intake, followed by two test sessions after 1 and 3 h. Testing was repeated for 7 days. Index finger tapping between two targets was performed as fast as possible with each hand. Self-reported ON-OFF status was also indicated. Reminders were sent for testing and medication intake. We studied task compliance, objective performance (frequency and inter-tap distance), classification accuracy and repeatability of tapping. Average compliance was 97.0% (± 3.3%), but 16 patients (50%) needed remote assistance. Self-reported ON-OFF scores and objective tapping were worse pre versus post medication intake (p < 0.0005). Repeated tests showed good to excellent test-retest reliability in ON (0.707 ≤ ICC ≤ 0.975). Although 7 days learning effects were apparent, ON-OFF differences remained. Discriminative accuracy for ON-OFF was particularly good for right-hand tapping (0.72 ≤ AUC ≤ 0.80). Medication dose was associated with ON-OFF tapping changes. Unsupervised tapping tests performed on a smartphone have the potential to classify ON-OFF fluctuations in the home setting, despite some learning and time effects. Replication of these results are needed in a wider sample of patients.

Transcranial direct current stimulation enhances motor learning in Parkinson's disease: a randomized controlled trial.

Writing training has shown clinical benefits in Parkinson's disease (PD), albeit with limited retention and insufficient transfer effects. It is still unknown whether anodal transcranial direct current stimulation (atDCS) can boost consolidation in PD and how this interacts with medication. To investigate the effects of training + atDCS versus training + sham stimulation on consolidation of writing skills when ON and OFF medication. Second, to examine the intervention effects on cortical excitability. In this randomized sham-controlled double-blind study, patients underwent writing training (one session) with atDCS (N = 20) or sham (N = 19) over the primary motor cortex. Training was aimed at optimizing amplitude and assessed during online practice, pre- and post-training, after 24-h retention and after continued learning (second session) when ON and OFF medication (interspersed by 2 months). The primary outcome was writing amplitude at retention. Cortical excitability and inhibition were assessed pre- and post-training. Training + atDCS but not training + sham improved writing amplitudes at retention in the ON state (p = 0.017, g = 0.75). Transfer to other writing tasks was enhanced by atDCS in both medication states (g between 0.72 and 0.87). Also, training + atDCS improved continued learning. However, no online effects were found during practice and when writing with a dual task. A post-training increase in cortical inhibition was found in the training + atDCS group (p = 0.039) but not in the sham group, irrespective of medication. We showed that applying atDCS during writing training boosted most but not all consolidation outcomes in PD. We speculate that atDCS together with medication modulates motor learning consolidation via inhibitory processes ( https://osf.io/gk5q8/ , 2018-07-17).

Novel insights into the effects of levodopa on the up- and downstrokes of writing sequences.

Motor control of automatized and overlearned sequences, such as writing, is affected in Parkinson's disease (PD), impacting patients' daily life. Medication effects on motor performance are not only task-specific, but also variable within tasks. The nature of this variance is still unclear. This study aimed to investigate whether medication affects writing sequences differently when producing up- or downstrokes. Writing was assessed in healthy controls (HC) (N = 31) and PD (N = 32), when ON and OFF medication in a randomized order (interspersed by two months). Subjects wrote a sequential pattern with an increasing size on a digital tablet. Writing outcomes were movement vigor (amplitude and velocity), error and end-point variability, and sequence continuation, calculated separately for up- and downstrokes. Results showed that PD patients OFF-medication reduced movement vigor (amplitude) for up- and downstrokes compared to HC. Clear deficits were found for up- but not for downstroke error in PD patients in OFF, suggesting a directional bias. Dopaminergic medication improved motor vigor by increasing writing amplitude and upstroke continuation, but this occurred at the cost of the downstroke trajectory. Other writing outcomes did not improve with medication intake. In conclusion, we interpret these findings as that the impact of dopamine is complex, highly task-specific, supporting the most highly energy demanding components of a writing sequence. As medication did not regulate downstroke writing, we recommend supplementary training to address task demands that were less modulated by dopamine (registration: https://osf.io/gk5q8/ , 17 July 2018).

Impaired Touchscreen Skills in Parkinson's Disease and Effects of Medication.

