The Cerebellum

Background: Spinocerebellar ataxia type 3 (SCA3) presents with significant clinical heterogeneity. Traditional case-control neuroimaging, based on group means, obscures inter-individual anatomical variability, hindering the identification of stratification biomarkers for interventions like Transcranial Magnetic Stimulation (TMS). Methods: To quantify individual neuroanatomical deviations, we constructed a cerebellar normative model using a multi-center dataset of 2,071 healthy controls with 2,549 MRI scans. Gray matter volume deviations (Z-scores) were mapped across 27 cerebellar lobules in 114 genetically confirmed SCA3 patients, and unsupervised clustering was applied to identify neuroanatomical biotypes. Clinical relevance was assessed by associating biotypes with ataxia severity and deep TMS (dTMS) outcomes in a longitudinal subset . Results: We identified two distinct biotypes: Biotype 1 exhibited relative structural preservation (positive deviations) predominantly in the posterior cerebellum (lobules VIIB, VIIIA), whereas Biotype 2 was characterized by extensive atrophy (negative deviations) centered on the anterior motor cerebellum (lobules I-VI). Clinically, Biotype 2 patients presented with significantly more severe baseline ataxia. However, regarding treatment response, an inverse relationship was observed: Biotype 2 patients demonstrated significantly greater symptomatic improvement following dTMS compared to Biotype 1. To further identify the optimal neuromodulatory strategy for each biotype, we compared the therapeutic efficacy of repetitive TMS (rTMS) and dTMS. While both biotypes showed clinical improvement following rTMS, Biotype 1 exhibited a superior therapeutic response to rTMS relative to dTMS. Furthermore, feature weight analysis identified atrophy of the right lobule VIIB as a critical predictor of clinical severity in Biotype 2. Conclusion: This study demonstrates that normative modeling can decode SCA3 heterogeneity. The identification of these biotypes reveals a dissociation between baseline structural integrity and neuromodulatory responsiveness, suggesting that patients with severe anterior cerebellar atrophy may, counterintuitively, derive greater therapeutic benefit from dTMS. Furthermore, by comparing the therapeutic efficacy of rTMS and dTMS, we further clarified biotype-specific treatment responses. These findings support the use of individualized neuroanatomical mapping for patient stratification in precision medicine.

While evidence suggests magnocellular deficits in the geniculostriate pathway in adults with dyslexia, neural deficits in the subcortical pathways during childhood remain unclear. Here, we used high-resolution fMRI to investigate subcortical abnormalities in Chinese children with developmental dyslexia. Fast achromatic motion stimuli and slowly drifting chromatic gratings were used to assess magnocellular (M) and parvocellular (P) functions, respectively. Relative to controls, children with dyslexia showed a selective reduction in responses to the M stimulus in the ventromedial pulvinar (vmPul) and the superficial layers of the superior colliculus (SCs), along with significantly reduced SCs-vmPul connectivity. Importantly, while vmPul responses to the M stimulus were positively associated with reading skills in healthy controls, this correlation was absent in children with dyslexia. Unlike previous findings in adults, the lateral geniculate nucleus (LGN) exhibited a non-selective reduction in responses to both stimuli, no volume reduction, and no correlation with reading ability. These findings demonstrate a selective deficit to achromatic motion processing in the colliculus-pulvinar pathway in children with dyslexia, which contributes to their reading difficulties. This early subcortical disruption differs from, and precedes, the neural deficits previously reported in the adult LGN, offering new insight into the developmental trajectory of dyslexia.

