Freezing of gait (FOG) is a disabling motor symptom in Parkinson's disease (PD), linked to impaired motor automaticity and cognitive control. Cognitive strategies like motor imagery (gait imagination, GI) and action observation (gait observation, GO) are used in rehabilitation, but their neural mechanisms are not well understood. This study used EEG to examine midfrontal oscillations during GI and GO in healthy controls (HC, n = 21), PD without FOG (PDFOG-, n = 16), and PD with FOG (PDFOG+, n = 34), with resting-state EEG (eyes-closed and eyes-open) as baseline. During GI, both PD groups showed increased midfrontal theta power compared to HC, while during GO this increase appeared only in PDFOG-. Differences in midfrontal beta oscillations distinguished the two PD subgroups across all conditions. Specifically, the PDFOG- group displayed higher power across alpha and beta frequency bands during GO compared to both HC and PDFOG+. In the GI task, PDFOG+ was characterized by significantly reduced beta power compared to the PDFOG- group. Slowing the pace of GI in PDFOG+ led to a significant reduction in delta activity, while slowing the pace of GO resulted in significant reductions in both delta and theta power; these frequency-shifts were descriptively closer to oscillatory patterns observed in healthy controls. These findings suggest GI and GO involve overlapping but distinct neural mechanisms. Slower pacing may reduce cognitive-motor load and promote compensatory midfrontal activity. Identifying these oscillatory patterns improves understanding of gait dysfunction and supports refining GI and GO as targeted rehabilitation strategies for people with PD and FOG.

Freezing of gait (FOG) in individuals with Parkinson’s Disease is associated with a loss of gait automaticity. This loss of automaticity is demonstrated by worsening gait performance while dual tasking. Functional connectivity between the cerebellar vermis and cortex have previously been associated with spatiotemporal measures of gait in PD. The objective of this study was to determine whether this corticocerebellar connectivity is associated with gait automaticity as measured by dual task interference in PD FOG. 55 participants with PD were recruited (38 FOG, 17 non-FOG controls) to undergo a resting-state functional magnetic resonance imaging scan. Gait automaticity was quantified using spatiotemporal metrics from single and dual task time up and go trials. FOG participants demonstrated shorter step length and gait velocity compared to non-FOG PD controls. A trend toward greater dual task interference of step length in the FOG group was found. Using a seed-based connectivity approach we observed that FOG participants have greater vermis connectivity than non-FOG PD participants to several cortical regions including the superior parietal lobe, supplemental motor area, precentral gyrus and posterior cingulate (voxel threshold p < 0.01, cluster FWE corrected p < 0.05). Meanwhile, vermis connectivity to the occipital cortex was reduced in FOG participants relative to non-FOG controls. Dual task interference of step length among the FOG group correlated with the degree of vermis connectivity to the sensorimotor cortex and superior parietal cortex (voxel threshold p < 0.01, cluster FWE corrected p < 0.05). We conclude that increased corticocerebellar connectivity may be associated with loss of gait automaticity in individuals with PD FOG.

Stroke and traumatic brain injury (TBI) are a significant cause of death and disability nationwide. Both are considered public health concerns in rural communities in the state of South Carolina (SC), particularly affecting the African American population resulting in considerable morbidity, mortality, and economic burden. Stem cell therapy (SCT) has emerged as a potential intervention for both diseases with increasing research trials showing promising results. In this perspective article, the authors aim to discuss the current research in the field of SCT, the results of early phase trials, and the utilization of outcome measures and biomarkers of recovery. We searched PubMed from inception to December 2023 for articles on stem cell therapy in stroke and traumatic brain injury and its impact on rural communities, particularly in SC. Early phase trials of SCT in Stroke and Traumatic Brain injury yield promising safety profile and efficacy results, but the findings have not yet been consistently replicated. Early trials using mesenchymal stem cells for stroke survivors showed safety, feasibility, and improved functional outcomes using broad and domain-specific outcome measures. Neuroimaging markers of recovery such as Functional Magnetic Resonance Imaging (fMRI) and electroencephalography (EEG) combined with neuromodulation, although not widely used in SCT research, could represent a breakthrough when evaluating brain injury and its functional consequences. This article highlights the role of SCT as a promising intervention while addressing the underlying social determinants of health that affect therapeutic outcomes in relation to rural communities such as SC. It also addresses the challenges ethical concerns of stem cell sourcing, the high cost of autologous cell therapies, and the technical difficulties in ensuring transplanted cell survival and strategies to overcome barriers to clinical trial enrollment such as the ethical concerns of stem cell sourcing, the high cost of autologous cell therapies, and the technical difficulties in ensuring transplanted cell survival and equitable healthcare.

