Search

Parkinson's Disease (PD) exhibits heterogeneous cognitive deficits that may represent different cognitive phenotypes. While previous studies have described them in a "macro" manner, only one study has applied Network Analysis (NA) in PD. NA represents a model to explore relationships between cognitive abilities, aiding in understanding cognitive phenotypes. This study aims to verify whether the cognitive system undergoes reorganization in PD with Mild Cognitive Impairment (PD-MCI) patients. To explore this, a Level II cognitive assessment was administered to 275 PD patients, who were classified into two diagnostic categories: PD-Cognitive Unimpaired (CU) (n = 171) and PD-MCI (n = 104). NA was applied to construct Gaussian Graphical Models for each diagnostic group, where nodes represent cognitive tests and demographic factors, and edges represent their interconnections. The NA revealed substantial differences between the cognitive networks of PD-CU and PD-MCI patients. Specifically, the network of PD-MCI patients appears less sparse, with some weakened relationships between nodes. Overall, the results support the presence of a cognitive reorganization in PD-MCI patients, potentially indicating a functional compensation mechanism. In conclusion, this study enhances the understanding of the cognitive mechanisms underlying cognitive decline in patients with PD., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Deep brain stimulation is a well-established treatment for improving motor symptoms in Parkinson's disease. However, persistent non-motor symptoms, such as excessive daytime sleepiness, remain a significant challenge and necessitate further investigation. In this study, we conducted repeated measurements of daytime sleepiness using a modified multiple sleep latency test in a healthy monkey (macaca fascicularis), which was later rendered parkinsonian through MPTP administration. Deep brain stimulation targeting the lateral hypothalamic area revealed frequency-dependent modulation of both sleepiness level and core body temperature. High-frequency stimulation (80 Hz) increased sleepiness in the healthy state, while low-frequency stimulation (20 Hz) promoted wakefulness in the parkinsonian state. These findings suggest a promising therapeutic approach for addressing sleep/wake disturbances, not only in Parkinson's disease but also in other severe sleep disorders., Competing Interests: Declarations Competing interests S.Chabardès declares that he has received consultation fees from Medtronic and Boston Scientific in the last 5 years. The other authors declare no competing interests. We used AI to improve readability and language of the work. Ethics approval In accordance with the Grenoble Alpes University, Grenoble Institut of Neurosciences (B3851610008) policies and with French legislation, experiments were performed in compliance with the European Community Council Directive of 2010 (2010/63/UE) for care of laboratory animals and in accordance with the ARRIVE guidelines. All procedures were reviewed and validated by the local ethic committee n˚004 and were authorized by the Direction Départementale des Services Vétérinaires de l’Isère – Ministère de l’Agriculture et de la Pêche, France., (© 2024. The Author(s).)

Parkinsonian tremor (PT) and Essential tremor (ET) exist as upper limb tremors in clinical practice. Notably, their types of trembling share similar presentations and overlapping frequencies. To enhance objectivity and efficiency in the diagnosis of these two diseases, there is a pressing need for more objective tremor classification procedures. This study proposes a novel multimodal fusion network based on a cross-attention mechanism (MFCA-Net) to automate the classification of upper limb tremors between PTs and ETs. To this end, 140 patients with PTs and ETs were recruited, and acceleration and surface electromyography (sEMG) signals were collected from the forearm during tremor episodes. To comprehensively capture the global and local features of input signals, a multiscale convolution in MFCA-Net was designed. Furthermore, the cross-attention mechanism was applied to fuse the features of the two input signals. The results demonstrate that the final classification accuracy exceeded 97.18% when MFCA-Net was used. Compared with the single acceleration signal and single sEMG signal inputs, the recognition accuracies increased by 18.91% and 10.04%, respectively. Therefore, the proposed MFCA-Net in this study serves as an objective and potential tool for assisting clinicians in the diagnosis of PT and ET patients., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics statement The study involving human participants was reviewed and approved by the Ruijin Hospital Ethics Committee of Shanghai Jiao Tong University School of Medicine (No. 2023 − 359). Patients/participants provided written informed consent to participate in this study. All the experiments were performed in accordance with the relevant guidelines and regulations., (© 2024. The Author(s).)

Parkinson's disease (PD) is characterized by motor and non-motor symptoms. Cognitive decline is crucial in disease progression and affect quality of life; however, their underlying mechanisms in PD remain unclear. We explored the relationship between cognitive impairment and functional connectivity (FC) using resting-state functional magnetic resonance imaging in 26 patients with sporadic PD, focusing on the changes in FC between on and off states. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) score. The correlation between MMSE scores and changes in FC values during on and off states was assessed using Pearson's correlation coefficient. The correlation between changes in FC during the on and off periods and cognitive function differed for each cognitive function item. MMSE memory scores were positively correlated with FC between the brainstem and the left cerebral hemisphere. MMSE attention scores were positively correlated with FC between the bilateral thalamus and frontal lobes and negatively correlated with FC between the left cerebral hemispheres. These findings may facilitate our understanding of the neural correlates underlying cognitive impairment in PD and help develop treatment strategies to preserve cognitive function., (© 2024. The Author(s).)

The ability to learn novel motor skills is essential for patients with Parkinson's disease (PD) to regain activities of daily living. However, the underlying mechanisms of motor learning in PD remain unclear. To identify motor features that are distinctively manifested in PD during motor learning, we quantified a rich set of variables reflecting various aspects of the learning process in a virtual throwing task. While the performance outcome improved similarly over 3 days of practice for both PD patients and age-matched controls, further analysis revealed distinct learning processes between the two groups. PD patients initially performed with a slow release velocity and gradually increased it as practice progressed, whereas the control group began with an unnecessarily rapid release velocity, which they later stabilized at a lower value. Performance characteristics related to the timing of ball release and the inter-release interval did not show significant group differences, although they were modulated across practice in both groups. After one week, both groups retained the performance outcomes and underlying kinematics developed over practice. This study underscores the importance of analyzing the multi-faceted learning process to characterize motor skill learning in PD. The findings may provide insights into PD pathophysiology and inform rehabilitation strategies., (© 2024. The Author(s).)

This study investigated the association between cognitive function and facial emotion recognition (FER) in patients with Parkinson's disease (PD) and mild cognitive impairment (PD-MCI). We enrolled 126 participants from Taiwan, including 63 patients with idiopathic PD and 63 matched healthy controls. The PD group was divided into two groups: those with normal cognitive function (PD-NC) and those with MCI (PD-MCI). Participants underwent a modality emotion recognition test and comprehensive cognitive assessment. Our findings reveal that patients with PD-MCI exhibit significantly impaired FER, especially in recognizing "disgust," compared with patients with PD-NC and healthy adults (P = .001). This deficit correlates with executive function, attention, memory, and visuospatial abilities. Attention mediates the relationship between executive function and "disgust" FER. The findings highlight how patients with PD-MCI are specifically challenged when recognizing "disgust" and suggest that cognitive training focusing on cognitive flexibility and attention may improve their FER abilities. This study contributes to our understanding of the nuanced relationship between cognitive dysfunction and FER in patients with PD-MCI, emphasizing the need for targeted interventions., (© The Author(s) 2024. Published by Oxford University Press.)

