The cerebellum undergoes substantial maturation with regionally distinct developmental trajectories. This study examined cerebellar gray matter volume (GMV) in healthy children, adolescents, and adults, using voxel-based morphometry, the ACAPULCO algorithm, and the SUIT toolbox for cerebellum-optimized analyses. A total of 104 typically developing children (n=31, 6-9 years), adolescents (n=35, 13-17 years), and adults (n=38, 30-40 years) were included. We hypothesized age-group differences in cerebellar GMV, with adolescents showing the greatest volume, specifically in posterolateral regions. Results revealed significant group differences in GMV. We observed region-specific volumetric patterns, with some areas (e.g., Crus II, lobule X) showing higher GMV in adolescents that in children, while other areas (e.g., lobules I-IV and VI, Crus I, vermis VI and VIIb) showed higher GMV in the adolescent group compared with both children and adults. These patterns were partly consistent with our hypothesis. Notably, no regions showed greater GMV in adults than adolescents, suggesting that the adolescent cerebellum shows a pattern consistent with transient highest GMV relative to both children and adults.Our findings indicate differential developmental patterns both between and within lobules of the cerebellum, and highlight adolescence as a period when GMV is higher relative to both childhood and adulthood, with potential implications for the development of cerebellar-supported cognitive and emotional functions that undergo significant changes during this period.

The key elements for fear extinction learning are unexpected omissions of expected aversive events, which are considered to be rewarding. Given its reception of reward information, we tested the hypothesis that the cerebellum contributes to reward-like prediction error processing driving extinction learning via its connections with the ventral tegmental area (VTA). Forty-three young and healthy participants performed a three-day fear conditioning paradigm in a 7T MR scanner. The cerebellum and VTA were active during unexpected omissions of aversive unconditioned stimuli in the initial extinction trials and in other learning phases, in line with the proposed role of prediction-error processing. Increased functional connectivity was observed between the cerebellum and VTA, indicating that they are functionally coupled during fear extinction learning. These results suggest that an interaction between the cerebellum and VTA should be incorporated into the existing model of the fear extinction network.

Rare neurological diseases often present with severe cognitive impairment but face significant challenges in access to specialized care. Telemonitoring and telerehabilitation are promising approaches to improve the standard of care in common neurological diseases and could prove even more beneficial to patients with rare neurological diseases. To review the available evidence on the usability and validity of cognitive telemonitoring or telerehabilitation in rare neurological diseases. We performed a scoping review, examining all studies published in the last 25 years on both synchronous and asynchronous cognitive telemonitoring or telerehabilitation approaches in rare neurological diseases of adulthood. Active digital cognitive tests show promising feasibility and validity, especially for people with Frontotemporal Dementia and Huntington’s Disease. However, methodological limitations remain, notably the high rate of dropouts for active telemonitoring and limited evidence of cognitive domain-specific sensitivity for passive telemonitoring. Cognitive telerehabilitation is emerging as a feasible and potentially effective approach for primary progressive aphasia. However, other rare neurological diseases still require proper investigation, and the available evidence is still largely preliminary, and is plagued by small sample sizes and heterogeneous methodology, which limits generalizability. Our review recognizes the promise of remote approaches in expanding access to both cognitive monitoring and rehabilitation for rare neurological diseases but emphasizes the need for rigorously designed trials to establish clinical utility and best practices. Key unmet needs include improvement of adherence to active telemonitoring, evaluation of clinical validity in reference to gold-standard clinical outcome measures for passive telemonitoring, evaluation of clinical utility via longitudinal studies, evaluation of feasibility across a wider range of disease severity, and technological literacy.