Background Chemotherapy-related cognitive impairment is a well-documented concern among cancer survivors, yet the neural mechanisms underlying deficits in cognitive control remain poorly understood. This study examined group differences in brain activation during a flanker task using functional MRI (fMRI) between chemotherapy-exposed participants and healthy controls. Methods Participants (21 survivors (24.9 years old; 71.4 % female; 15 years from diagnosis) and 21 healthy controls (26.7 years old; 61.9 % female) completed a flanker task during fMRI, with congruent and incongruent conditions. Reaction time, accuracy, and Flanker scores were collected. Whole-brain group comparisons were performed for congruent, incongruent, and incongruent > congruent contrasts. Associations between the incongruent > congruent contrast and cognitive performance were examined. Results Compared to controls, the Chemo group had longer reaction times in both congruent and incongruent conditions (p < .001) and lower NIH Flanker scores (p = .01), with no differences in accuracy. They showed reduced activation in the bilateral inferior frontal gyri, supplementary motor area, and bilateral caudate, but greater activation in the right inferior temporal and cerebellar regions. The incongruent > congruent contrast correlated with increased activation in the orbitofrontal cortex, inferior temporal gyri, and fusiform gyrus with cognitive performance. Conclusions Chemotherapy-exposed participants showed cognitive control deficits and altered neural activation during a flanker task, indicating disrupted recruitment of frontoparietal and subcortical regions key for conflict processing. These findings improve understanding of neural causes of chemotherapy-related cognitive impairment and may help identify at-risk survivors and guide personalized rehabilitation.

Background: The hydrodynamic model of hydrocephalus proposes that ventriculomegaly is driven by exaggerated intraventricular pulsations rather than impaired CSF circulation alone. Under this model, endoscopic third ventriculostomy with choroid plexus cauterization (ETV/CPC) treats hydrocephalus by creating a pulsation absorber and by reducing a primary source of intraventricular pulsation. However, direct intraoperative human evidence supporting this two-step mechanism is lacking. This study aimed to test the hypothesis that ETV followed by CPC would produce measurable, stepwise decreases in mean intraventricular pressure (ICP) and pulsation amplitude in infants with hydrocephalus. Methods: This single-institution proof-of-concept study included infants with symptomatic hydrocephalus undergoing ETV/CPC as the first definitive treatment. A fiber-optic ICP sensor was attached to the operative ventriculoscope and passively recorded mean and pulsatile ICP (pulsation amplitude) throughout the procedure. Longitudinal brain parenchymal volume (BPV) and cerebrospinal fluid volume (CSFV) were obtained through segmentation of clinically acquired T2-weighted MRI and converted to age- and sex-matched z-scores. All patients were followed for a minimum of 6 months postoperatively. Results: Five infants (median corrected age at ETV/CPC 8 months) were included. No surgical complications occurred, and no ETV/CPC failures were observed during follow-up. Overall, mean ICP decreased by 56-97% after the combined procedure in four patients. In three patients (Patients 1, 3, and 5), both mean ICP and pulsation amplitude decreased stepwise following ETV and then CPC, consistent with the hypothesized therapeutic mechanism. Patient 4 demonstrated a large reduction in mean ICP after ETV with minimal additional effect from CPC and no significant change in pulsation amplitude. Patient 2 demonstrated neither a reduction in mean ICP nor a meaningful change in pulsation amplitude after either procedure; this patient also had a delayed and atypical clinical response. Intracranial segmentation demonstrated BPV z-score stabilization within normal range and CSFV plateau in all patients after surgery. Conclusions: This proof-of-concept study provides the first direct intraoperative human evidence supporting the hydrodynamic mechanism of ETV/CPC in a subset of infant with hydrocephalus. Our findings suggest that determination of intraoperative ICP parameters is feasible, safe and might ultimately prove helpful in improving patient selection for ETV/CPC, warranting further investigation in larger cohorts.

It has been demonstrated that people who stutter exhibit atypical motor control not only in speech tasks but also movements in the non-speech effector system, such as finger or arm motion. Notably, studies have reported that people who stutter show limited sensorimotor adaptation (i.e., updating subsequent movements in response to sensory errors) in both speech auditory-motor (i.e., updating speech movements in response to altered auditory feedback) and upper limb visuo-motor (i.e., updating arm movements in response to altered visual feedback) tasks. Given that speech auditory-motor adaptation is mostly if not entirely implicit (i.e., participants are unaware of the learning), it is thought that people who stutter have limited implicit adaptation in the speech effector system. It remains unclear however, whether such limited implicit learning also extends to upper limb visuomotor adaptation. Here, we examined implicit visuomotor learning in adults who stutter through the means of arm reaching adaptation to clamped visual feedback which provides a cursor that is fixed in direction (8{degrees} counterclockwise from targets) regardless of the participants actual hand location. All participants gradually adjusted their reach angle towards the clockwise direction, adapting in response to clamped feedback, but adults who stutter showed less adaptation compared to adults who do not stutter. In addition, computational modeling suggests that this implicit adaptation difficulties in stuttering individuals may reflect reduced error sensitivity. Together, our findings suggest that implicit sensorimotor learning difficulties in adults who stutter may generalize across multiple effector systems, providing important implications for understanding sensorimotor mechanisms underlying stuttering. Significance statementBy employing the clamped visual feedback paradigm during arm reaching movements, we demonstrated that adults who stutter showed less implicit visuomotor adaptation compared to adults who do not stutter. This study provides the first evidence that implicit sensorimotor adaptation limitations in developmental stuttering generalize across multiple effector systems. Our findings not only add to a growing body of evidence that stuttering is associated with domain-general sensorimotor difficulties but also point to specific underlying processes that may lead to stuttering.

