The Cerebellum

Background and PurposeBrainstem tumors are rare but cause enduring behavioral issues, challenging patients and surgeons. Research on cerebellar changes in these patients limited, despite symptoms similar to cerebellar injuries. This study aims to investigate cerebellar damage pattern resulting from brainstem tumors and its association with behavioral disorders. MethodsIn this study, a U-Net-based segmentation algorithm was used to divide the cerebellum into 26 lobules, which were then used to build a normative model for assessing individual structural deviations. Furthermore, a behavior prediction model was developed using the total outlier count (tOC) index and brain volume as predictive features. ResultsMost patients were found to have negative deviations in cerebellar regions, particularly in anterior lobules like Left V. Higher tOC was significantly associated with severe social problems (r = 0.31, p = 0.001) and withdrawal behavior (r = 0.28, p = 0.001). Smaller size of cerebellar regions strongly correlated with more pronounced social problems (r = 0.27, p = 0.007) and withdrawal behavior (r = 0.25, p = 0.015). Notably, lobules Right X, V, IV, VIIB, Left IX, VIII, and X influenced social problems, while Left V, Right IV, Vermis VI, and VIII impacted withdrawal behavior. ConclusionsOur study revealed cerebellar damage patterns in patients with brainstem tumors, emphasizing the role of both anterior and posterior cerebellar lobes in social problems and withdrawal behavior. This research sheds light on the brain mechanisms underlying complex behavioral disorders in brainstem tumor patients.

Cerebellar dysfunction causes various movement disorders, including ataxia, dystonia, and tremor. Previous work demonstrated that spike patterns in cerebellar nuclei neurons were distinct between different movement disorder mouse models. However, often these changes arise from neural dysfunction in the cerebellar cortex, through misfiring, miswiring, or degenerating Purkinje cells. Even though Purkinje cells form the sole output from the cerebellar cortex, their information is relayed to other regions of the motor network via cerebellar nuclei cells. Purkinje cells make GABAergic synapses onto cerebellar nuclei cells, and it is often assumed that changes in Purkinje cell spike patterns result in inverse changes in nuclei cell spike patterns. Here, we test this hypothesis by answering the question of whether a reliable relationship between Purkinje cell and nuclei cell spike patterns exists. Single-cell, in vivo electrophysiology recordings of both cell types from six mouse models for cerebellar movement disorders were analyzed according to parameters relating to spike rate and irregularity. We investigated whether Purkinje cell spike patterns correlated with nuclei cell spike patterns. We found that some parameters for firing irregularity were positively correlated between Purkinje and nuclei cells but no - and particularly no inverse - relationship was observed between Purkinje and nuclei cell spike rate. Overall, this study begins to illuminate that the relationship between Purkinje cells and nuclei cell spike activity in a disease state is more complex and unpredictable. The data suggest Purkinje cell spike activity changes cannot accurately predict nuclei cell changes, which ultimately drive cerebellar disease states. Our findings underscore the importance of studying cerebellar nuclei cell function in cerebellar disease, as lack of changes in Purkinje cell firing patterns can mask disease-causing firing patterns in these cerebellar output cells.

