Freezing of gait assessment with inertial measurement units and deep learning: effect of tasks, medication states, and stops.

BACKGROUND: Freezing of gait (FOG) is an episodic and highly disabling symptom of Parkinson's Disease (PD). Traditionally, FOG assessment relies on time-consuming visual inspection of camera footage. Therefore, previous studies have proposed portable and automated solutions to annotate FOG. However, automated FOG assessment is challenging due to gait variability caused by medication effects and varying FOG-provoking tasks. Moreover, whether automated approaches can differentiate FOG from typical everyday movements, such as volitional stops, remains to be determined. To address these questions, we evaluated an automated FOG assessment model with deep learning (DL) based on inertial measurement units (IMUs). We assessed its performance trained on all standardized FOG-provoking tasks and medication states, as well as on specific tasks and medication states. Furthermore, we examined the effect of adding stopping periods on FOG detection performance. METHODS: Twelve PD patients with self-reported FOG (mean age 69.33 ± 6.02 years) completed a FOG-provoking protocol, including timed-up-and-go and 360-degree turning-in-place tasks in On/Off dopaminergic medication states with/without volitional stopping. IMUs were attached to the pelvis and both sides of the tibia and talus. A temporal convolutional network (TCN) was used to detect FOG episodes. FOG severity was quantified by the percentage of time frozen (%TF) and the number of freezing episodes (#FOG). The agreement between the model-generated outcomes and the gold standard experts' video annotation was assessed by the intra-class correlation coefficient (ICC). RESULTS: For FOG assessment in trials without stopping, the agreement of our model was strong (ICC (%TF) = 0.92 [0.68, 0.98]; ICC(#FOG) = 0.95 [0.72, 0.99]). Models trained on a specific FOG-provoking task could not generalize to unseen tasks, while models trained on a specific medication state could generalize to unseen states. For assessment in trials with stopping, the agreement of our model was moderately strong (ICC (%TF) = 0.95 [0.73, 0.99]; ICC (#FOG) = 0.79 [0.46, 0.94]), but only when stopping was included in the training data. CONCLUSION: A TCN trained on IMU signals allows valid FOG assessment in trials with/without stops containing different medication states and FOG-provoking tasks. These results are encouraging and enable future work investigating automated FOG assessment during everyday life.

Subthalamic Nucleus Activity during Cognitive Load and Gait Dysfunction in Parkinson's Disease.

BACKGROUND: Gait freezing is a common, disabling symptom of Parkinson's disease characterized by sudden motor arrest during walking. Adaptive deep brain stimulation devices that detect freezing and deliver real-time, symptom-specific stimulation are a potential treatment strategy. Real-time alterations in subthalamic nucleus firing patterns have been demonstrated with lower limb freezing, however, whether similar abnormal signatures occur with freezing provoked by cognitive load, is unknown. METHODS: We obtained subthalamic nucleus microelectrode recordings from eight Parkinson's disease patients performing a validated virtual reality gait task, requiring responses to on-screen cognitive cues while maintaining motor output. RESULTS: Signal analysis during 15 trials containing freezing or significant motor output slowing precipitated by dual-tasking demonstrated reduced θ frequency (3-8 Hz) firing compared to 18 unaffected trials. CONCLUSIONS: These preliminary results reveal a potential neurobiological basis for the interplay between cognitive factors and gait disturbances including freezing in Parkinson's disease, informing development of adaptive deep brain stimulation protocols. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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.

Validation of Commercial Activity Trackers in Everyday Life of People with Parkinson's Disease.

