Dopamine improves defective cortical and muscular connectivity during bilateral control of gait in Parkinson's disease.

Parkinson's Disease (PD)-typical declines in gait coordination are possibly explained by weakness in bilateral cortical and muscular connectivity. Here, we seek to determine whether this weakness and consequent decline in gait coordination is affected by dopamine levels. To this end, we compare cortico-cortical, cortico-muscular, and intermuscular connectivity and gait outcomes between body sides in people with PD under ON and OFF medication states, and in older adults. In our study, participants walked back and forth along a 12 m corridor. Gait events (heel strikes and toe-offs) and electrical cortical and muscular activities were measured and used to compute cortico-cortical, cortico-muscular, and intermuscular connectivity (i.e., coherences in the alpha, beta, and gamma bands), as well as features characterizing gait performance (e.g., the step-timing coordination, length, and speed). We observe that people with PD, mainly during the OFF medication, walk with reduced step-timing coordination. Additionally, our results suggest that dopamine intake in PD increases the overall cortico-muscular connectivity during the stance and swing phases of gait. We thus conclude that dopamine corrects defective feedback caused by impaired sensory-information processing and sensory-motor integration, thus increasing cortico-muscular coherences in the alpha bands and improving gait.

Using virtual reality-based neurocognitive testing and eye tracking to study naturalistic cognitive-motor performance.

Natural human behavior arises from continuous interactions between the cognitive and motor domains. However, assessments of cognitive abilities are typically conducted using pen and paper tests, i.e., in isolation from "real life" cognitive-motor behavior and in artificial contexts. In the current study, we aimed to assess cognitive-motor task performance in a more naturalistic setting while recording multiple motor and eye tracking signals. Specifically, we aimed to (i) delineate the contribution of cognitive and motor components to overall task performance and (ii) probe for a link between cognitive-motor performance and pupil size. To that end, we used a virtual reality (VR) adaptation of a well-established neurocognitive test for executive functions, the 'Color Trails Test' (CTT). The VR-CTT involves performing 3D reaching movements to follow a trail of numbered targets. To tease apart the cognitive and motor components of task performance, we included two additional conditions: a condition where participants only used their eyes to perform the CTT task (using an eye tracking device), incurring reduced motor demands, and a condition where participants manually tracked visually-cued targets without numbers on them, incurring reduced cognitive demands. Our results from a group of 30 older adults (>65) showed that reducing cognitive demands shortened completion times more extensively than reducing motor demands. Conditions with higher cognitive demands had longer target search time, as well as decreased movement execution velocity and head-hand coordination. We found larger pupil sizes in the more cognitively demanding conditions, and an inverse correlation between pupil size and completion times across individuals in all task conditions. Lastly, we found a possible link between VR-CTT performance measures and clinical signatures of participants (fallers versus non-fallers). In summary, performance and pupil parameters were mainly dependent on task cognitive load, while maintaining systematic interindividual differences. We suggest that this paradigm opens the possibility for more detailed profiling of individual cognitive-motor performance capabilities in older adults and other at-risk populations.

Supplementary Motor Area Activity Differs in Parkinson's Disease with and without Freezing of Gait.

The study aimed to investigate the neural changes that differentiate Parkinson's disease patients with freezing of gait and age-matched controls, using ambulatory electroencephalography event-related features. Compared to controls, definite freezers exhibited significantly less alpha desynchronization at the motor cortex about 300 ms before and after the start of overground walking and decreased low-beta desynchronization about 300 ms before and about 300 and 700 ms after walking onset. The late slope of motor potentials also differed in the sensory and motor areas between groups of controls, definite, and probable freezers. This difference was found both in preparation and during the execution of normal walking. The average frontal peak of motor potential was also found to be largely reduced in the definite freezers compared with the probable freezers and controls. These findings provide valuable insights into the underlying structures that are affected in patients with freezing of gait, which could be used to tailor drug development and personalize drug care for disease subtypes. In addition, the study's findings can help in the evaluation and validation of nonpharmacological therapies for patients with Parkinson's disease.

Heart-rate variability as a new marker for freezing predisposition in Parkinson's disease.

INTRODUCTION: Freezing of gait (FoG) is a debilitating symptom of advanced Parkinson's disease (PD) characterized by a sudden, episodic stepping arrest despite the intention to continue walking. The etiology of FoG is still unknown, but accumulating evidence unraveled physiological signatures of the autonomic nervous system (ANS) around FoG episodes. Here we aim to investigate for the first time whether detecting a predisposition for upcoming FoG events from ANS activity measured at rest is possible. METHODS: We recorded heart-rate for 1-min while standing in 28 persons with PD with FoG (PD + FoG), while OFF, and in 21 elderly controls (EC). Then, PD + FoG participants performed walking trials containing FoG-triggering events (e.g., turns). During these trials, n = 15 did experience FoG (PD + FoG+), while n = 13 did not (PD + FoG-). Most PD participants (n = 20: 10 PD + FoG+ and 10 PD + FoG-) repeated the experiment 2-3 weeks later, while ON, and none experienced FoG. We then analyzed heart-rate variability (HRV), i.e., the fluctuations in time intervals between adjacent heartbeats, mainly generated by brain-heart interactions. RESULTS: During OFF, HRV was significantly lower in PD + FoG + participants, reflecting imbalanced sympathetic/parasympathetic activity and disrupted self-regulatory capacity. PD + FoG- and EC participants showed comparable (higher) HRV. During ON, HRV did not differ among groups. HRV values did not correlate with age, PD duration, levodopa consumption, nor motor -symptoms severity scores. CONCLUSIONS: Overall, these results document for the first time a relation between HRV at rest and FoG presence/absence during gait trials, expanding previous evidence regarding the involvement of ANS in FoG.