Background: Motor sequence learning (MSL) underlies the acquisition of everyday skilled movements, and transcranial direct current stimulation (tDCS) has shown promise for enhancing it, although reported effects vary considerably. Before such interventions can be applied and interpreted reliably, the behavioural and neural signatures of the underlying task should be shown to be robust. This study therefore characterised an fMRI-based Serial Reaction Time Task (SRTT) protocol and evaluated the consistency of its behavioural and fMRI-based neural signatures in repeated measurements to identify potential network targets for tDCS. Methods: Twenty healthy young- to middle-aged adults (10 females; mean age 24, SD 4) performed the SRTT during 3T fMRI in two sessions about one week apart, each using one of two matched, non-overlapping task versions in counterbalanced order. We examined block-wise behaviour, task-related and sequence-specific brain activation (general task activation relative to baseline and the SEQ > RND contrast), and functional connectivity using two complementary approaches: the task and temporal dynamics of seed-based connectivity (SBC) within an a priori defined motor network (M1, SMA, PMC, putamen, and cerebellum), and whole brain generalised psychophysiological interaction (gPPI) for the SEQ > RND contrast. Results: Reaction time decreased steadily across sequence blocks and returned toward baseline during random blocks, confirming implicit sequence learning; this pattern was consistent across both sessions and both task versions. Test retest reliability was excellent for random-block reaction time (ICC = 80 to .85), and modest for sequence blocks (ICC = .29 to.53). General task activation (sequence and random performance relative to baseline) engaged the expected sensorimotor network, including the primary motor cortex (M1), premotor cortex, and SMA, with M1 more strongly engaged during sequence than random blocks. The sequence-specific contrast (SEQ > RND) additionally revealed six clusters spanning the left superior parietal cortex, bilateral supplementary and cingulate motor areas, bilateral secondary somatosensory cortex, and left ventral visual cortex together with cerebellar Crus I. The a priori defined motor network was engaged across all task phases and was anchored throughout by strong M1 to SMA coupling, with overall network coupling following a non-monotonic course across the session, consistent with successive stages of resource allocation, consolidation, and automatisation. The gPPI analysis identified four sequence-specific connectivity clusters, dominated by a right-lateralised visuomotor network and a somatosensory visual integration channel. Conclusions: Together, these findings indicate a two-component architecture for SRTT performance: a left hemispheric cortico striato cerebellar network that supports performance and acquisition of the sequence, and a right hemispheric network associated with monitoring its predictable structure. Within this protocol, the SRTT produced robust and stable group-level signatures of implicit motor learning, yielding well-defined network targets for future tDCS interventions..

