The Cerebellum

ImportanceRecovery after upper extremity peripheral nerve injury (PNI) surgery depends on changes in cortical neural patterns that support sensorimotor control. Task-based functional connectivity (FC) can characterize these changes, yet few studies have explored FC during ecologically fine motor valid tasks after PNI. ObjectiveTo investigate task-based FC with the left primary motor cortex (M1) during right hand drawing in individuals following right hand PNI surgery. ParticipantsForty-four right-handed adults, including 12 patients post PNI surgery (n = 8 with nerve repair, n = 4 with nerve transfer) and 32 healthy controls. MethodsAll participants underwent fMRI while performing a RH visuomotor precision drawing task. Seed-based connectivity analysis was performed to characterize the pattern of FC between left M1 and all voxels in the brain. We hypothesized that left M1 FC would differ between patients and controls, between Repair and Transfer groups, and covary with time since surgery. ResultsPatients (vs. controls) showed greater FC between left M1 and right visual and premotor cortices. Nerve transfer (vs. repair) showed greater FC between left M1 and right inferior parietal areas. Time since surgery was not linearly related to FC, though exploratory analyses suggested a negative association between log-time and FC between left M1 and right inferior parietal lobule. ConclusionAfter PNI surgery, visuomotor precision drawing involved distinct and behaviorally relevant neural patterns, which varied by task demand and potentially by surgical group despite clinical heterogeneity. Inferior parietal cortex may be especially engaged in early months after surgery (i.e. log-time). To improve recovery of upper limb function after PNI, clinical recommendations include incorporating early function-specific dexterous training, tailoring rehabilitation across surgical and recovery stages, and using multidimensional assessments of hand function.

PurposeTranscranial direct current stimulation (tDCS) can noninvasively modulate activity in targeted brain regions. It is well established that the excitability of motor-related regions can increase when the target region is located beneath the anode (anodal tDCS), suggesting its potential to increase motor performance. Although such attempts have been widely examined, the results remain inconclusive. The purpose of this study was to assess the conditions under which anodal tDCS may improve motor performance in healthy adults. MethodsWe conducted a systematic review of studies on the use of anodal tDCS for improving motor performance in healthy adults. A computerized search was performed using the Web of Science, Scopus, PubMed, JDreamIII, and Ichushi-Web to identify relevant studies published between January 1, 1990 and May 25, 2022. ResultsTwenty-five studies were included in the qualitative synthesis. For the meta-analysis, 25 trials (N=885) were extracted from 23 studies. There were significant effects of anodal tDCS on motor performance improvement, but with evidence of publication bias and substantial heterogeneity among the trials. Post-hoc analysis revealed that motor performance 24 hours after the application of anodal tDCS may benefit from stimulation. There was no marked effect related to stimulation intensity, duration, or whether stimulation was provided during motor performance. ConclusionsOur study clarified the current state of anodal tDCS use for motor performance enhancement and indicates that there is currently no reliable evidence to support its effectiveness. Further studies, particularly randomized controlled trials, are necessary to establish the reliability of these effects for future applications.

Tourette syndrome (TS) is a neurodevelopmental disorder of childhood onset characterised by vocal and motor tics and is associated with cortical-striatal-thalamic-cortical circuit [CSTC] dysfunction. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence. However, many individuals continue to have debilitating tics into adulthood. This indicates that there may be important differences between adults with TS for whom the clinical phenotype is more stable, and children and adolescents with the disorder who may be undergoing developmental neuroplastic changes linked to the reduction of their tics. Previous studies have used transcranial magnetic stimulation (TMS) to investigate changes in cortical motor excitability in individuals with TS, including measurement of resting motor threshold (RMT). However, the findings from these studies have been mixed, have varied between adult and child samples, and have often been based on small sample sizes. Here we report a multi-centre, mega-analytic, study in which RMT data collected from children and adults with TS at multiple research centres was pooled for analysis. Results confirmed that mean RMT was significantly increased in individuals with TS compared to neurotypical controls. However, this result can be explained by the more important findings that: (a) RMT for adults with TS did not differ from that of neurotypical adults; and (b) the rate that RMT decreases with age during childhood and adolescence is reduced in individuals with TS compared to controls. Thus, while neurotypical individuals reach an adult RMT level by ~12-13 years of age, individuals with TS are substantially delayed in doing so, and do not reach an adult RMT level until much later, at ~24 years of age. We conclude therefore that differences in measures of cortical excitability between children and adolescents with TS and chronologically age-matched neurotypical controls may likely reflect a developmental delay in the maturation of functional brain networks in individuals with TS, which may normalise with age.