Maintaining physical activity is an important clinical goal for people with Parkinson's disease (PwPD). We investigated the validity of two commercial activity trackers (ATs) to measure daily step counts. We compared a wrist- and a hip-worn commercial AT against the research-grade Dynaport Movemonitor (DAM) during 14 days of daily use. Criterion validity was assessed in 28 PwPD and 30 healthy controls (HCs) by a 2 × 3 ANOVA and intraclass correlation coefficients (ICC2,1). The ability to measure daily step fluctuations compared to the DAM was studied by a 2 × 3 ANOVA and Kendall correlations. We also explored compliance and user-friendliness. Both the ATs and the DAM measured significantly fewer steps/day in PwPD compared to HCs (p < 0.01). Step counts derived from the ATs showed good to excellent agreement with the DAM in both groups (ICC2,1 > 0.83). Daily fluctuations were detected adequately by the ATs, showing moderate associations with DAM-rankings. While compliance was high overall, 22% of PwPD were disinclined to use the ATs after the study. Overall, we conclude that the ATs had sufficient agreement with the DAM for the purpose of promoting physical activity in mildly affected PwPD. However, further validation is needed before clinical use can be widely recommended.

Melatonin for rapid eye movement sleep behavior disorder in Parkinson's disease: A randomised controlled trial.

BACKGROUND: Melatonin may reduce REM-sleep behavior disorder (RBD) symptoms in Parkinson's disease (PD), though robust clinical trials are lacking. OBJECTIVE: To assess the efficacy of prolonged-release (PR) melatonin for RBD in PD. METHODS: Randomized, double-blind, placebo-controlled, parallel-group trial with an 8-week intervention and 4-week observation pre- and postintervention (ACTRN12613000648729). Thirty PD patients with rapid eye movement sleep behavior disorder were randomized to 4 mg of prolonged-release melatonin (Circadin) or matched placebo, ingested orally once-daily before bedtime. Primary outcome was the aggregate of rapid eye movement sleep behavior disorder incidents averaged over weeks 5 to 8 of treatment captured by a weekly diary. Data were included in a mixed-model analysis of variance (n = 15 per group). RESULTS: No differences between groups at the primary endpoint (3.4 events/week melatonin vs. 3.6 placebo; difference, 0.2; 95% confidence interval = -3.2 to 3.6; P = 0.92). Adverse events included mild headaches, fatigue, and morning sleepiness (n = 4 melatonin; n = 5 placebo). CONCLUSION: Prolonged-release melatonin 4 mg did not reduce rapid eye movement sleep behavior disorder in PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Hitting the brakes: pathological subthalamic nucleus activity in Parkinson's disease gait freezing.

Gait freezing is a complex and devastating paroxysmal motor arrest commonly suffered in Parkinson's disease that causes significant impairment to mobility, commonly resulting in falls and subsequent injury. The neurobiological basis of gait freezing in Parkinson's disease is poorly understood and thus, currently available therapies are partially effective at best. We used a validated virtual reality gait paradigm to elicit freezing behaviour intraoperatively in eight patients undergoing subthalamic nucleus deep brain stimulation surgery while microelectrode recordings were obtained. This allowed us to directly test the hypothesis that increases in pathological multi-unit activity in the subthalamic nucleus are associated with freezing onset in real time, manifest as dysfunctional firing of lower limb muscles typical of freezing that were detected by EMG. We present evidence that freezing is related to transient increases in pathological subthalamic nucleus activity. We performed time-frequency analysis to characterize the oscillatory dynamics of subthalamic nucleus activity coincident with freezing onset, demonstrating an increase in pathological beta and theta rhythms that are followed by a temporal chain of activity culminating in characteristically abnormal lower limb muscle firing detected by EMG. Finally, we interrogate the potential clinical utility of our findings by contrasting the subthalamic nucleus activity signature during pathological freezing against purposeful stopping. These results advance our understanding of the neurobiological basis of gait freezing in Parkinson's disease, highlighting the role of the subthalamic nucleus and emergent synchronous activity in basal ganglia circuits in driving non-purposeful motor arrests in individuals with Parkinson's disease. Pathological subthalamic nucleus activity identified in association with freezing is discernible from that of volitional stopping, paving the way towards more effective therapeutics such as adaptive closed-loop deep brain stimulation protocols.

Identifying the neural correlates of doorway freezing in Parkinson's disease.