Objective: Working memory (WM) deficits are a co-occurring feature to numerous neuropsychiatric disorders, particularly attention-deficit/hyperactivity disorder (ADHD), and there remain no treatments that directly target WM. The coupling between the phase of theta band activity and amplitude of gamma band activity (i.e., TGC) is an established neural correlate of WM. However, no studies have examined WM-related TGC in ADHD or whether neuromodulation can modulate these oscillatory dynamics in youth. This set of studies examined the effects of intermittent theta burst stimulation (iTBS) to the left dorsolateral prefrontal cortex (DLPFC) and left posterior parietal cortex (PPC) on TGC in youth with ADHD. Methods: In two randomized, double-blind, sham-controlled crossover trials, adolescents with ADHD and clinically significant parent-reported WM symptoms first completed a single-session study comparing DLPFC versus PPC iTBS targeting (n = 47) and then a multi-session clinical trial comparing 10 sessions of active versus sham left DLPFC iTBS (n = 29). Participants completed a computerized visuospatial Sternberg WM task with concurrent electroencephalography (EEG) before and after the single sessions, as well as at baseline, midway through treatment, and approximately 24 hours after the final session within the multi-session trial. Phase-amplitude coupling between theta phase and gamma amplitude was quantified using the Kullback Leibler modulation index at frontoparietal electrodes. Linear mixed-effects models examined treatment effects and associations between change in TGC and WM status (including accuracy, reaction time, and clinical symptoms). Results: Across participants, lower TGC was associated with lower symptoms and better WM performance, including higher accuracy, faster and more consistent RT. Active iTBS increased frontoparietal TGC relative to sham stimulation, with effects observed both acutely after a single session and ~24 hours after multiple sessions. DLPFC-targeted iTBS increased TGC, whereas PPC-iTBS had no measurable effect. Change in TGC was associated with change in WM, such that a decrease in TGC was associated with faster RT and decreased RT variability. Higher baseline TGC was associated with greater improvement in WM. Active iTBS decoupled the TGC-WM association observed during sham iTBS, and greater electric field intensity of iTBS was associated with greater improvement in WM accuracy and greater decrease in TGC. Conclusions: Active iTBS to the left DLPFC modulated WM-related TGC in youth with ADHD. These findings provide preliminary evidence that neuromodulation may improve WW by modifying oscillatory dynamics within frontoparietal networks. Larger clinical trials with higher stimulation doses are needed to determine whether targeting oscillatory coupling represents a potential therapeutic strategy for WM deficits.

Objective: Aftereffects of 1 Hz repetitive transcranial magnetic stimulation (rTMS) often differ within and between subjects and thus show low reliability. In this study we investigated the mean and individual aftereffects of 1 Hz rTMS using two opposing current directions, their reliability and potential influences of current direction, participants' sex and state on cortical excitability modulations. Methods: Thirteen healthy, right-handed participants underwent four experimental sessions separated by at least 7 days receiving 2000 pulses of suprathreshold 1 Hz rTMS over the primary motor cortex per session. Two sessions were conducted with an induced current direction of anterior-posterior - posterior-anterior (AP-PA) and two sessions with a PA-AP current direction. Before and after rTMS, 100 single TMS pulses were administered with the respective current direction and electromyography was recorded from the first dorsal interosseous. Questionnaires on demographic data and subjective ratings were completed during the experiment. Results: Linear mixed effect model analysis revealed that 1 Hz rTMS induced an excitatory aftereffect when applied with the PA-AP current direction, and no aftereffect with AP-PA. There was a substantial interindividual variability with only three subjects showing an inhibition to 1 Hz rTMS overall. Also, current direction was the only predictor of rTMS aftereffect. Reliability values of these aftereffects were in the poor to moderate range. Conclusions: Current direction plays a crucial role in determining 1 Hz rTMS aftereffects. Reliability was found to be moderate at best. Additional to current direction, more factors need to be considered to tailor the 1 Hz rTMS aftereffects individually.

Contextual word learning is a fundamental mechanism for vocabulary acquisition during childhood. In adults, successful inference of word meaning from context is intrinsically rewarding, and is associated with greater enjoyment and greater activity in reward-related brain regions. Whether similar reward mechanisms support word learning in children, and whether they differ as a function of ability, remains unknown. We used functional magnetic resonance imaging (fMRI) to examine neural responses during contextual word learning in 25 children aged 11-13 years with typical reading skills and in 20 age-matched children with dyslexia. Neurotypical readers showed enhanced activation in core reward-processing regions, including the ventral striatum, when successfully learning the meanings of novel words. In contrast, children with dyslexia did not exhibit comparable reward-related responses despite performing the same task. Crucially, this group difference was specific to word learning, as no significant group differences were observed in ventral striatal responses during a non-linguistic monetary reward task. In addition, to confirm the behavioural relevance of these neural findings, we examined an age-matched, independent sample of children. We found that stronger reading skills were associated with greater enjoyment during successful word learning. Together, these results suggest that interactions between reward and language systems during contextual word learning is influenced by reading proficiency. Reduced intrinsic reward responses to successful language learning may contribute to differences in reading development and have implications for the design of more engaging and effective reading interventions for struggling readers.

