Thalamic morphology predicts the onset of freezing of gait in Parkinson's disease.

The onset of freezing of gait (FOG) in Parkinson's disease (PD) is a critical milestone, marked by a higher risk of falls and reduced quality of life. FOG is associated with alterations in subcortical neural circuits, yet no study has assessed whether subcortical morphology can predict the onset of clinical FOG. In this prospective multimodal neuroimaging cohort study, we performed vertex-based analysis of grey matter morphology in fifty-seven individuals with PD at study entry and two years later. We also explored the behavioral correlates and resting-state functional connectivity related to these local volume differences. At study entry, we found that freezers (N = 12) and persons who developed FOG during the course of the study (converters) (N = 9) showed local inflations in bilateral thalamus in contrast to persons who did not (non-converters) (N = 36). Longitudinally, converters (N = 7) also showed local inflation in the left thalamus, as compared to non-converters (N = 36). A model including sex, daily levodopa equivalent dose, and local thalamic inflation predicted conversion with good accuracy (AUC: 0.87, sensitivity: 88.9%, specificity: 77.8%). Exploratory analyses showed that local thalamic inflations were associated with larger medial thalamic sub-nuclei volumes and better cognitive performance. Resting-state analyses further revealed that converters had stronger thalamo-cortical coupling with limbic and cognitive regions pre-conversion, with a marked reduction in coupling over the two years. Finally, validation using the PPMI cohort suggested FOG-specific non-linear evolution of thalamic local volume. These findings provide markers of, and deeper insights into conversion to FOG, which may foster earlier intervention and better mobility for persons with PD.

Repetitive Motor Control Deficits Most Consistent Predictors of Conversion to Freezing of Gait in Parkinson's Disease: A Prospective Cohort Study.

BACKGROUND: The onset of freezing of gait (FOG) represents a turning point in the lives of patients with Parkinson's disease (PD). FOG increases fall risk and is associated with worse physical and mental health related quality of life, thus increasing disease burden. Moreover, therapeutic studies aiming to ameliorate freezing have had limited success. In a step towards pre-emptive therapy to delay or prevent the onset of FOG, this prospective cohort study set out to uncover clinical markers of conversion to FOG. OBJECTIVE: Investigate clinical markers of conversion to FOG. METHODS: Sixty PD patients without FOG were followed up for two years and underwent extensive clinical testing each year. FOG classification was made with the New Freezing of Gait Questionnaire. Clinical predictors of conversion to FOG were investigated using univariate analysis and through building a multivariable model using all measured components. RESULTS: Twelve patients developed FOG during the study (Incidence: 11.5% per year). Due to the large number of predictors, univariate analyses did not survive multiple comparison correction, precluding strong inference on any one predictor. Overall, the effect sizes suggested that motor deficits including difficulties with repetitive movement scaling (AUC: 0.71), coordination (AUC: 0.73) and consistency (AUC: 0.76) as well as gait asymmetry (AUC: 0.79) and variability (AUC: 0.71) were most predictive of conversion. Further, converters reported more subjective cognitive difficulty (AUC: 0.74), although their measured performance was similar to non-converters. Multivariable analyses further showed that the two components most consistently selected in the predictive model were: 1) an MDS-UPDRS component with worse axial motor, hand use and non-motor symptoms; and 2) finger tapping abnormalities. CONCLUSION: Conversion to FOG was predicted mainly by objective and clinical measures of motor dyscontrol, as non-motor disturbances were surfacing. Although based on a small cohort with limited converters, this novel finding informs future studies aimed at FOG prevention.

Influence of Cueing and an Attentional Strategy on Freezing of Gait in Parkinson Disease During Turning.