The 16p11.2 microduplication (16p11.2dp/+) is associated with several neuropsychiatric disorders including schizophrenia, autism spectrum disorder, bipolar disorder, intellectual disability, and attention deficit/hyperactivity disorder (ADHD). Cerebellar abnormalities have been increasingly implicated in these neuropsychiatric disorders, including those conferred by 16p11.2 microduplication. In 16p11.2dp/+ mouse models, the cerebellum is a site of transcriptional dysregulation, and cerebellar microcephaly has been reported in humans with 16p11.2 microduplication. Despite mounting evidence indicating a role for the cerebellum in neuropsychiatric disorders associated with this CNV, cerebellar cellular structure and cerebellar-dependent behavior in mice with 16p11.2 microduplication remain uncharacterized. To address this, we histologically labeled Purkinje cells (PCs) and molecular layer interneurons (MLIs) in a mouse model of 16p11.2 microduplication. We did not find any structural differences in cerebellar lobule IV/V, nor did we observe impairments in gait or motor coordination, behaviors that are associated with lobule IV/V. In contrast, we discovered a significant increase in calbindin/parvalbumin-positive PCs mislocalized to the granule layer of cerebellar lobule VI in 16p11.2dp/+ mice compared to wild-type (WT) littermates. Additionally, we found a significant decrease in parvalbumin-positive MLIs without a decrease in total DAPI-positive cell counts in lobule VI of 16p11.2dp/+ mice compared to WT littermates. Cerebellar lobule VI is associated with delay eyeblink conditioning, and 16p11.2dp/+ mice are impaired in cerebellum-dependent associative learning on this task. Specifically, 16p11.2dp/+ mice showed deficits in both conditioned response (CR) percentage and CR onset latency relative to WT mice. These results suggest that lobule VI-specific alterations to PC localization and MLI parvalbumin expression in 16p11.2dp/+ mice impair both cerebellar learning and adaptive timing of cerebellar-driven, conditioned responses. Thus, we have identified novel structural and functional alterations in the cerebellum that are associated with 16p11.2 microduplication. Importantly, individuals with schizophrenia and ADHD also show CR acquisition deficits in delay eyeblink conditioning. Together, these data suggest that the behavioral impairments in 16p11.2dp/+ mice resemble impairments seen in neuropsychiatric disorders linked to 16p11.2 microduplication in humans. Further investigation of cerebellar cortex neurons in 16p11.2dp/+ mice may provide insights into the pathogenesis of neuropsychiatric disorders linked to this copy number variant.

Cerebellar patients are impaired in motor adaptation. Further, motor adaptation can be divided into a fast component and a slow component, and the cerebellum is known to be especially crucial for the slow component. We tested whether the cerebellar deficit in motor adaptation can be ameliorated by training paradigms targeting slow learning using four visuomotor tasks: standard, gradual, overlearning and long intertrial intervals. We measured slow learning in patients and age-matched controls using a standard paradigm developed for reaching movements by Smith in 2006. The paradigm quantifies slow learning as the magnitude of spontaneous recovery of a previously learned and washed-out adaptation. Cerebellar patients had slower learning and reached a lower level of final adaptation, as seen in previous studies. Nevertheless, both groups had robust spontaneous recovery. Moreover, spontaneous recovery was increased in both groups in the overlearning paradigm with no significant difference between them. Computational modeling suggested that increased spontaneous recovery in the Control group reflects a changed slow adaptation system. That is, in the overlearning in controls, the slow system forgot more slowly and had a slower response to errors. In contrast, the same modeling suggests that no such change in the slow system occurred in the Cerebellar group. Rather, increased spontaneous recovery in this group seems to be the result of greater accumulated slow adaptation in the overlearning. We used our modeling results to predict that overlearning should have slower adaptation in the counterperturbation. Modeling further suggested we would not see these difference in the cerebellar patients. Follow-up analysis confirmed these model predictions. Taken together, our results imply that residual slow learning in cerebellar patients is expressed during increased training trials, but the primary cerebellar deficit is not improved.

Spinocerebellar ataxia type 7 (SCA7) is a rare neurodegenerative disorder characterized by progressive cerebellar ataxia and visual impairment. We investigated longitudinal changes in resting-state functional connectivity and their clinical associations. Resting-state functional MRI was acquired from 16 individuals with SCA7 and 16 age- and sex-matched healthy controls across three visits over 24 months. Network-to-network functional connectivity was quantified, and machine-learning models were trained using functional connectivity features. SCA7 showed lower MoCA (p = 0.045) and MMSE (p = 0.025) scores and progressive worsening of ataxia (SARA, p < 0.001). Significant Group x Visit interactions were observed for Visual-Default Mode (p = 0.012) and Somatomotor-Cerebellar Dorsal Attention connectivity (p = 0.038). Functional connectivity abnormalities involved cortical, cortico-cerebellar, and cerebellar networks that became more widespread at the final follow-up assessment, with the visual network emerging as the most consistently affected system across analyses. Functional connectivity abnormalities were associated with cognitive performance (MMSE: r = -0.62, p = 0.01) and disease severity (SARA: r = 0.589, p = 0.016). Functional connectivity features accurately classified SCA7 and healthy controls (accuracy = 96.4%, F1 = 0.969). These findings support resting-state functional connectivity as a candidate biomarker warranting further validation in larger, independent cohorts.