Background Friedreich ataxia (FRDA) is an inherited, progressive neurodegenerative disease. Interindividual heterogeneity in the rate and phenotypic profile of disease progression indicates a biologic variability in the pattern and spatial evolution of underlying changes, but the occurrence of possible FRDA subgroups, which could aid in clinical trial design and treatment, are still unknown. Purpose To obtain a structural MRI-based stratification of participants with FRDA using the Subtype and Stage Inference (SuStaIn) algorithm and determine whether these subgroups are biologically meaningful and clinically relevant. Materials and Methods This multicenter secondary analysis of prospectively acquired data included structural MRI and clinical-demographic data from participants from the ENIGMA-Ataxia working group. MRI biomarkers were analyzed using the SuStaIn algorithm to identify subgroups with distinct patterns and disease stages. The clinical and genetic relevance of these subgroups were assessed within a linear model framework. Results This study included 565 participants (mean age, 32 years ± 13.1 [SD]; 286 women; 275 participants with FRDA and 290 healthy controls). SuStaIn identified three subtypes: (a) a classical subtype (66.5% [183 of 275 participants]), characterized by an ascending gradient of damage from brainstem to cerebellar cortex to cerebrum; (b) an early cerebral subtype (25.8% [71 of 275 participants]) with cerebral atrophy preceding the involvement of cerebellar cortex; and (c) and an early cerebellar subtype (7.64% [21 of 275 participants]) showing cerebellar lobule atrophy before upper brainstem or cerebral involvement. More advanced disease stages (MRI-based SuStaIn stages) correlated with greater symptom duration (unstandardized coefficient B = 0.422, standard error = 0.065, P < .001) and severity (B = 1.404, standard error = 0.201, P < .001), and these relationships were moderated by subtype, with biologic stage progression in the early cerebral subtype mapping less strongly to clinical variables relative to the others (interaction term early cerebral subtype × stage: B = -0.925, standard error = 0.410, P = .02). Conclusion Using the SuStaIn algorithm, three distinct structural MRI-based subtypes of FRDA were identified, with different patterns of brain degeneration and associations with clinical severity. © RSNA, 2026 Supplemental material is available for this article.

Functional brain connectivity has been instrumental in uncovering the large-scale organization of the brain and its relation to various behavioral and clinical phenotypes. Understanding how this functional architecture relates to the brain’s dynamic activity repertoire is an essential next step towards interpretable generative models of brain function. We propose functional connectivity-based Attractor Neural Networks (fcANNs), a theoretically inspired model of macro-scale brain dynamics, simulating recurrent activity flow among brain regions based on first principles of self-organization. In the fcANN framework, brain dynamics are understood in relation to attractor states; neurobiologically meaningful activity configurations that minimize the free energy of the system. We provide the first evidence that large-scale brain attractors - as reconstructed by fcANNs - exhibit an approximately orthogonal organization, which is a signature of the self-orthogonalization mechanism of the underlying theoretical framework of free-energy-minimizing attractor networks. Analyses of seven distinct human neuroimaging datasets demonstrate that fcANNs can accurately reconstruct and predict brain dynamics under a wide range of conditions, including resting and task states, and brain disorders. By establishing a formal link between connectivity and activity, fcANNs offer a simple and interpretable computational alternative to conventional descriptive analyses.

Delay eyeblink conditioning is widely used to study cerebellar function and has been considered a biomarker of cerebellar dysfunction in neurological and psychiatric disorders. A major challenge for repeated testing is transfer of learning across sessions. We tested whether using conditioned stimuli (CSs) from different modalities reduces transfer in humans, whether participants can be stratified into Fast and Slow learners, and whether pupillometry-based blink detection can serve as an alternative to electromyography (EMG). In Experiment 1 (N = 32), participants completed a short screening and two task sessions with auditory and visual CSs paired with an air puff as unconditioned stimulus, followed by extinction training. Learning occurred in both sessions with no difference in overall conditioned response incidences (CRIs) between sessions. However, auditory CSs led to stronger conditioning than visual CSs. In Experiment 2 (N = 16), no screening session was performed, and both task sessions used visual CSs. Here, specific transfer was evident, with high CRIs from the first block of session 2 and a significant session effect. Similarly, transfer occurred from screening to task sessions in Experiment 1 when CSs matched in modality. Across experiments, participants could be stratified into Fast and Slow learners based on median CRIs in the second acquisition training block during screening (Experiment 1) or first task (Experiment 2) sessions. CRIs derived from EMG and pupillometry were highly correlated, confirming pupillometry-based blink detection as a valid MRI-compatible alternative. In sum, transfer is substantial with same-modality CSs, whereas cross-modal designs reduce transfer and enable repeated testing.

