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Freezing of Gait (FOG) is one of the most debilitating gait impairments in Parkinson’s disease (PD), leading to increased fall risk and reduced health-related quality of life. The utility of parkinsonian medications is often limited in the case of FOG and it frequently becomes dopamine resistant. Recent studies have suggested that pre-frontal cortex (PFC) dysfunction contributes to FOG; however, most previous findings provide only indirect evidence. To better understand the role of the PFC, we aimed to investigate the impact of high frequency, deep, repetitive transcranial magnetic stimulation (drTMS) of the medial PFC on FOG and its mediators. Nine patients with advanced PD participated in a randomized, cross-over exploratory study. We applied drTMS over the medial PFC for 16 weeks, with real and sham conditions; each condition included an intensive (i.e., 3 times a week) phase and a maintenance (once a week) phase. Scores on a FOG-provoking test, the motor part of the Unified Parkinson’s Disease Rating Scale, and gait variability significantly improved after real drTMS, but not after the sham condition. Self-report of FOG severity and cognitive scores did not improve. Due to discomfort and pain during treatment, two patients dropped out and the study was halted. These initial findings support the cause-and-effect role of the pre-frontal cortex in FOG among patients with PD. Due to the small sample size, findings should be interpreted cautiously. Further studies are needed to more fully assess the role of the medial PFC in the underlying mechanism of FOG and the possibility of using non-invasive brain stimulation to modify FOG.

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.

Freezing of gait (FOG) is a debilitating motor phenomenon that is common among individuals with advanced Parkinson’s disease. Objective and sensitive measures are needed to better quantify FOG. The present work addresses this need by leveraging wearable devices and machine-learning methods to develop and evaluate automated detection of FOG and quantification of its severity. Seventy-one subjects with FOG completed a FOG-provoking test while wearing three wearable sensors (lower back and each ankle). Subjects were videotaped before (OFF state) and after (ON state) they took their antiparkinsonian medications. Annotations of the videos provided the “ground-truth” for FOG detection. A leave-one-patient-out validation process with a training set of 57 subjects resulted in 84.1% sensitivity, 83.4% specificity, and 85.0% accuracy for FOG detection. Similar results were seen in an independent test set (data from 14 other subjects). Two derived outcomes, percent time frozen and number of FOG episodes, were associated with self-report of FOG. Both derived-metrics were higher in the OFF state than in the ON state and in the most challenging level of the FOG-provoking test, compared to the least challenging level. These results suggest that this automated machine-learning approach can objectively assess FOG and that its outcomes are responsive to therapeutic interventions.

Background The performance of a secondary task while walking increases motor-cognitive interference and exacerbates fall risk in older adults. Previous studies have demonstrated that transcranial direct current stimulation (tDCS) may improve certain types of dual-task performance, and, that tDCS delivered during the performance of a task may augment the benefits of stimulation, potentially reducing motor-cognitive interference. However, it is not yet known if combining multi-target tDCS with the simultaneous performance of a task related to the tDCS targets reduces or increases dual-task walking costs among older adults. The objectives of the present work were (1) To examine whether tDCS applied during the performance of a task that putatively utilizes the brain networks targeted by the neuro-stimulation reduces dual-task costs, and (2) to compare the immediate after-effects of tDCS applied during walking, during seated-rest, and during sham stimulation while walking, on dual-task walking costs in older adults. We also explored the impact on postural sway and other measures of cognitive function. Methods A double-blind, ‘within-subject’ cross-over pilot study evaluated the effects of 20 min of anodal tDCS targeting both the primary motor cortex (M1) and the left dorsolateral prefrontal cortex (lDLPFC) in 25 healthy older adults (73.9 ± 5.2 years). Three stimulation conditions were assessed in three separate sessions: (1) tDCS while walking in a complex environment (tDCS + walking), (2) tDCS while seated (tDCS + seated), and (3) walking in a complex environment with sham tDCS (sham + walking). The complex walking condition utilized virtual reality to tax motor and cognitive abilities. During each session, usual-walking, dual-task walking, quiet standing sway, and cognitive function (e.g., Stroop test) were assessed before and immediately after stimulation. Dual-task costs to gait speed and other measures were computed. Results The dual-task cost to gait speed was reduced after tDCS + walking (p = 0.004) as compared to baseline values. Neither tDCS + seated (p = 0.173) nor sham + walking (p = 0.826) influenced this outcome. Similar results were seen for other gait measures and for Stroop performance. Sway was not affected by tDCS. Conclusions tDCS delivered during the performance of challenging walking decreased the dual-task cost to walking in older adults when they were tested just after stimulation. These results support the existence of a state-dependent impact of neuro-modulation that may set the stage for a more optimal neuro-rehabilitation. Trial registration: Clinical Trials Gov Registrations Number: NCT02954328.

Evaluating freezing of gait (FOG) and quantifying its severity in patients with Parkinson’s disease (PD) is challenging; objective assessment is not sufficiently established. We aimed to improve the ability to objectively evaluate FOG severity by investigating the value of measuring the duration of the test and its components. Seventy-one patients with PD and FOG completed a previously validated FOG-provoking test. The test was performed under three conditions: (1) usual, single task; (2) dual task (walking while carrying a tray); and (3) triple task (walking while holding a tray and subtracting 7 s). FOG and festination were scored using standard procedures. We evaluated effect sizes based on both the original scoring and the test duration for the motor–cognitive cost and before and after anti-Parkinsonian medication intake. Additionally, video recording of the test and total time frozen were measured. As expected, the original test score and the test duration increased across the three conditions of the task and were higher in OFF than in the ON-medication state ( p  < 0.036). For motor–cognitive cost, higher effect sizes were observed for the test duration of each condition, compared to the original scoring in OFF state (0.85 vs. 0.68, respectively). Change in effect size category was more pronounced in the ON state vs. OFF (0.87 vs. 0.55, respectively). Test duration was the only independent predictor for the self-report of FOG severity and the total time frozen during the test. These findings suggest that quantifying the duration of each condition of the FOG-provoking test improves its sensitivity to medications and task complexity. Timing can be used to provide immediate, objective feedback of freezing severity, and a clear interpretation of a patient’s performance.