Freezing of gait (FOG) in Parkinson's disease (PD) is frequently triggered upon passing through narrow spaces such as doorways. However, despite being common the neural mechanisms underlying this phenomenon are poorly understood. In our study, 19 patients who routinely experience FOG performed a previously validated virtual reality (VR) gait paradigm where they used foot-pedals to navigate a series of doorways. Patients underwent testing randomised between both their "ON" and "OFF" medication states. Task performance in conjunction with blood oxygenation level dependent (BOLD) signal changes between "ON" and "OFF" states were compared within each patient. Specifically, as they passed through a doorway in the VR environment patients demonstrated significantly longer "footstep" latencies in the OFF state compared to the ON state. As seen clinically in FOG this locomotive delay was primarily triggered by narrow doorways rather than wide doorways. Functional magnetic resonance imaging revealed that footstep prolongation on passing through doorways was associated with selective hypoactivation in the presupplementary motor area (pSMA) bilaterally. Task-based functional connectivity analyses revealed that increased latency in response to doorways was inversely correlated with the degree of functional connectivity between the pSMA and the subthalamic nucleus (STN) across both hemispheres. Furthermore, increased frequency of prolonged footstep latency was associated with increased connectivity between the bilateral STN. These findings suggest that the effect of environmental cues on triggering FOG reflects a degree of impaired processing within the pSMA and disrupted signalling between the pSMA and STN, thus implicating the "hyperdirect" pathway in the generation of this phenomenon.

Functional MRI to Study Gait Impairment in Parkinson's Disease: a Systematic Review and Exploratory ALE Meta-Analysis.

PURPOSE OF REVIEW: Whilst gait impairment is a main cause for disability in Parkinson's disease (PD), its neural control remains poorly understood. We performed a systematic review and meta-analysis of neuroimaging studies of surrogate features of gait in PD. FINDINGS: Assessing the results from PET or SPECT scans after a period of actual walking as well as fMRI during mental imagery or virtual reality (VR) gait paradigms, we found a varying pattern of gait-related brain activity. Overall, a decrease in activation of the SMA during gait was found in PD compared to elderly controls. In addition, the meta-analysis showed that the most consistent gait-related activation was situated in the cerebellar locomotor region (CLR) in PD. Despite methodological heterogeneity, the combined neuroimaging studies of gait provide new insights into its neural control in PD, suggesting that CLR activation likely serves a compensatory role in locomotion.

The functional network signature of heterogeneity in freezing of gait.

Freezing of gait is a complex, heterogeneous, and highly variable phenomenon whose pathophysiology and neural signature remains enigmatic. Evidence suggests that freezing is associated with impairments across cognitive, motor and affective domains; however, most research to date has focused on investigating one axis of freezing of gait in isolation. This has led to inconsistent findings and a range of different pathophysiological models of freezing of gait, due in large part to the tendency for studies to investigate freezing of gait as a homogeneous entity. To investigate the neural mechanisms of this heterogeneity, we used an established virtual reality paradigm to elicit freezing behaviour in 41 Parkinson's disease patients with freezing of gait and examined individual differences in the component processes (i.e. cognitive, motor and affective function) that underlie freezing of gait in conjunction with task-based functional MRI. First, we combined three unique components of the freezing phenotype: impaired set-shifting ability, step time variability, and self-reported anxiety and depression in a principal components analysis to estimate the severity of freezing behaviour with a multivariate approach. By combining these measures, we were then able to interrogate the pattern of task-based functional connectivity associated with freezing (compared to normal foot tapping) in a sub-cohort of 20 participants who experienced sufficient amounts of freezing during task functional MRI. Specifically, we used the first principal component from our behavioural analysis to classify patterns of functional connectivity into those that were associated with: (i) increased severity; (ii) increased compensation; or (iii) those that were independent of freezing severity. Coupling between the cognitive and limbic networks was associated with 'worse freezing severity', whereas anti-coupling between the putamen and the cognitive and limbic networks was related to 'increased compensation'. Additionally, anti-coupling between cognitive cortical regions and the caudate nucleus were 'independent of freezing severity' and thus may represent common neural underpinnings of freezing that are unaffected by heterogenous factors. Finally, we related these connectivity patterns to each of the individual components (cognitive, motor, affective) in turn, thus exposing latent heterogeneity in the freezing phenotype, while also identifying critical functional network signatures that may represent potential targets for novel therapeutic intervention. In conclusion, our findings provide confirmatory evidence for systems-level impairments in the pathophysiology of freezing of gait and further advance our understanding of the whole-brain deficits that mediate symptom expression in Parkinson's disease.