Abstract Placebo analgesia has traditionally been explained by top–down cortical regulation of brainstem and spinal pathways. Recent circuit-level work in animal models identified a rostral anterior cingulate–pontine–cerebellar pathway that contributes to expectation-based analgesia, implicating cerebellum circuits in placebo effects 1 . Building on these findings, we examined pontine and cerebellar contributions within a large individual-participant meta-analysis of human neuroimaging studies of placebo analgesia 2 ( n = 603). We found that the effects of human pain and placebo converge in cerebellar territories embedded in higher-order cognitive 3,4 and action-mode networks 5 . These regions exhibit placebo-induced anticipatory increases and reduced responses during painful stimulation, which correlate with the magnitude of placebo analgesia, consistent with predictive configuration of the system. Pontine responses also correlate with individual differences in placebo analgesia. In independent Human Connectome Project data ( n = 820), pontine activity is functionally connected with cingulate and cerebellar regions implicated in placebo analgesia. Together, these findings support a model in which expectation effects are implemented via predictive configuration of a cortico–pontine–cerebellar system.

Objective: Spinocerebellar ataxia type 1 (SCA1) is a rare, inherited neurodegenerative disease characterised by progressive deterioration of motor and cognitive function. Here, we illustrate the pattern and evolution of brain atrophy in people with SCA1 using a large multisite dataset. Methods: Structural magnetic resonance imaging data from SCA1 (n=152) and healthy control (n=131) participants from seven sites and two consortia were analyzed using voxel-based morphometry. Cross-sectional stratification and correlations were undertaken with ataxia severity and duration to profile disease evolution. Cerebrocerebellar structural covariance analysis was used to understand the relationship between cerebral and cerebellar tissue atrophy. Results: Atrophy in SCA1 first manifests in the lower brainstem and cerebellar white matter (WM), before progressing to the pons, anterior cerebellum, and cerebellar lobule IX. The midbrain and peri-thalamic WM and the remainder of the cerebellar cortex are then affected, with preferential involvement of specific motor and cognitive areas. Finally, degeneration in the striatum and cerebral WM corresponding to the corticospinal tract become apparent. Atrophy and correlations with ataxia severity are most pronounced in the cerebellar WM and pons. Structural covariance analysis showed reduced correlations between cerebellar and cerebral WM volume in SCA1 participants. Interpretation: Cross-sectional stratification of a large SCA1 cohort by ataxia severity indicates a pattern of atrophy spread across the brainstem, cerebellum, and subcortical grey and white matter. Ongoing volume loss throughout the disease course is most evident in a core set of infra-tentorial brain regions. Atrophy of cerebellum spans both motor and cognitive functional zones. Cerebellar degeneration is not directly mirrored by downstream effects in the cerebrum. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by grants from the Australian National Health and Medical Research Council (NHMRC), Friedreich's Ataxia Research Alliance, FAPESP (Sao Paulo Research Foundation), German Research Foundation, German Federal Ministry of Education and Research, Italian Ministry of Health, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Mental Health (NIMH). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Monash University gave ethical approval for this work (project 12372). Ethics committee of University of Bonn Medical Faculty gave ethical approval for this work (project 176/16). Ethics committee of University of Campinas gave ethical approval for this work (project CAAE 29869520.8.3001.5404). Ethics Committee of University of Duisburg-Essen gave ethical approval for this work (project 15-6404-BO). Ethics Committee of Instituto Neurologico Carlo Besta gave ethical approval for this work (report N.14; 17 December 2014). Ethics committee of University of Minnesota gave ethics approval for this work (study number 0502M67488). Ethics committee of Sorbonne University gave ethics approval for the work (AOM10094, CPP Ile de France VI, Ref: 10510). Ethics committee of University Hospital Tubingen gave ethics approval for this work (project 303/2008BO2). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Introduction Parkinson's disease (PD) is a systems-level disorder, implicating basal ganglia-thalamo-cortical (BTC) and cerebello-thalamo-cortical (CTC) networks. While regional atrophy has been reported, network-wide volumetric profiles and their relevance for subtype classification and symptom association remain underexplored. Methods We acquired T1-weighted MRI and quantitative susceptibility mapping (QSM) from 40 PD patients and 21 healthy control participants (HC). Volumes were extracted from 19 regions of interest (ROI) within the BTC and CTC networks using a multimodal pipeline. We assessed asymmetry, group differences, and symptom associations using regression models, and applied ridge regression models for PD vs. HC and motor subtype classification. Results Network-level ROI volumes successfully classified PD vs. HC and PD motor subtypes, with the highest optimistic AUC of 0.88 for PD vs. HC (mean AUC of 0.63) and 0.95 for PD-TD vs. PD-PIGD (mean AUC reached 0.68). The thalamic nuclei and cerebellar lobules I-V, VIIIa, X were identified as key features. Atrophy in the dentate nucleus (DN), substantia nigra-subthalamic complex (SN-STN), and M1 predicted PD. Tremor severity correlated with the ventral lateral posterior thalamus (VLp), VIIb, and SN-STN volumes; bradykinesia severity with the thalamus; and postural instability and gait disturbance (PIGD) with lobule IV. No significant group-level differences for single volumes were found. Conclusion Multiregional volumetric analysis within the BTC and CTC motor networks uncovered group differences between PD and HC that were not apparent when examining single ROIs alone. These findings highlight that PD-related alterations manifest as distributed volumetric patterns across interconnected motor circuits, supporting their role as imaging biomarkers.

