Sensorimotor Network Segregation Predicts Long-Term Learning of Writing Skills in Parkinson's Disease.

The prediction of motor learning in Parkinson's disease (PD) is vastly understudied. Here, we investigated which clinical and neural factors predict better long-term gains after an intensive 6-week motor learning program to ameliorate micrographia. We computed a composite score of learning through principal component analysis, reflecting better writing accuracy on a tablet in single and dual task conditions. Three endpoints were studied-acquisition (pre- to post-training), retention (post-training to 6-week follow-up), and overall learning (acquisition plus retention). Baseline writing, clinical characteristics, as well as resting-state network segregation were used as predictors. We included 28 patients with PD (13 freezers and 15 non-freezers), with an average disease duration of 7 (±3.9) years. We found that worse baseline writing accuracy predicted larger gains for acquisition and overall learning. After correcting for baseline writing accuracy, we found female sex to predict better acquisition, and shorter disease duration to help retention. Additionally, absence of FOG, less severe motor symptoms, female sex, better unimanual dexterity, and better sensorimotor network segregation impacted overall learning positively. Importantly, three factors were retained in a multivariable model predicting overall learning, namely baseline accuracy, female sex, and sensorimotor network segregation. Besides the room to improve and female sex, sensorimotor network segregation seems to be a valuable measure to predict long-term motor learning potential in PD.

Effect of transcranial direct current stimulation on learning in older adults with and without Parkinson's disease: A systematic review with meta-analysis.

Older adults with and without Parkinson's disease show impaired retention after training of motor or cognitive skills. This systematic review with meta-analysis aims to investigate whether adding transcranial direct current stimulation (tDCS) to motor or cognitive training versus placebo boosts motor sequence and working memory training. The effects of interest were estimated between three time points, i.e. pre-training, post-training and follow-up. This review was conducted according to the PRISMA guidelines (PROSPERO: CRD42022348885). Electronic databases were searched from conception to March 2023. Following initial screening, 24 studies were eligible for inclusion in the qualitative synthesis and 20 could be included in the meta-analysis, of which 5 studies concerned motor sequence learning (total n = 186) and 15 working memory training (total n = 650). Results were pooled using an inverse variance random effects meta-analysis. The findings showed no statistically significant additional effects of tDCS over placebo on motor sequence learning outcomes. However, there was a strong trend showing that tDCS boosted working memory training, although methodological limitations and some heterogeneity were also apparent. In conclusion, the present findings do not support wide implementation of tDCS as an add-on to motor sequence training at the moment, but the promising results on cognitive training warrant further investigations.

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).

Associations between resting-state functional connectivity changes and prolonged benefits of writing training in Parkinson's disease.

BACKGROUND: Our earlier work showed that automaticity and retention of writing skills improved with intensive writing training in Parkinson's disease (PD). However, whether this training changed the resting-state networks in the brain and how these changes underlie retention of motor learning is currently unknown. OBJECTIVE: To examine changes in resting-state functional connectivity (rs-FC) and their relation to behavioral changes immediately after writing training and at 6 week follow-up. METHODS: Twenty-five PD patients underwent resting-state fMRI (ON medication) before and after 6 weeks writing training. Motor learning was evaluated with a dual task paradigm pre- and post-training and at follow-up. Next, pre-post within-network changes in rs-FC were identified by an independent component analysis. Significant clusters were used as seeds in ROI-to-ROI analyses and rs-FC changes were correlated with changes in behavioral performance over time. RESULTS: Similar to our larger cohort findings, writing accuracy in single and dual task conditions improved post-training and this was maintained at follow-up. Connectivity within the dorsal attentional network (DAN) increased pre-post training, particularly with the right superior and middle temporal gyrus (rS/MTG). This cluster also proved more strongly connected to parietal and frontal areas and to cerebellar regions. Behavioral improvements from pre- to post-training and follow-up correlated with increased rs-FC between rS/MTG and the cerebellum. CONCLUSIONS: Training-driven improvements in dual task writing led to functional reorganization within the DAN and increased connectivity with cerebellar areas. These changes were associated with the retention of writing gains and could signify task-specific neural changes or an inability to segregate neural networks.

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.

Virtual reality in research and rehabilitation of gait and balance in Parkinson disease.

Virtual reality (VR) technology has emerged as a promising tool for studying and rehabilitating gait and balance impairments in people with Parkinson disease (PD) as it allows users to be engaged in an enriched and highly individualized complex environment. This Review examines the rationale and evidence for using VR in the assessment and rehabilitation of people with PD, makes recommendations for future research and discusses the use of VR in the clinic. In the assessment of people with PD, VR has been used to manipulate environments to enhance study of the behavioural and neural underpinnings of gait and balance, improving understanding of the motor-cognitive neural circuitry involved. Despite suggestions that VR can provide rehabilitation that is more effective and less labour intensive than non-VR rehabilitation, little evidence exists to date to support these claims. Nevertheless, much unrealized potential exists for the use of VR to provide personalized assessment and rehabilitation that optimizes motor learning in both the clinic and home environments and adapts to changes in individuals over time. Design of such systems will require collaboration between all stakeholders to maximize useability, engagement, safety and effectiveness.