IntroductionWithin Pediatric Cerebellar Ataxias (PCAs), patients with non-progressive ataxia (NonP) surprisingly show postural motor behavior comparable to that of healthy controls, differently to slow-progressive ataxia patients (SlowP). This difference may depend on the building of the compensatory strategies of the intact areas in NonP brain network. MethodsEleven PCAs patients were recruited: five with NonP and six with SlowP. We assessed volumetric and axonal bundles alterations with a multimodal approach to investigate the connections between basal ganglia and cerebellum as putative compensatory tracts. ResultsCerebellar lobules were smaller in SlowP patients. NonP patients showed a lower number of streamlines in the cerebello-thalamo-cortical tracts but a generalized higher integrity of white matter tracts connecting the cortex and the basal ganglia with the cerebellum. DiscussionThis work reveals that the axonal bundles connecting the cerebellum with basal ganglia and cortex demonstrate a higher integrity in NonP patients. This evidence highlights the importance of the cerebellum-basal ganglia connectivity to explain the different postural motor behavior of NonP and SlowP patients and support the compensatory role of basal ganglia in patients with stable cerebellar malformation.

AIMChildren born preterm (PT) experience perinatal white matter injury and later reading deficits at school age. We used two complementary neuroimaging modalities to determine if reading skills would be associated with contemporaneous white matter properties in school-aged PT children. METHODIn 8-year-old PT children (N=29), we measured diffusivity (fractional anisotropy, FA), from diffusion MRI, and myelin content (relaxation rate, R1) from quantitative relaxometry. We assessed reading (Grays Oral Reading Test, Fifth Edition) in each child. Whole-brain deterministic tractography coupled with automatic segmentation and quantification were applied to extract FA and R1 along four tracts and assess their statistical association with reading scores. RESULTSReading-FA correlations were not significant along the four analyzed tracts. Reading-R1 correlations were significantly positive in portions of the left superior longitudinal fasciculus, right uncinate fasciculus, and left inferior longitudinal fasciculus. FA positively correlated with R1 in limited areas of reading-R1 associations, but did not contribute to the variance in reading scores. INTERPRETATIONCombining complementary neuroimaging approaches identified relations between reading and white matter properties not found using a single MRI measure. Associations of reading skills and white matter properties may vary across white matter tracts and metrics in PT children. What this paper adds{blacksquare} Preterm childrens reading was associated with white matter myelin content. {blacksquare}Preterm childrens reading was not associated with white matter diffusivity.