Predicting the onset of freezing of gait: A longitudinal study.

BACKGROUND: Freezing of gait is a disabling symptom of Parkinson's disease that ultimately affects approximately 80% of patients, yet very little research has focused on predicting the onset of freezing of gait and tracking the longitudinal progression of symptoms prior to its onset. The objective of the current study was to examine longitudinal data spanning the transition period when patients with PD developed freezing of gait to identify symptoms that may precede freezing and create a prediction model that identifies those "at risk" for developing freezing of gait in the year to follow. METHODS: Two hundred and twenty-one patients with PD were divided into 3 groups (88 nonfreezers, 41 transitional freezers, and 92 continuing freezers) based on their responses to the validated Freezing of Gait-Questionnaire item 3 at baseline and follow-up. Critical measures across motor, cognitive, mood, and sleep domains were assessed at 2 times approximately 1 year apart. RESULTS: A logistic regression model that included age, disease duration, gait symptoms, motor phenotype, attentional set-shifting, and mood measures could predict with 70% and 90% accuracy those patients who would and would not develop, respectively, freezing of gait over the next year. Notably, the Freezing of Gait-Questionnaire total and the anxiety section of the Hospital Anxiety and Depression Scale were the strongest predictors and alone could significantly predict if one might develop freezing of gait in the next 15 months with 82% accuracy. CONCLUSIONS: Our results suggest that it is possible to identify the majority of patients who will develop freezing of gait in the following year, potentially allowing targeted interventions to delay or possibly even prevent the onset of freezing. © 2017 International Parkinson and Movement Disorder Society.

Evidence for subtypes of freezing of gait in Parkinson's disease.

BACKGROUND: The purpose of this study is to identify and characterize subtypes of freezing of gait by using a novel questionnaire designed to delineate freezing patterns based on self-reported and behavioral gait assessment. METHODS: A total of 41 Parkinson's patients with freezing completed the Characterizing Freezing of Gait questionnaire that identifies situations that exacerbate freezing. This instrument underwent examination for construct validity and internal consistency, after which a data-driven clustering approach was employed to identify distinct patterns amongst individual responses. Behavioral freezing assessments in both dopaminergic states were compared across 3 identified subgroups. RESULTS: This novel questionnaire demonstrated construct validity (severity scores correlated with percentage of time frozen; r = 0.54) and internal consistency (Cronbach's α = .937), and thus demonstrated promising utility for identifying patterns of freezing that are independently related to motor, anxiety, and attentional impairments. CONCLUSIONS: Patients with freezing may be dissociable based on underlying neurobiological underpinnings that would have significant implications for targeting future treatments. © 2018 International Parkinson and Movement Disorder Society.

Dopamine depletion impairs gait automaticity by altering cortico-striatal and cerebellar processing in Parkinson's disease.