Aims: The exact cause of the parkinsonism gait remains uncertain. We first focus on understanding the underlying neurological reasons for these symptoms through the examination of both static functional network connectivity (SFNC) and dynamic functional network connectivity (DFNC)., Methods: We recruited 64 postural instability and gait disorder-dominated Parkinson's disease (PIGD-PD) patients, 31 non-PIGD-PD (nPIGD-PD) patients, and 54 healthy controls (HC) from Nanjing Brain Hospital. The GIFT software identified five distinct independent components: the basal ganglia (BG), cerebellum (CB), sensory networks (SMN), default mode network (DMN), and central executive network (CEN). We conducted a comparison between the SFNC and DFNC of the five networks and analyzed their correlations with postural instability and gait disorder (PIGD) symptoms., Results: Compared with nPIGD-PD patients, the PIGD-PD patients demonstrated reduced connectivity between CEN and DMN while spending less mean dwell time (MDT) in state 4. This is characterized by strong connections. Compared with HC, PIGD-PD patients exhibited enhanced connectivity in the SFNC between CB and CEN, as well as the network between CB and DMN. Patients with PIGD-PD spent more MDT in state 1, which is characterized by few connections, and less MDT in state 4. In state 3, there was an increase in the functional connectivity between the CB and DMN in patients with PIGD-PD. The nPIGD patients showed increased SFNC connectivity between CB and DMN compared to HC. These patients spent more MDT in state 1 and less in state 4. The MDT and fractional windows of state 2 showed a positive link with PIGD scores., Conclusion: Patients with PIGD-PD exhibit a higher likelihood of experiencing reduced brain connectivity and impaired information processing. The enhanced connection between the cerebellum and DMN networks is considered a type of dynamic compensation., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Cognitive decline in Parkinson's disease (PD) varies widely. While models to predict cognitive progression exist, comparing traditional probabilistic models to deep learning methods remains understudied. This study compares sequential modeling techniques to identify cognitive progression in individuals with and without PD. Using data from the Parkinson's Progression Marker Initiative, shallow Markov, deep recurrent (long short-term memory [LSTM]), and nonrecurrent (temporal fusion transformer [TFT]) models were compared to predict cognitive status over time. Cognitive status was categorized into normal cognition (NC), mild cognitive impairment (MCI), and dementia. Predictions were made annually for up to 3 years using clinical data, including demographics, cognitive assessments, PD severity, and medical history. Each approach was evaluated using inverse probability weighted (IPW-) F1 scores. An ensemble method combined outputs from the Markov, LSTM, and TFT models. The dataset included 917 individuals (53% PD; 30% at risk for PD; 17% Healthy Controls). The TFT model outperformed others across all annual periods (IPW-F1 = 0.468) compared to the Markov (IPW-F1 = 0.349) and LSTM (IPW-F1 = 0.414) models, with improved performance using an ensemble approach (IPW-F1 = 0.502). For MCI and dementia predictions, which were rarer occurrences compared to NC status (ratios: 50:8:1), the TFT model consistently outperformed competing models, achieving IPW-F1 scores of 0.496 and 0.533 for MCI and dementia, respectively. In conclusion, sequential deep learning models like TFT, which mitigate long-term memory loss and can interpret complex, high-dimensional data, perform best overall in predicting clinically important cognitive transitions. These methods should be further explored for predicting degenerative conditions., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Using regional homogeneity (ReHo) and functional connectivity (FC) to assess alterations in brain function and their potential relation to different Hoehn and Yahr (H&Y) stages in Parkinson's disease (PD)., Materials and Methods: 66 patients with PD and 57 age- and sex-matched healthy control (HC) participants were recruited. All subjects underwent clinical assessments and resting-state functional magnetic resonance imaging (rs-fMRI) scanning. We analyzed alterations in regional brain activity using ReHo analyses in all subjects and further explored their relationship to disease severity. Finally, the brain region significantly associated with disease severity was used as a seed point to analyze the FC changes between it and other brain regions in the whole brain., Results: Compared with HC participants, PD patients showed a significant decrease ReHo in the sensorimotor network (bilateral precentral and postcentral gyrus). The ReHo value of the left precentral gyrus in PD patients decreased with increasing H&Y stage and correlated negatively with Unified Parkinson's Disease Rating Scale (UPDRS) III scores. Further, FC analysis of the left precentral gyrus as a region of interest showed that functional activity between the left precentral gyrus and sensorimotor network, default network, and visual network was decreased., Conclusion: The left precentral gyrus plays an important role in the pathophysiological mechanisms of PD patients, and this finding further highlights the potential of the primary motor cortex (M1) as a non-invasive therapeutic target for neuromodulation in PD patients., Competing Interests: Declaration of Competing Interest The authors have not published, posted, or submitted any related papers from the same study. All authors have read and approved the submitted manuscript. The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Methods: This study assessed data from two cohorts of patients with alpha-synucleinopathies (University of Brescia and University of Rome Tor-Vergata cohorts). Consecutive participants with video-polysomnography-confirmed iRBD, Parkinson's disease (PD), dementia with Lewy bodies (DLB) and controls underwent neurological, clinical and 123 I-FP-CIT SPECT imaging assessments. Individuals with iRBD were longitudinally monitored to collect clinical phenoconversion to PD or DLB. The main outcome was to identify whole brain 123 I-FP-CIT SPECT measures reflecting monoaminergic deficits in each clinical group as compared to controls., Results: The cohort (n = 184) included 45 patients with iRBD, 47 PD, 42 DLB and 50 age-matched controls. Individuals with iRBD were categorized as RBD-DAT- (n = 32) and RBD-DAT+ (n = 13), according to nigrostriatal assessment used in clinical practice. Compared to controls, RBD-DAT- showed an early involvement of the left insula, which increased in RBD-DAT+, and was present in patients with Parkinson's disease and dementia with Lewy bodies. Longitudinal cox regression analyses revealed a higher risk of phenoconversion in individuals with iRBD and insular monoaminergic deficits [HR = 3.387; CI 95%: 1.18-10.27]., Interpretation: In this study, altered insular monoaminergic binding in iRBD was associated with phenoconversion to DLB or PD. These findings may provide a helpful stratification approach for future pharmacological or non-pharmacological interventions., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss, leading to motor and non-motor symptoms. Early detection before symptom onset is crucial but challenging. This study presents a framework integrating circuit modeling, non-equilibrium dynamics, and optimization to understand PD pathogenesis and enable precision interventions. Neuronal firing patterns, particularly oscillatory activity, play a critical role in PD pathology. The basal ganglia network, specifically the subthalamic nucleus-external globus pallidus (STN-GPe) circuitry, exhibits abnormal activity associated with motor dysfunction. The framework leverages the non-equilibrium landscape and flux theory to identify key connections generating pathological activity, providing insights into disease progression and potential intervention points. The intricate STN-GPe interplay is highlighted, shedding light on compensatory mechanisms within this circuitry may initially counteract changes but later contribute to pathological alterations as disease progresses. The framework addresses the need for comprehensive evaluation methods to assess intervention outcomes. Cross-correlations between state variables provide superior early warning signals compared to traditional indicators relying on critical slowing down. By elucidating compensatory mechanisms and circuit dynamics, the framework contributes to improved management, early detection, risk assessment, and potential prevention/delay of PD development. This pioneering research paves the way for precision medicine in neurodegenerative disorders., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) is an accepted therapy for Parkinson's disease (PD) with disabling motor complications. For elderly patients with poorer cognition and postural instability, GPi has been proposed as the preferable DBS target based on expert opinion, arguing GPi-DBS may be less complicated by depression, apathy, worsened verbal fluency, and executive dysfunction, resulting in greater improvement in quality of life (QoL). However, data supporting such patient-tailored approach are lacking., Objectives: The aims were to analyze whether the DBS target influences QoL in a PD cohort and a matched subgroup of frail patients with poor cognitive status and reduced postural stability, and whether other factors affect the QoL outcomes., Methods: In this retrospective study, we analyzed a single-center cohort of 138 PD patients who received bilateral STN-DBS (117) or GPi-DBS (21) using the mentioned approach for target selection. All patients underwent standardized clinical evaluations of motor- and nonmotor signs as well as QoL before and 1 year after surgery., Results: DBS of both targets improved motor signs, dyskinesias, and pain. QoL improved without significant difference between the targets, but with a trend for greater improvement across all QoL domains in favor of the STN, even in an STN subgroup matched to the GPi group., Conclusion: Our results contradict the prevailing belief that GPi-DBS is superior in frail PD patients with cognitive decline and postural instability, questioning the proposed patient-tailored approach of DBS target selection. Further studies are needed for a data-driven approach., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: A randomized trial suggested that reducing left-sided subthalamic stimulation amplitude could improve axial dysfunction., Objectives: To explore open-label tolerability and associations between trial outcomes and asymmetry data., Methods: We collected adverse events in trial participants treated with open-label lateralized settings for ≥3 months. We explored associations between trial outcomes, location of stimulation and motor asymmetry., Results: 14/17 participants tolerated unilateral amplitude reduction (left-sided = 10, right-sided = 4). Two hundred eighty-four left-sided and 1113 right-sided stimulated voxels were associated with faster gait velocity, 81 left-sided and 22 right-sided stimulated voxels were associated with slower gait velocity. Amplitude reduction contralateral to shorter step length was associated with 2.4-point reduction in axial MDS-UPDRS. Reduction contralateral to longer step length was associated with 10-point increase in MDS-UPDRS., Conclusions: Left-sided amplitude reduction is potentially more tolerable than right-sided amplitude reduction. Right-sided more than left-sided stimulation could be associated with faster gait velocity. Shortened step length might reflect contralateral overstimulation., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Exercise potentially improves gait, balance, and habitual physical activity in Parkinson's disease (PD). However, given the heterogeneous nature of the disease, it is likely that people respond differently to exercise interventions. Factors determining responsiveness to exercise interventions remain unclear., Objectives: To address this uncertainty, we explored the responsiveness to our highly challenging balance and gait intervention (HiBalance) in people with PD., Methods: Thirty-nine participants with mild-moderate PD who underwent the HiBalance intervention from our randomized controlled trial were included. We defined response in three domains: (1) balance based on Mini-BESTest, (2) gait based on gait velocity, and (3) physical activity based on accelerometry-derived steps per day. In each domain, we explored three responsiveness levels: high, low, or non-responders according to the change from pre- to post-intervention. Separate Random Forests for each responder domain classified these responsiveness levels and identified variable importance., Results: Only the Random Forest for the balance domain classified all responsiveness levels above the chance level indicated by a Cohen's kappa of "slight" agreement. Variable importance differed among the responsiveness levels. Slow gait velocity indicated high responders in the balance domain but showed low probabilities for low and non-responders. For low and non-responders, fall history or no falls, respectively, were more important., Conclusions: Among three responder domains and responsiveness levels, we could moderately classify responders in the balance domain, but not for the gait or physical activity domain. This can guide inclusion criteria for balance-targeted, personalized intervention studies in people with PD., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Deep brain stimulation (DBS) is a widely used therapy for Parkinson's disease (PD) but lacks dynamic responsiveness to changing clinical and neural states. Feedback control might improve therapeutic effectiveness, but the optimal control strategy and additional benefits of 'adaptive' neurostimulation are unclear. Here we present the results of a blinded randomized cross-over pilot trial aimed at determining the neural correlates of specific motor signs in individuals with PD and the feasibility of using these signals to drive adaptive DBS. Four male patients with PD were recruited from a population undergoing DBS implantation for motor fluctuations, with each patient receiving adaptive DBS and continuous DBS. We identified stimulation-entrained gamma oscillations in the subthalamic nucleus or motor cortex as optimal markers of high versus low dopaminergic states and their associated residual motor signs in all four patients. We then demonstrated improved motor symptoms and quality of life with adaptive compared to clinically optimized standard stimulation. The results of this pilot trial highlight the promise of personalized adaptive neurostimulation in PD based on data-driven selection of neural signals. Furthermore, these findings provide the foundation for further larger clinical trials to evaluate the efficacy of personalized adaptive neurostimulation in PD and other neurological disorders. ClinicalTrials.gov registration: NCT03582891 ., Competing Interests: Competing interests S.L. consults for Iota Biosciences. J.L.O. reports support from Medtronic and Boston Scientific for research and education and consults for AbbVie and Rune Labs. P.A.S. receives support from Medtronic and Boston Scientific for fellowship education. C.R.O., S.C., L.H.H., M.S., J.Y., A.H. and S.W. declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Orthostatic hypotension (OH) is a common condition in Parkinson's disease (PD) with a possible link to cognitive decline., Objective: The aim was to explore the association between OH and PD-associated mild cognitive impairment (PD-MCI) and dementia (PDD) over 9 years in a population-based incident PD cohort., Methods: We prospectively followed up patients from PD diagnosis with serial blood pressure measurements, clinical examinations, and neuropsychological assessments. We defined OH using (1) consensus-based criteria and (2) clinically significant OH by mean arterial pressure (MAP) in standing position ≤75 mmHg. PD-MCI and PDD were diagnosed according to acknowledged criteria. We applied generalized estimating equations models to investigate associations between OH measurements and cognitive impairment over time. Weibull accelerated failure time regression models were used to study if early OH (≤3 years of PD diagnosis) accelerates the time to incident PD-MCI and PDD., Results: Of 186 enrolled patients, consensus-based OH affected 68.8%, clinically significant OH 33.9%, PD-MCI 60.8%, and PDD 31.2%. Consensus-based OH was associated with PD-MCI (odds ratio [OR]: 2.04, 95% confidence interval: 1.44-2.90, P < 0.001), whereas clinically significant OH was associated with both PD-MCI (OR: 1.95, 1.11-3.43, P = 0.020) and PDD (OR: 3.66, 1.95-6.86, P < 0.001). Early clinically significant OH, but not early consensus-based OH, reduced time to incident PD-MCI by 54% (P = 0.021) and time to PDD by 44% (P = 0.003) independently of potential confounders, including supine hypertension and cardiovascular disease., Conclusions: MAP in standing position emerged as a stronger predictor of cognitive decline than OH determined using consensus-based criteria. These findings have implications for both research and clinical practice., (© 2024 International Parkinson and Movement Disorder Society.)