Background/ObjectivesWorking memory (WM) is a core component of cognition, supporting learning, reasoning, and daily functioning. In severe dyskinetic cerebral palsy (CP), profound motor impairments and involuntary movements make reliable cognitive assessment and access to cognitive interventions difficult. Eye-tracking technology offers an optimal computer interface for administering computerized cognitive assessments and training programs. This study explored the feasibility and efficacy of an adaptive, eye-tracking WM training in young people with severe dyskinetic CP. MethodsFour individuals with severe dyskinetic CP (age range 10-20 years old, 4 female) completed a 5-week intensive Cogmed WM training (five 30-45-minute sessions per week). Primary outcome was the Cogmed Improvement Index, reflecting near-transfer on trained WM tasks. Secondary outcomes included tests from the Wechsler Intelligence Scale for Children-Fifth Edition (WISC-V) to assess near-transfer on untrained WM tasks (Picture Span) and far-transfer to fluid reasoning (Matrix Reasoning, Figure Weights) and visual-spatial reasoning and planning (Visual Puzzles). Language comprehension was evaluated using the Computer-Based instrument for Low motor Language Testing (C-BiLLT), and executive functions behaviour using the Behavior Rating Inventory of Executive Function-2 (BRIEF-2). Descriptive statistics were used. ResultsParticipants completed 23-25 sessions (100% adherence). Cogmed Improvement Index increased by +10.5 to +27, and Picture Span by +12 to +21 post-intervention, mostly retained at 3-month follow-up. Far-transfer effects were variable, except language comprehension which improved consistently and remained stable. ConclusionsThese preliminary findings suggest the feasibility and potential cognitive benefits of adaptive eye-tracking WM training in severe dyskinetic CP. Randomized controlled trials are needed to confirm efficacy and generalisation effects.

People with cerebellar degeneration show characteristic ataxic motor impairments. Despite cerebellar dysfunction, they can still improve motor performance through sensorimotor training. Yet, how such training affects functional brain networks affected by cerebellar degeneration is unknown. We here investigated neuroplastic changes in the cortico-cerebellar network after a five-day forearm movement training in 40 patients with mild to severe cerebellar degeneration and 40 age- and sex-matched healthy controls. Participants were assigned to one of four motor training conditions, varying online visual feedback and explicit verbal feedback. Anatomical and resting-state fMRI was collected on the days before and after training. To overcome the limitations of standard brain templates that fail in the presence of severe anatomical abnormalities, we developed a specific template for comparing cerebellar patients with age-matched controls. Our new template reduced the spatial spread of cerebellar anatomical landmarks by 30% relative to existing templates and tripled fMRI noise classification accuracy. Using this pipeline, we found that patients showed impaired connectivity between cerebellar motor regions and neocortical visuomotor and premotor regions at baseline compared to controls, whereas their cortico-cortical connectivity remained intact. Training with vision strengthened connectivity in the cortico-cerebellar visuomotor network contralateral to the trained arm in all participants. Cerebellar patients exhibited additional increased connectivity ipsilateral to the training arm in this network. Further, training with explicit verbal feedback facilitated connectivity between a cerebellar cognitive region and dorsolateral prefrontal cortex. These results indicate that motor training in cerebellar degeneration leads to enhanced functional connectivity of the cortico-cerebellar network.

Background: Transcranial direct current stimulation (tDCS) is increasingly used as an adjunct to rehabilitation for young people with cerebral palsy (CP), yet considerable variability exists in clinical response. Individualised electric field modelling provides an opportunity to estimate the distribution of electrical fields generated by the stimulation delivered to the brain and explore potential relationships with functional outcomes. Methods: Structural MRI scans from nineteen participants (10-16 years) from a previously published randomised controlled trial (ISRCTN74235136) investigating the effects of tDCS combined with motor training, underwent participant-specific finite element modelling using SimNIBS. Electric field strength was quantified within anatomically defined motor regions of interest, including the primary motor cortex (M1), dorsal premotor cortex (PMd), supplementary motor area (SMA), and a combined motor network. Global grey matter electric field metrics and stimulation focality were also extracted. Results: Estimated electric field strength differed significantly across motor regions (p<0.001), with PMd receiving significantly greater stimulation than both M1 and SMA. Electric field strength within a control region (primary visual cortex) was significantly lower than within M1 (p<0.001). Despite inter-individual variability in regional and global electric field metrics, no significant associations were observed between estimated electric field strength or focality and changes in function following intervention. Conclusion: Individualised electric field modelling demonstrated that an M1-targeted tDCS montage preferentially stimulated PMd rather than M1 in young people with CP. These findings highlight the importance of subject-specific modelling when characterising current distribution and suggest that variability in electric field strength alone does not explain variability in behavioural response.

