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Background: Freezing of gait (FOG) is one of the most disabling gait disorders affecting 80% of patients with Parkinson's disease (PD). Clinical guidelines recommend a behavioral approach for gait rehabilitation, but there is a wide diversity of behavioral modalities., Objective: The objective of this network meta-analysis was to compare the effectiveness of different behavioral interventions for FOG management in PD patients., Methods: Six databases were searched for randomized controlled trials of behavioral interventions for FOG management among PD patients from 1990 to December 2021. Bayesian network meta-analysis was used to combine both direct and indirect trial evidence on treatment effectiveness, while the surface under the cumulative ranking (SUCRA) score was used to estimate the ranked probability of intervention effectiveness., Results: Forty-six studies were included in the qualitative synthesis. Among, 36 studies (1454 patients) of 72 interventions or control conditions (12 classes) were included in the network meta-analysis, with a mean intervention period of 10.3 weeks. After adjusting for the moderating effect of baseline FOG severity, obstacle training [SMD -2.1; 95% credible interval (Crl): -3.3, -0.86], gait training with treadmill (SMD -1.2; 95% Crl: -2.0, -0.34), action observation training (SMD -1.0; 95% Crl: -1.9, -0.14), conventional physiotherapy (SMD -0.70; 95% Crl: -1.3, -0.12) and general exercise (SMD -0.64; 95% Crl: -1.2, -0.11) demonstrated significant improvement on immediate FOG severity compared to usual care. The SUCRA rankings suggest that obstacle training, gait training on treadmill and general exercises are most likely to reduce FOG severity., Conclusion: Obstacle training, gait training on treadmill, general exercises, action observation training and conventional physiotherapy demonstrated immediate real-life benefits on FOG symptoms among patients with mild-moderate PD. With the promising findings, the sustained effects of high complexity motor training combined with attentional/cognitive strategy should be further explored. Future trials with rigorous research designs using both subjective and objective outcome measures, long-term follow-up and cost-effective analysis are warranted to establish effective behavioral strategies for FOG management., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objectives: Bilateral vestibulopathy (BVP) leads to unsteadiness when walking, which worsens in darkness or on uneven ground, as well as falls. Since simple balance tests struggle to distinguish between BVP and healthy participants, we aimed (1) to test if the Mini-BESTest is feasible in BVP, (2) how people with BVP perform on the Mini-BESTest and (3) to compare these scores with healthy reference data. Methods: Fifty participants with BVP completed the Mini-BESTest. 12-month falls incidence was obtained by questionnaire. To compare the overall and sub-scores between our participants with BVP and those of healthy participants from the literature (n = 327; obtained via PubMed searches), Mann–Whitney U tests were used. Sub scores within the BVP group were also compared. Spearman correlations were used to investigate the relationships between Mini-BESTest score and age. Results: No floor or ceiling effects were observed. Participants with BVP had significantly lower Mini-BESTest total scores than the healthy group. Anticipatory, reactive postural control and sensory orientation sub scores of the Mini-BESTest were significantly lower in BVP, while dynamic gait sub scores were not significantly different. A stronger negative correlation between age and Mini-BESTest total score was found in BVP than in the healthy group. Scores did not differ between patients with different falls history. Conclusion: The Mini-BESTest is feasible in BVP. Our results confirm the commonly reported balance deficits in BVP. The stronger negative association between age and balance in BVP might reflect the age-related decline in the remaining sensory systems with which people with BVP compensate. [ABSTRACT FROM AUTHOR]

Over the course of the disease, freezing of gait (FoG) will gradually impact over 80% of people with Parkinson's disease (PD). Clinical decision-making and research design are often based on classification of patients as 'freezers' or 'non-freezers'. We derived an objective measure of FoG severity from inertial sensors on the legs to examine the continuum of FoG from absent to possible and severe in people with PD and in healthy controls. One hundred and forty-seven people with PD (Off-medication) and 83 healthy control subjects turned 360° in-place for 1 minute while wearing three wearable sensors used to calculate a novel Freezing Index. People with PD were classified as: 'definite freezers', new FoG questionnaire (NFOGQ) score > 0 and clinically observed FoG; 'non-freezers', NFOGQ = 0 and no clinically observed FoG; and 'possible freezers', either NFOGQ > 0 but no FoG observed or NFOGQ = 0 but FoG observed. Linear mixed models were used to investigate differences in participant characteristics among groups. The Freezing Index significantly increased from healthy controls to non-freezers to possible freezers and to definite freezers and showed, in average, excellent test–retest reliability (ICC = 0.89). Unlike the Freezing Index, sway, gait and turning impairments were similar across non-freezers, possible and definite freezers. The Freezing Index was significantly related to NFOG-Q, disease duration, severity, balance confidence, and the SCOPA-Cog (p < 0.01). An increase in the Freezing Index, objectively assessed with wearable sensors during a turning- in-place test, may help identify prodromal FoG in people with PD prior to clinically-observable or patient-perceived freezing. Future work should follow objective measures of FoG longitudinally. [ABSTRACT FROM AUTHOR]