BACKGROUND: Deficits in fine motor skills may impair device manipulation including touchscreens in people with Parkinson's disease (PD). OBJECTIVES: To investigate the impact of PD and anti-parkinsonian medication on the ability to use touchscreens. METHODS: Twelve PD patients (H&Y II-III), OFF and ON medication, and 12 healthy controls (HC) performed tapping, single and multi-direction sliding tasks on a touchscreen and a mobile phone task (MPT). Task performance was compared between patients (PD-OFF, PD-ON) and HC and between medication conditions. RESULTS: Significant differences were found in touchscreen timing parameters, while accuracy was comparable between groups. PD-OFF needed more time than HC to perform single (P = 0.048) and multi-direction (P = 0.004) sliding tasks and to grab the dot before sliding (i.e., transition times) (P = 0.040; P = 0.004). For tapping, dopaminergic medication significantly increased performance times (P = 0.046) to comparable levels as those of HC. However, for the more complex multi-direction sliding, movement times remained slower in PD than HC irrespective of medication intake (P < 0.050 during ON and OFF). The transition times for the multi-direction sliding task was also higher in PD-ON than HC (P = 0.048). Touchscreen parameters significantly correlated with MPT performance, supporting the ecological validity of the touchscreen tool. CONCLUSIONS: PD patients show motor problems when manipulating touchscreens, even when optimally medicated. This hinders using mobile technology in daily life and has implications for developing adequate E-health applications for this group. Future work needs to establish whether touchscreen training is effective in PD.

tDCS-Enhanced Consolidation of Writing Skills and Its Associations With Cortical Excitability in Parkinson Disease: A Pilot Study.

Background. Learning processes of writing skills involve the re-engagement of previously established motor programs affected by Parkinson disease (PD). To counteract the known problems with consolidation in PD, transcranial direct current stimulation (tDCS) could be imperative to achieve a lasting regeneration of habitual motor skills. Objective. To examine tDCS-enhanced learning of writing and explore alterations in cortical excitability after stimulation in PD compared with healthy controls (HCs). Methods. Ten patients and 10 HCs received 2 training sessions combined with 20 minutes of 1-mA anodal tDCS or sham on the left primary motor cortex in a randomized crossover design. Writing skills on a tablet and paper were assessed at baseline, after training, and after 1 week of follow-up. Before and immediately after the intervention, cortical excitability and inhibition were measured during rest and activity. Results. Writing amplitude and velocity improved when practice was tDCS supplemented compared with sham in PD. Benefits were sustained at retention for trained and untrained tasks on the tablet as well as for writing on paper. No improvements were found for HCs. Reduced resting motor thresholds after tDCS indicated tDCS-enhanced cortical excitability. Additionally, increments in motor-evoked potential amplitudes correlated with improved writing in PD, whereas HCs showed the opposite pattern. Conclusion. Our results endorse the usefulness of tDCS-boosted learning in PD, at least when applied to improving writing capacity. Although further confirmatory studies are needed, these novel findings are striking because tDCS-mediated consolidation was found for learning a motor task directly affected by PD.

When motor control gets out of hand: Speeding up triggers freezing in the upper limb in Parkinson's disease.

INTRODUCTION: Patients with Parkinson's disease (PD) can suffer from sudden movement arrests during upper limb tasks. The current study investigated a test to assess freezing of the upper limbs (FOUL) at two speed conditions to improve the sensitivity of FOUL detection. METHODS: Forty-nine patients with PD and 10 age-matched controls (HC) performed a freezing-provoking writing task, requiring up- and down-stroke writing at varying sizes in-between visual target zones indicating funnel-shapes on a touch-sensitive tablet. They performed five trials at their preferred speed, referred to as the Normal Funnel Task (NFT) and five trials at maximum speed, referred to as the Fast Funnel Task (FFT), in a random order. RESULTS: Based on a combination of kinematic criteria and video analysis, 183 FOUL episodes were detected in 24 participants (23 PD, 1 HC). The number of patients with FOUL, number of FOUL episodes and percentage time frozen were significantly higher during FFT than NFT. Most FOUL episodes occurred during writing at small (51.6%) and decreasing size (36.3%). Additionally, FOUL outcomes significantly correlated with the Montreal Cognitive Assessment and New Freezing of Gait Questionnaire. CONCLUSION: As FOUL is more prevalent under higher task demands, these data offer support for the "threshold model", previously proposed to provide insight in freezing of gait (FOG) and underscoring the presupposed link between FOG and FOUL. As well, this study may provide a novel paradigm to assess FOUL in both laboratory and clinical settings.

Determinants of Dual-Task Training Effect Size in Parkinson Disease: Who Will Benefit Most?