Background: High school students may be able to communicate health topics to peers and adults. Yet, few studies have evaluated the role of high school students in community health initiatives, making them an underutilized group for disseminating health information. We pilot tested stroke education across five high schools using varied delivery approaches as a preliminary step toward evaluating youth stroke education to improve community health. Methods: In April-May 2025, five high schools in Connecticut and New York participated in stroke education. The format was designed to fit the needs of each school and included an 8-session classroom curriculum (Derby, CT), after-school club meetings (New Haven, CT; Long Island, NY), and one large assembly (Bridgeport, CT). Developed by teachers and neurology providers, the curriculum covered stroke risk factors, symptoms, and emergency response. Students completed a 15-point assessment adapted from the validated Stroke Action Test before, immediately after, and 4-6 weeks post-intervention; data were collected between April and July 2025. Results: Of 112 students completing the pre-test, 99 (88%) completed the immediate post-test and 51 (46%) the delayed follow-up. Average scores rose from 47% pre-intervention to 75% post and 70% at 4-6 weeks. All schools scored <50% on pre-tests suggesting poor baseline stroke knowledge. Conclusion: This pilot suggests that stroke education can be delivered to high school students across varied settings and may support knowledge gains up to 6 weeks. Limitations included small sample sizes and missing follow-up data. If validated in larger studies, this adaptable, teacher-supported approach could offer a scalable public health strategy for improving community stroke preparedness.

Response inhibition, the ability to suppress contextually inappropriate actions, is a cornerstone of cognitive control and is commonly assessed using paradigms such as the go/no-go task. However, traditional go/no-go paradigms rely on binary outcomes such as commission errors, which offer limited insight into the dynamic, graded behavioral adjustments underlying successful stopping. The present study developed a novel mouse-tracking go/no-go paradigm with a dynamic start to capture inhibitory processes during ongoing execution. Twenty-three healthy young adults completed the task in two sessions separated by approximately one week to evaluate the test-retest reliability of standard behavioral measures (error rates and reaction times), and three kinematic features: path length, mean velocity, and mean acceleration. Results revealed robust differences between go and no-go trials across all measures. Successful inhibition was characterized by significantly shorter path lengths and reduced mean velocity and acceleration compared to go trials. Critically, all measures demonstrated moderate-to-good test-retest reliability across sessions, with intraclass correlation coefficients ranging from .75 to .85 for go trials and from .59 to .83 for no-go trials. These findings establish construct validity and psychometric reliability of the current mouse-tracking go/no-go paradigm. The demonstrated stability of these measures provides the methodological foundation for their use in cross-sectional, longitudinal, and intervention research targeting inhibitory control.