Background: Depression and anxiety, the most prevalent neuropsychiatric manifestations in Parkinson’s disease (PD), negatively impact their quality of life., Aims: To determine whether the chronic nasal administration of kisspeptin-54 (KP-54) could. Alleviate symptoms of anxiety and depression in hemi-Parkinsonian rats., Study Design: Experimental study., Methods: This study included adult Sprague Dawley male rats who were administered either a vehicle (artificial cerebrospinal fluid) or 6-hydroxydopamine (6-OHDA) unilaterally into the medial forebrain bundle. The vehicle, or KP-54 (3 nmol/kg, applied topically to the rhinarium), was administered daily for a seven-day period. The sucrose preference test (SPT), elevated plus maze test (EPMT), and open field test (OFT) were implemented to evaluate depression- and anxiety-like behaviors, respectively, seven days following the lesion surgery. Gamma-aminobutyric acid (GABA) concentrations in the amygdala were quantified using mass spectrometry. Tyrosine hydroxylase in substantia nigra was analyzed using immunohistochemistry., Results: The nasal delivery of KP-54 significantly reduced depressionand anxiety-like behaviors that were induced by 6-OHDA, as indicated by the results of the SPT, OFT, and EPMT. Moreover, it was observed that nasal KP-54 effectively mitigated 6-OHDA-induced motor deficits and the loss of nigral dopaminergic neurons. The nasal administration of KP-54 augmented the decline in GABA levels in the amygdala induced by 6-OHDA. Furthermore, effective correlations were established between GABA concentrations and behavioral parameters., Conclusion: The nasal delivery of KP-54 could function as a viable therapeutic alternative for treating mood-related disorders in PD., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest.

Background: Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by motor dysfunctions and nonmotor symptoms. Current treatments do not alter disease progression, highlighting the need for alternative therapies. Music, dance, and mindfulness meditation have shown the potential to improve symptoms and quality of life in patients with PD., Objective: This study aims to evaluate the effectiveness of dance or music and meditation on PD progression, cognitive functions, mood, behavior, and caregiver burden., Methods: This study is a single-blinded, longitudinal, parallel, randomized controlled trial. The participants consist of 30 patients with mild to moderate PD residing in Mumbai, India, who can physically participate in the activities. The exclusion criteria include advanced PD, severe balance issues, age >80 years, and other movement disorders. Participants in the intervention group will engage in dance or music sessions and guided meditation thrice weekly for 6 months. The control group will continue their usual activities and medication. The primary outcome is the progression of PD symptoms, measured using the Unified Parkinson's Disease Rating Scale I-III, and quality of life, measured using the Parkinson's Disease Questionnaire-39. The secondary outcomes include cognitive functions (Mini-Mental State Examination), mood (Beck Depression Inventory and Parkinson Anxiety Scale), mobility (timed up and go and Berg Balance Test), behavioral disorders (Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale), and caregiver burden (Zarit Burden Interview and Parkinson's Disease Questionnaire-Carer)., Results: Data collection was completed in February 2024, with 28 participants finishing the study (intervention group: n=15, 54% and control group: n=13, 46%). Data analysis is underway, with results expected to be published in December 2024., Conclusions: This study aims to provide significant insights into the effectiveness of dance or music and meditation in improving the quality of life and slowing the progression of PD. The findings are anticipated to support using these nonpharmaceutical therapies as complementary approaches to managing PD., Trial Registration: CTRI/2023/03/051064; https://tinyurl.com/2xdus53j., International Registered Report Identifier (irrid): DERR1-10.2196/59018., (©Bhagyashree Mehrotra, Neha Rai, Rajani MR, Aparna Budhakar, Ritika Aggarwal, Raj Vinodkumar Agarbattiwala, Mona Thomas, Sampada Patole, Paresh Doshi. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 29.10.2024.)

Dual cognitive-walking treadmill training (DTT), designed to replicate real-life walking conditions, has shown promise effect in individuals with Parkinson's disease (PD). This study aims to compare the effects of DTT versus single treadmill training (STT) on cognitive and walking performance under both single and dual task conditions, as well as on fall, patients' subjective feeling, and quality of life. Sixteen individuals with PD were randomly assigned to DTT or STT group and underwent 8 weeks of training. The DTT group received treadmill training with cognitive loads, while the STT group received treadmill training without cognitive load. Outcome measures included gait parameters (speed, step length) and cognitive performance (reaction time, accuracy, composite score) under both single and dual task conditions. Unified Parkinson's Disease Rating Scale-part III (UPDRS-III), Falls Efficacy Scale (FES), Patient Global Impression of Change (PGIC), and Parkinson's Disease Questionnaire (PDQ-39) were also measured. Both DTT and STT groups showed increased comfortable walking speed and step length. Only the DTT group demonstrated significant improvements in cognitive composite score under both single and dual task conditions, as well as UPDRS-III, FES, and PDQ-39(p < 0.05). DTT can enhance cognitive function without compromising walking ability and also have real-world transferability., (© 2024. The Author(s).)