BACKGROUND AND PURPOSE: Individuals with Parkinson disease exhibit decreased axial head-pelvis rotation. Consequently, they turn more en bloc than healthy controls, which may contribute to freezing during turning. We wanted to understand the influence of auditory cueing and an attentional strategy on turning and how this related to freezing of gait (FOG). METHODS: Fifteen participants with Parkinson disease and FOG were asked to turn 180° during baseline condition, unilateral cueing, and an attentional strategy prompting to start the turn with head rotation first. FOG occurrence, axial rotation, center of mass (COM) deviation, knee-flexion amplitude, and total turn velocity were measured using 3D motion analysis while off-medication. Normal reference values were obtained from 14 age-matched controls. RESULTS: Thirty-nine FOG episodes occurred in 5 participants. FOG occurred in 52.8% of baseline trials compared with 34.6% of trials using the head-first strategy, and 3.8% of the auditory cueing trials. During the head first strategy, the initiation of head, trunk, and pelvic rotation as well as the head-pelvis separation resembled turning patterns of healthy controls, but the COM shift to the inside of the turn was exaggerated. By contrast, during cueing, turning became more en bloc, with decreased head-pelvis separation and knee-flexion amplitude. DISCUSSION AND CONCLUSIONS: Cueing reduced FOG but did not correct axial movement deficits. The head-first strategy improved head-pelvis dissociation but had only limited effects on FOG. These results suggest that axial and COM deviation impairments are not directly related to FOG but may rather indicate a compensatory mechanism. Cueing reinforced the en-bloc movement and might as such help prevent FOG by triggering an alternative neural mechanism for movement generation.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A163).

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.

Progression of postural control and gait deficits in Parkinson's disease and freezing of gait: A longitudinal study.

BACKGROUND AND AIMS: The relationship between impaired postural control and freezing of gait (FOG) in Parkinson's disease (PD) is still unclear. Our aim was to identify if postural control deficits and gait dysfunction progress differently in freezers compared to non-freezers and whether this relates to FOG development. METHODS: 76 PD patients, classified as freezer (n = 17) or non-freezer (n = 59), and 24 controls underwent a gait and postural control assessments at baseline and after 12 months follow-up. Non-freezers who developed FOG during the study period were categorized as FOG converters (n = 5). Gait was analyzed during walking at self-preferred pace. Postural control was assessed using the Mini-BESTest and its sub-categories: sensory orientation, anticipatory, reactive and dynamic postural control. RESULTS: Mini-BESTest scores were lower in PD compared to controls (p < 0.001), and in freezers compared to non-freezers (p = 0.02). PD has worse anticipatory (p = 0.01), reactive (p = 0.02) and dynamic postural control (p = 0.003) compared to controls. Freezers scored lower on dynamic postural control compared to non-freezers (p = 0.02). There were no baseline differences between converters and non-converters. Decline in postural control was worse in PD compared to controls (p = 0.02) as shown by a greater decrease in the total Mini-BESTest score. Similar patterns were found in freezers (p = 0.006), who also showed more decline in anticipatory (p < 0.001) and dynamic postural control (p = 0.02) compared to non-freezers. FOG converters had a greater decline in the total Mini-BESTest (p = 0.005) and dynamic postural control scores (p = 0.04) compared to non-converters. Gait outcomes showed no significant differences in any of the analyses. CONCLUSION: FOG is associated with more severe decline in postural control, which can be detected by the clinical Mini-BESTest.

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.

Relearning of Writing Skills in Parkinson's Disease After Intensive Amplitude Training.

BACKGROUND: Micrographia occurs in approximately 60% of people with Parkinson's disease (PD). Although handwriting is an important task in daily life, it is not clear whether relearning and consolidation (ie the solid storage in motor memory) of this skill is possible in PD. The objective was to conduct for the first time a controlled study into the effects of intensive motor learning to improve micrographia in PD. METHODS: In this placebo-controlled study, 38 right-handed people with PD were randomized into 2 groups, receiving 1 of 2 equally time-intensive training programs (30 min/day, 5 days/week for 6 weeks). The experimental group (n = 18) performed amplitude training focused at improving writing size. The placebo group (n = 20) received stretch and relaxation exercises. Participants' writing skills were assessed using a touch-sensitive writing tablet and a pen-and-paper test, pre- and posttraining, and after a 6-week retention period. The primary outcome was change in amplitude during several tests of consolidation: (1) transfer, using trained and untrained sequences performed with and without target zones; and (2) automatization, using single- and dual-task sequences. RESULTS: The group receiving amplitude training significantly improved in amplitude and variability of amplitude on the transfer and automatization task. Effect sizes varied between 7% and 17%, and these benefits were maintained after the 6-week retention period. Moreover, there was transfer to daily life writing. CONCLUSIONS: These results show automatization, transfer, and retention of increased writing size (diminished micrographia) after intensive amplitude training, indicating that consolidation of motor learning is possible in PD. © 2016 International Parkinson and Movement Disorder Society.

Functional connectivity alterations in the motor and fronto-parietal network relate to behavioral heterogeneity in Parkinson's disease.