BackgroundNeonatal cerebral venous sinus thrombosis (CVST) is associated with intracranial hemorrhage (ICH) and ischemic lesions. There is no scale to characterize the spectrum of brain injury secondary to neonatal CVST. ObjectiveTo develop the Neonatal CVST Hemorrhage Score (NeoCVST Score) to characterize ICH and brain injury in neonates with CVST. MethodsThis was a retrospective cohort study of neonates with CVST diagnosed using brain MRI/MRV. The NeoCVST Score was developed using the study cohort, integrating elements from previous hemorrhage classification systems and expert consensus. Logistic regression examined associations between NeoCVST score and neurodevelopmental outcomes (Pediatric Stroke Outcome Measure). Interrater reliability was assessed with intraclass correlation coefficient. ResultsThe study included 100 neonates (77% term and 23% preterm) with CVST. Thrombosis of multiple venous sinuses was present in 62%. ICH was present in 63%. Supratentorial hemorrhage was present in 57% and included germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) grades 1-2 (22%), GMH-IVH grade 3 (15%), parenchymal (43%) and thalamic (18%) hemorrhage. Infratentorial hemorrhage was present in 19% and included cerebellar (18%) and brainstem (4%) hemorrhage. Extra-axial hemorrhage was present in 32% and included epidural (2%), subdural (26%) and subarachnoid hemorrhage (6%). Ischemic brain injury was present in 67% and included lesions in the medullary vein distribution (13%), white matter (54%), basal ganglia (17%) and thalamus (25%). Neurodevelopmental outcomes included 40% with normal outcomes and 60% with neurodevelopmental impairments. NeoCVST total score (OR=1.1, P=0.02) and subscores for thalamic hemorrhage (OR=1.9, P=0.04), thalamic ischemia (OR=2.2, P=0.005) and bilateral thalamic ischemia (OR=2.8, P=0.01) were predictors of adverse neurodevelopmental outcome. Inter-rater reliability showed moderate-good agreement between reviewers with an intraclass correlation coefficient of 0.71. ConclusionsThe NeoCVST Score is a simple clinical tool to characterize ICH and brain injury secondary to neonatal CVST. Increasing NeoCVST total score and subscores for thalamic hemorrhage and ischemia were associated with worse neurodevelopmental outcomes.

PurposeParkinsons disease (PD) is a neurodegenerative disease that affects motor control but can also influence sensory perception. Changes in vision and proprioception are well-documented but less is known about how PD alters auditory perception, particularly perception of speech acoustic properties. The current study examined perception of speech rate and intensity in PD and the relationship of auditory perception to disease severity. MethodPeople with PD were compared to age- and hearing-matched controls using perceptual tasks focused on discrimination and learning of speech rate and intensity. For rate discrimination, speech, non-speech, and visual stimuli were included to determine whether performance differences for PD participants and controls were specific to speech. Disease severity was assessed using the MDS-Unified Parkinsons Disease Rating Scale (MDS-UPDRS) and the relationship to performance on perceptual discrimination and learning tasks was evaluated. ResultsPeople with PD performed significantly worse than controls in the rate discrimination task for all types of stimuli. There were no significant group differences for intensity discrimination. However, participants with greater PD disease severity demonstrated significantly poorer intensity discrimination accuracy. Performance on learning tasks utilizing rate and intensity manipulations did not differ between PD and control participants and was unrelated to PD disease severity. ConclusionsPeople with PD had difficulty discriminating rate differences across speech, non-speech, and visual stimuli, indicating that challenges with rate perception are not limited to speech. The relationship between intensity discrimination and disease severity suggests common dopaminergic networks between motor symptoms and auditory perception in PD.

Background and Objectives Patients with peripheral neuropathies (PN) commonly exhibit balance impairment. In clinical practice, balance is typically assessed using the Rombergs test and ataxia scales, which rely on examiner interpretation, while objective biomarkers for quantifying balance remain lacking. Wearable sensors are valuable tools for objectively quantifying gait abnormalities in PN patients and may capture clinically meaningful changes over time. By integrating these parameters, artificial intelligence (AI) can assist in generating a digital score that enables easy, objective, and reproducible monitoring of patients postural balance. This study aims to generate and assess an AI-generated digital Rombergs test to quantify balance impairments in a cohort of PN patients. Methods PN patients were assessed in a longitudinal study using a wearable system composed of inertial sensors placed on the trunk and plantar pressure sensors integrated in insoles. Patients performed the Rombergs test under both eyes-open and eyes-closed conditions and were classified according to ataxia severity (mild, moderate, or severe) following the score obtained in item 1 of MICARS and SARA scales. Results We included 97 patients with PN (including autoimmune and hereditary polyneuropathies), and 117 healthy controls (HC). Significant differences in trunk sway and center of pressure (COP) were observed between groups, particularly with eyes closed. Using wearable sensor parameters, we developed an AI digital Rombergs test, which correlated with clinician-rated Rombergs test performance and distinguished patients with and without ataxia (AUC=0.632) and across different PN pathologies. Longitudinally, digital Rombergs test and iRODS showed concordant trajectories. Also, changes [&ge;]25% in the score were associated with clinical changes in ataxia severity measured by an increase in MICARS-SARA score (+1.42 points), whereas improvement was associated with a decrease (-0.20 points) in the scale. Discussion This study demonstrates that wearable sensors are useful to detect and quantify balance impairment. The AI-generated Rombergs test is an objective and reproducible tool for postural balance assessment, with robust discriminatory performance across clinical ataxia severity in PN. Scores longitudinal changes aligned with clinical severity, supporting its potential for monitoring disease progression and treatment response. Its strong association with balance measures reinforces its role as a quantitative biomarker of postural control in ataxia patients.

