New Insights into Freezing of Gait in Parkinson's Disease from Spectral Dynamic Causal Modeling.

BACKGROUND: Freezing of gait is one of the most disturbing motor symptoms of Parkinson's disease (PD). However, the effective connectivity between key brain hubs that are associated with the pathophysiological mechanism of freezing of gait remains elusive. OBJECTIVE: The aim of this study was to identify effective connectivity underlying freezing of gait. METHODS: This study applied spectral dynamic causal modeling (DCM) of resting-state functional magnetic resonance imaging in dedicated regions of interest determined using a data-driven approach. RESULTS: Abnormally increased functional connectivity between the bilateral dorsolateral prefrontal cortex (DLPFC) and the bilateral mesencephalic locomotor region (MLR) was identified in freezers compared with nonfreezers. Subsequently, spectral DCM analysis revealed that increased top-down excitatory effective connectivity from the left DLPFC to bilateral MLR and an independent self-inhibitory connectivity within the left DLPFC in freezers versus nonfreezers (>99% posterior probability) were inversely associated with the severity of freezing of gait. The lateralization of these effective connectivity patterns was not attributable to the initial dopaminergic deficit nor to structural changes in these regions. CONCLUSIONS: We have identified novel effective connectivity and an independent self-inhibitory connectivity underlying freezing of gait. Our findings imply that modulating the effective connectivity between the left DLPFC and MLR through neurostimulation or other interventions could be a target for reducing freezing of gait in PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Which Gait Tasks Produce Reliable Outcome Measures of Freezing of Gait in Parkinson's Disease?

Background: Measurement of freezing of gait (FOG) relies on the sensitivity and reliability of tasks to provoke FOG. It is currently unclear which tasks provide the best outcomes and how medication state plays into this. Objective: To establish the sensitivity and test-retest reliability of various FOG-provoking tasks for presence and severity of FOG, with (ON) and without (OFF) dopaminergic medication. Methods: FOG-presence and percentage time frozen (% TF) were derived from video annotations of a home-based FOG-provoking protocol performed in OFF and ON. This included: the four meter walk (4MW), Timed Up and Go (TUG) single (ST) and dual task (DT), 360° turns in ST and DT, a doorway condition, and a personalized condition. Sensitivity was tested at baseline in 63 definite freezers. Test-retest reliability was evaluated over 5 weeks in 26 freezers. Results: Sensitivity and test-retest reliability were highest for 360° turns and higher in OFF than ON. Test-retest intra-class correlation coefficients of % TF varied between 0.63-0.90 in OFF and 0.18-0.87 in ON, and minimal detectable changes (MDCs) were high. The optimal protocol included TUG ST, 360° turns ST, 360° turns DT and a doorway condition, provoking FOG in all freezers in OFF and 91.9% in ON and this could be done reliably in 95.8% (OFF) and 84.0% (ON) of the sample. Combining OFF and ON further improved outcomes. Conclusions: The highest sensitivity and reliability was achieved with a multi-trigger protocol performed in OFF + ON. However, the high MDCs for % TF underscore the need for further optimization of FOG measurement.

Freezing of gait is a very burdensome and episodic symptom in Parkinson's disease that is difficult to measure. Measurement of freezing is needed to determine whether someone has freezing and how severe this is, and relies on observation during a freezing-triggering protocol. However, it is unclear what protocol is sufficiently sensitive to trigger freezing in many freezers, and whether freezing can be triggered reliably at different timepoints. Here, we investigated 1) which tasks can trigger freezing-presence and freezing-severity sensitively and reliably, 2) how medication state influences this, and 3) what task combination was most reliable. Sixty-three patients with daily freezing performed several freezing-triggering tasks in their homes, both with (ON) and without (OFF) anti-Parkinsonian medication. In twenty-six patients, the measurement was repeated 5 weeks later to determine test-retest reliability. First, we found that performing 360° turns in place with a cognitive dual task was the most sensitive and reliable task to trigger FOG. Second, sensitivity and reliability were better in OFF than in ON. Third, the most reliable protocol included: the Timed-Up and Go, 360° turns in place with and without the dual task, and a doorway condition. This protocol triggered freezing in all patients in OFF and 91.9% in ON and did so reliably in 95.8% (OFF) and 84.0% (ON) of the sample. We recommend to measure freezing with this protocol in OFF + ON, which further improved reliability. However, the measurement error for freezing-severity was high, even for this optimal protocol, underscoring the need for further optimization of freezing measurement.