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder characterized by both motor and non-motor symptoms, many of which are resistant to currently available treatments. Since the discovery that non-invasive transcranial magnetic stimulation (TMS) can cause dopamine release in PD patients, there has been growing interest in the use of TMS to fill existing gaps in the treatment continuum for PD. This review evaluates the safety and efficacy of a unique multifocal, bilateral Deep TMS protocol, which has been evaluated as a tool to address motor and non-motor symptoms of PD. Six published clinical trials have delivered a two-stage TMS protocol with an H-Coil targeting both the prefrontal cortex (PFC) and motor cortex (M1) bilaterally (220 PD patients in total; 108 from two randomized, sham-controlled studies; 112 from open label or registry studies). In all studies TMS was delivered to M1 bilaterally (Stage 1) and then to the PFC bilaterally (Stage 2) with approximately 900 pulses per stage. For Stage 1 (M1), two studies delivered 10 Hz at 90% motor threshold (MT) while four studies delivered 1 Hz at 110% MT. For Stage 2 (PFC), all studies delivered 10 Hz at 100% MT. The results suggest that this two-stage Deep TMS protocol is a safe, moderately effective treatment for motor symptoms of PD, and that severely impaired patients have the highest benefits. Deep TMS also improves mood symptoms and cognitive function in these patients. Further research is needed to establish optimal dosing and the long-term durability of treatment effects.

Restoring motor function after stroke necessitates involvement of numerous cognitive systems. However, the impact of damage to motor and cognitive network organization on recovery is not well understood. To discover correlates of successful recovery, we explored imaging characteristics in chronic stroke subjects by combining noninvasive brain stimulation and fMRI. Twenty stroke survivors (6 months or more after stroke) were randomly assigned to a single session of transcranial direct current stimulation (tDCS) or sham during image acquisition. Twenty healthy subjects were included as controls. tDCS was limited to 10 min at 2 mA to serve as a mode of network modulation rather than therapeutic delivery. Fugl-Meyer Assessments (FMA) revealed significant motor improvement in the chronic stroke group receiving active stimulation (p = 0.0005). Motor changes in this group were correlated in a data-driven fashion with imaging features, including functional connectivity (FC), surface-based morphometry, electric field modeling and network topology, focusing on relevant regions of interest. We observed stimulation-related changes in FC in supplementary motor (p = 0.0029), inferior frontal gyrus (p = 0.0058), and temporo-occipital (p = 0.0095) areas, though these were not directly related to motor improvement. The feature most strongly associated with FMA improvement in the chronic stroke cohort was graph topology of the dorsal attention network (DAN), one of the regions surveyed and one with direct connections to each of the areas with FC changes. Chronic stroke subjects with a greater degree of motor improvement had lower signal transmission cost through the DAN (p = 0.029). While the study was limited by a small stroke cohort with moderate severity and variable lesion location, these results nevertheless suggest a top-down role for higher order areas such as attention in helping to orchestrate the stroke recovery process.

Background Up to 10 % of Parkinson's disease (PD) populations carry a genetic risk variant, which may not only increase one's chance of developing PD but also affect disease presentation and progression. We hypothesize motor impairment in genetic carriers of PD correlate to different patterns of microstructural changes over time. Design/methods Data were accessed from the Parkinson's Progression Markers Initiative (PPMI) project. Connectometry analyses were performed for GBA1+ PD, LRRK2+ PD, and sporadic PD correlating white matter structural changes, as measured by quantitative anisotropy (QA), with motor impairment, as measured by MDS-UPDRS III. Results There was a negative correlation between QA and MDS-UPDRS III in all 3 cohorts at 48 months. In GBA1+ PD (n = 12), the white matter tracts identified were cortical and subcortical, while in the LRRK2+ PD (n = 18) and sporadic PD (n = 45) cohorts white tracts identified were primarily subcortical and within the brainstem. Conclusions Our findings highlight the association between motor symptom progrerssion and structural connectivity in individuals with GBA1+ PD, LRRK2+ PD, and sporadic PD. Due to the small sample size, larger studies are needed in the future to confirm the findings.