Cognitive impairments significantly impact the daily life of people with Down syndrome (DS). Overinhibition mediated by interneurons in the central nervous system was proposed as a key pathophysiological mechanism. Previous studies demonstrated cognitive rescue in the Ts65Dn mouse model using 5IA, a negative allosteric modulator of the 5 subunit-containing GABAA receptors. Here, we evaluated the effect of this drug in a mouse model carrying a more accurate duplication of the orthologous region to the human chromosome 21, namely the Dp(16)1Yey mouse model. First, we expanded the phenotypic characterization of Dp(16)1Yey mice using translationally more relevant behavioral tests. We confirmed spatial memory deficits in Dp(16)1Yey mice in the Barnes maze, and highlighted robust learning deficits in the pattern dissociation task and impairments in motor coordination. Next, we evaluated the effect of 5IA treatment on cognitive and motor performance. While 5IA treatment improved motor coordination in the Dp(16)1Yey mice, it failed to restore cognitive performance in the Barnes maze or in the pattern dissociation task. These findings could suggest divergent pathophysiological mechanisms between the Dp(16)1Yey and the Ts65Dn models. Potentially, it could explain the limited efficacy of similar pharmacological intervention in clinical trials for DS. Further preclinical studies should prioritize refined behavioral paradigms and probably the use of more complex DS models to enhance the translational potential of candidate therapies.

PurposeTo examine speech iconicity for shape in aphasia, we compared iconicity ratings from people with aphasia to those from neurologically intact individuals and evaluated how iconicity relates to phonological and semantic processing profiles in aphasia. MethodEleven people with aphasia and 11 age- and gender-matched neurologically intact participants rated how rounded or pointed 50 auditory pseudowords sounded using a 5-point scale. Ratings from participants with aphasia were compared to predicted iconicity ratings derived from reference ratings from prior work and to ratings from neurologically intact participants. For each participant with aphasia, correlations between individual ratings and predicted ratings were related to measures of phonological and semantic processing. ResultsRatings from people with aphasia were significantly correlated with both the predicted ratings and the ratings from neurologically intact participants. The strength of the correlation between individual ratings and predicted ratings did not differ significantly between groups, although there was a trend toward weaker correlations in the aphasia group. There were indications that greater language impairment was associated with greater disruption of iconicity ratings; in particular, deficits in phonological segmentation and semantic processing were associated with reduced sensitivity to shape iconicity. ConclusionThese findings suggest that sensitivity to shape iconicity is preserved in individuals with aphasia to varying degrees. The specific nature of language impairment appears to play an important role in determining iconicity processing in aphasia.

Background and Objectives: Cervical spondylotic myelopathy (CSM) is a leading cause of neurological disability in older adults. However, validated, scalable tools to quantify disease severity and changes over time are lacking. Recent advances in smartphone technology have opened new avenues for longitudinal, objective, and remote monitoring of neurological conditions. We performed a preliminary evaluation of the reliability and validity of SynapTrack, a smartphone-based digital platform for objective remote CSM assessments. Methods: In this single-center prospective cohort study, 265 participants (151 with CSM, 114 healthy controls) completed in-person SynapTrack assessments related to tapping, pinching, and vibratory detection, along with reference laboratory measures of dexterity (Box and Block Test, 9-Hole Peg Test) and vibratory sensation (tuning fork). A subset completed repeated home-based testing to assess test-retest reliability. We evaluated convergent validity, construct validity against the modified Japanese Orthopedic Association (mJOA) score, known-groups validity, and test-retest reliability (intraclass correlation coefficient, ICC). Results: Smartphone-derived metrics demonstrated good-to-excellent test-retest reliability, with the strongest stability for vibratory detection threshold (ICC = 0.92), overall and non-dominant tapping speed (ICC = 0.90 each), and pinching successful targets (ICC = 0.90). Convergent validity was supported by moderate-to-strong correlations between digital metrics and reference laboratory dexterity tests ({rho} up to 0.60 for tapping speed; up to -0.65 for the vibratory threshold). Construct validity against the mJOA was strongest for the vibratory threshold ({rho} = -0.53 to -0.54) and Level 2 non-dominant pinching errors ({rho} = -0.45). Selected metrics distinguished CSM patients from controls with good discrimination, including non-dominant tapping speed (AUROC = 0.76, 95% CI 0.68-0.85), Level 2 dominant pinching successful targets (AUROC = 0.78, 95% CI 0.62-0.94), and the non-dominant vibratory threshold (AUROC = 0.77, 95% CI 0.64-0.90). Conclusions and Relevance: A smartphone-based battery of upper-extremity sensorimotor tasks demonstrated preliminary reliability and validity in CSM. Furthermore, to our knowledge, the novel vibratory detection task represents the first smartphone-based sensory assessment used for CSM. Collectively, these findings position SynapTrack as a scalable platform for objective, remote neurological monitoring of CSM.