Impairments in motor automaticity cause patients with Parkinson's disease to rely on attentional resources during gait, resulting in greater motor variability and a higher risk of falls. Although dopaminergic circuitry is known to play an important role in motor automaticity, little evidence exists on the neural mechanisms underlying the breakdown of locomotor automaticity in Parkinson's disease. This impedes clinical management and is in great part due to mobility restrictions that accompany the neuroimaging of gait. This study therefore utilized a virtual reality gait paradigm in conjunction with functional MRI to investigate the role of dopaminergic medication on lower limb motor automaticity in 23 patients with Parkinson's disease that were measured both on and off dopaminergic medication. Participants either operated foot pedals to navigate a corridor ('walk' condition) or watched the screen while a researcher operated the paradigm from outside the scanner ('watch' condition), a setting that controlled for the non-motor aspects of the task. Step time variability during walk was used as a surrogate measure for motor automaticity (where higher variability equates to reduced automaticity), and patients demonstrated a predicted increase in step time variability during the dopaminergic "off" state. During the "off" state, subjects showed an increased blood oxygen level-dependent response in the bilateral orbitofrontal cortices (walk>watch). To estimate step time variability, a parametric modulator was designed that allowed for the examination of brain regions associated with periods of decreased automaticity. This analysis showed that patients on dopaminergic medication recruited the cerebellum during periods of increasing variability, whereas patients off medication instead relied upon cortical regions implicated in cognitive control. Finally, a task-based functional connectivity analysis was conducted to examine the manner in which dopamine modulates large-scale network interactions during gait. A main effect of medication was found for functional connectivity within an attentional motor network and a significant condition by medication interaction for functional connectivity was found within the striatum. Furthermore, functional connectivity within the striatum correlated strongly with increasing step time variability during walk in the off state (r=0.616, p=0.002), but not in the on state (r=-0.233, p=0.284). Post-hoc analyses revealed that functional connectivity in the dopamine depleted state within an orbitofrontal-striatal limbic circuit was correlated with worse step time variability (r=0.653, p<0.001). Overall, this study demonstrates that dopamine ameliorates gait automaticity in Parkinson's disease by altering striatal, limbic and cerebellar processing, thereby informing future therapeutic avenues for gait and falls prevention.

Estimation of dynamic functional connectivity using Multiplication of Temporal Derivatives.

Functional connectivity provides an informative and powerful framework for exploring brain organization. Despite this, few statistical methods are available for the accurate estimation of dynamic changes in functional network architecture. To date, the majority of existing statistical techniques have assumed that connectivity structure is stationary, which is in direct contrast to emerging data that suggests that the strength of connectivity between regions is variable over time. Therefore, the development of statistical methods that enable exploration of dynamic changes in functional connectivity is currently of great importance to the neuroscience community. In this paper, we introduce the 'Multiplication of Temporal Derivatives' (MTD) and then demonstrate the utility of this metric to: (i) detect dynamic changes in connectivity using data from a novel state-switching simulation; (ii) accurately estimate graph structure in a previously-described 'ground-truth' simulated dataset; and (iii) identify task-driven alterations in functional connectivity. We show that the MTD is more sensitive than existing sliding-window methods in detecting dynamic alterations in connectivity structure across a range of correlation strengths and window lengths in simulated data. In addition to the temporal precision offered by MTD, we demonstrate that the metric is also able to accurately estimate stationary network structure in both simulated and real task-based data, suggesting that the method may be used to identify dynamic changes in network structure as they evolve through time.

Dopaminergic basis for impairments in functional connectivity across subdivisions of the striatum in Parkinson's disease.

The pathological hallmark of Parkinson's disease is the degeneration of dopaminergic nigrostriatal neurons, leading to depletion of striatal dopamine. Recent neuroanatomical work has identified pathways for communication across striatal subdivisions, suggesting that the striatum provides a platform for integration of information across parallel corticostriatal circuits. The aim of this study was to investigate whether dopaminergic dysfunction in Parkinson's disease was associated with impairments in functional connectivity across striatal subdivisions, which could potentially reflect reduced integration across corticostriatal circuits. Utilizing resting-state functional magnetic resonance imaging (fMRI), we analyzed functional connectivity in 39 patients with Parkinson's disease, both "on" and "off" their regular dopaminergic medications, along with 40 age-matched healthy controls. Our results demonstrate widespread impairments in connectivity across subdivisions of the striatum in patients with Parkinson's disease in the "off" state. The administration of dopaminergic medication significantly improved connectivity across striatal subdivisions in Parkinson's disease, implicating dopaminergic deficits in the pathogenesis of impaired striatal interconnectivity. In addition, impaired striatal interconnectivity in the Parkinson's disease "off" state was associated with pathological decoupling of the striatum from the thalamic and sensorimotor (SM) networks. Specifically, we found that although the strength of striatal interconnectivity was positively correlated with both (i) the strength of internal thalamic connectivity, and (ii) the strength of internal SM connectivity, in both healthy controls and the Parkinson's disease "on" state, these relationships were absent in Parkinson's disease when in the "off" state. Taken together our findings emphasize the central role of dopamine in integrated striatal function and the pathological consequences of striatal dopamine denervation in Parkinson's disease.