Background: To date, there has been no medication that has prevented the progression of Parkinson's disease (PD). Many benefits of intensive and multidisciplinary rehabilitation program for PD are supported by clinical, epidemiological, and experimental data. The main question is whether high-intensity motor and cognitive exercises have an effect on the disease's biological mechanisms., Objective: This study protocol is a Randomized Controlled Trial (RCT) designed to determine the efficacy of an experimental, intensive, and multidisciplinary treatment in comparison to a home-based self-treatment in improving biomolecular and functional parameters in PD., Methods: A total of 72 participants will be randomly allocated to two different groups, experimental (n = 36) and control group (n = 36). The rehabilitation program will last 6 consecutive weeks and will involve the execution of a total of 30 sessions, one for each day of the week from Monday to Friday. Participants allocated to the control group will carry out a home-based self-treatment program that includes muscle-stretching and active mobilization exercises for 40'/day for 6 consecutive weeks. The primary outcome measure is the effects of both treatments on a new set of molecular biomarkers such as oligomeric alpha-synuclein and neurotrophic factors measured in peripheral neural derived extracellular vesicles (NDEVs). Secondary outcomes will include changes of motor and non-motor symptoms, balance and gait performance and cognitive functioning. This RCT has been registered as "Intensive Multidisciplinary Rehabilitation and Biomarkers in Parkinson's Disease" on 30 May, 2022 to ClinicalTrials.gov with the Study ID number: NCT05452655., Discussion: This rehabilitation program is believed to be crucial in modifying biomolecular and functional parameters in people with PD. We expect that this study will provide additional evidence to understand the impact of an aerobic and intensive rehabilitation program on brain plasticity in patients with PD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Saibene et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: In this case series, results from daily visual exposure to intense polychromatic light of 2000 to 4000 LUX is presented. Bright light treatment is a standard procedure for treating seasonal affective disorder and prodromal Parkinson's disease with high success. With the post-encephalitic symptoms of long-COVID closely approximating those of prodromal Parkinson's disease, we treated insomnia and sleep-related parameters in these patients, including total sleep, number of awakenings, tendency to fall back to sleep, and fatigue, to determine whether mending sleep could improve quality of life., Case Presentation: We present three female and two male Caucasian patients aged 42-70 years with long-COVID that persisted from 12 weeks to 139 weeks after contracting coronavirus disease., Conclusion: A light presentation protocol was adapted for long-COVID that not only restored sleep in all patients, but also unexpectedly repaired the depression, anxiety, and cognitive changes (brain fog) as well. A robust pattern of recovery commencing 4-5 days after treatment and was maintained for weeks to months without relapse. These preliminary findings represent a novel, minimally invasive approach for managing the most debilitating symptoms of long-COVID, making it an ideal candidate for the drug hypersensitive, post-encephalitic brain. That a compromised circadian mechanism seen in Parkinson's disease may also underlie post-encephalitic long-COVID implicates a compromised role of the circadian system in these disorders., (© 2024. The Author(s).)

Abstract: Parkinson's disease (PD) is a neurodegenerative disease characterized by various motor and non-motor symptoms. The complexity of its symptoms suggests that PD is a heterogeneous neurological disorder. Its pathological changes are not limited to the substantia nigra-striatal system, but gradually extending to other regions including the cerebellum. The cerebellum is connected to a wide range of central nervous system regions that form essential neural circuits affected by PD. In addition, altered dopaminergic activity and α-synuclein pathology are found in the cerebellum, further suggesting its role in the PD progression. Furthermore, an increasing evidence obtained from imaging studies has demonstrated that cerebellar structure, functional connectivity, and neural metabolism are altered in PD when compared to healthy controls, as well as among different PD subtypes. This review provides a comprehensive summary of the cerebellar pathophysiology and results from neuroimaging studies related to both motor and non-motor symptoms of PD, highlighting the potential significance of cerebellar assessment in PD diagnosis, differential diagnosis, and disease monitoring., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

The basal ganglia contribute to internal timekeeping, and dopaminergic medication has been observed to moderate timing deficits associated with Parkinson's Disease (PD) during single joint movements. However, it is unclear whether similar effects can be observed in multi-joint movements. Twenty-five people with PD and twelve healthy peers performed repetitive reaching and stepping-in-place tasks with and without auditory cues at their self-selected maximal cadence. The PD group was measured ON and OFF medication. Reduced cadence error was found for both groups and tasks when cued, and ON PD exhibited decreased cadence compared to OFF PD. Overall timing variability was no different from controls, but differences were found in estimates of clock and motor variance using the Wing-Kristofferson model of interval timing. A medication and cueing interaction during the reaching task produced increased clock variance in uncued, ON PD. During the stepping task, clock and motor variance of the PD group were unaffected by cues, in contrast to the control group. Serial lag-one correlation was reduced in both groups for cued reaching, but was unaffected by cueing or medication in the PD group when stepping-in-place. These findings suggest that overall timing variability may not capture timing deficits in PD., (© 2024. The Author(s).)

Motor subtypes in Parkinson's Disease (PD) are unstable over time, limiting mechanistic insights and biomarker discovery. We focused on Rest Tremor (RT) as a symptom to test for phenotype stability and link it to specific circuits and disease mechanisms. Using the PPMI cohort data over 5 years we found that RT is more stable than classical Tremor-Dominant definitions, a stability also seen for RT response to therapy. At time of diagnosis, the population of therapy-resistant RT patients was enriched with a brain-first PD profile as predicted by a-Synuclein origin site and connectome (SOC) model. Resistant-RT patients have lower gastrointestinal and cardiovascular symptoms, lower prevalence of probable REM-Sleep behaviour disorder, and higher dopaminergic asymmetry compared to therapy-responsive or no tremor patients. Treating RT as a distinct phenomenon revealed a relative phenotypic stability with treatment response being linked to different patterns of disease progression., Competing Interests: Declaration of competing interest Marcelo Mendonça has received, payment, honoraria or other support from Medtronic, Bial, Pharacademy, Evidenze, AbbVie and Stada. RB has received, payment, honoraria or other support from Medtronic and AbbVie. Other authors report no conflict of interest. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Marcelo Mendonca reports a relationship with Medtronic that includes: travel reimbursement. Marcelo Mendonca reports a relationship with Bial that includes: consulting or advisory and speaking and lecture fees. Marcelo Mendonca reports a relationship with AbbVie Ltd. that includes: speaking and lecture fees. Marcelo Mendonca reports a relationship with STADA Arzneimittel AG that includes: consulting or advisory. Marcelo Mendonca reports a relationship with Evidenze Group Europe SL that includes: consulting or advisory and speaking and lecture fees. Marcelo Mendonca reports a relationship with Pharacademy that includes: speaking and lecture fees. Raquel Barbosa reports a relationship with Medtronic that includes: speaking and lecture fees and travel reimbursement. Raquel Barbosa reports a relationship with AbbVie Inc. that includes: travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Beta band oscillations in the sensorimotor cortex and subcortical structures, such as the subthalamic nucleus (STN) and internal pallidum (GPi), are closely linked to motor control. Recent research suggests that low-beta (14.5-23.5 Hz) and high-beta (23.5-35 Hz) cortico-STN coherence arise through distinct networks, possibly reflecting indirect and hyperdirect pathways. In this study, we sought to probe whether low- and high-beta coherence also exhibit different functional roles in facilitating and inhibiting movement. Twenty patients with Parkinson's disease who had deep brain stimulation electrodes implanted in either STN or GPi performed a classical go/nogo task while undergoing simultaneous magnetoencephalography and local field potentials recordings. Subjects' expectations were manipulated by presenting go- and nogo-trials with varying probabilities. We identified a lateral source in the sensorimotor cortex for low-beta coherence, as well as a medial source near the supplementary motor area for high-beta coherence. Task-related coherence time courses for these two sources revealed that low-beta coherence was more strongly implicated than high-beta coherence in the performance of go-trials. Accordingly, average pre-stimulus low-beta but not high-beta coherence or spectral power correlated with overall reaction time across subjects. High-beta coherence during unexpected nogo-trials was higher compared to expected nogo-trials at a relatively long latency of 3 s after stimulus presentation. Neither low- nor high-beta coherence showed a significant correlation with patients' symptom severity at baseline assessment. While low-beta cortico-subcortical coherence appears to be related to motor output, the role of high-beta coherence requires further investigation., Competing Interests: Declaration of competing interest We declare that we have no competing financial interests or personal relationships that could have appeared to influence the work reported in our manuscript ‘Low-beta versus high-beta band cortico-subcortical coherence in movement inhibition and expectation’., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: Parkinson's disease (PD) tremor is associated with dysfunction in the basal ganglia (BG), cerebellum (CB), and sensorimotor networks (SMN). We investigated tremor-related static functional network connectivity (SFNC) and dynamic functional network connectivity (DFNC) in PD patients., Methods: We analyzed the resting-state functional MRI data of 21 tremor-dominant Parkinson's disease (TDPD) patients and 29 healthy controls. We compared DFNC and SFNC between the three networks and assessed their associations with tremor severity., Results: TDPD patients exhibited increased SFNC between the SMN and BG networks. In addition, they spent more mean dwell time (MDT) in state 2, characterized by sparse connections, and less MDT in state 4, indicating stronger connections. Furthermore, enhanced DFNC between the CB and SMN was observed in state 2. Notably, the MDT of state 2 was positively associated with tremor scores., Conclusion: The enhanced dynamic connectivity between the CB and SMN in TDPD patients suggests a potential compensatory mechanism. However, the tendency to remain in a state of sparse connectivity may contribute to the severity of tremor symptoms., Competing Interests: Declaration of competing interest All authors declare no financial or non-financial competing interests., (Copyright © 2024. Published by Elsevier Inc.)