BACKGROUND: Insight into the neural mechanisms of postural instability and gait disorder (PIGD) and tremor dominant (TD) subtypes in Parkinson's disease (PD) is indispensable for generating pathophysiology hypotheses underlying this phenotyping. This cross-sectional study aimed to gain insight in specific and brain-wide functional connectivity (FC) and its correlation with motor deterioration and preservation in PD subtypes. METHODS: 68 PD patients classified as PIGD (n = 41), TD (n = 19) or indeterminate (n = 8) and 19 age-matched controls underwent resting-state fMRI while 'off' medication to assess FC between regions of interest (ROIs) in the motor and fronto-parietal network and on a whole-brain level using a parcellated template. FC alterations were correlated with quantitative behavioral measures. RESULTS: ROI-analyses showed decreased FC between the caudate and putamen in PIGD compared to TD. This hypo-connectivity was correlated with behavioral impairment. In contrast, TD-specific hyper-connectivity between motor cortical areas and the inferior parietal lobule correlated with less behavioral impairment, suggesting compensatory mechanisms. Both subgroups showed hyper-connectivity between the left supplementary motor area and pedunculopontine nucleus, whereas PIGD-specific right lateralized hyper-connectivity was shown between this nucleus and the premotor cortex. Whole-brain analyses revealed 65% hypo-connectivity and 35% hyper-connectivity in PIGD compared to TD. TD also revealed primarily hypo-connectivity compared to controls, but had more pronounced hyper-connectivity involving temporo-occipital areas. CONCLUSION: This multilevel analysis showed differential connectivity alterations in large scale neural networks and between motor and cognitive control areas that related to behavioral heterogeneity in PD, underscoring the classic TD-PIGD phenotypical classification.

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.

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.

Distal motor deficit contributions to postural instability and gait disorder in Parkinson's disease.

Clinical subtypes in Parkinson's disease (PD) are often based on the presence of clustered motor symptoms. In contrast to the tremor dominant (TD) subtype, the postural instability and gait disorder (PIGD) subtype is characterized by predominantly axial motor involvement and increased cognitive impairment. It is, however, unclear if subtypes represent distinct underlying neuropathological mechanisms or reflect more severe disease progression. We aimed to clarify the validity of PD subtypes by investigating behavioral outcomes at multiple levels. Therefore, spatiotemporal kinematics of gait, upper and lower limb repetitive movements in combination with a balance and cognitive assessment were recorded in 73 patients with PD. We classified patients as PIGD (n=43), TD (n=22) or indeterminate (n=8) while 'off' medication and recruited 20 age-matched controls. Surprisingly, differences between PIGD and TD were more prominent during repetitive distal motor tasks than during gait. Gait impairment in PIGD was only shown by reduced step length and gait speed. However, motor scaling and coordination of distal movements were more affected in PIGD than in TD patients. PIGD patients also had impaired postural control compared to TD patients as shown by lower mini-BESTest scores. There were no cognitive differences between patient subgroups. Distal movement was not significantly different in TD patients from controls, except for greater movement asymmetry. The results indicate a widespread impairment within PIGD with more pronounced distal than axial motor deficits. This suggests involvement of different neurotransmitter systems in the neuropathology of PD subtypes, which are at least partially independent of disease progression.

Microstructural changes in white matter associated with freezing of gait in Parkinson's disease.

In Parkinson's disease (PD), freezing of gait (FOG) is associated with widespread functional and structural gray matter changes throughout the brain. Previous study of freezing-related white matter changes was restricted to brainstem and cerebellar locomotor tracts. This study was undertaken to determine the spatial distribution of white matter damage associated with FOG by combining whole brain and striatofrontal seed-based diffusion tensor imaging. Diffusion-weighted images were collected in 26 PD patients and 16 age-matched controls. Parkinson's disease groups with (n = 11) and without freezing of gait (n = 15) were matched for age and disease severity. We applied tract-based spatial statistics to compare fractional anisotropy and mean diffusivity of white matter structure across the whole brain between groups. Probabilistic tractography was used to evaluate fractional anisotropy and mean diffusivity of key subcortico-cortical tracts. Tract-based spatial statistics revealed decreased fractional anisotropy in PD with FOG in bilateral cerebellar and superior longitudinal fascicle clusters. Increased mean diffusivity values were apparent in the right internal capsule, superior frontal cortex, anterior corona radiata, the left anterior thalamic radiation, and cerebellum. Tractography showed consistent white matter alterations in striatofrontal tracts through the putamen, caudate, pallidum, subthalamic nucleus, and in connections of the cerebellar peduncle with subthalamic nucleus and pedunculopontine nucleus bilaterally. We conclude that FOG is associated with diffuse white matter damage involving major cortico-cortical, corticofugal motor, and several striatofrontal tracts in addition to previously described cerebello-pontine connectivity changes. These distributed white matter abnormalities may contribute to the motor and non-motor correlates of FOG.

