Brain modulation after exergaming training in advanced forms of Parkinson's disease: a randomized controlled study.

BACKGROUND: Physical activity combined with virtual reality and exergaming has emerged as a new technique to improve engagement and provide clinical benefit for gait and balance disorders in people with Parkinson's disease (PD). OBJECTIVE: To investigate the effects of a training protocol using a home-based exergaming system on brain volume and resting-state functional connectivity (rs-FC) in persons with PD. METHODS: A single blind randomized controlled trial was conducted in people with PD with gait and/or balance disorders. The experimental (active) group performed 18 training sessions at home by playing a custom-designed exergame with full body movements, standing in front of a RGB-D Kinect® motion sensor, while the control group played using the computer keyboard. Both groups received the same training program. Clinical scales, gait recordings, and brain MRI were performed before and after training. We assessed the effects of both training on both the grey matter volumes (GVM) and rs-FC, within and between groups. RESULTS: Twenty-three patients were enrolled and randomly assigned to either the active (n = 11) or control (n = 12) training groups. Comparing pre- to post-training, the active group showed significant improvements in gait and balance disorders, with decreased rs-FC between the sensorimotor, attentional and basal ganglia networks, but with an increase between the cerebellar and basal ganglia networks. In contrast, the control group showed no significant changes, and rs-FC significantly decreased in the mesolimbic and visuospatial cerebellar and basal ganglia networks. Post-training, the rs-FC was greater in the active relative to the control group between the basal ganglia, motor cortical and cerebellar areas, and bilaterally between the insula and the inferior temporal lobe. Conversely, rs FC was lower in the active relative to the control group between the pedunculopontine nucleus and cerebellar areas, between the temporal inferior lobes and the right thalamus, between the left putamen and dorsolateral prefrontal cortex, and within the default mode network. CONCLUSIONS: Full-body movement training using a customized exergame induced brain rs-FC changes within the sensorimotor, attentional and cerebellar networks in people with PD. Further research is needed to comprehensively understand the neurophysiological effects of such training approaches. Trial registration ClinicalTrials.gov NCT03560089.

Longitudinal Changes of Clinical, Imaging, and Fluid Biomarkers in Preataxic and Early Ataxic Spinocerebellar Ataxia Type 2 and 7 Carriers.

BACKGROUND AND OBJECTIVES: Brain MRI abnormalities and increases in neurofilament light chain (NfL) have mostly been observed in cross-sectional studies before ataxia onset in polyglutamine spinocerebellar ataxias. Our study aimed to identify longitudinal changes in biological, clinical, and/or imaging biomarkers in spinocerebellar ataxia (SCA) 2 and SCA7 carriers over 1 year. METHODS: We studied SCA2 and SCA7 carriers and controls (expansion-negative relatives) at the Paris Brain Institute. Inclusion criteria included Scale for the Assessment and Rating of Ataxia (SARA) scores between 0 and 15. Assessments at baseline, 6 months, and 12 months comprised neurologic, quality of life, orofacial motor, neuropsychological, and ophthalmologic examinations, along with gait and oculomotor recordings, brain MRI, CSF, and blood sampling. The primary outcome was the longitudinal change in these assessments over 1 year. RESULTS: We included 15 SCA2 carriers, 15 SCA7 carriers, and 10 controls between May 2020 and April 2021. At baseline, the ages were similar (41 [37, 46] for SCA2, 38 [28.5, 39.8] for SCA7, and 39.5 [31, 54.5] for controls, p = 0.78), as well the sex (p = 0.61); SARA scores were low but different (4 [1.25, 6.5] in SCA2, 2 [0, 11.5] in SCA7, and 0 in controls, p < 0.01). Pons and medulla volumes were smaller in SCAs (p < 0.05) and cerebellum volume only in SCA2 (p = 0.01). Plasma NfL levels were higher in SCA participants (SCA2: 14.2 pg/mL [11.52, 15.89], SCA7: 15.53 [13.27, 23.23]) than in controls (4.88 [3.56, 6.17], p < 0.001). After 1-year follow-up, in SCA2, there was significant pons (-144 ± 60 mm3) and cerebellum (-1,508 ± 580 mm3) volume loss and a worsening of gait assessment; in SCA7, SARA score significantly increased (+1.3 ± 0.4) and outer retinal nuclear layer thickness decreased (-15.4 ± 1.6 µm); for both SCA groups, the orofacial motor assessment significantly worsened. For preataxic and early ataxic carriers, the strongest longitudinal deterioration on outcome measures was orofacial motility in SCA2 and retinal thickness in SCA7. DISCUSSION: Despite the limitation of the small sample size, we detected annual changes in preataxic and early ataxic SCA individuals across brain MRI imaging, clinical scores, gait parameters, and retinal thickness. These parameters could serve as potential end points for future therapeutic trials in the preataxic phase. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT04288128.