Impaired reading, i.e., alexia, is common after left hemisphere stroke. The most common deficit in alexia is a difficulty reading aloud pronounceable novel words, also called pseudowords. While semantic and phonological processes both subserve reading real words, pseudoword reading deficits in alexia are typically ascribed to phonological deficits alone. Some theories, however, suggest that pseudoword reading relies in part on lexical-semantic knowledge, such that semantic deficits could also contribute to poor pseudoword reading in alexia. Leveraging a large sample of left-hemisphere stroke survivors, we examine the cognitive and neural substrates of pseudoword reading accuracy and two error types: lexicalization errors, where a pseudoword is incorrectly read as a real word, and nonword errors, where a pseudoword is read as an incorrect nonword. 76 left-hemisphere stroke survivors read 60 pseudowords aloud, and performed two pseudoword repetition tasks to assess phonological processing and two picture naming tasks to assess mappings between lexical semantics and phonology. Regression models assessed how pseudoword repetition and naming related to overall accuracy and rates of lexicalization and nonword errors in pseudoword reading. Voxel-based and connectome lesion-symptom mapping localized the neural territory responsible for these errors. Both pseudoword repetition and naming independently related to pseudoword reading accuracy. Pseudoword repetition but not naming deficits predicted higher rates of lexicalization errors, while naming but not pseudoword repetition deficits predicted higher rates of nonword errors. Greater nonword error rate also predicted smaller imageability effects in real word reading (t(71)=-3.2, p=0.002). Lexicalization errors were associated with lesions to and disconnections of the left putamen and basal ganglia. Nonword errors were associated with lesions to the superior and middle temporal gyri, as well as broad temporo-parietal disconnections, overlapping with previous lesion-mapping results implicating these regions in semantic contributions to word reading. These results suggest that lexicalization errors result from impaired planning and execution of novel motor plans, causing a reliance on the well-learned motor plans associated with lexical items. In contrast, greater rates of nonword errors, relative to lexicalization errors, occur when semantic contributions to reading are impaired. Overall, these findings demonstrate that semantic processes are involved in reading pseudowords, at least in stroke alexia. These findings support connectionist accounts of reading in which damage in the direct orthography to phonology route for reading leads to reliance on semantic representations, even for pseudowords, suggesting a reinterpretation of pseudoword reading as a pure measure of phonological reading deficits.