BackgroundAlthough ET is a phenomenologically heterogeneous condition, thalamic DBS appears to be equally effective across subtypes. We hypothesized stimulation sites optimized for individuals with essential tremor (ET) would differ from individuals with essential tremor plus syndrome (ET-plus). We examined group differences in optimal stimulation sites within the ventral thalamus and their overlap of with relevant white matter tracts. By capturing these differences, we sought to determine whether ET subtypes are associated with anatomically distinct neural pathways.MethodsA retrospective chart review was conducted on ET patients undergoing VIM DBS at MUSC between 01/2012 and 02/2022. Clinical, demographic, neuroimaging, and DBS stimulation parameter data were collected. Clinical characteristics and pre-DBS videos were reviewed to classify ET and ET-plus cohorts. Patients in ET-plus cohorts were further divided into ET with dystonia, ET with ataxia, and ET with others. DBS leads were reconstructed using Lead-DBS1 and the volume of tissue activated (VTA) overlap was performed using normative connectomes. Tremor improvement was measured by reduction in a subscore of tremor rating scale (TRS) post-DBS lateralized to the more affected limb.ResultsSixty-eight ET patients were enrolled after initial screening, of these 10 ET and 24 ET-plus patients were included in the final analyses. ET group had an earlier age at onset (p = 0.185) and underwent surgery at a younger age (p = 0.096). Both groups achieved effective tremor control. No significant differences were found in lead placement or VTA overlap within ventral thalamus. The VTA center of gravity (COG) in the ET-plus cohort was located dorsal to that of the ET cohort. No significant differences were found in VTA overlap with the dentato-rubral-thalamic (DRTT) tracts or the ansa lenticularis. Dystonia was more prevalent than ataxia in the ET-plus subgroups (n = 18 and n = 5, respectively). ET-plus with dystonia subgroup had a more medial COG compared to ET-plus with ataxia.ConclusionVIM DBS therapy is efficacious in patients with ET and ET-plus. There were no significant differences in optimal stimulation site or VTA overlap with white-matter tracts between ET, ET-plus and ET-plus subgroups.

Children with hemiparesis (CWH) due to stroke early in life face lifelong impairments in motor function. Transcranial direct current stimulation (tDCS) may be a safe and feasible adjuvant therapy to augment reha-bilitation. Given the variability in outcomes following tDCS, tailored protocols of tDCS are required. We eval-uated the safety, feasibility, and preliminary effects of a single session of targeted anodal tDCS based on individual corticospinal tract organization on corticospinal excitability. Fourteen CWH (age = 13.8 +/- 3.63) were stratified into two corticospinal organization subgroups based on transcranial magnetic stimulation (TMS)-confirmed motor evoked potentials (MEP): ipsilesional MEP presence (MEPIL+) or absence (MEPIL-). Subgroups were randomized to real anodal or sham tDCS (1.5 mA, 20 min) applied to the ipsilesional (MEPIL + group) or contralesional (MEPIL- group) hemisphere combined with hand training. Safety was assessed with question-naires and motor function evaluation, and corticospinal excitability was assessed at baseline and every 15 min for 1 h after tDCS. No serious adverse events occurred and anticipated minor side effects were reported and were self-limiting. Six of 14 participants had consistent ipsilesional MEPs (MEPIL + group). Paretic hand MEP amplitude increased in 5/8 participants who received real anodal tDCS to either the ipsilesional or contralesional hemisphere (+80% change). Application of tDCS based on individual corticospinal organization was safe and feasible with expected effects on excitability, indicating the potential for tailored tDCS protocols for CWH. Additional research involving expanded experimental designs is needed to confirm these effects and to determine if this approach can be translated into a clinically relevant intervention.

Introduction:Cognitive deficits within the first years of Parkinson's disease (PD) diagnosis are commonly reported, and progression to dementia greatly impacts independence. Identifying measures sensitive to early changes is critical for trials of symptomatic therapies and neuroprotection. Methods:A sample of 253 newly diagnosed PD patients and 134 Health Controls (HC) completed a brief cognitive battery annually over a 5-year period through the Parkinson's Progression Markers Initiative (PPMI). The battery included standardized measures of memory, visuospatial functions, processing speed, working memory, and verbal fluency. Inclusion criterion for HCs was performance above a cutoff for possible Mild Cognitive Impairment (pMCI) on cognitive screening (MoCA ⩾ 27) The PD sample was therefore divided to match HCs on baseline cognitive testing (PD-normal n = 169; PD-pMCI n = 84). The multivariate approach to repeated measures examined rates of change between groups on cognitive measures. Results:An interaction indicating slightly greater decline over time in PD-normal relative to HCs was observed on a measure of working memory: letter-number sequencing. Differential rates of change were not observed on any other measures. Motor symptoms on the dominant right upper extremity accounted for performance differences on a test with writing demands (Symbol-Digit Modality Test). PD-pMCI performed worse than PD-normal on all cognitive measures at baseline, but did not decline faster. Discussion:Working memory appears to decline slightly faster in early PD compared to HCs, while other domains remain similar. Within PD, faster decline was not associated with lower baseline cognition. These findings have implications for clinical trial outcome selection and study design.