Effects of repetitive transcranial magnetic stimulation of the right inferior parietal lobe on the body image perception in anorexia nervosa: A pilot randomized controlled study.

INTRODUCTION: Restrictive anorexia nervosa (AN) is associated with distorted perception of body shape, previously linked to hypoactivity and reduced excitability of the right inferior parietal lobe (rIPL). Here, we investigated the impact of high-frequency repetitive transcranial magnetic stimulation (HF rTMS) of the rIPL on body shape perception in patients with AN. METHODS: Seventeen patients with AN (median [Q1_Q3] age, 35 [27_39] years; disease duration, 12 [6_18] years) were randomly assigned to receive real or sham HF (10 Hz) rTMS of the rIPL over a period of 2 weeks, comprising 10 sessions. The primary outcome measure was the Body Shape Questionnaire (BSQ). Secondary outcomes included eating disorder symptoms, body mass index, mood, anxiety, and safety. Data collection were done at baseline, post-rTMS, and at 2 weeks and 3 months post-rTMS. RESULTS: Following both real and sham rTMS of the rIPL, no significant differences were observed in body shape perception or other parameters. Both real and sham rTMS interventions were deemed safe and well tolerated. Notably, serious adverse events were associated with the underlying eating and mood disorders, resulting in hospitalization for undernutrition (five patients) or suicidal attempts (two patients). CONCLUSION: This pilot study does not support the use of rTMS of the rIPL as an effective method for improving body shape perception in individuals with the restrictive form of AN. Further research is warranted to comprehensively explore both the clinical and neurophysiological effects of HF rTMS in this population.

Inhibitory control of gait initiation in humans: An electroencephalography study.

Response inhibition is a crucial component of executive control. Although mainly studied in upper limb tasks, it is fully implicated in gait initiation. Here, we assessed the influence of proactive and reactive inhibitory control during gait initiation in healthy adult participants. For this purpose, we measured kinematics and electroencephalography (EEG) activity (event-related potential [ERP] and time-frequency data) during a modified Go/NoGo gait initiation task in 23 healthy adults. The task comprised Go-certain, Go-uncertain, and NoGo conditions. Each trial included preparatory and imperative stimuli. Our results showed that go-uncertainty resulted in delayed reaction time, without any difference for the other parameters of gait initiation. Proactive inhibition, that is, Go uncertain versus Go certain conditions, influenced EEG activity as soon as the preparatory stimulus. Moreover, both proactive and reactive inhibition influenced the amplitude of the ERPs (central P1, occipito-parietal N1, and N2/P3) and theta and alpha/low beta band activities in response to the imperative-Go-uncertain versus Go-certain and NoGo versus Go-uncertain-stimuli. These findings demonstrate that the uncertainty context; induced proactive inhibition, as reflected in delayed gait initiation. Proactive and reactive inhibition elicited extended and overlapping modulations of ERP and time-frequency activities. This study shows the protracted influence of inhibitory control in gait initiation.

Digital Gait Measures Capture 1-Year Progression in Early-Stage Spinocerebellar Ataxia Type 2.