High-intensity physical activity is a non-pharmacological intervention that has been tested as a treatment for Parkinson's disease (PD). The objective of the study was to investigate the benefits of high-intensity physical exercise on the number of neurons and astrocytes in a a rat model of Parkinson's disease submitted to training before and after the inducing injury. Seventy Wistar rats were used, distributed as follows: nine rats trained before PD induction (DP-Exa), nine trained after PD induction (DP-Exd), 10 trained before and after PD induction (DP-Exad), and nine sedentary rats (DP-Sed). There were also the same groups but with the rats exposed to the sham surgery (control). High-intensity physical exercise on a vertical ladder was performed before and/or after PD induction for 5 days/week, 30-45 min a day, for 4 weeks. PD was induced with an electrolytic lesion (AP -4.9, ML 1.7, and DV 8.1). At the end of the experiment, the brain was removed for Nissl staining and immunohistochemistry of glial fibrillary acidid protein (GFAP) in the substantia nigra and striatum. The DP-Exa, Sham-Exa, DP-Exad, and Sham-Exad groups showed a greater number of neurons and higher expression of GFAP in the substantia nigra and stiatum compared with the the DP-Exd, Sham-Exd, DP-Sed, and Sham-Sed groups. Thus, rats that performed high-intensity training before or before and after PD induction had higher densities of neurons and astrocytes.

From a game of darts to neurorehabilitation, the ability to explore and fine tune our movements is critical for success. Past work has shown that exploratory motor behaviour in response to reinforcement (reward) feedback is closely linked with the basal ganglia, while movement corrections in response to error feedback is commonly attributed to the cerebellum. While our past work has shown these processes are dissociable during adaptation, it is unknown how they uniquely impact exploratory behaviour. Moreover, converging neuroanatomical evidence shows direct and indirect connections between the basal ganglia and cerebellum, suggesting that there is an interaction between reinforcement-based and error-based neural processes. Here we examine the unique roles and interaction between reinforcement-based and error-based processes on sensorimotor exploration in a neurotypical population. We also recruited individuals with Parkinson's disease to gain mechanistic insight into the role of the basal ganglia and associated reinforcement pathways in sensorimotor exploration. Across three reaching experiments, participants were given either reinforcement feedback, error feedback, or simultaneously both reinforcement & error feedback during a sensorimotor task that encouraged exploration. Our reaching results, a re-analysis of a previous gait experiment, and our model suggests that in isolation, reinforcement-based and error-based processes respectively boost and suppress exploration. When acting in concert, we found that reinforcement-based and error-based processes interact by mutually opposing one another. Finally, we found that those with Parkinson's disease had decreased exploration when receiving reinforcement feedback, supporting the notion that compromised reinforcement-based processes reduces the ability to explore new motor actions. Understanding the unique and interacting roles of reinforcement-based and error-based processes may help to inform neurorehabilitation paradigms where it is important to discover new and successful motor actions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Roth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Digital gait monitoring is increasingly used to assess locomotion and fall risk. The aim of this work is to analyze the changes in the foot-floor contact sequences of Parkinson's Disease (PD) patients in the year following the implantation of Deep Brain Stimulation (DBS). During their best-ON condition, 30 PD patients underwent gait analysis at baseline (T0), at 3 months after subthalamic nucleus DBS neurosurgery (T1), and at 12 months (T2) after subthalamic nucleus DBS neurosurgery. Thirty age-matched controls underwent gait analysis once. Each subject was equipped with bilateral foot-switches and a 5 min walk was recorded, including both straight-line and turnings. The walking speed, turning time, stride time variability, percentage of atypical gait cycles, stance, swing, and double support duration were estimated. Overall, the gait performance of PD patients improved after DBS, as also confirmed by the decrease in their UPDRS-III scores from 19.4 ± 1.8 to 10.2 ± 1.0 (T0 vs. T2) ( p < 0.001). In straight-line walking, the percentages of atypical cycles of PD on the more affected side were 11.1 ± 1.5% (at T0), 3.1 ± 1.5% (at T1), and 5.1 ± 2.4% (at T2), while in controls it was 3.1 ± 1.3% ( p < 0.0005). In turnings, this percentage was 13.7 ± 1.1% (at T0), 7.8 ± 1.1% (at T1), and 10.9 ± 1.8% (at T2), while in controls it was 8.1 ± 1.0% ( p < 0.001). Therefore, in straight-line walking, the atypical cycles decreased by 72% at T1, and by 54% at T2 (with respect to baseline), while, in turnings, atypical cycles decreased by 43% at T1, and by 20% at T2. The percentage of atypical gait cycles proved an informative digital biomarker for quantifying PD gait changes after DBS, both in straight-line paths and turnings.

We proposed a deep learning method using a convolutional neural network on time-series (TS) images to detect and differentiate affected body parts in people with Parkinson's disease (PD) and freezing of gait (FOG) during 360° turning tasks. The 360° turning task was performed by 90 participants (60 people with PD [30 freezers and 30 nonfreezers] and 30 age-matched older adults (controls) at their preferred speed. The position and acceleration underwent preprocessing. The analysis was expanded from temporal to visual data using TS imaging methods. According to the PD vs. controls classification, the right lower third of the lateral shank (RTIB) on the least affected side (LAS) and the right calcaneus (RHEE) on the LAS were the most relevant body segments in the position and acceleration TS images. The RHEE marker exhibited the highest accuracy in the acceleration TS images. The identified markers for the classification of freezers vs. nonfreezers vs. controls were the left lateral humeral epicondyle (LELB) on the more affected side and the left posterior superior iliac spine (LPSI). The LPSI marker in the acceleration TS images displayed the highest accuracy. This approach could be a useful supplementary tool for determining PD severity and FOG., (© 2024. The Author(s).)

High-sensitivity acceleration sensors have been independently developed by our research group to detect vibrations that are > 10 dB smaller than those detected by conventional commercial sensors. This study is the first to measure high-frequency micro-vibrations in muscle fibers, termed micro-mechanomyogram (MMG) in patients with Parkinson's disease (PwPD) using a high-sensitivity acceleration sensor. We specifically measured the extensor pollicis brevis muscle at the base of the thumb in PwPD and healthy controls (HC) and detected not only low-frequency MMG (< 15 Hz) but also micro-MMG (≥ 15 Hz), which was preciously undetectable using commercial acceleration sensors. Analysis revealed remarkable differences in the frequency characteristics of micro-MMG between PwPD and HC. Specifically, during muscle power output, the low-frequency MMG energy was greater in PwPD than in HC, while the micro-MMG energy was smaller in PwPD compared to HC. These results suggest that micro-MMG detected by the high-sensitivity acceleration sensor provides crucial information for distinguishing between PwPD and HC. Moreover, a deep learning model trained on both low-frequency MMG and micro-MMG achieved a high accuracy (92.19%) in classifying PwPD and HC, demonstrating the potential for a diagnostic system for PwPD using micro-MMG., (© 2024. The Author(s).)

To assess the intrarater reliability and agreement of blood pressure (BP), arterial stiffness, and heart rate variability (HRV) assessments in patients with Parkinson`s disease (PD). Twenty patients with PD visited the laboratory three times, during which brachial and central BP (auscultatory and applanation tonometry, respectively), arterial stiffness (carotid-femoral pulse wave velocity and augmentation index), and HRV assessments were performed at rest. Brachial and central systolic BP presented greater values on visit 1 when compared to visits 2 and 3 (122±13 vs. 116±16 vs. 120±15, p=0.029). There were no significant differences (p>0.05) among the experimental visits for other parameters. Brachial and central BP showed an intraclass correlation coefficient (ICC) above 0.842 and a standard error of measurement (SEM) lower than 5.0%. Bland-Altman plots indicated low agreement between visits 1 and 2 and good agreement between visits 2 and 3. Arterial stiffness indices exhibited ICC values between 0.781 and 0.886, and SEM ranged from 7.3% to 25.2%. Bland-Altman plots indicated moderate to good agreement among visits for arterial stiffness parameters. HRV indices presented ICC values ranging from 0.558 to 0.854 and SEM values ranging from 5.1% to 76.0%. Bland-Altman plots indicated moderate agreement among visits for HRV parameters. In PD patients, brachial and central BP present low intrarater reliability and agreement between visits 1 and 2 and good intrarater reliability and agreement between visits 2 and 3. In general, arterial stiffness and HRV assessments present acceptable intrarater reliability and agreement among visits, except for cardiac sympathovagal balance.