BACKGROUND:Biallelic SPG7 mutations cause one of the most common forms of hereditary spastic paraplegia (HSP). Several reports have suggested that heterozygous SPG7 variants may also play a role in HSP, but also in amyotrophic lateral sclerosis (ALS). However, it remains controversial whether heterozygous SPG7 mutations are pathogenic on their own, or if other mechanisms are at play. We recently provided evidence for non-Mendelian inheritance in spastic paraplegia 7 (SPG7), as heterozygous carriers of SPG7 mutations often also carried mutations in other disease-related genes, including AFG3L2, more frequently than expected by chance. Given that SPG7 and AFG3L2 encode interacting subunits of the mitochondrial m-AAA protease complex, we hypothesized that combined heterozygous mutations in these genes may act synergistically to disrupt mitochondrial function and contribute to disease. In this study, we aimed to examine whether digenic heterozygous mutations in SPG7 and AFG3L2 can lead to a spectrum of neurodegenerative disorders. METHODS:We first analyzed genome and exome sequencing data of 6644 unrelated individuals including 4817 motor neuron disorder (MND) and ataxia patients and 1827 controls. We next analyzed an additional 18,748 exome data from rare disease cohorts to further examine the occurrence of variants in SPG7 and AFG3L2. RESULTS:Among the first 4817 MND and ataxia patients, we identified a total of 6 patients, 4 of whom were unrelated, who carried potentially pathogenic variants in both SPG7 and AFG3L2, in contrast to none in 1827 unrelated controls. Further analysis of the 18,748 additional patients with rare disease, as well as a comprehensive literature review, identified 6 more patients, 5 of whom were unrelated, who had digenic mutations in SPG7 and AFG3L2. In the two families we identified, digenic mutations in SPG7 and AFG3L2 perfectly segregated with the disease. The 12 patients reported here exhibited predominant signs of motor neuron and cerebellar involvement. CONCLUSIONS:Our findings demonstrate that digenic inheritance of concurrent heterozygous mutations in SPG7 and AFG3L2 may cause motor neuron and cerebellar disorders. Screening of the entire SPG7 and AFG3L2 genes in genetically undiagnosed cases of MND and spastic ataxia may help to increase the diagnostic yield.