Assessing impaired bed mobility in patients with Parkinson's disease: a scoping review.

BACKGROUND: Although most patients with Parkinson's disease (PD) experience difficulties in bed mobility, evidence on the suitability of the methods for assessing impaired bed mobility in PD are lacking. OBJECTIVES: To identify objective methods for assessing impaired bed mobility in PD and to discuss their clinimetric properties and feasibility for use in clinical practice. DATA SOURCES: PubMed, Web of Science, and Cochrane Library were searched between 1995 and 2022. SELECTION CRITERIA: Studies were included if they described an objective assessment method for assessing impaired bed mobility in PD. DATA EXTRACTION AND DATA SYNTHESIS: Characteristics of the identified measurement methods such as clinimetric properties and feasibility were extracted by two authors. The methodological quality of studies was evaluated using the Appraisal of studies tool. RESULTS: Twenty-three studies were included and categorised into three assessment methods: sensor-based assessments (48%), rating scales (39%), and timed-tests (13%). The risk of bias was low for all but one study, which was medium. LIMITATIONS: Despite applying wide selection criteria, a relatively small number of studies were identified in our results. CONCLUSION: Rating scales may be the most preferred for assessing impaired bed mobility in PD in clinical practice, until clinimetric validity are adequately demonstrated in the other assessment methods. CONTRIBUTION OF PAPER.

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.

Gait asymmetry and symptom laterality in Parkinson's disease: two of a kind?

BACKGROUND: The laterality of motor symptoms is considered a key feature of Parkinson's disease (PD). Here, we investigated whether gait and turning asymmetry coincided with symptom laterality as determined by the MDS-UPRDS part III and whether it was increased compared to healthy controls (HC). METHODS: We analyzed the asymmetry of gait and turning with and without a cognitive dual task (DT) using motion capture systems and wearable sensors in 97 PD patients mostly from Hoehn & Yahr stage II and III and 36 age-matched HC. We also assessed motor symptom asymmetry using the bilateral sub-items of the MDS-UPDRS-III. Finally, we examined the strength of the association between gait asymmetry and symptom laterality. RESULTS: Participants with PD had increased gait but not more turning asymmetry compared to HC (p < 0.05). Only 53.7% of patients had a shorter step length on the more affected body side as determined by the MDS-UPDRS-III. Also, 54% took more time and 29% more steps during turns toward the more affected side. The degree of asymmetry in the different domains did not correlate with each other and was not influenced by DT-load. CONCLUSIONS: We found a striking mismatch between the side and the degree of asymmetry in different motor domains, i.e., in gait, turning, and distal symptom severity in individuals with PD. We speculate that motor execution in different body parts relies on different neural control mechanisms. Our findings warrant further investigation to understand the complexity of gait asymmetry in PD.

Towards a better understanding of anticipatory postural adjustments in people with Parkinson's disease.

INTRODUCTION: Previous studies have shown that anticipatory postural adjustments (APAs) are altered in people with Parkinson's disease but its meaning for locomotion is less understood. This study aims to investigate the association between APAs and gait initiation, gait and freezing of gait and how a dynamic postural control challenging training may induce changes in these features. METHODS: Gait initiation was quantified using wearable sensors and subsequent straight walking was assessed via marker-based motion capture. Additionally, turning and FOG-related outcomes were measured with wearable sensors. Assessments were conducted one week before (Pre), one week after (Post) and 4 weeks after (Follow-up) completion of a training intervention (split-belt treadmill training or regular treadmill training), under single task and dual task (DT) conditions. Statistical analysis included a linear mixed model for training effects and correlation analysis between APAs and the other outcomes for Pre and Post-Pre delta. RESULTS: 52 participants with Parkinson's disease (22 freezers) were assessed. We found that APA size in the medio-lateral direction during DT was positively associated with gait speed (p<0.001) and stride length (p<0.001) under DT conditions at Pre. The training effect was largest for first step range of motion and was similar for both training modes. For the associations between changes after the training (pooled sample) medio-lateral APA size showed a significant positive correlation with first step range of motion (p = 0.033) only in the DT condition and for the non-freezers only. CONCLUSIONS: The findings of this work revealed new insights into how APAs were not associated with first step characteristics and freezing and only baseline APAs during DT were related with DT gait characteristics. Training-induced changes in the size of APAs were related to training benefits in the first step ROM only in non-freezers. Based on the presented results increasing APA size through interventions might not be the ideal target for overall improvement of locomotion.