AimTo examine how healthy preschoolers born very preterm (VPT) with and without significant movement impairments differ from full term (FT) controls in subcortical brain volume measures and white matter diffusion properties.\n\nMethodA case-control, observational study of fifty-four VPT-born and 32 FT-born children were administered the Movement Assessment Battery for Children - Second Edition (MABC-2) and underwent MRI within 6-months of starting kindergarten. Selected subcortical structural volumes, fractional anisotropy (FA), and mean diffusivity (MD) of selected white matter tracts were compared across VPT children with movement impairments (VPT-abnormal), and VPT and FT children without movement impairments.\n\nResultsThe VPT-abnormal group had higher MD in the corpus callosum and inferior frontal-occipital fasciculus and lower FA in the anterior thalamic radiations, corpus callosum, and cingulum than the FT group. The forceps major was particularly affected in the VPT-abnormal group compared with the VPT and FT groups without movement impairments. Both VPT groups had reduced brainstem and cerebellar white matter volumes and larger lateral ventricles compared to the FT group.\n\nInterpretationMovement impairments in healthy VPT preschoolers were associated with more abnormalities in white matter integrity and reduced subcortical brain volumes most likely reflecting a greater extent of white matter damage associated with their very preterm birth.

The field of neuromodulation lacks predictors of individual differences in plasticity that influence responses to repetitive transcranial magnetic stimulation (rTMS). Continuous theta burst stimulation (cTBS), a form of rTMS known for its inhibitory effects, shows variable responses between individuals, potentially due to differences in neuroplasticity. Predicting individual cTBS effects could vastly enhance its clinical and experimental utility. This study explores whether motor evoked potential (MEP) input-output (IO) parameters measured prior to neuromodulation can predict motor cortex responses to cTBS. IO curves were sampled from healthy adults by recording MEPs over a range of single pulse TMS intensities to obtain parameters including MEPmax and S50 (midpoint intensity). Subjects later received cTBS over the same location of motor cortex and their MEPs before and after stimulation were compared. Both MEPmax and S50 predicted responses, significantly correlating (p<0.05, R2>0.25) with individuals MEP changes at 10, 20, and 30 minutes after cTBS. Further, we introduced and validated an easily implementable biomarker that does not require the time-consuming sampling of full IO curve: MEP130RMT (median of 10 MEPs at 130% RMT). MEP130RMT was also a strong predictor of cTBS response (p<0.005, R2>0.3). Head-to-head comparison against a previously studied genetic biomarker of rTMS responses (BDNF polymorphism) showed that IO based predictors had a superior performance in explaining more response variability. Thus, IO curves derived prior to cTBS administration can reliably predict cTBS-induced changes in cortical excitability. This work points toward an accessible strategy for tailoring stimulation procedures in both diagnostic and therapeutic applications of rTMS, and potentially boosting response rate to other brain stimulation approaches. HIGHLIGHTSO_LIBaseline TMS-MEP Input-Output (IO) Curve parameters significantly predict MEP responses to M1 cTBS. C_LIO_LIHigher MEPmax at baseline predicts more robust inhibitory response to cTBS, while higher midpoint intensity (S50) is associated with less response. C_LIO_LID We developed and validated a new biomarker MEP130RMT, which predicts cTBS response using just 10 baseline MEPs from single TMS pulses of 130% RMT intensity. C_LIO_LIHead to head comparison against BDNF genotyping shows superior performance of IO biomarkers. C_LI

Primary motor cortex (M1) plays a major role in motor memory acquisition and retention in humans, but its role in interleaved practice (as opposed to repetitive practice) remains unknown. We anticipated that the improved retention typically associated with interleaved practice depends on M1, and thus cathodal transcranial direct current (ctDCS) stimulation to M1 during training would disrupt this improved retention. The benefits of interleaved practice have been reported to occur from more effective consolidation, manifested as rapid skill memory stabilization followed by more long-term enhancement. While we observed the expected decline in retention performance following interleaved practice paired with ctDCS, this reduced retention resulted from more modest encoding of novel skill memory during acquisition rather than from disruption of offline consolidation processes. These data highlight the broad role played by motor cortex for both encoding and retention of novel skill memory.