Introduction Functional neurological disorder (FND) is a common cause of neurological disability and is associated with substantial healthcare utilisation and cost. Most available treatments target specific symptom subtypes, and prospective evidence regarding the effect of treatment on health-system costs remains limited. We evaluated the real-world clinical and economic outcomes of a transdiagnostic outpatient intervention, attention-based rehabilitation (ABR). Methods We conducted a pragmatic waitlist-controlled study in 54 consecutively referred patients with neurologist-diagnosed FND attending a specialist outpatient service. Clinical outcomes--including quality of life (Short Form-36), social and occupational participation (Work and Social Adjustment Scale), symptom severity, and mental health (Hospital Anxiety and Depression Scale)--were assessed at waitlist entry, treatment commencement, treatment completion, and 6 and 12 months post-treatment. Healthcare utilisation and costs were obtained prospectively from health-service financial records for the 6 months preceding treatment, the treatment period, and two consecutive 6-month post-treatment periods. Longitudinal clinical outcomes and healthcare costs were analysed using Bayesian mixed-effects and mixture models, respectively. Results All clinical measures remained stable or worsened during the waitlist control period. Across treatment, six of eight SF-36 domains, WSAS, employment status, and both HADS subdomains improved, with maintenance through 12 months. Patient-reported symptom improvement persisted post-treatment. Expected monthly health system costs approximately halved post-treatment, with net cost savings by approximately 50 days. Conclusion A fixed-duration, symptom-agnostic outpatient ABR programme was associated with durable improvements in functioning and quality of life, alongside substantial reductions in healthcare utilisation and cost, supporting scalable symptom-agnostic treatment models for FND.

BACKGROUND: Dual task walking requires simultaneous management of cognitive and motor demands and is associated with changes in gait and cortical activation. However, the relationship between task related cortical recruitment and dual task related gait adjustments in healthy young adults remains unclear. This study aimed to investigate the effects of dual tasking on gait performance and cortical activation, and to examine the association between changes in cortical activity and dual-task costs. METHODS: This cross sectional study included 33 healthy young adults. Participants performed three conditions: single task walking, cognitive single task (verbal fluency), and dual task walking. Each condition was repeated 10 times using a repeated short block design with randomized trial presentation. Gait performance was assessed using an instrumented walkway, and cortical activation was measured using functional near infrared spectroscopy. Dual task costs were calculated for gait and cognitive outcomes. Statistical analysis included repeated measures analysis of variance (ANOVA) and Wilcoxon signed rank tests, with false discovery rate correction for multiple comparisons. Associations between changes in cortical activation and dual task costs were examined using correlation analyses. RESULTS: Dual task walking resulted in significant changes in gait, including reduced speed, step and stride length, and increased base of support, stance, and double support (all p < 0.05), while cognitive performance remained unchanged. Dual tasking was associated with increased cortical activation in left prefrontal and motor related regions. Greater increases in cortical activation were associated with lower dual task costs across most gait parameters, with significant correlations observed in the left dorsolateral prefrontal cortex (r {approx} 0.42 to 0.47 for speed and stride length; p < 0.05). Double support showed a distinct pattern, suggesting a specific temporal adjustment within the gait cycle. CONCLUSIONS: Dual task walking in young adults is associated with coordinated behavioral and cortical adaptations. Increased cortical recruitment is linked to reduced motor interference, suggesting that broader engagement of cortical networks may contribute to performance under cognitive motor load.

Two decades of research have provided evidence for gray matter volume (GMV) differences in developmental dyslexia (or reading disability, RD) in the left perisylvian cortex. However, there are concerns about result inconsistencies, likely attributable to small sample sizes, lenient statistical thresholds, and insufficient accounting for demographic variables and global GMV (Ramus et al., 2018). To address these concerns, we conducted a Discovery and Replication Study (N=262) using data from the Adolescent Brain Cognitive Development Study. We found GMV differences between the RD and Control Groups did not replicate across the Discovery and Replication Studies using voxel-based morphometry (VBM) in Statistical Parametric Mapping (SPM), and that a more conservative threshold yielded far fewer results. We then conducted Reproducibility Studies and first found that when using surface-based morphometry in FreeSurfer instead of VBM, the Discovery and the Replication Study results again failed to converge. Second, we combined all groups in a factorial VBM/SPM analysis and the interaction analysis provided quantitative confirmation for diverging between-group difference results across the two studies. Third, we tested for the role of covariates of no interest and found that when total GMV is not controlled for, this divergence dissipates and group differences in RD (main effect of Reading Ability) are amplified. In conclusion, replication of GMV differences in RD is low, even when using large, well-matched groups, and analyses approaches play a modulating role. As such, results from prior studies using lenient statistical thresholds and not accounting for total GMV should therefore be viewed with caution.