Retention of touchscreen skills is compromised in Parkinson's disease.

Fine motor skill impairments likely have a severe impact on the use of touchscreens in Parkinson's disease (PD). Although recent work showed positive effects of intensive writing training, many questions remained regarding the consolidation of motor learning in PD. The current study examined the effects of PD on practicing the manipulation of touchscreen technology and whether this can lead to 24h-retention and transfer. We developed the Swipe-Slide Pattern (SSP)-task, similar to handling a touchscreen unlock-trace. On day 1, 11 patients and 10 healthy, age-matched controls underwent two consecutive runs of early and late learning (9 × 36 s SSP and 36 s rest). This was followed by a retention test after 24 h, including the assessment of transfer. Movement time (MT, s), Euclidean distance (ED) and a performance index (PI = MT/ED) were compared across the learning phases (early, late, retention and transfer) for both groups. Additionally, a learning, retention and transfer index were compared between groups and correlated to clinical characteristics. Both groups significantly improved in MT and PI across practice. However, while healthy adults showed further improvements after a 24h-retention period, patients presented with impaired retention indices. This was correlated with disease duration, disease severity and performance on a daily life mobile phone task. Finally, transfer to a similar, but untrained pattern was comparable between both groups. Overall, short-term practice of the SSP-task results in improvements for PD patients, albeit with impaired retention. Future work should investigate whether prolonged touchscreen skill training can be retained in motor memory 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.

Towards understanding neural network signatures of motor skill learning in Parkinson's disease and healthy aging.

In the past decade, neurorehabilitation has been shown to be an effective therapeutic supplement for patients with Parkinson's disease (PD). However, patients still experience severe problems with the consolidation of learned motor skills. Knowledge on the neural correlates underlying this process is thus essential to optimize rehabilitation for PD. This review investigates the existing studies on neural network connectivity changes in relation to motor learning in healthy aging and PD and critically evaluates the imaging methods used from a methodological point of view. The results indicate that despite neurodegeneration there is still potential to modify connectivity within and between motor and cognitive networks in response to motor training, although these alterations largely bypass the most affected regions in PD. However, so far training-related changes are inferred and possible relationships are not substantiated by brain-behavior correlations. Furthermore, the studies included suffer from many methodological drawbacks. This review also highlights the potential for using neural network measures as predictors for the response to rehabilitation, mainly based on work in young healthy adults. We speculate that future approaches, including graph theory and multimodal neuroimaging, may be more sensitive than brain activation patterns and model-based connectivity maps to capture the effects of motor learning. Overall, this review suggests that methodological developments in neuroimaging will eventually provide more detailed knowledge on how neural networks are modified by training, thereby paving the way for optimized neurorehabilitation for patients.

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.

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.

Training for Micrographia Alters Neural Connectivity in Parkinson's Disease.

Despite recent advances in clarifying the neural networks underlying rehabilitation in Parkinson's disease (PD), the impact of prolonged motor learning interventions on brain connectivity in people with PD is currently unknown. Therefore, the objective of this study was to compare cortical network changes after 6 weeks of visually cued handwriting training (= experimental) with a placebo intervention to address micrographia, a common problem in PD. Twenty seven early Parkinson's patients on dopaminergic medication performed a pre-writing task in both the presence and absence of visual cues during behavioral tests and during fMRI. Subsequently, patients were randomized to the experimental (N = 13) or placebo intervention (N = 14) both lasting 6 weeks, after which they underwent the same testing procedure. We used dynamic causal modeling to compare the neural network dynamics in both groups before and after training. Most importantly, intensive writing training propagated connectivity via the left hemispheric visuomotor stream to an increased coupling with the supplementary motor area, not witnessed in the placebo group. Training enhanced communication in the left visuomotor integration system in line with the learned visually steered training. Notably, this pattern was apparent irrespective of the presence of cues, suggesting transfer from cued to uncued handwriting. We conclude that in early PD intensive motor skill learning, which led to clinical improvement, alters cortical network functioning. We showed for the first time in a placebo-controlled design that it remains possible to enhance the drive to the supplementary motor area through motor learning.

Being on Target: Visual Information during Writing Affects Effective Connectivity in Parkinson's Disease.