Purpose: The primary aim of this study is to develop an effective and reliable diagnostic system for neurodegenerative diseases by utilizing gait data transformed into QR codes and classified using convolutional neural networks (CNNs). The objective of this method is to enhance the precision of diagnosing neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Huntington's disease (HD), through the introduction of a novel approach to analyze gait patterns., Methods: The research evaluates the CNN-based classification approach using QR-represented gait data to address the diagnostic challenges associated with neurodegenerative diseases. The gait data of subjects were converted into QR codes, which were then classified using a CNN deep learning model. The dataset includes recordings from patients with Parkinson's disease (n = 15), Huntington's disease (n = 20), and amyotrophic lateral sclerosis (n = 13), and from 16 healthy controls., Results: The accuracy rates obtained through 10-fold cross-validation were as follows: 94.86% for NDD versus control, 95.81% for PD versus control, 93.56% for HD versus control, 97.65% for ALS versus control, and 84.65% for PD versus HD versus ALS versus control. These results demonstrate the potential of the proposed system in distinguishing between different neurodegenerative diseases and control groups., Conclusion: The results indicate that the designed system may serve as a complementary tool for the diagnosis of neurodegenerative diseases, particularly in individuals who already present with varying degrees of motor impairment. Further validation and research are needed to establish its wider applicability., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Introduction: Patients with Parkinson's disease (PD) may benefit from deep brain stimulation (DBS). Perifocal brain edema sometimes occurs after DBS surgery, but it is transient and does not affect the final prognosis. Transient deterioration of cognitive function has been reported in patients with frontal edema in the first postoperative week. This study aimed to investigate the effect of Goreisan in preventing edematous changes after DBS and determine the influence of edema on cognition., Methods: We included 29 patients with PD who underwent bilateral subthalamic nucleus (STN) DBS and who were divided into 2 groups: those using (11 patients) and those not using Goreisan (18 patients). At 1 week postoperatively, all patients underwent magnetic resonance imaging. We measured the volume of edema either in the frontal white matter or STN on fluid-attenuated inversion recovery (FLAIR) images. Finally, brain edema, motor function, and cognitive function were compared between the groups with and without Goreisan., Results: In the FLAIR image 1 week postoperatively, the average postoperative frontal subcortical edema (FE) volume of the group with Goreisan was significantly lower than that without Goreisan (2249 ± 2186 mm 3 , 6261 ± 7213 mm 3 , respectively, p = 0.023). Multivariate analysis with age, preoperative Mini-Mental State Examination (MMSE) score, FE, and peri-STN edema (SE) as factors, and MMSE at 1 week postoperatively as the dependent variable showed that preoperative MMSE score and SE were significant as associated factors., Conclusions: FE after DBS surgery may be alleviated using Goreisan. SE and preoperative MMSE scores were associated with MMSE scores 1 week postoperatively., Trial Registration: Not applicable., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Background: Tremor-dominant (TD) and nontremor-dominant (NTD) Parkinson's disease (PD) showed different responses to rehabilitation. However, the neural mechanism behind this remains unclear., Methods: This cohort study explores changes in motor function, brain activation, and functional connectivity following 2 weeks of rehabilitation in TD-PD and NTD-PD patients, respectively. A total of 11 TD-PD patients, 24 NTD-PD patients, and 21 age-matched healthy controls (HCs) were included. At baseline, all participants underwent functional magnetic resonance imaging (fMRI) while performing the foot tapping task. Motor symptoms, gait, balance, and task-based fMRI were then evaluated in patients before and after rehabilitation., Results: Compared to HCs, TD-PD patients showed increased activity in the left inferior frontal gyrus and the right insula, and NTD-PD patients showed increased activations in the left postcentral gyrus and decreased within-cerebellar connectivity at baseline. Rehabilitation improved motor function in PD patients regardless of motor subtype. TD-PD patients showed increased recruitments of the sensorimotor cortex and the bilateral thalamus after rehabilitation, and NTD-PD patients showed increased cerebellar activation and within-cerebellar connectivity that was associated with better motor performance., Conclusions: This study demonstrated that rehabilitation-induced brain functional reorganization varied by motor subtypes in PD, which may have important implications for making individualized rehabilitation programs., Trial Registration: ClinicalTrials.gov identifier: ChiCTR1900020771., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Objective: Levodopa-induced dyskinesia (DYS) adversely affects the quality of life of Parkinson's disease (PD) patients. However, few studies have focused on the relationship between DYS and sleep and electroencephalography (EEG). Our study aimed to establish the objective physiological indicators assessed by polysomnography (PSG) that are associated with DYS in PD patients., Methods: We enrolled 122 patients with PD, divided into two groups: PD with DYS (n = 27) and PD without DYS group (non-DYS, n = 95). The demographics and clinical characteristics and sleep assessment in the two groups were collected. More importantly, overnight six-channel PSG parameters were compared in the two groups. We also compared different bands and brain regions of average power spectral density within each group., Results: Compared with the non-DYS group, the DYS group tended to have a significantly higher percentage of nonrapid eye movement sleep (NREM). Gender, levodopa equivalent daily dose (LEDD), rapid eye movement (REM) sleep (min), and the NREM percentage were positively correlated with the occurrence of DYS. After adjusting for gender, disease duration, LEDD, taking amantadine or not, and Montreal Cognitive Assessment (MoCA), NREM%, N3%, and REM (min), the percentage of NREM sleep (p = 0.035), female (p = 0.002), and LEDD (p = 0.005), and REM sleep time (min) (p = 0.012) were still associated with DYS. There was no significant difference in whole-night different bands of average power spectral density between two groups. There was no significant difference in normalized average power spectral density of slow wave activity (SWA) (0.5-2 Hz, 0.5-4 Hz, and 2-4 Hz) of early and late NREM sleep in the DYS group. Dynamic normalized average power spectral density of SWA of low-frequency (0.5-2 Hz) reduction in the frontal region (p = 0.013) was associated with DYS in logistic regression after adjusting for confounding factors., Conclusion: PD patients with DYS have substantial sleep structure variations. Higher NREM percentage and less REM percentage were observed in PD patients with DYS. Dynamic normalized average power spectral density of low-frequency (0.5-2 Hz) SWA reduction in the frontal area could be a new electrophysiological marker of DYS in PD., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objective: To determine whether an accelerated protocol of 48 Hz cerebellar repetitive transcranial magnetic stimulation results in improved motor function in individuals with Parkinson's disease., Methods: In this double-blind randomized sham-controlled study, 35 individuals with Parkinson's disease and stable medical treatment were randomized to either sham or verum transcranial magnetic stimulation. The stimulation was applied bilaterally and medial over the cerebellum and comprised a novel accelerated protocol encompassing two sessions per day on 5 consecutive days. Patients were assessed at baseline, on day 5 after the last stimulation and 1 month post intervention. Measurements included dynamic posturography, UPDRS III, 8-Meter walk test, and Timed Up and Go test., Results: The accelerated protocol was safe and feasible in an outpatient setting. Patients in the verum group showed significant improvement (p < 0.001) of motor symptoms as measured in the UPDRS III. Improvement was mainly carried by the domains rigor, bradykinesia, and gait and persisted after 1 month (p = 0.009), whereas tremor remained unchanged., Interpretation: The effect of a high-dose transcranial magnetic stimulation in patients with Parkinson's disease is encouraging and comparable to other studies using much longer stimulation protocols. This short-term intervention of 5 days facilitates the future application in an outpatient setting. Reduction in hospitalization rates directly benefits patients with motor impairment., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: Novel technology-based interventions have the potential to improve motor symptoms and gait in Parkinson's disease (PD). Promising treatments include virtual-reality (VR) training, robotic assistance, and biofeedback. Their effectiveness remains unclear, and thus, we conducted a Bayesian network meta-analysis., Methods: We searched the Medline, Embase, Cochrane CENTRAL, and Clinicaltrials.gov databases until 2 April 2024 and only included randomized controlled trials. Outcomes included changes in UPDRS-III/MDS-UPDRS-III score, stride length, 10-meter walk test (10MWT), timed up-and-go (TUG) test, balance scale scores and quality-of-life (QoL) scores. Results were reported as mean differences (MD) or standardized mean differences (SMD), with 95% credible intervals (95% CrI)., Results: Fifty-one randomized controlled trials with 2095 patients were included. For UPDRS (motor outcome), all interventions had similar efficacies. VR intervention was the most effective in improving TUG compared with control (MD: -4.36, 95% CrI: -8.57, -0.35), outperforming robotic, exercise, and proprioceptive interventions. Proprioceptive intervention significantly improved stride length compared to control intervention (MD: 0.11 m, 95% CrI: 0.03, 0.19), outperforming VR, robotic and exercise interventions. Virtual reality improved balance scale scores significantly compared to exercise intervention (SMD: 0.75, 95% CrI: 0.12, 1.39) and control intervention (SMD: 1.42, 95% CrI: 0.06, 2.77). Virtual reality intervention significantly improved QoL scores compared to control intervention (SMD: -0.95, 95% CrI: -1.43, -0.52), outperforming Internet-based interventions., Interpretation: VR-based and proprioceptive interventions were the most promising interventions, consistently ranking as the top treatment choices for most outcomes. Their use in clinical practice could be helpful in managing motor symptoms and QoL in PD., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: Freezing of Gait (FOG) is prevalent in people with Parkinson's disease (PD) and severely disrupts mobility. Detecting the exact boundaries of FOG episodes may facilitate new technologies in "breaking" FOG in real-time. This study investigates the performance of automatic device-based FOG detection., Methods: Eight machine-learning classifiers (including Neural Networks, Ensemble methods, and Support Vector Machines) were developed using (i) accelerometer and (ii) combined accelerometer and gyroscope data from a waist-worn device. While wearing the device, 107 people with PD completed mobility tasks designed to elicit FOG. Two clinicians independently annotated exact FOG episodes using synchronized video and a flowchart algorithm based on international guidelines. Device-detected FOG episodes were compared to annotated episodes using 10-fold cross-validation and Interclass Correlation Coefficients (ICC) for agreement., Results: Development used 50,962 windows of data and annotated activities (>10 hours). Strong agreement between clinicians for precise FOG episodes was observed (90% sensitivity, 92% specificity, and ICC1,1 = 0.97 for total FOG duration). Device performance varied by method, complexity, and cost matrix. The Neural Network using 67 accelerometer features achieved high sensitivity to FOG (89% sensitivity, 81% specificity, and ICC1,1 = 0.83) and stability (validation loss 5%)., Conclusion: The waist-worn device consistently reported accurate detection of precise FOG episodes and compared well to more complex systems. The strong clinician agreement indicates room for improvement in future device-based FOG detection., Significance: This study may enhance PD care by reducing reliance on visual FOG inspection, demonstrating that high sensitivity in automatic FOG detection is achievable.