BACKGROUND AND PURPOSE: Dual-task interventions show positive effects in people with Parkinson disease (PD), but it remains unclear which factors determine the size of these benefits. As a secondary analysis of the DUALITY trial, the aim of this study was to assess the determinants of the effect size after 2 types of dual-task practice. METHODS: We randomly allocated 121 participants with PD to receive either integrated or consecutive dual-task training. Dual-task walking performance was assessed during (i) a backward digit span task (digit), (ii) an auditory Stroop task (Stroop), and (iii) a functional mobile phone task. Baseline descriptive, motor, and cognitive variables were correlated with the change in dual-task gait velocity after the intervention. Factors correlated with the change in dual-task gait velocity postintervention (P < 0.20) were entered into a stepwise forward multiple linear regression model. RESULTS: Lower dual-task gait velocity and higher cognitive capacity (Scales for Outcomes in Parkinson's Disease-Cognition [ScopaCog]) at baseline were related to larger improvements in dual-task gait velocity after both integrated and consecutive dual-task training for all 3 tasks (ß[gait] = -0.45, ß[ScopaCog] = 0.34, R = 0.23, P < 0.001, for digit; ß[gait] = -0.52, ß[ScopaCog] = 0.29, R = 0.26, P < 0.001, for Stroop; and ß[gait] = -0.40, ß[ScopaCog] = 0.30, R = 0.18, P < 0.001, for mobile phone task). DISCUSSION AND CONCLUSIONS: Participants with PD who showed a slow dual-task gait velocity and good cognitive functioning at baseline benefited most from the dual-task training, irrespective of the type of training and type of dual-task outcome.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A242).

Does transcranial direct current stimulation during writing alleviate upper limb freezing in people with Parkinson's disease? A pilot study.

Transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) can boost motor performance in Parkinson's disease (PD) when it is applied at rest. However, the potential supplementary therapeutic effect of the concurrent application of tDCS during the training of motor tasks is largely unknown. The present study examined the effects of tDCS on upper limb motor blocks during a freezing-provoking writing task (the funnel task) requiring up- and down-stroke movements at alternating amplitudes. Ten PD patients and 10 age-matched controls underwent two sessions of writing combined with 20 min of anodal or sham tDCS on the left M1 in a randomized cross-over design. The primary outcome was the number of upper limb freezing episodes during five trials of the funnel task on a touch-sensitive tablet. PD patients showed a significant reduction in freezing episodes during tDCS compared to sham. No effects of tDCS were found for the amplitude, variability and speed of the strokes outside the freezing episodes. However, patients who reported freezing episodes in daily life (N = 6) showed a beneficial effect of tDCS on stroke characteristics. These results indicate a subgroup-dependent variability in response to non-invasive brain stimulation applied during the performance of motor tasks in PD. This warrants future studies to examine tDCS as an adjuvant tool for training programs aimed to reduce motor deficits related to freezing.

Altered effective connectivity contributes to micrographia in patients with Parkinson's disease and freezing of gait.

Recently, it was shown that patients with Parkinson's disease (PD) and freezing of gait (FOG) can also experience freezing episodes during handwriting and present writing problems outside these episodes. So far, the neural networks underlying increased handwriting problems in subjects with FOG are unclear. This study used dynamic causal modeling of fMRI data to investigate neural network dynamics underlying freezing-related handwriting problems and how these networks changed in response to visual cues. Twenty-seven non-freezers and ten freezers performed a pre-writing task with and without visual cues in the scanner with their right hand. The results showed that freezers and non-freezers were able to recruit networks involved in cued and uncued writing in a similar fashion. Whole group analysis also revealed a trend towards altered visuomotor integration in patients with FOG. Next, we controlled for differences in disease severity between both patient groups using a sensitivity analysis. For this, a subgroup of ten non-freezers matched for disease severity was selected by an independent researcher. This analysis further exposed significantly weaker coupling in mostly left hemispheric visuo-parietal, parietal - supplementary motor area, parietal - premotor, and premotor-M1 pathways in freezers compared to non-freezers, irrespective of cues. Correlation analyses revealed that these impairments in connectivity were related to writing amplitude and quality. Taken together, these findings show that freezers have reduced involvement of the supplementary motor area in the motor network, which explains the impaired writing amplitude regulation in this group. In addition, weaker supportive premotor connectivity may have contributed to micrographia in freezers, a pattern that was independent of cueing.

Handwriting training in Parkinson's disease: A trade-off between size, speed and fluency.