Introduction: Autism spectrum disorder, or autism, is a common neurodevelopmental condition characterized by socio-communicative problems together with restrictive and repetitive behaviors. Typically, the latter is manifested as deficits in behavioral flexibility, i.e. changing routine behaviors to adapt to environmental changes. Despite noticeable difficulties with flexible behavior in autism, there is to date not adequate knowledge about the intricacies of such challenges and neurobiological processes that may subserve them. This study aims to investigate both cognitive and motor flexibility in autistic compared with neurotypical adults using a novel combination of detailed methods for brain imaging and behavioral investigations in relation to probabilistic reversal learning (PRL) paradigms. In addition, the experiences of autistic adults on flexible behavior in education and everyday activities will be explored. Methods and analysis: Differences in cognitive flexibility between autistic (n[&ge;]20) and neurotypical (n[&ge;]20) adults (18-35 years) will be investigated in terms of brain activations, measured by functional magnetic resonance imaging (fMRI), during two-choice PRL performance (cognitive task). In addition, group differences in microcirculation as measured by arterial spin labelling (ASL) will be evaluated. Group differences in motor flexibility will be investigated as expressed in movement planning and execution (spatio-temporal parameters), measured by a robotic manipulandum platform (KinArm End-Point Robot), during two-choice PRL performance (motor task). Semi-structured interviews will be conducted individually with autistic participants (n=15). Questions concern own experiences of cognitive and motor behavior, and strategies used to support flexibility in these behaviors. Data from this qualitative approach will be analyzed by thematic analysis. Ethics and dissemination: Ethical approval has been obtained from the Swedish Ethical Review Authority (ref:2025-07939-01) and the study will be conducted in accordance with the Declaration of Helsinki, the European Union General Data Protection Regulation (GDPR) and national guidelines for the storing of personal data. The different investigations included are well-established, non-invasive and safe. Study outcomes will be published in peer-reviewed international scientific journals (open access), presented at national and international conferences, and to any interested audience/stakeholders.

Hereditary spastic paraplegia type 7 (SPG7) is a neurodegenerative disorder characterized by progressive motor impairment and cerebellar dysfunction. Mutations in the SPG7 gene, encoding the mitochondrial metalloprotease paraplegin, disrupt mitochondrial homeostasis and lead to neuronal vulnerability and deficits in motor coordination. Recent studies have identified defective flickering of the mitochondrial permeability transition pore (mPTP) in SPG7 models, suggesting that altered pore dynamics may represent a functional biomarker of mitochondrial dysfunction. Here, we investigated whether pharmacological modulation of mPTP activity could improve mitochondrial function and motor performance in SPG7 models. Mitochondrial flickering was assessed in vitro, while motor behavior was evaluated in vivo following chronic treatment with berberine, a natural isoquinoline alkaloid known to modulate mitochondrial bioenergetics. Spg7-/- mice and age-matched Spg7+/ littermate controls received daily oral berberine administration for several weeks, and motor coordination was assessed using the accelerating rotarod test. Untreated Spg7-/- mice exhibited reduced rotarod performance compared with controls, indicating impaired motor coordination. Berberine treatment significantly improved motor performance in pre-symptomatic mutant mice. These findings indicate that pharmacological modulation of mitochondrial permeability transition pore dynamics can ameliorate motor dysfunction associated with SPG7 deficiency and highlight mPTP flickering as a functional readout of mitochondrial health.

Aphasia diagnosis in Indonesia remains challenging due to limited culturally and linguistically appropriate instruments. Widely used tools such as the Boston Diagnostic Aphasia Examination (BDAE) and Western Aphasia Battery (WAB) are not adapted to the Indonesian context, while Tes Afasia untuk Diagnosis, Informasi, dan Rehabilitasi (TADIR) provides screening but lacks diagnostic accuracy. To address this gap, we developed the Instrumen Diagnosis dan Evaluasi Afasia (IDEA) for native Indonesian speakers and evaluated its validity, reliability, and normative cutoff values in cognitively healthy Indonesian adults. Eighty-three cognitively normal adults (screened using MoCA-Ina) with no history of neurological disease were assessed using IDEA, which evaluates six language domains. Items were adapted from existing tools and reviewed by experts. Content validity, internal consistency (Cronbachs alpha), and construct validity (Exploratory Factor Analysis) were analyzed using SPSS v25. A total of 83 participants were included (median age = 55.81 years, 54% secondary education). IDEA demonstrated good feasibility, with an average completion time of 45-60 minutes depending on participant engagement. Content validity was established by unanimous expert consensus. Construct validity showed meritorious sampling adequacy (KMO = .872) and significant sphericity (Bartletts test {chi}^2 (15) = 278.523, p<.001), supporting factor analysis. Internal consistency showed good reliability across six domains (Cronbachs = 0.896). IDEA is a valid and reliable tool for assessing aphasia in Indonesian natives. It is a culturally appropriate assessment tool which offers structured, domain-based evaluation and supports differential diagnosis of both classical and progressive aphasia syndromes. Keywords: Aphasia, Language Assessment, Indonesian, IDEA, Validity