BACKGROUND: With disease-modifying drugs in reach for cerebellar ataxias, fine-grained digital health measures are highly warranted to complement clinical and patient-reported outcome measures in upcoming treatment trials and treatment monitoring. These measures need to demonstrate sensitivity to capture change, in particular in the early stages of the disease. OBJECTIVE: Our aim is to unravel gait measures sensitive to longitudinal change in the-particularly trial-relevant-early stage of spinocerebellar ataxia type 2 (SCA2). METHODS: We performed a multicenter longitudinal study with combined cross-sectional and 1-year interval longitudinal analysis in early-stage SCA2 participants (n = 23, including nine pre-ataxic expansion carriers; median, ATXN2 CAG repeat expansion 38 ± 2; median, Scale for the Assessment and Rating of Ataxia [SARA] score 4.8 ± 4.3). Gait was assessed using three wearable motion sensors during a 2-minute walk, with analyses focused on gait measures of spatio-temporal variability that have shown sensitivity to ataxia severity (eg, lateral step deviation). RESULTS: We found significant changes for gait measures between baseline and 1-year follow-up with large effect sizes (lateral step deviation P = 0.0001, effect size rprb = 0.78), whereas the SARA score showed no change (P = 0.67). Sample size estimation indicates a required cohort size of n = 43 to detect a 50% reduction in natural progression. Test-retest reliability and minimal detectable change analysis confirm the accuracy of detecting 50% of the identified 1-year change. CONCLUSIONS: Gait measures assessed by wearable sensors can capture natural progression in early-stage SCA2 within just 1 year-in contrast to a clinical ataxia outcome. Lateral step deviation represents a promising outcome measure for upcoming multicenter interventional trials, particularly in the early stages of cerebellar ataxia. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Home-based exergaming to treat gait and balance disorders in patients with Parkinson's disease: A phase II randomized controlled trial.

BACKGROUND: Exergaming has been proposed to improve gait and balance disorders in Parkinson's disease (PD) patients. We aimed to assess the efficacy of a home-based, tailored, exergaming training system designed for PD patients with dopa-resistant gait and/or balance disorders in a controlled randomized trial. METHODS: We recruited PD patients with dopa-resistant gait and/or balance disorders. Patients were randomly assigned (1:1 ratio) to receive 18 training sessions at home by playing a tailored exergame with full-body movements using a motion capture system (Active group), or by playing the same game with the computer's keyboard (Control group). The primary endpoint was the between-group difference in the Stand-Walk-Sit Test (SWST) duration change after training. Secondary outcomes included parkinsonian clinical scales, gait recordings, and safety. RESULTS: Fifty PD patients were enrolled and randomized. After training, no significant difference in SWST change was found between groups (mean change SWST duration [SD] -3.71 [18.06] s after Active versus -0.71 [3.41] s after Control training, p = 0.61). Some 32% of patients in the Active and 8% in the Control group were considered responders to the training program (e.g., SWST duration change ≥2 s, p = 0.03). The clinical severity of gait and balance disorders also significantly decreased after Active training, with a between-group difference in favor of the Active training (p = 0.0082). Home-based training induced no serious adverse events. CONCLUSIONS: Home-based training using a tailored exergame can be performed safely by PD patients and could improve gait and balance disorders. Future research is needed to investigate the potential of exergaming.

Brain dysfunction in gait disorders of Caribbean atypical Parkinsonism and progressive supranuclear palsy patients: A comparative study.

INTRODUCTION: Gait disorders and falls occur early in progressive supranuclear palsy (PSP-RS) and Caribbean atypical parkinsonism (Caribbean AP). However, the link between these signs and brain lesions has never been explored in these patient populations. Here, we investigate and compare the imaging factors that relate to gait and balance disorders in Caribbean AP and PSP-RS patients. METHODS: We assessed gait and balance using clinical scales and gait recordings in 16 Caribbean AP and 15 PSP-RS patients and 17 age-matched controls. We measured the grey and white matter brain volumes on 3 T brain MRI images. We performed a principal component analysis (PCA) including all the data to determine differences and similarities between groups, and explore the relationship between gait disorders and brain volumes. RESULTS: Both Caribbean AP patients and PSP-RS have marked gait and balance disorders with similar severity. In both groups, gait and balance disorders were found to be most strongly related to structural changes in the lateral cerebellum, caudate nucleus, and fronto-parietal areas. In Caribbean AP patients, gait disorders were also related to additional changes in the cortex, including frontal, insular, temporal and cuneus lobes, whereas in PSP-RS patients, additional white matter changes involved the mesencephalon and parahippocampal gyrus. CONCLUSION: Gait and balance disorders in Caribbean AP patients are mainly related to dysfunction of cortical brain areas involved in visuo-sensorimotor processing and self-awareness, whereas these signs mainly result from premotor-brainstem-cerebellar network dysfunction in PSP-RS patients, brain areas involved in initiation and maintenance of locomotor pattern and postural adaptation.