Background: Vibrotactile stimulation has been studied in its efficacy of reducing freezing of gait (FOG) in patients with Parkinson's disease (PD). However, the results are still controversial. We evaluated the efficacy of a newly developed vibrotactile foot device on freezing severity and gait measures in PD patients with FOG., Objective: To evaluate the efficacy of vibrotactile foot device on PD patients with FOG., Methods: Thirty-three PD patients with FOG were examined during their "off" medication state. The efficacy of the vibrotactile foot device was evaluated using a gait protocol comprising walking trials with vibrotactile stimulation "off" and "on." Walking trials were videotaped for the offline rating by two movement disorder specialists. The Opal inertial sensor unit (128 Hz; Mobility Lab; APDM Inc., Portland, OR, USA) was used for quantitative gait analysis., Results: The results demonstrated 33.1% reduction in number of FOG episodes (P < 0.001) and 32.6% reduction of freezing episodes (P < 0.001). Quantitative gait analysis showed a significant increase in step length (P = 0.033). A moderate negative correlation was observed between the change of percent time frozen and age (r = -0.415, P = 0.016). 73% of participants reported minimal to substantial improvement in walking with this vibrating stimulation delivered by the vibrotactile foot device., Conclusions: The vibrotactile foot device is an efficient device that could significantly reduce freezing severity and provide gait regulation to patients with PD experiencing frequent freezing. It could potentially be used in the home environment for improving the quality of life., (© 2024 International Parkinson and Movement Disorder Society.)

Objective: Locomotion is an automated voluntary movement sustained by coordinated neural synchronization across a distributed brain network. The cerebral cortex is central for adapting the locomotion pattern to the environment and alterations of cortical network dynamics can lead to gait impairments. Gait problems are a common symptom with a still unclear pathophysiology and represent an unmet therapeutical need in Parkinson's disease. Little is known about the cortical network dynamics of locomotor control in these patients., Methods: We studied the cortical basis of parkinsonian gait by combining metabolic brain imaging with high-density EEG recordings and kinematic measurements performed at rest and during unperturbed overground walking., Results: We found significant changes in functional connectivity between frontal, sensorimotor, and visuomotor cortical areas during walking as compared to resting. Specifically, hypokinetic gait was associated with poor information flow from the supplementary motor area (SMA) to precuneus and from calcarine to lingual gyrus, as well as high information flow from calcarine to cuneus., Interpretation: Our findings support a role for visuomotor integration processes in PD-related hypokinetic gait and suggest that reinforcing visual information may act as a compensatory strategy to allow SMA-mediated feedforward locomotor control in PD., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

A mounting body of research points to cerebrovascular dysfunction as a fundamental element in the pathophysiology of Parkinson's disease (PD). In the current feasibility study, blood-oxygen-level-dependent (BOLD) MRI was used to measure cerebrovascular reactivity (CVR) in response to hypercapnia in 26 PD patients and 16 healthy controls (HC), and aimed to find a multivariate pattern specific to PD. Whole-brain maps of CVR amplitude (i.e., magnitude of response to CO 2 ) and latency (i.e., time to reach maximum amplitude) were computed, which were further analyzed using scaled sub-profile model principal component analysis (SSM-PCA) with leave-one-out cross-validation. A meaningful pattern based on CVR latency was identified, which was named the PD CVR pattern (PD-CVRP). This pattern was characterized by relatively increased latency in basal ganglia, sensorimotor cortex, supplementary motor area, thalamus and visual cortex, as well as decreased latency in the cerebral white matter, relative to HC. There were no significant associations with clinical measures, though sample size may have limited our ability to detect significant associations. In summary, the PD-CVRP highlights the importance of cerebrovascular dysfunction in PD, and may be a potential biomarker for future clinical research and practice., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Pirio Richardson has received honoraria for lectures from the International Parkinson’s Disease and Movement Disorders Society and the American Academy of Neurology. Dr. Pirio Richardson serves on the Scientific Advisory Boards for private foundations including the Benign Essential Blepharospasm Research Foundation and the Dystonia Medical Research Foundation. She has received royalties from Springer. The remaining authors declare they have no competing financial interests.

Freezing of gait (FOG) leads to an increased risk of falls and limited mobility in individuals with Parkinson's disease (PD). However, existing research ignores the fine-grained quantitative assessment of FOG severity. This paper provides a double-hurdle model that uses typical spatiotemporal gait features to quantify the FOG severity in patients with PD. Moreover, a novel multi-output random forest algorithm is used as one hurdle of the double-hurdle model, further enhancing the model's performance. We conduct six experiments on a public PD gait database. Results demonstrate that the designed random forest algorithm in the double-hurdle model-hyperparameter independence framework achieves outstanding performances with the highest correlation coefficient (CC) of 0.972 and the lowest root mean square error (RMSE) of 2.488. Furthermore, we study the effect of drug state on the gait patterns of PD patients with or without FOG. Results show that "OFF" state amplifies the visibility of FOG symptoms in PD patients. Therefore, this study holds significant implications for the management and treatment of PD.