Most patients with a rare movement disorder (MD) do not receive a molecular diagnosis, and the underlying genetic variants and mediating genes remain elusive. Here, we evaluate the diagnostic accuracy of conventional and next-generation sequencing-based genetic testing strategies in a cohort of 2,811 individuals with ataxia, spastic paraplegia and dystonia. Exome sequencing establishes genetic diagnoses in 19.3% of cases, and specificity of phenotypic features and age at testing are positive predictors. Genome analysis 'beyond the exome' increases the diagnostic yield by 7.5%, mostly due to the improved detection of structural variants and repeat expansions. Unsolved cases are included in the Solve-RD cohort and subjected to gene-burden analysis, providing evidence for loss-of-function variants in X-chromosomal CD99L2 causing spastic ataxia. Cellular studies show that the transmembrane protein CD99L2 occurs mainly in a ubiquitinated form and serves as an activating interactor of the calcium-dependent protease CAPN1. Ablation of cytoplasmic or extracellular domains of CD99L2 leads to its intracellular mislocalization and abrogation of its interplay with CAPN1. Transcriptome analysis in CD99L2 patient-derived fibroblasts reveals synaptic function-specific disturbances. Impaired CAPN1 activation and dysregulation of downstream neuronal pathways constitute the likely molecular cause for neurodegeneration.

BACKGROUND:Spinocerebellar Ataxia 27B (SCA27B) is a novel, frequent and likely treatable late-onset autosomal-dominant ataxia caused by GAA repeat-expansions in FGF14. For understanding disease evolution and imminent trial planning, metrics of the most widely used clinical outcome assessment (Scale for the Assessment and Rating of Ataxia/SARA), longitudinal progression and modifiers thereof are warranted. METHODS:Multicentre intercontinental observational study (2015-2024) of 661 assessments from 219 patients with SCA27B (age: 68 ± 10 years; SARA: 9 ± 6 points) with item-level distribution-based analyses to characterise SARA metrics relative to ageing-related impairment in 390 healthy controls; and linear mixed-effects modelling to determine longitudinal progression and demographic or genetic modifiers. FINDINGS:Ataxia severity in SCA27B as assessed by SARA was primarily attributable to gait, stance, and lower-limb impairment; other ataxia domains scored ≤1 SARA point in 79-94% of patients. Discrimination of SCA27B motor performance from controls decreased with age due to ageing-related motor variability captured by SARA, thus limiting potential metric response windows for symptomatic treatments. Disease progression was faster in the presence of interfering ageing-related comorbidities in 14 (6%) patients. Overall longitudinal progression of SCA27B was 0.54 SARA points/year [95% CI: 0.37-0.71]. Expansions of (GAA)> 180 repeats were frequent also on the shorter allele (n = 18 (8%), range: 196-348 repeats), and associated with faster progression (+1.6 SARA points/year, [95% CI: 0.9-2.2]), including also otherwise less affected ataxia domains speech and sitting. INTERPRETATION:Disease progression in SCA27B is characterised by mild progression, ageing-related motor variabilities and comorbidities, and associated with repeat size on both alleles. FUNDING:Else-Kröner-Fresenius-Stiftung, EU, DFG, BMBF, CIHR, NAF, Ataxia-UK, CSC.

BACKGROUND:Neuropsychological deficits have been observed in patients with cerebellar damage, but never thoroughly investigated in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). OBJECTIVES:The goal is the characterization of presence, severity, and profile of neuropsychological deficits in ARSACS using the cerebellar cognitive-affective syndrome (CCAS) scale. METHODS:Prospective study including a discovery cohort from Saguenay/Canada (n = 31, median [inter-quartile range] age: 57 [54-62] years), and a validation cohort from Tübingen, Germany (n = 17, 35 [21-43] years) with matched controls (n = 19). RESULTS:All ARSACS patients failed in multiple CCAS-related subtests and exceeded cutoffs for "definite CCAS." Even the younger validation cohort failed more subtests than controls (5 [3-7] vs. 1 [1-2], P < 0.001) and had lower CCAS total scores (81 [67-86] vs. 101 [91-106], P < 0.001). Total scores worsened in the older discovery cohort (40 [25-52], P < 0.001) and correlated with age/disease duration (ρ = -0.575, P < 0.001) and ataxia severity (Scale for the Assessment and Rating of Ataxia: ρ = -0.527, P = 0.003). CONCLUSIONS:Neuropsychological deficits consistent with CCAS are consistent in ARSACS, present early, and progress in the disease course. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

