Rett syndrome is a neurodevelopmental disorder caused by an X-linked mutation of the MeCP2 gene. Individuals with Rett syndrome, as well as rodent models of this disorder, demonstrate abnormal cortical responses to sound, which impair auditory discrimination ability. Vagus nerve stimulation (VNS) paired with tones has been shown to drive robust changes in the auditory cortex physiology of Mecp2+/- rats and has the potential to improve the communication abilities of individuals with Rett syndrome. The aim of this study was to describe the proteomic differences present in the auditory cortex of the Mecp2+/- rat model of Rett syndrome, as well as the molecular effect of VNS paired with tones. This study used global proteomic analysis of auditory cortex tissue taken from Mecp2+/- rats exposed to VNS paired with tones compared to untreated Mecp2+/- rats and wild-type (WT) littermate controls with no VNS exposure. Our results demonstrate dysregulation of mitochondrial and synaptic proteins in the Mecp2+/- rat auditory cortex. In addition, we show that VNS-tone pairing induces significant alterations to the auditory cortex proteome of Mecp2+/- rats by changing the expression of proteins involved in regulating synaptic vesicles and synaptic transmission. This work provides evidence of key mechanisms that may drive auditory processing dysfunction in Rett syndrome and demonstrates that VNS-tone pairing is sufficient to alter protein expression in the auditory cortex.
Depression is a common comorbidity of chronic pain. Gonadotropin-releasing hormone (GnRH) and its receptor (GnRHR) expressed in the central nervous system are involved in non-reproductive functions. Herein, we aimed to elucidate the role and mechanism of action of GnRH in pain-related depression like behaviour in a mouse model. And we found that both GnRH and GnRHR were down-regulated in the anterior cingulate cortex of mice that were subjected to chronic pain-induced depression with complete Freund's adjuvant. Specifically, either systemic treatment with GnRH agonists or GnRH overexpression in the anterior cingulate cortex effectively ameliorated the chronic pain-induced depression-like behaviour via GnRHR signalling. Moreover, GnRHR co-localized with both excitatory and inhibitory neurons, and GnRH agonists or overexpressed GnRH rescued the complete Freund's adjuvant-stimulated imbalance of excitatory-inhibitory neurons in the anterior cingulate cortex. Chemogenetic activation of anterior cingulate cortex neurons reversed GnRH agonist-induced improvement in depression-like behaviour in complete Freund's adjuvant-treated mice. Furthermore, this specific role of GnRH was dependent on the activation of protein kinase C and Erb-B2 receptor tyrosine kinase 4 signalling pathway. Therefore, our findings indicate that GnRH/GnRHR is involved in the development of chronic pain-related depression, which may through rebalancing the excitatory-inhibitory neurons via the activation of protein kinase C/Erb-B2 receptor tyrosine kinase 4 pathway. Thus, GnRH could be a potential target for the treatment of chronic pain-related depression.
Parietal cortex is thought to support visually guided actions, but whether it contains distinct regions specialized for different actions-such as navigation, reaching, and grasping-remains unknown. Prior work implicates the superior parietal lobule (SPL) in navigation and the superior parietal occipital cortex (SPOC) in reaching and grasping, yet whether these are truly dissociable is unclear. We addressed this using fMRI in adults. Participants viewed four stimulus types: Dynamic Scenes (first-person motion through scenes), Static Scenes (static images from these movies), Contextual Reaching and Grasping (first-person reaching and grasping on a scene background), and Isolated Reaching and Grasping (reaching and grasping actions on a black background). A double dissociation emerged: SPL responded significantly more to Dynamic than Static Scenes-consistent with its role in visually-guided navigation-and, critically, more to Dynamic Scenes than either reaching and grasping condition. By contrast, SPOC responded significantly more to both reaching and grasping conditions than to either scene condition. Resting-state functional connectivity further supported this double dissociation: SPL showed stronger connectivity with "leg-motor" than "arm-motor" cortex, whereas SPOC showed the opposite pattern. These findings reveal two distinct parietal systems: SPL for visually-guided navigation and SPOC for visually-guided reaching and grasping-clarifying how the parietal cortex organizes visually guided action.