Motor switching and motor adaptation deficits contribute to freezing of gait in Parkinson's disease.

BACKGROUND: Patients with freezing of gait (FOG) have more difficulty with switching tasks as well as controlling the spatiotemporal parameters of gait than patients without FOG. Objective. To compare the ability of patients with and without FOG to adjust their gait to sudden speed switching and to prolonged walking in asymmetrical conditions. METHODS: Gait characteristics of 10 freezers, 12 non-freezers, and 12 controls were collected during tied-belt conditions (3 and 4 km/h), motor switching and reswitching (increase of speed in one belt from 3 to 4 km/h and vice versa), and adaptation (adjustment to asymmetrical gait) and re-adaptation (returning to symmetrical gait) on a split-belt treadmill. RESULTS: Following switching, freezers showed the largest increase of step length asymmetry (P = .001). All groups gradually adapted their gait to asymmetrical conditions, but freezers were slower and demonstrated larger final asymmetry than the other 2 groups (P = .001). After reswitching, freezers again showed the largest step length asymmetry (P = .01). During re-adaptation, both controls and non-freezers reached symmetrical levels, but freezers did not. Interestingly, only immediately after switching did one episode of FOG and one episode of festination occur in 2 different patients. CONCLUSIONS: Freezers have more difficulties adapting their gait during both suddenly triggered and continued gait speed asymmetry. The impaired ability of freezers during both switching and reswitching would suggest that they have an adaptive deficit rather than difficulties with asymmetry per se. Future work needs to address whether these adaptation problems can be ameliorated with rehabilitation.

Which Aspects of Postural Control Differentiate between Patients with Parkinson's Disease with and without Freezing of Gait?

This exploratory study aimed to identify which aspects of postural control are able to distinguish between subgroups of patients with Parkinson's disease (PD) and controls. Balance was tested using static and dynamic posturography. Freezers (n = 9), nonfreezers (n = 10), and controls (n = 10) stood on a movable force platform and performed 3 randomly assigned tests: (1) sensory organization test (SOT) to evaluate the effective use of sensory information, (2) motor control test (MCT) to assess automatic postural reactions in response to platform perturbations, and (3) rhythmic weight shift test (RWS) to evaluate the ability to voluntarily move the center of gravity (COG) mediolaterally and anterior-posteriorly (AP). The respective outcome measures were equilibrium and postural strategy scores, response strength and amplitude of weight shift. Patients were in the "on" phase of the medication cycle. In general, freezers performed similarly on SOT and MCT compared to nonfreezers. Freezers showed an intact postural strategy during sensory manipulations and an appropriate response to external perturbations. However, during voluntary weight shifting, freezers showed poorer directional control compared to nonfreezers and controls. This suggests that freezers have adequate automatic postural control and sensory integration abilities in quiet stance, but show specific directional control deficits when weight shifting is voluntary.

Relearning of writing skills in Parkinson's disease: a literature review on influential factors and optimal strategies.

Patients with Parkinson's disease (PD) suffer from severe motor symptoms which can only be partly alleviated by means of dopaminergic medication. Motor rehabilitation, i.e. relearning of a known motor skill through intensive practice, can be an effective and lasting therapeutic supplement in chronic neurodegenerative diseases. Recent studies on motor learning in PD provide insights for the development of optimal motor rehabilitation strategies, with a particular focus on achieving consolidated learning and retention. In this review, findings from the last couple of years are discussed with specific interest in the potential benefits from cueing and feedback strategies as means to achieve lasting changes. In addition, current neuroscientific insights on the impact of dopamine and cognitive functioning on learning are summarized. Finally, the knowledge on these topics is combined to propose an optimal strategy for relearning of writing skills in PD, a frequently reported motor deficit also known as micrographia.