Objective: To investigate structural connectivity in people with Parkinson's disease with or without visual hallucinations. Background: Up to 70% of people with Parkinson's disease (PwP) experience visual hallucinations (VH) during the course of the disease. The mechanisms through which the PD neurodegenerative process leads to VH remain largely undetermined. The purpose of this study was to determine to what extent whole-brain structural connectivity is different in PwP experiencing VH (PD-VH+) from those not experiencing VH (PD-VH−). Design/Methods: Sixty-nine PwP and eighteen subjects with essential tremor (ET) participated in a neuropsychological evaluation and MRI imaging to determine eligibility for deep brain stimulation. As a part of the evaluation, participants were asked if they had experienced VH. Diffusion Kurtosis Imaging (DKI) scans were processed using a connectometry approach in DSI studio to determine whole-brain group differences in white-matter connectivity. Results: Sixty-nine PwP (mean age = 64 +/− 7.5 years, disease duration = 9.2 +/− 4.8 years) were included in the study. Twenty-four (35%) participants in the PD group reported VH. No subjects with ET reported VH. Relative to PD-VH+ and ET groups, the PD-VH− group had decreased structural connectivity within prefrontal white-matter fibers, including the bilateral anterior frontostriatal tracts and the corpus callosum-forceps minor (FDR corrected p=0.000082). Structural connectivity in these tracts did not differ between the PD-VH+ and ET groups. Analyses included correction for sex, age, handedness, and disease duration. Conclusions: These results suggest that the integrity of frontostriatal and callosal structural connectivity is necessary for the emergence of VH in PD. This aligns with the proposed top-down processing mechanisms of VH in PD. Disclosure: Emma Wetmore has nothing to disclose. Dr. Lench has nothing to disclose. The institution of Dr. Revuelta has received research support from NIH. Dr. Turner has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for VeraSci. Dr. Turner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Saccadous. Dr. Turner has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acadia. The institution of Dr. Turner has received research support from NIH. The institution of Dr. Turner has received research support from Aker BioMarine. An immediate family member of Dr. Rodriguez-Porcel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Anmeal. Dr. Rodriguez-Porcel has received publishing royalties from a publication relating to health care.

•Remotely-instructed tDCS is safe and tolerable in children and young adults with cerebral palsy.•Participants and caregivers reported and demonstrated that at-home tDCS setup was feasible.•Results support further studies to evaluate efficacy of remotely-instructed tDCS in children.

Cognition in Parkinson’s Disease can be impacted by the wearing-off phenomenon which results from changes in dopaminergic tone throughout the day. Given the well-established role of the cholinergic basal forebrain in cognition, we hypothesized that the Nucleus Basalis of Meynert may support cognitive processes during wearing-off periods. Specifically, we evaluated whether worsening of cognitive symptoms during wearing-off is more likely to occur with structural degeneration of the Nucleus Basalis of Meynert. Cognitive wearing-off was evaluated via the Movement Disorders Society Non-Motor Fluctuation Assessment Questionnaire in 33 Parkinson’s Disease participants undergoing evaluation for deep brain stimulation. Pre-operative diffusion MRIs were used to measure brain diffusion metrics of the Nucleus Basalis of Meynert and control regions (caudate and putamen). The number of cognitive symptoms which worsened during OFF periods positively correlated with mean diffusivity (ρ = 0.561, p = 0.0007) and generalized fractional anisotropy (ρ=-0.447, p = 0.009) within the Nucleus Basalis of Meynert but not in the caudate or putamen. Meanwhile, stable cognitive symptoms, and ON-state cognitive performance as measured by the DRS-2 did not correlate with Nucleus Basalis of Meynert metrics. Correlations were corrected for age, sex, scanner type, disease duration, education and LEDD. Our study suggests that reduced structural integrity of the Nucleus Basalis of Meynert is associated with worsening of participant-reported cognitive deficits during OFF periods, but not overall cognitive functioning in the ON-state. These findings support the hypothesis that structural integrity of the cholinergic Nucleus Basalis of Meynert may provide resilience to cognitive worsening during dopamine-related wearing-off.