Bilateral leg stepping coherence as a predictor of freezing of gait in patients with Parkinson's Disease walking with wearable sensors.

Freezing of Gait (FOG) is among the most debilitating symptoms of Parkinson's Disease (PD), characterized by a sudden inability to generate effective stepping. In preparation for the development of a real-time FOG prediction and intervention device, this work presents a novel FOG prediction algorithm based on detection of altered interlimb coordination of the legs, as measured using two inertial movement sensors and analyzed using a wavelet coherence algorithm. METHODS: Fourteen participants with PD (in OFF state) were asked to walk in challenging conditions (e.g. with turning, dual-task walking, etc.) while wearing inertial motion sensors (waist, 2 shanks) and being videotaped. Occasionally, participants were asked to voluntarily stop (VOL). FOG and VOL events were identified by trained researchers based on videos. Wavelet analysis was performed on shank sagittal velocity signals and a synchronization loss threshold (SLT) was defined and compared between FOG and VOL. A proof-of-concept analysis was performed for a subset of the data to obtain preliminary classification characteristics of the novel measure. RESULTS: 128 FOG and 42 VOL episodes were analyzed. SLT occurred earlier for FOG (MED=1.81 sec prior to stop, IQR=1.57) than for VOL events (MED=0.22 sec, IQR=0.76) (Z=-4.3, p<0.001, ES=1.15). These time differences were not related with measures of disease severity. Preliminary results demonstrate sensitivity of 98%, specificity of 42% (mostly due to 'turns' detection) and balanced accuracy of 70% for SLT-based prediction, with good differentiation between FOG and VOL. CONCLUSIONS: Wavelet analysis provides a relatively simple, promising approach for prediction of FOG in people with PD.

Dopaminergic medication reduces interhemispheric hyper-synchronization in Parkinson's disease.

INTRODUCTION: We previously reported on interhemispheric cortical hyper synchronization in PD. The aim of the present study was to address the hypothesis that increased interhemispheric cortical synchronization in PD is related to dopamine deficiency and is correlated with motor function. METHODS: We studied participants with PD and characterized cortical synchronization with reference to brain regions. Electroencephalography (EEG) was recorded from 20 participants with PD while OFF and ON their dopaminergic medications (two separate visits), during quiet standing and straight-line walking. Cortical interactions in the theta, alpha, beta, and gamma brain wave frequency bands were evaluated using interhemispheric phase synchronization (inter-PS). RESULTS: Inter-PS values were found to be significantly higher during the OFF state as compared to the ON state in standing and walking trials for theta, alpha and beta bands. In addition, inter-PS reduction from OFF to ON was associated with mobility improvement evaluated by the Timed Up and Go test, and with daily levodopa equivalent dose across individuals. Higher differences in inter-PS values between OFF and ON states were evident mainly in the occipital-parietal cortex. CONCLUSIONS: Persons with PD have increased inter-PS during the OFF state compared to their ON state, and this increase in inter-PS is associated with the clinical improvement between OFF and ON. We speculate that these findings, together with previous evidence of higher inter-PS in PD as compared to healthy older adults, reflect neuronal processes consequential to asymmetric subcortical dopamine deficiency.

Novel Design of Peripheral Infusion Catheter Improves the Kinetics of Intravenous Drug Release.

Short peripheral catheters are ubiquitous in today's healthcare environment, enabling effective and direct delivery of fluids and medications intravenously. A commonly associated complication of their use is thrombophlebitis-thrombus formation-involved inflammation of the vein wall. A novel design of a very short peripheral catheter showed promising results in a pig model in reducing the mechanical irritation to the vein wall. Here, the kinetics of drug release through the novel catheter was compared to a standard commercial catheter using experimental and computational models. In a good agreement, in vitro and in silico models reveal the superiority of the novel catheter design with faster washout time, favorable spatial distribution within the vein, and substantially lower wall shear stress. We submit therefore that the novel design has an improved drug removal profile compared to the conventional catheter and can potentially reduce chemical irritation to the vein wall and minimize the risk for thrombophlebitis. CLINICAL RELEVANCE: Short peripheral catheters are ubiquitous in today's healthcare environment, allowing effective and direct delivery of fluids and medications intravenously. It is well known, however, that prolonged exposure to an irritant drug may lead to its absorption in the endothelial layer lining the vein wall, promoting among other, thrombophlebitis that may lead to increased morbidity, delayed treatment, and prolonged hospitalization. There have been multiple calls to consider low infusion rates with various infusion protocols and to place the catheter tip as central as possible to promote faster drug clearance and reduce the potential vessel damage, but the requisite device had not been available, and the short peripheral catheter is still, and for decades, the standard of care. Towards this end, we recently introduced a novel very short peripheral catheter design, and here, we demonstrate using experimental and computational models its favorable spatial and temporal drug-releasing profiles compared with the standard catheter. The clinically potential relevance is underscore both by the more efficient perfusion of IV drugs and lower irritation to the vein wall at the site of injection. Graphical abstract.