An estimated 30%-50% of male individuals with fragile X syndrome (FXS) meet criteria for autism spectrum disorder (ASD), indicating phenotypic overlap but potentially distinct neurobiology. Here, we aimed to characterize shared and divergent cortical features between FXS and ASD. High-resolution, motion-corrected quantitative MRI was used to compare cortical morphometry and relaxometry in 61 male participants (9-18 years) with FXS or ASD. To increase power, ASD participants were pooled from multiple MPnRAGE studies and harmonized across protocols using ComBat. Cortical thickness and R1 (longitudinal relaxation rate; proxy for myelination) were computed across the cerebral cortex. Relative to ASD, FXS exhibited greater cortical thickness predominantly in early sensory cortices implicated in low-level visual and auditory processing spanning occipital, parietal, and temporal regions. No significant group differences in R1 were found. Thicker cortex in FXS within primary and early associative sensory areas suggests divergent early sensory processing mechanisms between FXS and ASD. Characterizing different neuroanatomical features between the two disorders provides a grounding to develop more disorder-specific interventions despite similar behavioral difficulties. Future work should test developmental trajectories, include females and comorbidities, and link imaging markers to individual sensory/clinical profiles to inform and improve personalized therapies and interventions.
Adaptive behavior relies on the ability to translate abstract rules and goals into actions suited to the current context. Neural population activity in the prefrontal cortex (PFC) has been proposed to support such flexible computations through high-dimensional dynamics, whereas activity in the primary motor cortex (M1) is related more directly to movement execution. How contextual representations in PFC are transformed into ensuing action plans within M1 remains unknown. Previous work suggests that low-dimensional coding subspaces might organize interareal communication, but direct evidence for such population-level communication mechanisms in humans is lacking. Here we use intracranial recordings from human PFC and M1 to identify a communication subspace embedded within high-dimensional PFC activity, that selectively relays behaviorally relevant information at the single-trial level. Activity in this subspace predicts context-dependent action more strongly than either region, revealing a fundamental coding principle by which coordinated interareal population dynamics filter and relay predictive information to guide context-dependent actions.
Neuronal populations in primary visual cortex adapt both to stimulus contrast and to the probability of occurrence of visual patterns. Previous work showed that the magnitude of the population response follows a separable power-law function of contrast and stimulus probability, suggesting the existence of a shared gain mechanism. Here we ask whether a similar equivalence extends beyond response magnitude to the full distribution of activity across neurons within a trial. Across a wide range of adaptation states, we find that population responses are highly sparse and well described by a zero-inflated log-normal distribution. In this model, a fraction P0 of neurons remain silent, while the non-zero responses follow a log-normal distribution characterized by the mean (µ) and variance (σ2) of log activity. We find that both contrast and pattern adaptation produce coordinated changes in µ and P0 while leaving σ2 approximately invariant. As a result, responses across all adaptation conditions collapse onto a one-dimensional manifold in parameter space. A simple linear-nonlinear population model with fixed nonlinearity and input variance reproduces these observations when adaptation acts solely by modulating the mean input to the population. Together, these findings support the idea that contrast and pattern adaptation rely on a shared gain control mechanism that shifts the operating point of cortical populations while preserving the overall structure of their response distribution.
Autism spectrum disorder is a complex neurological and developmental disorder that is characterized by altered brain structures and interconnectivity, which results in a vast array of psychosocial and physiological irregularities. This is due to the complex genetic topography of autism and to the intersectionality of genetic and environmental factors that contribute to the development of this disorder. To better understand the genetic factors that cause autism, the gene linc00896, which encodes a long noncoding intergenic RNA, was biochemically and biologically analyzed primarily through circular dichroism, liquid chromatography, and mass spectrometry. From this analysis, it was determined that LINC00896 RNA has a vast interactome and that through this interactome, LINC00896 RNA influences numerous cellular processes that contribute to the symptoms of autistic patients. Additionally, the structural analysis of LINC00896 RNA indicated stable but flexible secondary and tertiary structures that support the numerous binding interactions identified in the interactome. Through these empirical findings, the linc00896 gene was identified as being an important genetic factor that contributes to the development of autism.
Fatigue is one of the most prevalent and debilitating symptoms in individuals with multiple sclerosis (MS). We recorded somatosensory high-frequency oscillatory (HFO) thalamocortical activity in a group of MS patients without history of optic neuritis (ON). Furthermore, we examined if, like what was previously observed in response to visual stimuli, patients exhibit diminished amplitude habituation, and whether this may further exacerbate fatigue in individuals with MS. Twenty patients diagnosed with relapsing-remitting MS were prospectively enrolled. The MS cohorts were compared with a cohort of 20 healthy volunteers (HV). Fatigue Severity Scale (FSS) was employed to evaluate the trait levels of reported fatigue. We assessed the N20 somatosensory evoked potentials (SSEPs) parameters and N20-P25 amplitude habituation, and, following the application of a band-pass filter (450-750 Hz), we evaluated electrophysiological parameters of pre- and post-synaptic HFOs. The latency and amplitude of the N20 SSEP and its habituation do not exhibit significant differences between MS patients and HVs. MS patients exhibited delayed latency of negative oscillatory maximum and reduced maximum peak-to-peak amplitude of the pre-synaptic HFOs (all p < 0.01). In patients, post-synaptic HFOs showed a significant delayed latency and a trend towards a reduction in the maximal peak-to-peak amplitude. The pre-synaptic HFO latency of the negative oscillatory maximum, reflecting thalamocortical activity, shows a correlation with the FSS in MS patients (r = 0.522, p = 0.018). No significant ophthalmological anomalies were identified. Our data revealed a significant reduction and slowing of somatosensory thalamocortical network activity in MS patients without history of ON. Furthermore, our findings showed that fatigue levels may be affected by slowed thalamocortical activity, but not by habituation of cortical responses. Our findings suggest a potential role of the thalamo-cortical network on the genesis of MS-related fatigue.