Impaired cognitive control in Parkinson's disease patients with freezing of gait in response to cognitive load.

Freezing of gait is a frequent and disabling symptom experienced by many patients with Parkinson's disease. A number of executive deficits have been shown to be associated with the phenomenon suggesting a common underlying pathophysiology, which as of yet remains unclear. Neuroimaging studies have also implicated the role of the cognitive control network in patients with freezing. To explore this concept, the current study examined error-monitoring as a measure of cognitive control. Thirty-four patients with and 38 without freezing of gait, who were otherwise well matched on disease severity, completed a colour-word interference task that allowed the specific assessment of error monitoring during conflict. Whilst both groups performed colour-naming and word-reading tasks equally well, those patients with freezing showed a pattern between conditions whereby they were better able to monitor performance and self-correct errors in the pure inhibition task but not after a switching rule was introduced. The novel results shown here provide insight into possible pathophysiological mechanisms involved in cognitive load and error monitoring in patients with freezing of gait. These results provide further evidence for the role of functional frontostriatal circuitry impairments in patients with freezing of gait and have implications for future studies and possible therapeutic interventions.

The role of dysfunctional attentional control networks in visual misperceptions in Parkinson's disease.

Visual misperceptions and hallucinations represent a problematic symptom of Parkinson's disease. The pathophysiological mechanisms underlying these symptoms remain poorly understood, however, a recent hypothesis has suggested that visual misperceptions and hallucinations may arise from disrupted processing across attentional networks. To test the specific predictions of this hypothesis, 22 patients with Parkinson's disease underwent 3T fMRI while performing the Bistable Percept Paradigm, a task that has previously been shown to identify patients with hallucinations. Subjects are required to study a battery of randomly assigned "monostable" and "bistable" monochromatic images for the presence or absence of a bistable percept. Those patients who scored a high percentage of misperceptions and missed images on the task were less able to activate frontal and parietal hubs of the putative Dorsal Attention Network. Furthermore, poor performance on the task was significantly correlated with the degree of decreased activation in a number of these hubs. At the group level, the difference between processing a bistable versus a monostable cue was associated with increased recruitment of the anterior insula. In addition, those patients with impaired performance on the paradigm displayed decreased resting state functional connectivity between hubs of the Ventral and Dorsal Attention Networks. These same patients had significantly decreased gray matter in the insula bilaterally. In addition, a combined analysis of the separate neuroimaging approaches revealed significant relationships across the impaired networks. These findings are consistent with specific predictions from a recently proposed hypothesis that implicates dysfunction within attentional networks in Parkinsonian hallucinations.

Investigating rapid eye movement sleep without atonia in Parkinson's disease using the rapid eye movement sleep behavior disorder screening questionnaire.

Rapid eye movement (REM) sleep behavior disorder (RBD) is frequently observed in patients with Parkinson's disease (PD). Accurate diagnosis is essential for managing this condition. Furthermore, the emergence of idiopathic RBD in later life can represent a premotor feature, heralding the development of PD. Reliable, accurate methods for identifying RBD may offer a window for early intervention. This study sought to identify whether the RBD screening questionnaire (RBDSQ) and three questionnaires focused on dream enactment were able to correctly identify patients with REM without atonia (RWA), the neurophysiological hallmark of RBD. Forty-six patients with PD underwent neurological and sleep assessment in addition to completing the RBDSQ, the RBD single question (RBD1Q), and the Mayo Sleep Questionnaire (MSQ). The REM atonia index was derived for all participants as an objective measure of RWA. Patients identified to be RBD positive on the RBDSQ did not show increased RWA on polysomnography (80% sensitivity and 55% specificity). However, patients positive for RBD on questionnaires specific to dream enactment correctly identified higher degrees of RWA and improved the diagnostic accuracy of these questionnaires. This study suggests that the RBDSQ does not accurately identify RWA, essential for diagnosing RBD in PD. Furthermore, the results suggest that self-report measures of RBD need to focus questions on dream enactment behavior to better identify RWA and RBD. Further studies are needed to develop accurate determination and quantification of RWA in RBD to improve management of patients with PD in the future.