Neural correlates of weight-shift training in older adults: a randomized controlled study.

Mediolateral weight-shifting is an important aspect of postural control. As it is currently unknown whether a short training session of mediolateral weight-shifting in a virtual reality (VR) environment can improve weight-shifting, we investigated this question and also probed the impact of practice on brain activity. Forty healthy older adults were randomly allocated to a training (EXP, n = 20, age = 70.80 (65-77), 9 females) or a control group (CTR, n = 20, age = 71.65 (65-82), 10 females). The EXP performed a 25-min weight-shift training in a VR-game, whereas the CTR rested for the same period. Weight-shifting speed in both single- (ST) and dual-task (DT) conditions was determined before, directly after, and 24 h after intervention. Functional Near-Infrared Spectroscopy (fNIRS) assessed the oxygenated hemoglobin (HbO2) levels in five cortical regions of interest. Weight-shifting in both ST and DT conditions improved in EXP but not in CTR, and these gains were retained after 24 h. Effects transferred to wider limits of stability post-training in EXP versus CTR. HbO2 levels in the left supplementary motor area were significantly increased directly after training in EXP during ST (change < SEM), and in the left somatosensory cortex during DT (change > SEM). We interpret these changes in the motor coordination and sensorimotor integration areas of the cortex as possibly learning-related.

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

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

Test-retest reliability of functional near-infrared spectroscopy during a finger-tapping and postural task in healthy older adults.

Significance: Functional near-infrared spectroscopy (fNIRS) is increasingly employed in studies requiring repeated measurements, yet test-retest reliability is largely unknown. Aim: To investigate test-retest reliability during a postural and a finger-tapping task with and without cap-removal. Approach: Twenty healthy older adults performed a postural and a finger-tapping task. The tasks were repeated twice in one session and once the next day. A portable fNIRS system measured cortical hemodynamics (HbO2) in five regions of interest for the postural task and in the hand motor region for finger-tapping. Results: Test-retest reliability without cap-removal was excellent for the prefrontal cortex (PFC), the premotor cortex (PMC) and the somatosensory cortex (SSC) (intraclass correlation coefficient (ICC)≥0.78), and fair for the frontal eye fields (FEF) and the supplementary motor area (SMA) (ICC≥0.48). After cap-removal, reliability reduced for PFC and SSC (ICC≥0.50), became poor for SMA (ICC=0.01) and PMC (ICC=0.00) and remained good for FEF (ICC=0.64). Similarly, good reliability (ICC=0.66) was apparent for the hand motor region without cap-removal, which deteriorated after cap-removal (ICC=0.38). Conclusions: Test-retest reliability of fNIRS measurements during two separate motor tasks in healthy older adults was fair to excellent when the cap remained in place. However, removing the fNIRS cap between measurements compromised reliability.

Neural underpinnings of freezing-related dynamic balance control in people with Parkinson's disease.

INTRODUCTION: People with Parkinson's disease (PD) with freezing of gait (FOG; freezers) show impaired dynamic balance and experience falls more frequently compared to those without (non-freezers). Here, we explore the neural underpinnings of these freezing-related balance problems. METHODS: 12 freezers, 16 non-freezers and 14 controls performed a dynamic balance task in the lab. The next day, the same task was investigated in the MRI-scanner through motor imagery (MI). A visual imagery (VI) control task was also performed. Imagery engagement was determined by comparing the performance times between the dynamic balance task, and its MI- and VI-variants. Balance-related brain activations in regions of interest were contrasted between groups based on an MI > rest versus VI > rest contrast. RESULTS: Freezers and non-freezers were matched for age, cognition and disease severity. Similar performance times between the balance control task and the MI-conditions revealed excellent imagery engagement. Compared to non-freezers, freezers showed decreased activation in regions of interest located in the left mesencephalic locomotor region (MLR; p = 0.006), right anterior cerebellum (p = 0.017) and cerebellar vermis (p < 0.001). Intriguingly, non-freezers showed higher activations in the cerebellar vermis than controls (p = 0.010). CONCLUSION: Overall, we showed that decreased activation in the left MLR, and cerebellar regions in freezers relative to non-freezers could explain why dynamic balance is more affected in freezers. As non-freezers displayed increased cerebellar vermis activation compared to controls, it is possible that freezers show an inability to recruit sufficient compensatory cerebellar activity for effective dynamic balance control.