Aims: i) to compare 30-s sit-to-stand (STS) test repetitions and power between older adults with and without Parkinson's disease (PD) and ii) to evaluate the relationship of STS repetitions and power with functional measures in older people with PD., Methods: STS repetitions and power (Alcazar's equation) during the 30-s STS test were assessed in forty-six age- and sex-matched older adults with and without PD. Functional measures included habitual (HGS) and maximum gait speed (MGS), timed-up-and-go (TUG) test and the Mini-Balance Evaluation System Test (Mini-BEST). PD-specific tests were as follows: the motor subscale of the Unified Parkinson's Disease Rating Scale (UPDRS-III), quality of life [Parkinson's Disease Questionnaire (PDQ-39)], perceived freezing of gait (FOG questionnaire), and fear of falling [Falls Efficacy Scale (FES)]. T scores, repeated measures ANOVA and linear regression analyses were used., Results: T scores for older adults with PD were - 2.7 ± 4.5 for STS repetitions, -5.2 ± 4.2 for absolute STS power, and - 3.1 ± 4.6 for relative STS power compared to older adults without PD. T scores for absolute STS power were lower than T scores for STS repetitions (p < 0.001) and relative STS power (p < 0.001). Both absolute and relative STS power and STS repetitions showed similar correlations with functional measures (r = 0.44 to 0.59; both p < 0.05). Relative STS power (r = -0.55; p < 0.05) and STS repetitions (r = -0.47 to -0.55; p < 0.05) but not absolute STS power were correlated to PD-specific tests., Conclusions: STS repetitions and power values estimated through the 30-s STS test were lower in older people with PD than without PD. Overall, STS power measures were similarly associated with functional performance as STS repetitions, indicating these power equations can be implemented when assessing lower extremity function in older people with PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Little is known about the characteristics and occurrence frequencies of rapid eye movements (REMs) during REM sleep in movement disorders., Objectives: The aim of this study was to detect and characterize REMs during polysomnographically defined REM sleep as recorded by electro-oculography (EOG) in 12 patients with progressive supranuclear palsy (PSP), 13 patients with Parkinson's disease (PD) and 12 healthy controls., Methods: Using a modified EOG montage, we developed an algorithm that automatically detects and characterizes REMs during REM sleep based on their presumptive saccadic kinematics., Results: Compared to PD and healthy controls, REM densities and REM peak velocities were significantly reduced in PSP. These effects were most pronounced in vertical REMs., Conclusion: Ocular motor dysfunction, one of the cardinal features of PSP, seems to be equally at play during REM sleep and wakefulness. For future studies, we provide a novel tool for the unbiased analysis of REMs during REM sleep in movement disorders., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Pathological gait in patients with Hakim's disease (HD, synonymous with idiopathic normal-pressure hydrocephalus; iNPH), Parkinson's disease (PD), and cervical myelopathy (CM) has been subjectively evaluated in this study. We quantified the characteristics of upper and lower limb movements in patients with pathological gait. We analyzed 1491 measurements of 1 m diameter circular walking from 122, 12, and 93 patients with HD, PD, and CM, respectively, and 200 healthy volunteers using the Three-Dimensional Pose Tracker for Gait Test. Upper and lower limb movements of 2D coordinates projected onto body axis sections were derived from estimated 3D relative coordinates. The hip and knee joint angle ranges on the sagittal plane were significantly smaller in the following order: healthy > CM > PD > HD, whereas the shoulder and elbow joint angle ranges were significantly smaller, as follows: healthy > CM > HD > PD. The outward shift of the leg on the axial plane was significantly greater, as follows: healthy < CM < PD < HD, whereas the outward shift of the upper limb followed the order of healthy > CM > HD > PD. The strongest correlation between the upper and lower limb movements was identified in the angle ranges of the hip and elbow joints on the sagittal plane. The lower and upper limb movements during circular walking were correlated. Patients with HD and PD exhibited reduced back-and-forth swings of the upper and lower limbs.

The heterogeneity of Parkinson's disease (PD) presents considerable challenges for accurate diagnosis, particularly during early-stage disease, when the symptoms may be extremely subtle. This study aimed to assess the accuracy of a convolutional neural network (CNN) technique based on the 6-min walk test (6MWT) measured using wearable sensors to distinguish patients with early-stage PD (n = 78) from healthy controls (n = 50). The participants wore six sensors, and performed the 6MWT. The time-series data were converted into new images. The results revealed that the gyroscopic vertical component of the lumbar spine displayed the highest classification accuracy of 83.5%, followed by those of the thoracic spine (83.1%) and right thigh (79.5%) segment. These findings suggest that the 6MWT and CNN models may facilitate earlier diagnosis and monitoring of PD symptoms, enabling clinicians to provide timely treatment during the critical transition from normal to pathologic gait patterns., (© 2024. The Author(s).)

Background: Postural instability and gait disturbances (PIGD) represent a significant cause of disability in Parkinson's disease (PD). Cholinergic system dysfunction has been implicated in falls in PD. The occurrence of falls typically results in fear of falling (FoF) that in turn may lead to poorer balance self-efficacy. Balance self-efficacy refers to one's level of confidence in their ability to balance while completing activities of daily living like getting dressed, bathing, and walking. Lower self-efficacy, or greater FoF during these activities is a function of motor, cognitive, and emotional impairments and may impact quality of life in PD. Unlike known cholinergic reduction, especially in the right lateral geniculate and caudate nuclei, little is known about the role of cholinergic transporters in FoF or mobility self-efficacy in PD., Methods: [ 18 F]fluoroethoxybenzovesamicol ([ 18 F]FEOBV) positron emission tomography (PET) studies were conducted to assess vesicular acetylcholine transporter (VAChT) expression in 126 patients with PD (male (m) = 95, female (f) = 31). Participants had a mean age of 67.3 years (standard deviation (SD) = 7.1) and median Hoehn Yahr stage of 2.5. Patients also completed the Short Falls Efficacy Scale (sFES-I) as a survey measure of concerns about falling. [ 18 F]FEOBV data were processed in Statistical Parametric Mapping (SPM) using a voxel-wise regression model with sFES-I scores as the outcome measure., Results: Reduced [ 18 F]FEOBV binding in tectum, metathalamic (lateral more than medial geniculate nuclei), thalamus proper, bilateral mesiotemporal (hippocampal, parahippocampal, fusiform gyri and fimbriae), and right cerebellar lobule VI significantly associated with higher sFES-I scores ( p < 0.05, family-wise error (FWE) correction after Threshold-Free Cluster Enhancement (TFCE))., Conclusions: Unlike the more limited involvement of the brainstem-thalamic complex and caudate nuclei cholinergic topography associated with falls in PD, cholinergic reductions in the extended connectivity between the thalamic complex and the temporal limbic system via the fimbriae associates with FoF. Additional cholinergic changes were seen in the cerebellum. The temporal limbic system plays a role not only in episodic memory but also in spatial navigation, scene and contextual ( e.g. , emotional) processing. Findings may augur novel therapeutic approaches to treat poor mobility self-efficacy in PD., Clinical Trial Registration: No: NCT02458430. Registered 18 March, 2015, https://www., Clinicaltrials: gov/study/NCT02458430; No: NCT05459753. Registered 01 July, 2022, https://www., Clinicaltrials: gov/study/NCT05459753., (© 2024 The Author(s). Published by IMR Press.)

Parkinson's disease (PD) is typically a sporadic late-onset disorder, which has made it difficult to model in mice. Several transgenic mouse models bearing mutations in SNCA , which encodes alpha-Synuclein (α-Syn), have been made, but these lines do not express SNCA in a physiologically accurate spatiotemporal pattern, which limits the ability of the mice to recapitulate the features of human PD. Here, we generated knock-in mice bearing the G51D SNCA mutation. After establishing that their motor symptoms begin at 9 mo of age, we then sought earlier pathologies. We assessed the phosphorylation at Serine 129 of α-Syn in different tissues and detected phospho-α-Syn in the olfactory bulb and enteric nervous system at 3 mo of age. Olfactory deficit and impaired gut transit followed at 6 mo, preceding motor symptoms. The Snca G51D mice thus parallel the progression of human PD and will enable us to study PD pathogenesis and test future therapies., Competing Interests: Competing interests statement:H.Y.Z. cofounded Cajal Neuroscience, is a Director of Regeneron Pharmaceuticals board, and is on the scientific advisory board of Cajal Neuroscience and the Column Group.

Background: The loss of gait automaticity is a key cause of motor deficits in Parkinson's disease (PD) patients, even at the early stage of the disease. Action observation training (AOT) shows promise in enhancing gait automaticity. However, effective assessment methods are lacking. We aimed to propose a novel gait normalcy index based on dual task cost (NIDTC) and evaluate its validity and responsiveness for early-stage PD rehabilitation., Methods: Thirty early-stage PD patients were recruited and randomly assigned to the AOT or active control (CON) group. The proposed NIDTC during straight walking and turning tasks and clinical scale scores were measured before and after 12 weeks of rehabilitation. The correlations between the NIDTCs and clinical scores were analyzed with Pearson correlation coefficient analysis to evaluate the construct validity. The rehabilitative changes were assessed using repeated-measures ANOVA, while the responsiveness of NIDTC was further compared by t tests., Results: The turning-based NIDTC was significantly correlated with multiple clinical scales. Significant group-time interactions were observed for the turning-based NIDTC (F = 4.669, p = 0.042), BBS (F = 6.050, p = 0.022) and PDQ-39 (F = 7.772, p = 0.011) tests. The turning-based NIDTC reflected different rehabilitation effects between the AOT and CON groups, with the largest effect size (p = 0.020, Cohen's d = 0.933)., Conclusion: The turning-based NIDTC exhibited the highest responsiveness for identifying gait automaticity improvement by providing a comprehensive representation of motor ability during dual tasks. It has great potential as a valid measure for early-stage PD diagnosis and rehabilitation assessment. Trial registration Chinese Clinical Trial Registry: ChiCTR2300067657., (© 2024. The Author(s).)