Exploring the cortical and subcortical functional magnetic resonance imaging changes associated with freezing in Parkinson's disease.

Freezing of gait is a devastating symptom of advanced Parkinson's disease yet the neural correlates of this phenomenon remain poorly understood. In this study, severity of freezing of gait was assessed in 18 patients with Parkinson's disease on a series of timed 'up and go' tasks, in which all patients suffered from episodes of clinical freezing of gait. The same patients also underwent functional magnetic resonance imaging with a virtual reality gait paradigm, performance on which has recently been shown to correlate with actual episodes of freezing of gait. Statistical parametric maps were created that compared the blood oxygen level-dependent response associated with paroxysmal motor arrests (freezing) to periods of normal motor output. The results of a random effects analysis revealed that these events were associated with a decreased blood oxygen level-dependent response in sensorimotor regions and an increased response within frontoparietal cortical regions. These signal changes were inversely correlated with the severity of clinical freezing of gait. Motor arrests were also associated with decreased blood oxygen level-dependent signal bilaterally in the head of caudate nucleus, the thalamus and the globus pallidus internus. Utilizing a mixed event-related/block design, we found that the decreased blood oxygen level-dependent response in the globus pallidus and the subthalamic nucleus persisted even after controlling for the effects of cognitive load, a finding which supports the notion that paroxysmal increases in basal ganglia outflow are associated with the freezing phenomenon. This method also revealed a decrease in the blood oxygen level-dependent response within the mesencephalic locomotor region during motor arrests, the magnitude of which was positively correlated with the severity of clinical freezing of gait. These results provide novel insights into the pathophysiology underlying freezing of gait and lend support to models of freezing of gait that implicate dysfunction across coordinated neural networks.

Effect of dopamine on limbic network connectivity at rest in Parkinson's disease patients with freezing of gait.

Background: Freezing of gait (FOG) in Parkinson's disease (PD) has a poorly understood pathophysiology, which hinders treatment development. Recent work showed a dysfunctional fronto-striato-limbic circuitry at rest in PD freezers compared to non-freezers in the dopamine "OFF" state. While other studies found that dopaminergic replacement therapy alters functional brain organization in PD, the specific effect of dopamine medication on fronto-striato-limbic functional connectivity in freezers remains unclear. Objective: To evaluate how dopamine therapy alters resting state functional connectivity (rsFC) of the fronto-striato-limbic circuitry in PD freezers, and whether the degree of connectivity change is related to freezing severity and anxiety. Methods: Twenty-three PD FOG patients underwent MRI at rest (rsfMRI) in their clinically defined "OFF" and "ON" dopaminergic medication states. A seed-to-seed based analysis was performed between a priori defined limbic circuitry ROIs. Functional connectivity was compared between OFF and ON states. A secondary correlation analyses evaluated the relationship between Hospital Anxiety and Depression Scale (HADS)-Anxiety) and FOG Questionnaire with changes in rsFC from OFF to ON. Results: PD freezers' OFF compared to ON showed increased functional coupling between the right hippocampus and right caudate nucleus, and between the left putamen and left posterior parietal cortex (PPC). A negative association was found between HADS-Anxiety and the rsFC change from OFF to ON between the left amygdala and left prefrontal cortex, and left putamen and left PPC. Conclusion: These findings suggest that dopaminergic medication partially modulates the frontoparietal-limbic-striatal circuitry in PD freezers, and that the influence of medication on the amygdala, may be related to clinical anxiety in freezer.