BackgroundInjury to brain myelin disrupts motor performance and learning, however it is not clear if myelination is modulated by skilled motor practice or by recovery after stroke. Multi-component relaxation imaging can be used to measure water trapped between myelin bilayers which is expressed as myelin water fraction. The purpose of this study was to examine the effect of experience-dependent learning on myelin plasticity using multi-component relaxation imaging in individuals with stroke. MethodsThirty-two individuals with chronic stroke (>6 months) and twenty-seven healthy controls completed 4 weeks of skilled motor practice using a complex, gamified reaching task. Multi-component relaxation imaging-derived myelin water fraction was obtained before and after training. Seven brain regions associated with motor learning and sensorimotor function were investigated. ResultsAll participants improved task-specific reaching movements after training. In individuals with stroke: 1) pre-training myelin water fraction was lower in motor brain regions but higher in the cingulum compared to controls, 2) pre-training myelin water fraction in motor and sensorimotor regions was positively associated with learning rate, and 3) myelin water fraction was increased in the ipsilesional (contralateral to the trained arm) superior longitudinal fasciculus following skilled motor practice. ConclusionsFindings indicate that after stroke, myelin water fraction is related to measures of motor learning and modulated by 4 weeks of skilled motor practice with the paretic limb. Myelin water fraction can be enhanced in the chronic stage of stroke and may be an important target for upper-limb motor recovery.

Cerebellar pathways form extensive structural circuits linking the cerebellum with the brainstem, thalamus, and cerebrum, underlying motor, cognitive, and affective functions. Diffusion MRI tractography provides the only non-invasive method for mapping these pathways in vivo, but reconstruction of cerebellar connectivity remains challenging due to crossing fibers, peduncular bottlenecks, decussations, multi-synaptic circuits, and numerous small nuclei that define pathway origins and terminations. Here we introduce Anatomically Constrained and CURAted Tractography (ACCURAT), an open framework for reconstructing cerebellar pathways from diffusion MRI using anatomical priors and rule-based streamline queries. ACCURAT combines anatomical segmentation, densely seeded tractography, and vertex-level evaluation of anatomical constraints along streamline trajectories, enabling the isolation of pathway segments within specific nuclei while preventing their propagation across synaptic boundaries. To define these constraints, we provide a concise, pathway-by-pathway synthesis of cerebellar connectional anatomy based on experimental tract-tracing literature and organized for tractography applications. We identify pathway-specific origins, trajectories, terminations, decussation patterns, and tractography challenges, and use this information to inform tractography-ready cerebellar pathway definitions. Using ultra-high-resolution submillimeter diffusion MRI (0.76 mm gSlider acquisition) from healthy participants, we reconstruct multiple extrinsic and intrinsic cerebellar pathways, including specific components of the inferior, middle, and superior cerebellar peduncles; challenging decussating pathways such as the olivocerebellar and dentato-olivary projections; and intrinsic cerebellar pathways, including Purkinje corticonuclear projections and intracortical parallel fibers. ACCURAT generalizes across tractography algorithms, producing comparable reconstructions with both probabilistic parallel transport tractography and deterministic unscented Kalman filter tractography. Together, the ACCURAT framework and accompanying neuroanatomical reference provide an anatomically grounded, tractography-oriented resource for reconstructing cerebellar pathways in vivo and for supporting future development and evaluation of cerebellar tractography methods.