Multimodal imaging approaches that combine structural and functional neuroimaging provide a robust framework for examining neuroplastic adaptations that may not be captured by any single modality. The present study investigated the effects of a four-week expiratory muscle strength training (EMST) program on structural and resting-state functional connectivity in healthy young adults. Five healthy young adult males (aged 19-35 years) completed a standard four-week EMST protocol and underwent pre- and post-training imaging assessments. Structural neuroimaging included T1-weighted and diffusion-weighted MRI, which were analyzed using voxel-based morphometry, surface-based morphometry, and white-matter structural connectivity. Functional neuroimaging consisted of resting-state fMRI to assess training-related changes in functional architecture, network connectivity, and global network measures. Structural MRI analyses revealed no significant changes in gray or white matter volume, cortical morphology, or white-matter structural connectivity following EMST (all FWE- or FDR-corrected p > .05). In contrast, resting-state fMRI demonstrated a significant increase in whole-brain functional connectivity (FDR-corrected p = .036), accompanied by greater network integration, reflected in increased local efficiency and transitivity and reduced modularity. Network-level analyses showed enhanced within- and between-network connectivity in sensorimotor and cognitive circuits. Our findings demonstrate robust functional reorganization following EMST, despite the absence of detectable macrostructural or large-scale white-matter connectivity changes, at least within the timescale and sample characteristics of the current study. These results reflect early-stage neuroplasticity, both globally and within the networks underlying speech and swallowing control and suggest that functional reorganization occurs early in training and likely precedes longer-term structural modifications in these networks.

Objective: Pediatric epilepsy patients undergoing stereo-electroencephalography (sEEG) for ictal onset evaluation provide a rare window to study the developing brain. While methodological frameworks for task-based sEEG research are well-established in adults, pediatric-specific guidance remains underdeveloped. Furthermore, many pediatric epilepsy patients have comorbidities that might typically exclude them from participating in research. We examine factors that influence research participation and discuss considerations for conducting sEEG research in children. Methods: Here, we present a retrospective analysis of task-based research participation patterns from an NIH-funded study of speech and language representations (1R01DC018579) in 66 patients (ages 4-24) undergoing sEEG monitoring at Texas Children's Hospital to determine whether specific comorbidities influenced research participation. Results: Eighty-nine percent (n=66) of patients approached for consent agreed to participate in the study. Despite high rates of comorbidities including neurocognitive disorder (66.67%), language delay (31.75%), global developmental delay (23.81%), mood disorders (33.33%), ADHD (46.03%), autism spectrum disorder (14.29%) or other cognitive/intellectual disabilities (36.51%), all participants engaged in at least one task. While the majority of these diagnoses did not appear to influence subject participation, global developmental delay was associated with a significant reduction in time spent on active tasks. Discussion: Despite high prevalence of neuropsychological comorbidities among participants, our evidence suggests that these participants contribute meaningfully to studies investigating important developmental questions. We suggest strategies for tailoring task-based research to accommodate the unique needs of individuals in this population. Such practices are important for ensuring that research studies reflect the true diversity of the population.