Split-Belt Treadmill Training to Improve Gait Adaptation in Parkinson's Disease.

BACKGROUND: Gait deficits in people with Parkinson's disease (PD) are triggered by circumstances requiring gait adaptation. The effects of gait adaptation training on a split-belt treadmill (SBT) are unknown in PD. OBJECTIVE: We investigated the effects of repeated SBT versus tied-belt treadmill (TBT) training on retention and automaticity of gait adaptation and its transfer to over-ground walking and turning. METHODS: We recruited 52 individuals with PD, of whom 22 were freezers, in a multi-center randomized single-blind controlled study. Training consisted of 4 weeks of supervised treadmill training delivered three times per week. Tests were conducted pre- and post-training and at 4-weeks follow-up. Turning (primary outcome) and gait were assessed over-ground and during a gait adaptation protocol on the treadmill. All tasks were performed with and without a cognitive task. RESULTS: We found that SBT-training improved gait adaptation with moderate to large effects sizes (P < 0.02) compared to TBT, effects that were sustained at follow-up and during dual tasking. However, better gait adaptation did not transfer to over-ground turning speed. In both SBT- and TBT-arms, over-ground walking and Movement Disorder Society-Unified Parkinson's Disease Rating Scale III (MDS-UPDRS-III scores were improved, the latter of which reached clinically meaningful effects in the SBT-group only. No impact was found on freezing of gait. CONCLUSION: People with PD are able to learn and retain the ability to overcome asymmetric gait-speed perturbations on a treadmill remarkably well, but seem unable to generalize these skills to asymmetric gait off-treadmill. Future study is warranted into gait adaptation training to boost the transfer of complex walking skills. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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.

Determinants of impaired bed mobility in Parkinson's disease: Impact of hip muscle strength and motor symptoms.

BACKGROUND: Although most patients with Parkinson's disease (PD) present difficulties of bed mobility, the contributing factors to impaired bed mobility in PD are unknown. OBJECTIVE: To compare bed mobility and muscle strength between PD patients and healthy controls, and investigate the determinants of bed mobility in PD. METHODS: Sixteen patients with PD and ten age- and sex-matched healthy controls (HC) were enrolled. Time and pattern to get out of bed to their preferred side at usual speed, muscle torque in lower extremities and motor symptom burden were also measured. RESULTS: PD exhibited significantly slower speed in bed mobility and lower torque in the hip adductor/abductor/flexor muscle than HC. Slower movement time in PD was correlated with weaker hip adductor torque on the more affected side (Rs = -0.56, p < 0.05) and with higher score in arm rigidity both sides (Rs≥0.79, p < 0.01). There were no significant differences between the categorised movement patterns and movement time in PD (p = 0.31). CONCLUSIONS: Reduced hip adductors torque and severe arm rigidity are associated with slowness of getting out of bed, implying that these components could be used as targets for rehabilitation practice to improve bed mobility in PD.

Striatal Acetylcholine-Dopamine Imbalance in Parkinson Disease: In Vivo Neuroimaging Study with Dual-Tracer PET and Dopaminergic PET-Informed Correlational Tractography.