Abstract Background: Transcranial direct current stimulation (tDCS) paired with behavioral language therapy can improve naming in persons with aphasia (PWA), yet naming errors persist. Little is known about how naming error patterns change after non-invasive brain stimulation is combined with language treatment. Aims: To examine whether right cerebellar tDCS plus computerized aphasia therapy changes the types of naming errors in people with chronic aphasia across timepoints, and to determine whether effects differ by cerebellar tDCS polarity (anode vs. cathode). Methods and Procedures: In a randomized, double-blind, sham-controlled, within-subject crossover study, we retrospectively analyzed behavioral data from 24 individuals with post-stroke aphasia. Each participant completed two 15-session intervention periods (3-5 sessions/week) with active cerebellar tDCS + computerized aphasia therapy and sham + computerized aphasia therapy, separated by a two-month washout. General linear models (GLMs) assessed longitudinal changes in six error types (semantic, phonological real word, phonological nonword, no response, mixed, unrelated) on an untrained picture naming task (Philadelphia Naming Test; PNT) and a trained task (Naming 80; N80). Additional GLMs evaluated polarity effects with 2 (Group: anode vs. cathode) x 2 (Treatment) interactions, and treatment-order effects with 2 (Group: tDCS-first vs. sham-first) x 2 (Treatment) interactions. Outcomes and Results: Active cerebellar tDCS did not significantly change error types for trained items (N80). For untrained items (PNT), active tDCS reduced several error types relative to sham, with the clearest and most durable reduction in phonological nonword errors; more moderate reductions occurred for phonological real word and unrelated errors. Mixed errors showed a marginally opposite pattern, tending to increase after tDCS and decrease after sham. Polarity analyses indicated broadly similar effects across anodal and cathodal stimulation overall, but only the anode group showed a reliable treatment effect for phonological nonword errors on the PNT. Treatment-order analyses revealed no significant order effects. Conclusions: Our results indicate a shift in naming error types, particularly after tDCS treatment for the untrained naming task (PNT). These findings may help guide the course of treatment approaches of those with aphasia and what error naming pattern types may show changes post stroke when combining non-invasive brain stimulation and computerized aphasia therapy. Clinical Trial Registration: Cerebellar Transcranial Direct Current Stimulation and Aphasia Treatment [NCT02901574] Keywords: aphasia, naming errors, non-invasive brain stimulation, cerebellar tDCS, computerized aphasia treatment

AO_SCPLOWBSTRACTC_SCPLOWThe neural underpinnings of inhibitory control, an executive cognitive control function, has been a topic of interest for several decades due to both its clinical significance and the maturation of cognitive science disciplines. Behavioral, imaging, and electrophysiological studies suggest that the pre-supplementary motor area (preSMA) serves as a primary hub in a network of regions engaged in inhibition. High-definition transcranial direct current stimulation (HD-tDCS) allows us to modulate neural function to assess cortical contribution to cognitive functioning. The present study targeted HD-tDCS modulation of preSMA to affect inhibition. Participants were randomly assigned to receive 20 min of Sham, Anodal, or Cathodal stimulation prior to completing a semantically cued go/nogo task while electroencephalography (EEG) data were recorded. Both anodal and cathodal stimulation improved inhibitory performance as measured by faster reaction times and increased (greater negative) N2 event-related potentials (ERPs). In contrast, the Sham group did not show such changes. We did not find support for the anodal/cathodal dichotomy for HD neural stimulation. These findings constitute an early investigation into role of the preSMA in inhibitory control and in exploring application of HD-tDCS to the preSMA in order to improve inhibitory control.