Motor–cognitive training in Parkinson's disease (PD) can positively affect gait and balance, but whether motor–cognitive (dual-task) performance improves is unknown. This meta-analysis, therefore, aimed to establish the current evidence on the effects of motor–cognitive training on dual-task performance in PD. Systematic searches were conducted in five databases and 11 studies with a total of 597 people (mean age: 68.9 years; mean PD duration: 6.8 years) were included. We found a mean difference in dual-task gait speed (0.12 m/s (95% CI 0.08, 0.17)), dual-task cadence (2.91 steps/min (95% CI 0.08, 5.73)), dual-task stride length (10.12 cm (95% CI 4.86, 15.38)) and dual-task cost on gait speed (− 8.75% (95% CI − 14.57, − 2.92)) in favor of motor–cognitive training compared to controls. The GRADE analysis revealed that the findings were based on high certainty evidence. Thus, we can for the first time systematically show that people with PD can improve their dual-task ability through motor–cognitive training. [ABSTRACT FROM AUTHOR]

Gait and balance disorders are common signs in several neurodegenerative diseases such as Parkinson's disease, atypical parkinsonism, idiopathic normal pressure hydrocephalus, cerebrovascular disease, dementing disorders and multiple sclerosis. According to each condition, patients present with different gait and balance alterations depending on the structural and functional brain changes through the disease course. In this review, we will summarize the main clinical characteristics of gait and balance disorders in the major neurodegenerative conditions, providing an overview of the significant structural and functional MRI brain alterations underlying these deficits. We also will discuss the role of neurorehabilitation strategies in promoting brain plasticity and gait/balance improvements in these patients. [ABSTRACT FROM AUTHOR]

Objectives: To assess whether dual-task gait/balance training with action observation training (AOT) and motor imagery (MI) ameliorates cognitive performance and resting-state (RS) brain functional connectivity (FC) in Parkinson's disease (PD) patients with postural instability and gait disorders (PIGD)., Methods: 21 PD-PIGD patients were randomized into 2 groups: (1) DUAL-TASK + AOT-MI group performed a 6-week training consisting of AOT-MI combined with practicing observed-imagined gait and balance exercises; and (2) DUAL-TASK group performed the same exercises combined with landscape-videos observation. At baseline and after training, all patients underwent a computerized cognitive assessment, while 17 patients had also RS-fMRI scans. Cognitive and RS-FC changes (and their relationships) over time within and between groups were assessed., Results: After training, all PD-PIGD patients improved accuracy in a test assessing executive-attentive (mainly dual-task) skills. DUAL-TASK + AOT-MI patients showed increased RS-FC within the anterior salience network (aSAL), and reduced RS-FC within the anterior default mode network (aDMN), right executive control network and precuneus network. DUAL-TASK patients showed increased RS-FC within the visuospatial network, only. Group × Time interaction showed that, compared to DUAL-TASK group, DUAL-TASK + AOT-MI cases had reduced RS-FC within the aDMN, which correlated with higher accuracy in a dual-task executive-attentive test., Conclusions: In PD-PIGD patients, both trainings promote cognitive improvement and brain functional reorganization. DUAL-TASK + AOT-MI training induced specific functional reorganization changes of extra-motor brain networks, which were related with improvement in dual-task performance., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

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. [ABSTRACT FROM AUTHOR]