ObjectiveAccurate classification of ion channel variants of uncertain significance (VUS) remains a persistent challenge in clinical genomics, limiting diagnostic resolution in neurological disorders. MethodsWe developed a calibrated electrophysiological framework to generate functional evidence for clinical interpretation of CACNA1G variants encoding the low-voltage-activated calcium channel Cav3.1. Functional metrics derived from automated patchclamp recordings were calibrated against benign/likely benign (B/LB) and pathogenic/likely pathogenic (P/LP) reference variants to enable conservative application of ACMG/AMP functional criteria within clinical variant interpretation workflows. ResultsCalibration using 25 B/LB and 16 P/LP CACNA1G variants showed that more than 80% of P/LP variants exhibited reduced current density (CD). Deactivation kinetics ({tau}Deact) provided complementary discriminatory information by identifying gating abnormalities in variants with preserved CD. Application of this dual-metric framework to five VUS identified in Australian patients revealed two variants (Cav3.1-R186Q and R1394Q) with abnormal functional profiles consistent with voltage-sensor perturbation, supporting reassessment as likely pathogenic under ACMG/AMP guidelines. The remaining VUS displayed functional properties overlapping the benign reference distribution. ConclusionThese findings establish a calibrated functional framework for generating electrophysiological evidence that supports clinical interpretation of CACNA1G missense variants under ACMG/AMP guidelines. When applied as external functional evidence, this approach improves resolution of CACNA1G-associated VUS while maintaining conservative standards for variant classification.

Background: The clinical applicability of large language models (LLMs) in Parkinson's disease (PD) management remains insufficiently characterized, particularly in generative responses to clinical vignette scenarios. Objective: To evaluate the quality of clinical assessments and management plans generated by a general-purpose LLM (Gemini 1.5 Pro) and a medically specialized LLM (OpenEvidence), and to compare their performance. Methods: Models generated free-text responses to 45 open clinical queries, focused on assessment of the situation, and recommended management plan. Two movement disorders fellows rated outputs using 5-point Likert scales, dichotomized into clinically appropriate ([&ge;]4) versus inappropriate ([&le;]3). Discrepancies were adjudicated by a senior movement disorders specialist. Paired comparisons used McNemar's test; qualitative analysis examined severe errors. Results: Gemini 1.5 Pro and OpenEvidence showed high rates of clinically appropriate assessments (80.0% vs. 86.7%) but lower performance in management plans (48.9% vs. 57.8%). Cases in which both assessment and plan were clinically appropriate occurred in 46.7% and 55.6% of cases, respectively. None of these differences reached statistical significance. Severe errors were uncommon in assessments (6.7% vs. 8.9%) but more frequent in plans (26.7% in both), predominantly reflecting treatment strategy errors. Conclusions: In generative clinical reasoning tasks involving Parkinson's disease management vignettes, LLMs demonstrated reasonable performance in assessment, but consistent limitations in plan generation. The medically specialized LLM demonstrated several qualitative advantages but no statistically significant performance benefit over the general-purpose model. Therefore, these tools should be used with appropriate caution in Parkinson's disease management, particularly regarding treatment recommendations.