Cerebellar Transcranial Alternating Current Stimulation in Essential Tremor Patients with Thalamic Stimulation: A Proof-of-Concept Study.

Essential tremor (ET) is a disabling condition resulting from a dysfunction of cerebello-thalamo-cortical circuitry. Deep brain stimulation (DBS) or lesion of the ventral-intermediate thalamic nucleus (VIM) is an effective treatment for severe ET. Transcranial cerebellar brain stimulation has recently emerged as a non-invasive potential therapeutic option. Here, we aim to investigate the effects of high-frequency non-invasive cerebellar transcranial alternating current stimulation (tACS) in severe ET patients already operated for VIM-DBS. Eleven ET patients with VIM-DBS, and 10 ET patients without VIM-DBS and matched for tremor severity, were included in this double-blind proof-of-concept controlled study. All patients received unilateral cerebellar sham-tACS and active-tACS for 10 min. Tremor severity was blindly assessed at baseline, without VIM-DBS, during sham-tACS, during and at 0, 20, 40 min after active-tACS, using kinetic recordings during holding posture and action ('nose-to-target') task and videorecorded Fahn-Tolosa-Marin (FTM) clinical scales. In the VIM-DBS group, active-tACS significantly improved both postural and action tremor amplitude and clinical (FTM scales) severity, relative to baseline, whereas sham-tACS did not, with a predominant effect for the ipsilateral arm. Tremor amplitude and clinical severity were also not significantly different between ON VIM-DBS and active-tACS conditions. In the non-VIM-DBS group, we also observed significant improvements in ipsilateral action tremor amplitude, and clinical severity after cerebellar active-tACS, with a trend for improved postural tremor amplitude. In non-VIM-DBS group, sham- active-tACS also decreased clinical scores. These data support the safety and potential efficacy of high-frequency cerebellar-tACS to reduce ET amplitude and severity.

Freezing of gait depends on cortico-subthalamic network recruitment following STN-DBS in PD patients.

INTRODUCTION: Subthalamic deep-brain-stimulation (STN-DBS) is an effective means to treat Parkinson's disease (PD) symptoms. Its benefit on gait disorders is variable, with freezing of gait (FOG) worsening in about 30% of cases. Here, we investigate the clinical and anatomical features that could explain post-operative FOG. METHODS: Gait and balance disorders were assessed in 19 patients, before and after STN-DBS using clinical scales and gait recordings. The location of active stimulation contacts were evaluated individually and the volumes of activated tissue (VAT) modelled for each hemisphere. We used a whole brain tractography template constructed from another PD cohort to assess the connectivity of each VAT within the 39 Brodmann cortical areas (BA) to search for correlations between postoperative PD disability and cortico-subthalamic connectivity. RESULTS: STN-DBS induced a 100% improvement to a 166% worsening in gait disorders, with a mean FOG decrease of 36%. We found two large cortical clusters for VAT connectivity: one "prefrontal", mainly connected with BA 8,9,10,11 and 32, and one "sensorimotor", mainly connected with BA 1-2-3,4 and 6. After surgery, FOG severity positively correlated with the right prefrontal VAT connectivity, and negatively with the right sensorimotor VAT connectivity. The right prefrontal VAT connectivity also tended to be positively correlated with the UPDRS-III score, and negatively with step length. The MDRS score positively correlated with the right sensorimotor VAT connectivity. CONCLUSION: Recruiting right sensorimotor and avoiding right prefrontal cortico-subthalamic fibres with STN-DBS could explain reduced post-operative FOG, since gait is a complex locomotor program that necessitates accurate cognitive control.