Background and Purpose-Aneurysmal subarachnoid hemorrhage (aSAH) remains a devastating cerebrovascular event, with delayed cerebral ischemia (DCI) representing its most feared complication. High-altitude environments induce profound cerebrovascular adaptations, yet no study has systematically examined aSAH outcomes in chronically hypoxic populations. We characterized clinical features and identified DCI predictors among aSAH patients on the Tibetan Plateau. Methods-This single-center retrospective cohort included 256 consecutive aSAH patients admitted at a tertiary neurosurgical center in Tibet (altitude 2,330-4,920 m) between 2013 and 2015. The primary outcome was DCI per consensus criteria. Multivariable logistic regression identified independent predictors; receiver operating characteristic analysis evaluated model performance. Altitude and hemoglobin were specifically evaluated as altitude-related risk factors. Results-DCI occurred in 26 patients (10.2%). In-hospital mortality was 1.6%. Most patients presented with good-grade aSAH (Hunt-Hess I-II, 73.0%; Fisher I-II, 73.1%). On multivariable analysis, only Fisher grade independently predicted DCI (odds ratio, 3.63 [95% CI, 1.14-11.52]; P=0.029). Neither altitude (P=0.697) nor hemoglobin concentration (P=0.858) was associated with DCI risk. The predictive model achieved an area under the curve of 0.812. At 1-year follow-up, 77.8% achieved favorable functional outcomes (modified Rankin Scale 0-2). Conclusions-Fisher grade is the sole independent predictor of DCI in high-altitude aSAH patients, while chronic hypoxia and compensatory hemoglobin elevation do not significantly modify DCI risk. Established sea-level prognostic frameworks remain valid in high-altitude settings, supporting their continued use for clinical risk stratification. Keywords: aneurysmal subarachnoid hemorrhage; high altitude; delayed cerebral ischemia; Fisher grade; Tibetan Plateau; prognosis

Accumulating evidence suggests alterations in neurocognitive, affective, interoceptive and autonomic processing in functional neurological disorder (FND), yet interventions targeting these processes remain underexplored. This study investigated the possible immediate and longer-term effects of a somatic yoga intervention on cognitive control, emotion regulation, state dissociation and affect, autonomic arousal, and interoceptive processing in FND. Twenty-three adults with FND completed six weeks of somatic yoga (N=12) or six weeks of a music-based relaxation control (N=11). At baseline, post-single session, and post-six weeks, participants completed laboratory measures of sustained attention, response inhibition, interoception, emotion regulation, and state dissociation and affect. Electrocardiography and galvanic skin conductance were recorded throughout. Linear mixed effects models assessed potential change on day one, immediately pre/post a single session, and from day 1 to the end of the six-week programme. After one session, stop signal reaction time, negative affect, and heartrate decreased in both groups ({Delta}=.69-.75). After one session and at six weeks, improved sustained attention, elevated positive affect, and reduced dissociation were seen in both groups, with a larger magnitude of change in yoga ({Delta}=.50-1.10). The yoga group exhibited fewer direction errors on the response inhibition task and shorter response times on the sustained attention task, with the opposite seen in the music group ({Delta}=.50-1.17). Both in the short- and longer-term, somatic yoga might lead to adaptive changes in attention and executive functioning, arousal, state affect and dissociation.

Dravet syndrome is a severe epileptic encephalopathy caused by SCN1A haploinsufficiency, which leads to reduced NaV1.1 expression in parvalbumin (PV)-expressing interneurons and disrupted excitatory-inhibitory balance in the brain. We developed an AAV-based CRISPR activation system (AAV9-E2-dCas9-VP64) to selectively upregulate SCN1A from its endogenous locus in PV interneurons. An in vitro saturating guide RNA (gRNA) screen across the human SCN1A promoter identified a lead guide with robust and highly specific engagement of the SCN1A locus. This lead gRNA was validated in human Dravet syndrome model GABAergic neurons, where dose-dependent and specific SCN1A upregulation was observed. Intracerebroventricular (ICV) administration in a mouse model of Dravet syndrome produced dose-dependent improvement in survival as well as reduced susceptibility to hyperthermia-induced seizures and increased NaV1.1 protein expression, with maintained PV interneuron selectivity and minimal off-target expression. In a study in juvenile cynomolgus macaques, MRI-guided ICV administration of the vector was well tolerated, achieved broad cortical biodistribution, and maintained strong detargeting of peripheral tissues, with substantially lower peripheral dCas9 expression relative to the brain. These results support PV interneuron-selective SCN1A gene modulation via CRISPR activation as a promising therapeutic strategy for Dravet syndrome. AAV9-E2-dCas9-VP64 (RT101) is currently in preclinical development and is being advanced toward evaluation in the clinic.