Gait abnormalities and cognitive dysfunction are common in patients with Parkinson's disease (PD) and get worse with disease progression. Recent evidence has suggested a strong relationship between gait abnormalities and cognitive dysfunction in PD patients and impaired cognitive control could be one of the causes for abnormal gait patterns. However, the pathophysiological mechanisms of cognitive dysfunction in PD patients with gait problems are unclear. Here, we collected scalp electroencephalography (EEG) signals during a 7-s interval timing task to investigate the cortical mechanisms of cognitive dysfunction in PD patients with (PDFOG +, n = 34) and without (PDFOG–, n = 37) freezing of gait, as well as control subjects (n = 37). Results showed that the PDFOG + group exhibited the lowest maximum response density at around 7 s compared to PDFOG– and control groups, and this response density peak correlated with gait abnormalities as measured by FOG scores. EEG data demonstrated that PDFOG + had decreased midfrontal delta-band power at the onset of the target cue, which was also correlated with maximum response density and FOG scores. In addition, our classifier performed better at discriminating PDFOG + from PDFOG– and controls with an area under the curve of 0.93 when midfrontal delta power was chosen as a feature. These findings suggest that abnormal midfrontal activity in PDFOG + is related to cognitive dysfunction and describe the mechanistic relationship between cognitive and gait functions in PDFOG +. Overall, these results could advance the development of novel biosignatures and brain stimulation approaches for PDFOG +. [ABSTRACT FROM AUTHOR]

Background: In the last few years, virtual reality (VR) has been increasingly used to strengthen the effect of balance training (BT) in Parkinson's disease (PD). Objective: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the effects of VR-BT relative to BT alone for improving balance and mobility PD subjects with balance/mobility difficulties. Methods: Four electronic databases were searched: two reviewers independently selected RCTs, extracted data, and applied the Cochrane risk-of-bias tool for randomized trials (version 2) and the GRADE framework for assessing the certainty of evidence. Primary outcomes were balanced (Berg Balance Scale-BBS), mobility (Timed Up and Go-TUG) and walking speed. Secondary outcomes were falls, walking distance and stability, spatial gait parameters, balance confidence, sensory integration ability, motor signs and quality of life. Results: We included 22 studies (901 patients). Meta-analysis on fourteen trials (430 patients) showed a mean difference (MD) of 2.09 points (95% confidence interval [CI] 0.86–3.33) on BBS favoring VR-BT compared to BT (low certainty evidence). Subgroup analyses showed higher balance improvement in most affected subjects (moderate certainty evidence) and using VR rehabilitation-specific systems vs. VR non-specific systems. Eight trials (236 patients) assessing mobility showed a MD of 1.55 s (95% CI 0.04–3.06) on TUG favoring VR-BT (very low certainty evidence). No differences were observed in walking speed. Estimated effects were not maintained for any outcome at follow-up. Conclusions: This review suggests that VR-BT is more effective than BT to improve balance in PD subjects immediately after training, particularly in individuals with higher postural instability at baseline. [ABSTRACT FROM AUTHOR]

The "levodopa-overdose hypothesis" posits that dopaminergic replacement therapy (1) increases performance on tasks that depend on the nigrostriatal-pathway (e.g., motor-control circuits), yet (2) decreases performance on tasks that depend upon the mesocorticolimbic-pathway (e.g., prefrontal cortex, PFC). Previous work in Parkinson's disease (PD) investigated this model while focusing on cognitive function. Here, we evaluated whether this model applies to gait in patients with PD and freezing of gait (FOG). Forty participants were examined in both the OFF anti-Parkinsonian medication state (hypo-dopaminergic) and ON state (hyper-dopaminergic) while walking with and without the concurrent performance of a serial subtraction task. Wireless functional near-infrared spectroscopy measured PFC activation during walking. Consistent with the "overdose-hypothesis", performance on the subtraction task decreased (p = 0.027) after dopamine intake. Moreover, the effect of walking condition on PFC activation depended on the dopaminergic state (i.e., interaction effect p = 0.001). Gait significantly improved after levodopa administration (p < 0.001). Nonetheless, PFC activation was higher (p = 0.013) in this state than in the OFF state during usual-walking. This increase in PFC activation in the ON state suggests that dopamine treatment interfered with PFC functioning. Otherwise, PFC activation, putatively a reflection of cognitive compensation, should have decreased. Moreover, in contrast to the OFF state, in the ON state, PFC activation failed to increase (p = 0.313) during dual-tasking, perhaps due to a "ceiling effect". These findings extend the "levodopa-overdose hypothesis" and suggest that it also applies to gait in PD patients. While dopaminergic therapy improves certain aspects of motor performance, optimal treatment should consider the "double-edged sword" of levodopa. [ABSTRACT FROM AUTHOR]