Previous studies of animal models of Parkinson disease (PD) suggest an imbalance between striatal acetylcholine and dopamine, although other studies have questioned this. To our knowledge, there are no previous in vivo neuroimaging studies examining striatal acetylcholine-dopamine imbalance in PD patients. Using cholinergic and dopaminergic PET (18F-fluoroethoxybenzovesamicol [18F-FEOBV] and 11C-dihydrotetrabenazine [11C-DTBZ], respectively) and correlational tractography, our aim was to investigate the acetylcholine-dopamine interaction at 2 levels of dopaminergic loss in PD subjects: integrity loss of the nigrostriatal dopaminergic white matter tract and loss at the presynaptic-terminal level. Methods: The study involved 45 subjects with mild to moderate PD (36 men, 9 women; mean age, 66.3 ± 6.3 y, disease duration, 5.8 ± 3.6 y; Hoehn and Yahr stage, 2.2 ± 0.6) and 15 control subjects (9 men, 6 women; mean age, 69.1 ± 8.6 y). PET imaging was performed using standard protocols. We first estimated the integrity of the dopaminergic nigrostriatal white matter tracts in PD subjects by incorporating molecular information from striatal 11C-DTBZ PET into the fiber tracking process using correlational tractography (based on quantitative anisotropy [QA], a measure of tract integrity). Subsequently, we used voxel-based correlation to test the association of the mean QA of the nigrostriatal tract of each cerebral hemisphere with the striatal 18F-FEOBV distribution volume ratio (DVR) in PD subjects. The same analysis was performed for 11C-DTBZ DVR in 12 striatal subregions (presynaptic-terminal level). Results: Unlike 11C-DTBZ DVR in striatal subregions, the mean QA of the nigrostriatal tract of the most affected hemisphere showed a negative correlation with a striatal cluster of 18F-FEOBV DVR in PD subjects (corrected P = 0.039). We also found that the mean 18F-FEOBV DVR within this cluster was higher in the PD group than in the control group (P = 0.01). Cross-validation analyses confirmed these findings. We also found an increase in bradykinesia ratings associated with increased acetylcholine-dopamine imbalance in the most affected hemisphere (r = 0.41, P = 0.006). Conclusion: Our results provide evidence for the existence of striatal acetylcholine-dopamine imbalance in early PD and may provide an avenue for testing in vivo effects of therapeutic strategies aimed at restoring striatal acetylcholine-dopamine balance in PD.

Dual Task Turning in Place: A Reliable, Valid, and Responsive Outcome Measure of Freezing of Gait.

BACKGROUND: Freezing of gait (FOG) is a complex symptom in Parkinson's disease (PD) that is both elusive to elicit and varied in its presentation. These complexities present a challenge to measuring FOG in a sensitive and reliable way, precluding therapeutic advancement. OBJECTIVE: We investigated the reliability, validity, and responsiveness of manual video annotations of the turning-in-place task and compared it to the sensor-based FOG ratio. METHODS: Forty-five optimally medicated people with PD and FOG performed rapid alternating 360° turns without and with an auditory stroop dual task, thrice over two consecutive days. The tasks were video recorded, and inertial sensors were placed on the lower back and shins. Interrater reliability between three raters, criterion validity with self-reported FOG, and responsiveness to single-session split-belt treadmill (SBT) training were investigated and contrasted with the sensor-based FOG ratio. RESULTS: Visual ratings showed excellent agreement between raters for the percentage time frozen (%TF) (ICC [intra-class correlation coefficient] = 0.99), the median duration of a FOG episode (ICC = 0.90), and the number of FOG episodes (ICC = 0.86). Dual tasking improved the sensitivity and validity of visual FOG ratings resulting in increased FOG detection, criterion validity with self-reported FOG ratings, and responsiveness to a short SBT intervention. The sensor-based FOG ratio, on the contrary, showed complex FOG presentation-contingent relationships with visual and self-reported FOG ratings and limited responsiveness to SBT training. CONCLUSIONS: Manual video annotations of FOG during dual task turning in place generate reliable, valid, and sensitive outcomes for investigating therapeutic effects on FOG. © 2021 International Parkinson and Movement Disorder Society.

Repeated Gait Perturbation Training in Parkinson's Disease and Healthy Older Adults: A Systematic Review and Meta-Analysis.