Transcranial photobiomodulation (PBM) is an emerging non-invasive brain stimulation method that is thought to increase neural metabolism by stimulating ATP production by the mitochondria. However, the mechanisms of action and the effects on the human brain are still unclear. In the present study, we investigated the potential of this method to enhance Blood Oxygen Level Dependent (BOLD) responses during the execution of a motor task in young and aged participants. Sixty young and aged participants were included in this single-blinded, sham-controlled, randomised, crossover study. They underwent an fMRI recording before and after 24-min stimulation with a 80-LEDs helmet emitting transcranially red and near infrared light. Post vs Pre BOLD signal was compared between PBM and SHAM, in each group. At baseline, aged participants showed reduced BOLD signal compared to young ones, in key regions of the sensorimotor processing, principally the left primary motor cortex and striatum. Transcranial PBM did not have a real impact in the young group. However in aged participants it increased BOLD signal in some regions that were underactivated compared to the young group at baseline. In particular, regional analysis showed increased BOLD response in the left primary motor cortex, and right dorsal and ventral premotor regions and striatum. These results suggest that transcranial PBM can increase fMRI BOLD activity in the task-related regions, particularly in aged subjects. Further research are needed to distinguish neural from vascular effects in transcranial PBM.

Background: Down syndrome (DS) is associated with persistent language and cognitive impairments and with abnormalities in cortical oscillatory activity, including in the gamma range. Transcranial photobiomodulation (tPBM) is a noninvasive neuromodulatory intervention with potential benefits for cortical physiology, language, and cognition. Methods: We conducted a pilot randomized, double-blind, sham-controlled trial of repeated 40-Hz near-infrared tPBM in adolescents and young adults with DS. Fourteen participants were randomized 1:1 to active tPBM or sham and received 18 sessions over 6 weeks, followed by short-term and long-term follow-up. Outcomes included resting-state EEG gamma power, connected-speech measures, language and cognitive indices, and selected computerized tasks. Results: Active tPBM did not significantly increase global resting-state EEG gamma power relative to sham at either follow-up. Pre-registered analyses did not show broad treatment benefit across outcomes, although they did identify a significant short-term advantage for active tPBM on grammatical morpheme accuracy in connected speech; in contrast, picture naming favored sham at long-term follow-up. Exploratory mechanistic analyses did not show a robust biological treatment signal. Both active and sham procedures were well tolerated, with no serious adverse events. Conclusions: In this underpowered pilot sample, 6 weeks of 40-Hz near-infrared tPBM--delivered unilaterally, at low power, on target areas--did not demonstrate a meaningful effect size in DS. A dose-finding study for tPBM in DS, also accounting for age of participants, is recommended.

Sensorimotor adaptation is a motor learning process that contributes to movement flexibility and is thought to arise from the interaction of fast and slow adaptive processes. Evidence suggests that declarative memory contributes to adaptation through its influence on the fast process. Although adaptation deficits are common following stroke, the mechanisms underlying these deficits remain unclear. This study investigated differences in locomotor adaptation rate and forgetting between individuals with chronic stroke and age-matched controls and examined how these measures were associated with immediate declarative memory performance. Individuals with chronic stroke (n = 23) and age- and education-matched controls (n = 21) completed four 4-minute bouts of split-belt treadmill adaptation separated by rest breaks. Adaptation rate, adaptation magnitude, and forgetting were quantified from exponential fits to normalized step-length asymmetry data. Immediate declarative memory was quantified using the Repeatable Battery for the Assessment of Neuropsychological Status, and associations between adaptation measures and immediate declarative memory were evaluated using robust linear regression. Participants with stroke adapted less (p = 0.001) and more slowly (p = 0.039) than controls during early adaptation and forgot less of the adapted behavior during the first rest break (p = 0.024). Notably, poorer immediate declarative memory performance was associated with reduced forgetting during the initial rest break, irrespective of group assignment (p = 0.035). This relationship supports the hypothesis that declarative memory contributes to adaptation through a cognitively mediated fast process. These findings suggest that cognitive impairment contributes to altered adaptation following stroke and highlight the importance of considering cognitive factors when investigating motor learning mechanisms and rehabilitation outcomes in neurological populations.