Background: Protective steps are critical for fall prevention and are altered in people with Parkinson’s disease (PD). Previous work suggests that perturbation training, in which patients are exposed to repeated slips, may improve protective postural responses. However, these studies typically take the average performance of several postural responses before and after training. To reduce falls in the community, training must improve protective stepping after the first perturbation exposure. To date, no investigations have examined whether first-trial protective stepping is improved after training in people with PD.Methods: First-trial protective stepping was measured in 14 people with PD and 9 healthy adults before and 24 h after 1 day of perturbation training. The primary outcome was margin of stability after a perturbation, a measure of protective stepping effectiveness.Results: Margin of stability for the first perturbation was significantly (p = 0.001) improved on day 2 compared to before perturbation practice (day 1) in both groups. Furthermore, improvement in margin of stability was correlated with age and baseline stepping performance, such that older individuals and people with worse baseline performance showed the most pronounced improvement.Conclusions: Improving the first loss of balance after training is critical if such training is to reduce falls in people with PD. The observed improvement in first-trial protective stepping provides further support for perturbation training as a potential tool to improve protective steps and reduce falls in people with PD. [ABSTRACT FROM AUTHOR]

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

Protective postural responses to external perturbations are hypokinetic in people with Parkinson's disease (PD), and improving these responses may reduce falls. However, the ability of people with PD to improve postural responses with practice is poorly understood. Our objective was to determine whether people with PD can improve protective postural responses similarly to healthy adults through repeated perturbations, and whether improvements are retained or generalize to untrained perturbations. Twelve healthy adults and 15 people with PD underwent 25 forward and 25 backward translations of the support surface, eliciting backward, and forward protective steps, respectively. We assessed whether: (1) performance improved over one day of practice, (2) changes were retained 24 h later, and (3) improvements generalized to untrained (lateral) postural responses. People with PD and healthy adults improved postural response characteristics, including center of mass displacement after perturbations ( p < 0.001), margin of stability at first footfall ( p = 0.001), step latency ( p = 0.044), and number of steps ( p = 0.001). However, unlike controls, improvements in people with PD occurred primarily in the first block of trials. Improvements were more pronounced during backward protective stepping than forward, and with the exception of step latency, were retained 24 h later. Improvements in forward-backward stepping did not generalize to lateral protective stepping. People with PD can improve protective stepping over the course of 1 day of perturbation practice. Improvements were generally similar to healthy adults, and were retained in both groups. Perturbation practice may represent a promising approach to improving protective postural responses in people with PD; however, additional research is needed to understand how to enhance generalization. [ABSTRACT FROM AUTHOR]

Body-fixed sensors (BFS), e.g., accelerometers worn for several days, can be used to augment the traditional clinical assessment. Long-term recordings obtained with BFS have been applied to study tremor, postural control, freezing of gait, turning abilities, motor response fluctuations and fall risk among older adults and patients with Parkinson's disease (PD). We aimed to test whether BFS-derived measures of transitions differ between patients with PD and healthy controls, and to evaluate whether there are differences among patients with mild PD, compared to more severe patients, and to controls. We also explored the added value of the metrics extracted from the sensor as compared to traditional testing in the lab. Ninety-nine patients with PD and 38 healthy older adults (HOA) participated in this study and wore a body-fixed sensor for 3 days. Walk-to-sit ( n = 3286) and Sit-to-walk ( n = 2858) transitions were analyzed and a machine learning algorithm was applied to distinguish between the groups. Significant differences in transitions were observed between PD patients and HOA, between mild and severe PD, and between mild PD and HOA, both in temporal and distribution features. The machine learning algorithm discriminated patients from HOA (accuracy = 92.3 %), mild from severe patients (accuracy = 89.8 %), and mild patients from HOA (accuracy = 85.9 %). These initial results suggest that body-fixed sensor-derived metrics of everyday transitions can characterize disease severity and differentiate mild PD patients from healthy older adults. Perhaps this approach can help with the integration of BFS into clinical care and the tracking of disease progression and the response to therapy. [ABSTRACT FROM AUTHOR]