OBJECTIVE:Spinocerebellar ataxia type 3 (SCA3) is a genetically defined ataxia. The Scale for Assessment and Rating of Ataxia (SARA) is a clinician-reported outcome that measures ataxia severity at a single time point. In its standard application, SARA fails to capture short-term fluctuations, limiting its sensitivity in trials. To overcome this, we employed SARAhome, a video-based, self-administered tool for high-frequency, remote ataxia assessment. METHODS:We assessed feasibility and validity of SARAhome in 65 SCA3 patients from seven centers. Participants recorded SARAhome twice daily for 14 days using a mobile e-health app. We analyzed adherence, intraindividual fluctuations and their predictors, and evaluated sensitivity to change in a longitudinal substudy of 11 patients. RESULTS:Adherence to the study protocol was generally high (80.2%) with valid scores in 79.2% of 1459 recordings. Maximum adherence occurred over a 4-day period (84.8%). Fluctuations ranged 3.0 points between lowest and highest scores (IQR: 2.5-4.5) and 1.0 point based on score IQRs (IQR: 0.5-1.5), corresponding to 10.7% and 3.6% of the maximal SARAhome score. Fluctuations showed rough agreement with patient global impression. Greater disease severity and longer CAG repeats were associated with smaller relative fluctuations. Over a median follow-up of 411 days, SARAhome showed higher sensitivity to change than conventional SARA (SRM: 0.67 vs. 0.37). INTERPRETATION:SARAhome is a feasible, innovative video-based tool for remote, high-frequency monitoring of ataxia severity. A 4-day recording effectively captures relevant fluctuations and enhances sensitivity to change, supporting its use in future SCA3 trials.

Focal transcranial direct current stimulation (tDCS) using center-surround electrode montages enables region-specific cortical targeting, and holds promise for both cognitive neuroscience and clinical interventions. However, systematic examinations of dose-response relationships and their regional differences are lacking, hampering informed selections of suited stimulation parameters.In this preparatory methodological study, we present a modeling-based framework to support harmonized empirical dose-response studies of focal tDCS across different target areas. It covers three steps: Determining the approximate electric field strength that had led to behavioral and physiological effects in related prior tDCS studies. In our case, this led to a field strength of 0.2 V/m on average across magnetic resonance images (MRIs) from 43 participants and eight target areas related to different cognitive and motor functions. Second, optimizing the radii of center-surround montages for each target area to - on average across participants - achieve the intended field strength while maximizing focality. An additional test of cross-sample generalization in an independent sample confirms that the intended target field strength is achieved on average for new participants. Third, the pre-determined montage radii and a method for the individualized positioning of the center-surround electrode montages are provided for prospective planning in empirical dose-response studies.By harmonizing the electric field strength between different target regions at the group level, but preserving inter-individual variability, our framework will enable systematic analyses to relate the field strength to behavioral and neuroimaging outcomes, and to assess differences of these relations across regions. The described computational tools are open-source, allowing other researchers to tailor our framework to their specific research questions; and are currently used in a multi-center study involving approximately 1,000 datasets.