BACKGROUND: In previous work, we found that intensive amplitude training successfully improved micrographia in Parkinson's disease (PD). Handwriting abnormalities in PD also express themselves in stroke duration and writing fluency. It is currently unknown whether training changes these dysgraphic features. OBJECTIVE: To determine the differential effects of amplitude training on various hallmarks of handwriting abnormalities in PD. METHODS: We randomized 38 right-handed subjects in early to mid-stage of PD into an experimental group (n = 18), receiving training focused at improving writing size during 30 minutes/day, five days/week for six weeks, and a placebo group (n = 20), receiving stretch and relaxation exercises at equal intensity. Writing skills were assessed using a touch-sensitive tablet pre- and post-training, and after a six-week retention period. Tests encompassed a transfer task, evaluating trained and untrained sequences, and an automatization task, comparing single- and dual-task handwriting. Outcome parameters were stroke duration (s), writing velocity (cm/s) and normalized jerk (i.e. fluency). RESULTS: In contrast to the reported positive effects of training on writing size, the current results showed increases in stroke duration and normalized jerk after amplitude training, which were absent in the placebo group. These increases remained after the six-week retention period. In contrast, velocity remained unchanged throughout the study. CONCLUSION: While intensive amplitude training is beneficial to improve writing size in PD, it comes at a cost as fluency and stroke duration deteriorated after training. The findings imply that PD patients can redistribute movement priorities after training within a compromised motor system.

Validity and reliability of a new tool to evaluate handwriting difficulties in Parkinson's disease.

BACKGROUND: Handwriting in Parkinson's disease (PD) features specific abnormalities which are difficult to assess in clinical practice since no specific tool for evaluation of spontaneous movement is currently available. OBJECTIVE: This study aims to validate the 'Systematic Screening of Handwriting Difficulties' (SOS-test) in patients with PD. METHODS: Handwriting performance of 87 patients and 26 healthy age-matched controls was examined using the SOS-test. Sixty-seven patients were tested a second time within a period of one month. Participants were asked to copy as much as possible of a text within 5 minutes with the instruction to write as neatly and quickly as in daily life. Writing speed (letters in 5 minutes), size (mm) and quality of handwriting were compared. Correlation analysis was performed between SOS outcomes and other fine motor skill measurements and disease characteristics. Intrarater, interrater and test-retest reliability were assessed using the intraclass correlation coefficient (ICC) and Spearman correlation coefficient. RESULTS: Patients with PD had a smaller (p = 0.043) and slower (p<0.001) handwriting and showed worse writing quality (p = 0.031) compared to controls. The outcomes of the SOS-test significantly correlated with fine motor skill performance and disease duration and severity. Furthermore, the test showed excellent intrarater, interrater and test-retest reliability (ICC > 0.769 for both groups). CONCLUSION: The SOS-test is a short and effective tool to detect handwriting problems in PD with excellent reliability. It can therefore be recommended as a clinical instrument for standardized screening of handwriting deficits in PD.

Handwriting Impairments in People With Parkinson's Disease and Freezing of Gait.

BACKGROUND: Recent studies show that patients with Parkinson's disease (PD) and freezing of gait (FOG) experience motor problems outside their gait freezing episodes. Because handwriting is also a sequential movement, it may be affected in PD patients with FOG relative to those without. OBJECTIVE: The current study aimed to assess the quality of writing in PD patients with and without FOG in comparison to healthy controls (CTs) during various writing tasks. METHODS: Handwriting was assessed by the writing of cursive loops on a touch-sensitive writing tablet and by means of the Systematic Screening of Handwriting Difficulties (SOS) test in 30 PD patients with and without freezing and 15 healthy age-matched CTs. The tablet tests were performed at 2 different sizes, either continuously or alternatingly, as indicated by visual target lines. RESULTS: Patients with freezing showed decreased writing amplitudes and increased variability compared with CTs and patients without freezing on the writing tablet tests. Writing problems were present during both tests but were more pronounced during writing at alternating compared with writing at continuous size. Patients with freezing also had a higher total score on the SOS test than patients without freezing and CTs, reflecting more extensive handwriting problems, particularly with writing fluency. CONCLUSIONS: Writing is more severely affected in PD patients with FOG than in those without FOG. These results indicate that deficient movement sequencing and adaptation is a generic problem in patients with FOG.

Impaired Retention of Motor Learning of Writing Skills in Patients with Parkinson's Disease with Freezing of Gait.

BACKGROUND: Patients with Parkinson's disease (PD) and freezing of gait (FOG) suffer from more impaired motor and cognitive functioning than their non-freezing counterparts. This underlies an even higher need for targeted rehabilitation programs in this group. However, so far it is unclear whether FOG affects the ability for consolidation and generalization of motor learning and thus the efficacy of rehabilitation. OBJECTIVE: To investigate the hallmarks of motor learning in people with FOG compared to those without by comparing the effects of an intensive motor learning program to improve handwriting. METHODS: Thirty five patients with PD, including 19 without and 16 with FOG received six weeks of handwriting training consisting of exercises provided on paper and on a touch-sensitive writing tablet. Writing training was based on single- and dual-task writing and was supported by means of visual target zones. To investigate automatization, generalization and retention of learning, writing performance was assessed before and after training in the presence and absence of cues and dual tasking and after a six-week retention period. Writing amplitude was measured as primary outcome measure and variability of writing and dual-task accuracy as secondary outcomes. RESULTS: Significant learning effects were present on all outcome measures in both groups, both for writing under single- and dual-task conditions. However, the gains in writing amplitude were not retained after a retention period of six weeks without training in the patient group without FOG. Furthermore, patients with FOG were highly dependent on the visual target zones, reflecting reduced generalization of learning in this group. CONCLUSIONS: Although short-term learning effects were present in both groups, generalization and retention of motor learning were specifically impaired in patients with PD and FOG. The results of this study underscore the importance of individualized rehabilitation protocols.