In this study, we investigated the effect of dopaminergic medication on reactive stepping responses to forward and backward balance perturbations in patients with moderately severe Parkinson's disease (PD). Twelve PD patients, Hoehn and Yahr stage ranging from 2 to 3, and 15 healthy controls were exposed to multidirectional translational stance perturbations on a moveable platform. Perturbations were unpredictable in terms of amplitude, timing and direction. Patients were tested in the medication ON and OFF (at least 12 h of dopaminergic medication withdrawal) state on two separate days. Forward and backward stepping responses were quantified in terms of (1) presence, onset and amplitude of anticipatory postural adjustments (APAs); (2) spatiotemporal step variables (step onset, length and velocity); and (3) leg inclination angle at first stepping-foot contact. When perturbed forward, patients performed worse than controls in terms of step length (0.32 ± 0.07 vs. 0.38 ± 0.05 m, p = 0.01) and step velocity (1.21 ± 0.16 vs. 1.37 ± 0.13 m/s, p = 0.01), while step onset was not different. The number of steps with an APA was larger in patients in the OFF state than in controls which was, however, only significant after forward perturbations (43 vs. 20 %, p = 0.01). Following backward perturbations, leg angles at foot contact were smaller in patients compared to controls (−2.71° ± 4.29° vs. 0.26° ± 2.80°, p = 0.04) reflecting a poorer mechanical efficiency of the step. Dopaminergic medication had no significant effect on any of these outcomes. In conclusion, dopaminergic medication does not improve underscaling of stepping responses in PD. Therefore, other interventions are needed to improve these important defense postural reactions. [ABSTRACT FROM AUTHOR]

Freezing of gait is an episodic gait disorder, characterized by the inability to generate effective forward stepping movements. The pathophysiology underlying freezing of gait remains insufficiently understood, and this hampers the development of better treatment strategies. Preliminary evidence suggests that impaired force control during walking may contribute to freezing episodes, with difficulty to unload the swing leg and initiate the swing phase. Here, we used external loading to manipulate force control and to investigate its influence on freezing of gait. Twelve Parkinson's disease patients with freezing of gait performed three contrasting tasks: (1) loaded gait while wearing a belt fortified with lead weights; (2) weight-supported gait using a parachute harness connected to a rigid metal cable running above the gait trajectory; and (3) normal gait. Gait tasks were used to provoke freezing episodes, including rapid 360° turns. Freezing episodes were quantified using blinded, videotaped clinical assessment. Furthermore, ground reaction forces and body kinematics were recorded. Loading significantly increased the mean number of freezing episodes per trial compared to the normal gait condition ( P < 0.05), but the effect of weight support was not consistent. Loading particularly increased the number of freezing episodes during rapid short steps. Step length was significantly smaller during loaded gait compared to normal gait ( P < 0.05), but changes in anticipatory postural adjustments were not different. Our results may point to impaired force control playing a key role in freezing of gait. Future studies should further investigate the mechanism, i.e., the contribution of deficient load feedback, and evaluate which forms of weight support might offer treatment opportunities. [ABSTRACT FROM AUTHOR]

The pathology of Parkinson's disease (PD) is not confined to the nigrostriatal dopaminergic pathway, but also involves widespread cerebral cortical areas. Such non-nigrostriatal lesions may contribute to disabling dopa-resistant parkinsonian motor deficits. We performed cortical thickness analysis to identify cerebral cortical brain areas in which thickness correlates with the severity of parkinsonian motor deficits. We performed T1-weighted brain magnetic resonance imaging studies in 142 PD patients. Motor scores on the Unified Parkinson's Disease Rating Scale (UPDRS) were measured, and subscores were calculated for bradykinesia, rigidity, tremor, and axial motor deficits. Using FreeSurfer software, we studied cortical areas in which thickness correlates with disease duration or the severity of parkinsonian motor deficits. The cortical thickness of the parieto-temporal association cortex, including the inferior parietal and posterior parietal cortices, showed a negative correlation with disease duration, total UPDRS motor score, and UPDRS subscores for bradykinesia and axial motor deficits. We found no cortical areas in which thickness correlated with subscores for tremor and rigidity. In addition to nigrostriatal dopaminergic deficit, progressive thinning of the parieto-temporal sensory association cortices related to disease duration seems to be related in part to the exacerbation of bradykinesia and the axial motor symptoms of PD. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Staircase climbing is not solely a visual compensation strategy to alleviate freezing of gait in Parkinson's disease," by M. Gilat et al. which appears in the same issue.