A common motor symptom of Parkinson's disease (PD) is micrographia, characterized by a decrease in writing amplitude. Despite the relevance of this impairment for activities of daily living, the underlying neural network abnormalities and the impact of cueing strategies on brain connectivity are unknown. Therefore, we investigated the effects of visual cues on visuomotor network interactions during handwriting in PD and healthy controls (HCs). Twenty-eight patients with early disease, ON dopaminergic medication, and 14 age-matched controls performed a pre-writing task with and without visual cues in the scanner. Patients displayed weaker right visuo-parietal coupling than controls, suggesting impaired visuomotor integration during writing. Surprisingly, cueing did not have the expected positive effects on writing performance. Patients and controls, however, did activate similar networks during cued and uncued writing. During cued writing, the stronger influence of both visual and motor areas on the left superior parietal lobe suggested that visual cueing induced greater visual steering. In the absence of cues, there was enhanced coupling between parietal and supplementary motor areas (SMA) in line with previous findings in HCs during uncued motor tasks. In conclusion, the present study showed that patients with PD, despite their compromised brain function, were able to shift neural networks similar to controls. However, it seemed that visual cues provided a greater accuracy constraint on handwriting rather than offering unequivocal beneficial effects. Altogether, the results suggest that the effectiveness of using compensatory neural networks through applying external stimuli is task dependent and may compromise motor control during writing.

Cueing for people with Parkinson's disease with freezing of gait: A narrative review of the state-of-the-art and novel perspectives.

Freezing, which manifests during gait and other movements, is an incapacitating motor symptom experienced by many patients with Parkinson's disease (PD). In rehabilitation, auditory and visual cueing methods are commonly applied to evoke a more goal-directed type of motor control and, as such, reduce freezing severity in patients with PD. In this narrative review, we summarize the current evidence regarding the effects of external cueing in patients with PD with freezing of gait (FOG) and provide suggestions on how to further improve cueing effectiveness with emerging technological developments. For this paper, we reviewed 24 articles describing the assessment of the effects of cues in patients with FOG (n=354). Because these studies mostly involved quasi-experimental designs, no methodological analysis was undertaken. In general, the evidence suggests that cue-augmented training can reduce FOG severity, improve gait parameters and improve upper-limb movements immediately after training. However, findings were not univocal, and long-term consolidation and transfer of the effects appear to be hampered specifically in this subgroup. With the increasing use of wearable technology, new possibilities are allowing for adapting the cue type, cue content and dose of cues to the needs of individual patients, which may boost the clinical use and efficiency of cued training in PD patients with FOG.

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.

Technology-Assisted Rehabilitation of Writing Skills in Parkinson's Disease: Visual Cueing versus Intelligent Feedback.

Recent research showed that visual cueing can have both beneficial and detrimental effects on handwriting of patients with Parkinson's disease (PD) and healthy controls depending on the circumstances. Hence, using other sensory modalities to deliver cueing or feedback may be a valuable alternative. Therefore, the current study compared the effects of short-term training with either continuous visual cues or intermittent intelligent verbal feedback. Ten PD patients and nine healthy controls were randomly assigned to one of these training modes. To assess transfer of learning, writing performance was assessed in the absence of cueing and feedback on both trained and untrained writing sequences. The feedback pen and a touch-sensitive writing tablet were used for testing. Both training types resulted in improved writing amplitudes for the trained and untrained sequences. In conclusion, these results suggest that the feedback pen is a valuable tool to implement writing training in a tailor-made fashion for people with PD. Future studies should include larger sample sizes and different subgroups of PD for long-term training with the feedback pen.

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.

Structural Brain Alterations in Motor Subtypes of Parkinson's Disease: Evidence from Probabilistic Tractography and Shape Analysis.

BACKGROUND AND OBJECTIVES: The postural instability and gait disorder (PIGD) and tremor dominant (TD) subtypes of Parkinson's disease (PD) show different patterns of alterations in functional connectivity (FC) between specific brain regions. This study aimed to investigate the relation between symptomatic heterogeneity in PD and structural alterations underlying these FC changes. METHODS: 68 PD patients classified as PIGD (n = 41) or TD (n = 19) and 19 age-matched controls underwent Magnetic Resonance Imaging (MRI). Diffusion-weighted images were used to assess fractional anisotropy (FA) and mean diffusivity (MD) at the whole-brain level using tract-based spatial statistics (TBSS). In addition, structural connectivity was assessed between regions that previously showed altered FC using probabilistic tractography. Anatomical images were used to determine shape and volume of the putamen, caudate and pallidum. RESULTS: TBSS revealed widespread FA reductions in PIGD compared to controls involving the superior longitudinal fasciculi and corpus callosum. No such differences were found in TD. Both PD subgroups had increased MD compared to controls in tracts connecting the left caudate with the bilateral ventral putamen. TD patients additionally showed increased MD compared to PIGD and controls in tracts connecting the right inferior parietal lobule with the right premotor and primary motor cortex, which previously showed altered FC. We also found grey matter atrophy in the rostrodorsal head of the caudate in PIGD compared to controls. CONCLUSION: Microstructural changes in white matter tracts, particularly in those connecting striatal sub-areas, partly underlie FC alterations in PD subtypes. Caudate shape alterations further implicate the striatum in PIGD pathophysiology.