BACKGROUND:Spinocerebellar ataxia type 3 (SCA3) is a rare, inherited neurodegenerative disease characterized by progressive loss of motor coordination. OBJECTIVES:We undertook a multisite magnetic resonance imaging study to profile the spatial spread of atrophy across the brain, determine whether atrophy preferentially maps onto specific functional networks, and investigate the relationship between cerebellar and cerebral atrophy. METHODS:Whole-brain grey and white matter (GM and WM) voxel-based morphometry was performed on 408 individuals with SCA3 (82 pre-ataxic) and 293 controls. The SCA3 cohort was stratified by ataxia severity to study progression. Cerebellar GM atrophy was mapped onto a task-based functional atlas. Cerebrocerebellar volumetric covariance was assessed to determine whether cerebral and cerebellar atrophy were coupled. RESULTS:The atrophy pattern is spatially consistent but progressive in magnitude across the disease course. The greatest atrophy (Cohen's d > 1.5) occurred in the pons, cerebellar WM, and cerebellar peduncles; correlations with ataxia severity and duration were also strongest (-0.4 > r > -0.65) in those regions. Cerebellar GM atrophy was greatest (d ≅ 0.7) in functional regions associated with motor planning/execution, attention, and emotional processing. Sparse cerebral cortical atrophy appears only in the most severe disease subgroup, while striatal atrophy begins in the earliest stages but does not worsen with increasing clinical severity. Reduced cerebrocerebellar volumetric covariance is observed in SCA3 participants versus controls. CONCLUSIONS:Cerebellar and brainstem atrophy underlies greater ataxia severity in SCA3, but the spatial pattern of structural changes remains relatively consistent across the course of the disease. Cerebellar GM atrophy is spatially non-uniform, and occurs maximally in regions consistent with the motor and cognitive clinical presentation of SCA3. Cerebellar atrophy is not mirrored by corresponding cerebral structural changes. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Friedreich's ataxia (FRDA) is an inherited neurodegenerative disorder characterized by progressive ataxia and multisystem manifestations resulting from involvement of the peripheral and central nervous systems. While regional atrophy is known to be associated with symptoms, functional network alterations may represent a critical pathological mechanism; however, their specific contribution to motor and cognitive impairment remains unclear. We combined T1-weighted anatomical MRI and resting-state functional MRI (rs-fMRI) in 37 individuals with FRDA and 41 age- and sex-matched healthy controls and explored how functional connectivity differences are related to atrophy, clinical severity and cognitive performance. Regional volumes were quantified using morphometry analyses, spontaneous rs-fMRI activity was assessed via amplitudes of low-frequency fluctuations, and functional co-activation was evaluated among regions showing structural and neuronal activity alterations. Volume reductions were most pronounced in the brainstem, cerebellar white matter, hemisphere of lobules VI, X, and thalamus. Functionally, individuals with FRDA showed decreased fronto-cerebellar connectivity alongside increased intracerebellar, thalamo-striatal, and hippocampal-cerebellar coupling. Infratentorial and thalamic volume loss correlated strongly with clinical disease severity, whereas reduced frontal co-activation with cerebellar lobules VI, Crus I and II was moderately associated with poorer motor and cognitive performance. In contrast, increased intracerebellar and hippocampal-cerebellar coupling was observed particularly in individuals with more advanced disease and was partly associated with better cognitive outcomes. These findings indicate widespread disruptions of long-range cerebro-cerebellar connectivity together with increased intraregional coupling and potential network reorganization, underscoring the importance of network-level mechanisms for understanding clinical heterogeneity in FRDA and guiding future prognostic and therapeutic studies.

Although the neural network underlying fear extinction has been extensively studied, the cerebellum's role has received little attention - despite its well-established involvement in associative learning. Our study therefore aimed to provide additional evidence that the cerebellum is part of the circuitry supporting fear-extinction processes, and to get a better understanding of how the cerebellum may contribute to fear extinction learning. In this study, 6 Hz cerebellar transcranial alternating current stimulation (ctACS) or sham stimulation was applied during extinction training in a two-day differential fear conditioning paradigm in young, healthy participants undergoing 3T fMRI, using a double-blind randomized design. Acquisition and extinction training occurred on day 1, followed by extinction recall on day 2. Skin conductance responses showed that 6 Hz ctACS applied during extinction training reduced spontaneous fear recovery during recall. During extinction training, differential fMRI activation (CS+ > CS-) was significantly higher in the occipital cortex in the verum compared to the sham group. During recall, differential fMRI activation was significantly higher in the precentral gyrus in the sham compared to the verum group at the time the aversive unconditioned response (US) was expected but did not occur. Furthermore, in recall, parametric modulation based on trial-by-trial model-derived prediction errors for no-US events revealed significantly higher activation in frontal cortical areas, including the anterior cingulate cortex, and parietal cortical areas in the sham compared to the verum group. Volume of interest analyses showed significantly higher beta values towards the CS+ compared to the CS- in the sham group, but not in the verum group in the right insula related to the prediction of the US and its unexpected omission in early recall. Although direct stimulation effects cannot be ruled out, 6 Hz ctACS-related increases in activation in visual regions during extinction training may indicate enhanced attention to CS-related visual and/or contextual cues. Furthermore, 6 Hz ctACS facilitated the downregulation of brain regions involved in fear conditioning during recall, potentially reducing spontaneous recovery. Future studies are warranted to further evaluate whether enhancement of cerebellar theta oscillations can help to stabilize extinction effects and therefore support exposure therapy.