Voluntary contraction in one limb can facilitate motor output in a distant limb, a phenomenon commonly referred to as the remote effect. However, the neural mechanisms underlying this remote interlimb facilitation remain unclear. This study investigated cortical and spinal contributions to the remote effect in able-bodied participants. Transcranial magnetic stimulation (TMS) was applied over the hand area of the primary motor cortex using posterior-anterior (PA) and anterior-posterior (AP) current directions, which are sensitive to different cortical inputs. Cortical excitability was assessed using single- and paired-pulse paradigms to measure short-interval intracortical inhibition (SICI), short-interval intracortical facilitation (SICF), and short-latency afferent inhibition (SAI). Spinal motoneuron excitability was assessed from F-waves elicited by peripheral nerve stimulation. During voluntary lower-limb contractions, single-pulse TMS elicited larger motor evoked potentials in hand muscles across current directions, indicating a broad increase in net corticospinal output. However, only AP-sensitive paired-pulse measures showed reduced SICI and enhanced SICF during contraction, whereas PA-sensitive SICI and SICF were not significantly altered, suggesting that cortical modulation during the remote effect is expressed more clearly in AP-sensitive measures. SAI with PA stimulation was less consistently expressed during contraction, suggesting that afferent-related inhibitory modulation may also be influenced during the remote effect. In parallel, F-wave amplitude and persistence increased, consistent with enhanced spinal motoneuron excitability. Together, these results provide converging evidence that the remote effect in humans involves broad corticospinal and spinal facilitation, accompanied by current direction-dependent modulation of cortical excitability measures. KEY POINTS SUMMARYO_LIVoluntary contraction in one limb can facilitate motor output in a distant limb, but the mechanisms underlying this remote interlimb facilitation remain unclear. C_LIO_LIWe tested whether remote lower-limb contraction modulates corticospinal output, intracortical excitability, and spinal motoneuron excitability in a resting hand muscle. C_LIO_LISingle-pulse transcranial magnetic stimulation showed that motor evoked potentials in the hand were facilitated during remote lower-limb contraction across multiple current directions, indicating a broad increase in net corticospinal output. C_LIO_LIPaired-pulse measures were modulated preferentially with anterior-posterior stimulation, with reduced short-interval intracortical inhibition and increased short-interval intracortical facilitation, suggesting current direction-dependent modulation of cortical excitability measures. C_LIO_LIF-wave amplitude and persistence were also enhanced during remote lower-limb contraction, indicating increased spinal motoneuron excitability. These findings provide converging evidence that the remote effect involves both cortical and spinal contributions. C_LI

BackgroundEmotional and cognitive difficulties often co-occur in neurodevelopmental conditions. While transdiagnostic, dimensional approaches offer a more precise framework for understanding mental health than diagnostic categories, their neural correlates in youth with learning difficulties remain poorly understood. This study investigates associations between transdiagnostic mental health dimensions and resting-state functional connectivity in struggling learners. MethodsCross-sectional behavioural data from the Centre for Attention, Learning and Memory (CALM) for struggling learners (N = 378) was used to replicate a hierarchical model of mental health from the Conners Parent Rating Short Form, the Revised Childrens Anxiety and Depression Scale and the Strengths and Difficulties Questionnaire. Functional connectomes were derived from resting-state fMRI data (N = 67), and partial least squares regression related mental health dimensions to connectivity within and between large-scale brain networks. ResultsThe replicated model comprised a general p-factor, two broad domains (internalising and externalising), and three specific dimensions (specific internalising, neurodevelopmental and social maladjustment). Symptom severity was associated with two connectivity patterns: greater default mode network coupling to frontoparietal and attention networks, and reduced connectivity between visual and somatomotor systems. These effects were strongest for the neurodevelopmental and social maladjustment dimensions, respectively. ConclusionsThese findings align with population-level evidence linking mental health dimensions to brain network organization, extending it to struggling learners and offering new insight into the neural basis of mental health vulnerability in neurodevelopmentally at-risk youth.

Freezing of gait is a disabling episodic symptom of Parkinson's disease, typically emerging during complex locomotor tasks such as turning, obstacle negotiation, and gait initiation. These tasks require effective motor planning and proactive visual search of the intended walking route. Current evidence suggests that people with Parkinson's disease and freezing of gait show different patterns of visual search compared to those without freezing of gait and healthy older adults. However, existing reports are based on relatively simple tasks that lack common triggers for freezing of gait and do not adequately control for other factors likely to influence visual search, such as motor symptom severity and balance ability. This study examined visual search behaviour in 24 healthy older adults and 37 people with Parkinson's disease (21 with freezing of gait, 16 without) during a complex walking task requiring repeated turning and navigation through narrow spaces. Visual search characteristics were compared between people with Parkinson's disease and healthy controls, and relationships between visual search, freezing of gait, motor symptom severity, and balance ability were explored within the Parkinson's disease group. Compared with healthy controls, people with Parkinson's disease showed significantly fewer fixations toward areas outside the walking path, longer average fixation durations, and reduced saccade amplitudes, with no differences in proactive visual planning of the intended route. No relationship was found between visual search outcomes and freezing of gait. Reduced fixations to outside-path areas were associated with poorer functional balance independently of motor symptom severity. These findings indicate that restricted visual sampling in Parkinson's disease is primarily associated with balance impairment rather than freezing of gait or motor symptom severity.