Background: Gait impairments are common in healthy older adults (HOA) and people with Parkinson's disease (PwPD), especially when adaptations to the environment are required. Traditional rehabilitation programs do not typically address these adaptive gait demands in contrast to repeated gait perturbation training (RGPT). RGPT is a novel reactive form of gait training with potential for both short and long-term consolidation in HOA and PwPD. The aim of this systematic review with meta-analysis is to determine whether RGPT is more effective than non-RGPT gait training in improving gait and balance in HOA and PwPD in the short and longer term. Methods: This review was conducted according to the PRISMA-guidelines and pre-registered in the PROSPERO database (CRD42020183273). Included studies tested the effects of any form of repeated perturbations during gait in HOA and PwPD on gait speed, step or stride length. Studies using balance scales or sway measures as outcomes were included in a secondary analysis. Effects of randomized controlled trials (RCT) on RGPT were pooled using a meta-analysis of final measures. Results: Of the 4421 studies, eight studies were deemed eligible for review, of which six could be included in the meta-analysis, totaling 209 participants (159 PwPD and 50 HOA). The studies were all of moderate quality. The meta-analysis revealed no significant effects of RGPT over non-RGPT training on gait performance (SMD = 0.16; 95% CI = -0.18, 0.49; Z = 0.92; P = 0.36). Yet, in some individual studies, favorable effects on gait speed, step length and stride length were observed immediately after the intervention as well as after a retention period. Gait variability and asymmetry, signifying more direct outcomes of gait adaptation, also indicated favorable RGPT effects in some individual studies. Conclusion: Despite some promising results, the pooled effects of RGPT on gait and balance were not significantly greater as compared to non-RGPT gait training in PwPD and HOA. However, these findings could have been driven by low statistical power. Therefore, the present review points to the imperative to conduct sufficiently powered RCT's to verify the true effects of RGPT on gait and balance in HOA and PwPD. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php? Identifier: CRD42020183273.

A systematic review on exercise and training-based interventions for freezing of gait in Parkinson's disease.

Freezing of gait (FOG) in Parkinson's disease (PD) causes severe patient burden despite pharmacological management. Exercise and training are therefore advocated as important adjunct therapies. In this meta-analysis, we assess the existing evidence for such interventions to reduce FOG, and further examine which type of training helps the restoration of gait function in particular. The primary meta-analysis across 41 studies and 1838 patients revealed a favorable moderate effect size (ES = -0.37) of various training modalities for reducing subjective FOG-severity (p < 0.00001), though several interventions were not directly aimed at FOG and some included non-freezers. However, exercise and training also proved beneficial in a secondary analysis on freezers only (ES = -0.32, p = 0.007). We further revealed that dedicated training aimed at reducing FOG episodes (ES = -0.24) or ameliorating the underlying correlates of FOG (ES = -0.40) was moderately effective (p < 0.01), while generic exercises were not (ES = -0.14, p = 0.12). Relevantly, no retention effects were seen after cessation of training (ES = -0.08, p = 0.36). This review thereby supports the implementation of targeted training as a treatment for FOG with the need for long-term engagement.

How many gait initiation trials are necessary to reliably detect anticipatory postural adjustments and first step characteristics in healthy elderly and people with Parkinson's disease?

BACKGROUND: The gait initiation (GI) process can be characterized by anticipatory postural adjustments (APAs) and first step characteristics. However, even within a constrained environment, it is unclear how many trials are necessary to obtain a reliable measurement of the GI process within one assessment. RESEARCH QUESTION: How many gait initiation trials are necessary to reliably detect APAs and first step characteristics in healthy elderly (HC) and people with Parkinson's disease with Freezing of Gait (PD + FOG) under single (ST) and dual task (DT) conditions and are there any potential systematic errors? METHODS: Thirty-eight PD + FOG (ON-medication) and 30 HC performed 5 trials of GI under ST and DT (auditory stroop test). APAs and first-step-outcomes were captured with IMUs placed on the lower back and on each foot. Intraclass correlation coefficients (ICCs) and the standard error of measurement (SEM) were computed to investigate reliability and mixed model analysis to find potential systematic errors. Additionally, we computed an estimation for the number of necessary trials to reach acceptable reliability (ICC = 0.75) for each outcome. RESULTS: ICCs varied from low reliability to excellent reliability across outcomes in PD + FOG and HC. ICCs were comparable under ST and DT for most outcomes. SEM results confirmed the ICC results. A systematic error was found for the first trial in first step ROM. Number of necessary trials varied largely across outcomes. SIGNIFICANCE: Within-session reliability varied across outcomes but was similar for PD + FOG and HC, and ST and DT. ML size of APA and first step ROM were most reliable, whereas APA duration and latency were least reliable. Depending on the outcome of interest, future studies should conduct multiple trials of GI to increase reliability.

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.