BackgroundIn pre-clinical animal models of Parkinson's disease (PD), vagus nerve stimulation (VNS) can rescue motor deficits and protect susceptible neuronal populations. Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a non-invasive alternative to traditional invasive cervical VNS. This is the first report summarizing the safety, feasibility, and preliminary efficacy of repeated sessions of taVNS in participants with PD.ObjectivesTo evaluate the feasibility, safety, and possible efficacy of taVNS for motor and non-motor symptoms in mild to moderate PD.MethodsThis is a double-blind, sham controlled RCT (NCT04157621) of taVNS in 30 subjects with mild to moderate PD without cognitive impairment. Participants received 10, 1-h taVNS sessions (25 Hz, 200% of sensory threshold, 500 μs pulse width, 60 s on and 30 s off) over a 2-week period. Primary outcome measures were feasibility and safety of the intervention; secondary outcomes included the MDS-UPDRS, cognitive function and self-reported symptom improvement.ResultstaVNS treatment was feasible, however, daily in-office visits were reported as being burdensome for participants. While five participants in the taVNS group and three in the sham group self-reported one or more minor adverse events, no major adverse events occurred. There were no group differences on blood pressure and heart rate throughout the intervention. There were no group differences in MDS-UPDRS scores or self-reported measures. Although global cognitive scores remained stable across groups, there was a reduction in verbal fluency within the taVNS group.ConclusionstaVNS was safe, and well-tolerated in PD participants. Future studies of taVNS for PD should explore at-home stimulation devices and optimize stimulation parameters to reduce variability and maximize engagement of neural targets.

IntroductionFreezing of gait (FOG) is a prevalent and debilitating feature of Parkinson's Disease (PD). The subthalamic nucleus (STN) is a center for controlled locomotion and a common DBS target. The objective of this study was to identify STN circuitry associated with FOG response to dopaminergic medication. In this study, we compare BOLD functional connectivity of the subthalamic nucleus (STN) in participants with and without dopa-responsive FOG.Methods55 PD participants either with FOG (n = 38) or without FOG (n = 17) were recruited. Among FOG participants 22 were dopa-responsive and 16 were dopa-unresponsive. STN whole-brain connectivity was performed using CONN toolbox. The relationship between the degree of self-reported FOG dopa-response and STN connectivity was evaluated using partial correlations corrected for age, disease duration, and levodopa equivalent daily dose.ResultsRight STN connectivity with the cerebellar locomotor region and the temporal/occipital cortex was greater in the dopa-responsive FOG group (voxel threshold p < 0.01, FWE corrected p < 0.05). Left STN connectivity with the occipital cortex was greater in the dopa-responsive FOG group and connectivity with the postcentral gyrus was greater in the dopa-unresponsive FOG group. Strength of connectivity to these regions correlated with l-dopa induced improvement in UPDRS Item-14 (FOG), but not UPDRS Part-III (overall motor score).DiscussionWe demonstrate that dopa-unresponsive FOG is associated with changes in BOLD functional connectivity between the STN and locomotor as well as sensory processing regions. This finding supports the conceptual framework that effective treatment for freezing of gait likely requires the engagement of both locomotor and sensory brain regions.

BACKGROUND:Pediatric applications of non-invasive brain stimulation using transcranial direct current stimulation (tDCS) have demonstrated its safety with few adverse events reported. Remotely monitored tDCS, as an adjuvant intervention to rehabilitation, may improve quality of life for children with cerebral palsy (CP) through motor function improvements, reduced treatment costs, and increased access to tDCS therapies. Our group previously evaluated the feasibility of a remotely monitored mock tDCS setup in which families and children successfully demonstrated the ability to follow tDCS instructional guidance.METHODS AND DESIGN:Here, we designed a protocol to investigate the feasibility, safety, and tolerability of at-home active transcranial direct current stimulation in children with CP with synchronous supervision from laboratory investigators. Ten participants will be recruited to participate in the study for 5 consecutive days with the following sessions: tDCS setup practice on day 1, sham tDCS on day 2, and active tDCS on days 3-5. Sham stimulation will consist of an initial 30-second ramp up to 1.5 mA stimulation followed by a 30-second ramp down. Active stimulation will be delivered at 1.0 - 1.5 mA for 20 minutes and adjusted based on child tolerance. Feasibility will be evaluated via photographs of montage setup and the quality of stimulation delivery. Safety and tolerability will be assessed through an adverse events survey, the Box and Blocks Test (BBT) motor assessment, and a setup ease/comfort survey.DISCUSSION:We expect synchronous supervision of at-home teleneuromodulation to be tolerable and safe with increasing stimulation quality over repeated sessions when following a tDCS setup previously determined to be feasible. The findings will provide opportunity for larger clinical trials exploring efficacy and illuminate the potential of remotely monitored tDCS in combination with rehabilitation interventions as a means of pediatric neurorehabilitation. This will demonstrate the value of greater accessibility of non-invasive brain stimulation interventions and ultimately offer the potential to improve care and quality of life for children and families with CP.TRIAL REGISTRATION:October 8, 2021( https://clinicaltrials.gov/ct2/show/NCT05071586 ).