BackgroundTranscranial direct current stimulation (tDCS) targeting the primary motor cortex (M1) has previously been shown to enhance motor learning in older adults. However, findings across studies are inconsistent, which may be partly due to variability in stimulation parameters and montages across experimental protocols. ObjectiveWe aimed to replicate the effect of 1mA conventional anodal tDCS over the M1 hotspot during one session of motor sequence learning on retention (24h) compared to sham stimulation in older adults. In addition, we aimed to compare the effect of high definition (HD tDCS) versus conventional tDCS on motor sequence learning to explore if stimulation montage and according focality affects the effect sizes found. MethodsIn a pre-registered, double-blind, randomized, sham-controlled, parallel study design including 52 older adults, we investigated the effects of conventional and HD tDCS on motor sequence learning in a serial reaction time task (SRTT), using a crossover design for the stimulation montage. ResultsAlthough all groups showed motor sequence learning over time, both during practice sessions (main effect of time: p < 0.0001), as well as across session (main effect of time: p < 0.0001), we observed no significant effects on learning between stimulation groups (main effect of stimulation: p = 0. 68) or montages (main effect of montage: p = 0. 66). For all groups, motor sequence learning improvements were maintained but not further enhanced after 24 hours of consolidation (HD tDCS: p = 0.64; conventional tDCS: p = 0.76; HD sham: p = 0.69; conventional sham: p = 0.57). ConclusionOur findings indicate that neither conventional nor HD tDCS enhanced motor sequence learning in older adults. To better understand potential long-term or cumulative effects, we recommend that future studies investigate the effects of repeated tDCS sessions administered throughout the motor learning process.

BackgroundCerebellar damage is common in people with multiple sclerosis (pwMS) and is associated with worse progression and relapse recovery. Studies into the importance of the cerebellum in pwMS are hampered by limited understanding of cerebellar damage and its relation to cerebellar function in pwMS. ObjectiveExamine axonal loss, as a primary driver of progressive neurological decline, in the cerebellum using advanced diffusion MRI and compare axonal loss with cerebellar dysfunction in pwMS MethodsWe recruited 55 pwMS and 14 healthy controls. Clinical assessments included scale for the assessment and rating of ataxia (SARA), and Bain tremor ratings. Subjects underwent FLAIR, T1-weighted and diffusion MRI. Cerebellar grey and white matter and lesion volume were calculated. Cerebellar axonal loss was examined with fibre-specific markers. Fibre density and cross-section (FDC) accounts for microscopic and macroscopic changes in a fibre bundle. ResultsLoss of cerebellar FDC was associated with increased SARA (r=-0.42, p<0.01) and tremor severity (rho=-0.35, p=0.01). Cerebellar lesion volume correlated with SARA (r=0.49, p<0.01) and tremor severity (rho=0.41, p=0.01). ConclusionFibre-specific measures of cerebellar pathology could provide a functionally relevant marker of cerebellar damage in MS. Future trials using fibre-specific markers are needed to further characterize cerebellar pathology in pwMS and understand its significance in disease progression.

ObjectivesThis study aimed to compare the effects of short versus intensive bimanual training on spatiotemporal features of bimanual coordination in children with unilateral cerebral palsy (UCP). MethodsIn a prospective, repeated-measures design, 28 children with UCP completed two training regimens: a short dose (75 repetitions of speed stacking; [~]1-1.5 hours) and an intensive dose (30 hours of Hand arm bimanual intensive training). Bimanual learning was indexed by average time to complete nine stacking trials. Spatiotemporal kinematics were evaluated using three-dimensional motion analysis. For the bimanual coordination task, (3-2-1 stacking) outcomes included normalized movement overlap, total task duration, and participation time. For a symmetric bimanual task (simultaneous two-cup transfer), task synchronization and completion time were analyzed. Peak tangential velocity and hand trajectory were assessed across both tasks. General linear models with repeated measures were used to analyze the effects of training dose and extremity. ResultsThere was a significant main effect of training dose on movement time (p < 0.001), with both doses improving bimanual learning. The intensive dose yielded significantly greater gains in normalized movement overlap, total task duration, hand trajectory, and participation time (all p = 0.001) during the bimanual coordination task. A dose-by-extremity interaction was identified for peak tangential velocity (p = 0.03), demonstrating greater velocity gains in the more affected limb. In the symmetric task, a main effect of dose was found only for hand trajectory (p < 0.03). ConclusionsBoth short and intensive bimanual training enhanced bimanual learning and coordination in children with UCP. While intensive training yielded greater improvements, even brief, ecologically valid tasks produced measurable gains, highlighting the importance of training intensity and task specificity in pediatric neurorehabilitation.