Opposite Effects of Visual Cueing During Writing-Like Movements of Different Amplitudes in Parkinson's Disease.

BACKGROUND: Handwriting is often impaired in Parkinson's disease (PD). Several studies have shown that writing in PD benefits from the use of cues. However, this was typically studied with writing and drawing sizes that are usually not used in daily life. OBJECTIVE: This study examines the effect of visual cueing on a prewriting task at small amplitudes (≤1.0 cm) in PD patients and healthy controls to better understand the working action of cueing for writing. METHODS: A total of 15 PD patients and 15 healthy, age-matched controls performed a prewriting task at 0.6 cm and 1.0 cm in the presence and absence of visual cues (target lines). Writing amplitude, variability of amplitude, and speed were chosen as dependent variables, measured using a newly developed touch-sensitive tablet. RESULTS: Cueing led to immediate improvements in writing size, variability of writing size, and speed in both groups in the 1.0 cm condition. However, when writing at 0.6 cm with cues, a decrease in writing size was apparent in both groups (P < .001) and the difference in variability of amplitude between cued and uncued writing disappeared. In addition, the writing speed of controls decreased when the cue was present. CONCLUSIONS: Visual target lines of 1.0 cm improved the writing of sequential loops in contrast to lines spaced at 0.6 cm. These results illustrate that, unlike for gait, visual cueing for fine-motor tasks requires a differentiated approach, taking into account the possible increases of accuracy constraints imposed by cueing.

Amplitude Manipulation Evokes Upper Limb Freezing during Handwriting in Patients with Parkinson's Disease with Freezing of Gait.

BACKGROUND: Recent studies show that besides freezing of gait (FOG), many people with Parkinson's disease (PD) also suffer from freezing in the upper limbs (FOUL). Up to now, it is unclear which task constraints provoke and explain upper limb freezing. OBJECTIVE: To investigate whether upper limb freezing and other kinematic abnormalities during writing are provoked by (i) gradual changes in amplitude or by (ii) sustained amplitude generation in patients with and without freezing of gait. METHODS: Thirty-four patients with PD, including 17 with and 17 without FOG, performed a writing task on a touch-sensitive writing tablet requiring writing at constant small and large size as well as writing at gradually increasing and decreasing size. Patients of both groups were matched for disease severity, tested while 'on' medication and compared to healthy age-matched controls. RESULTS: Fifty upper limb freezing episodes were detected in 10 patients, including 8 with and 2 without FOG. The majority of the episodes occurred when participants had to write at small or gradually decreasing size. The occurrence of FOUL and the number of FOUL episodes per patient significantly correlated with the occurrence and severity of FOG. Patients with FOUL also showed a significantly smaller amplitude in the writing parts outside the freezing episodes. CONCLUSIONS: Corroborating findings of gait research, the current study supports a core problem in amplitude control underlying FOUL, both in maintaining as well as in flexibly adapting the cycle size.

Transcranial direct current stimulation in Parkinson's disease: Neurophysiological mechanisms and behavioral effects.

Recent research has highlighted the potential of transcranial direct current stimulation (tDCS) to complement rehabilitation effects in the elderly and in patients with neurological diseases, including Parkinson's disease (PD). TDCS can modulate cortical excitability and enhance neurophysiological mechanisms that compensate for impaired learning in PD. The objective of this systematic review is to provide an overview of the effects of tDCS on neurophysiological and behavioral outcome measures in PD patients, both as a stand-alone and as an adjunctive therapy. We systematically reviewed the literature published throughout the last 10 years. Ten studies were included, most of which were sham controlled. Results confirmed that tDCS applied to the motor cortex had significant results on motor function and to a lesser extent on cognitive tests. However, the physiological mechanism underlying the long-term effects of tDCS on cortical excitability in the PD brain are still unclear and need to be clarified in order to apply this technique optimally to a wider population in the different disease stages and with different medication profiles.