Intermittent theta burst stimulation (iTBS) targeting the dorsolateral prefrontal cortex (DLPFC) shows promise for enhancing cognitive performance. However, behavioral findings remain inconsistent, likely due to methodological limitations in prior research and the poorly understood role of individual variability in neural responsiveness. Only one prior study has utilized individualized targeting. The effects of iTBS on resting-state functional networks remain unexplored. We employed fMRI during an N-back task to identify individualized left DLPFC stimulation targets, based on the 2-back > 1-back contrast. A total of 56 healthy participants were randomly assigned to receive a single session of either active or sham iTBS (28 per group). Resting-state and task-based fMRI (2-back and 3-back) were acquired before and after stimulation. Compared to sham, iTBS increased neural activity in the middle cingulate cortex (MCC) and calcarine cortex during the 3-back task. Moreover, iTBS increased FC between the stimulation target and insula whilst reduced FCs within the default mode network (DMN) and between the DMN and frontoparietal network (FPN). Notably, in the iTBS group, greater MCC activation and enhanced target-insula FC were associated with faster 3-back reaction time (RT), whereas greater DMN FC reductions correlated with improved 3-back accuracy. Behaviorally, individuals with slower baseline 3-back RT in the iTBS group exhibited faster post-stimulation RT - an effect absent in the sham. These findings suggest that individualized iTBS modulates neural activity and distributed functional networks to support cognitive improvement - particularly in individuals with lower baseline ability - and highlight its potential for personalized cognitive interventions.
Aggression is a complex social behaviour observed in many animal species, including dogs, and remains a major global concern due to its serious implications for public safety and animal welfare. This study focuses on Pit Bull dogs, a breed frequently associated with severe aggression episodes in many countries, making them an appropriate model for investigating the neuroanatomical factors underlying canine aggression. To better understand its underlying mechanisms, this study investigated neuroanatomical and biochemical factors associated with aggression in Pit bulls. 14 dogs were selected for MRI analysis based on their aggression scores obtained through a aggression assesment survey derived from Canine Behavioral Assessment and Research Questionnaire. The dogs underwent MRI scans and blood and urine sampling and were divided into control and aggressive groups. MRI analyses focused on the prefrontal cortex, amygdala, and hippocampus. Biochemical analyses included serum or plasma levels of serotonin, dopamine, vasopressin, adrenaline, noradrenaline, testosterone, cortisol, and adrenocorticotropic hormone, along with urinary concentrations of their metabolites; metanephrine, vanillylmandelic acid, homovanillic acid, and 5-hydroxyindoleacetic acid. Results showed significantly decreased prefrontal cortex volumes and increased amygdala volumes in aggressive dogs compared to controls. Testosterone and dopamine levels were also significantly higher in the aggressive group. These findings suggest that structural alterations in key brain regions, combined with hormonal and neurotransmitter imbalances, may contribute to a maladaptive neurocognitive profile. Reduced top-down control by the prefrontal cortex may fail to inhibit exaggerated threat perception and emotional reactivity mediated by the amygdala, leading to aggressive behaviour in Pit bulls.
Narrative generation requires the integration of linguistic, social, and conceptual knowledge to transform internal representations into coherent discourse. Few studies have examined how the distinct stages of comprehension and production are supported by the brain. In this fMRI study, 27 participants viewed a nine-panel cartoon, planned a story, and then orally produced it during scanning. Story comprehension elicited greater activation than fixation within the default mode network (DMN), including medial prefrontal cortex, posterior cingulate cortex, and precuneus, as well as the right insula, regions implicated in situation model construction, emotional inference, and mental simulation. Story production engaged a broader bilateral network encompassing hippocampus, basal ganglia, right temporoparietal junction (TPJ), and left anterior temporal lobe (ATL), reflecting additional demands on lexical selection, memory retrieval, and social-cognitive processes. Exploratory regression analyses revealed that higher lexical diversity (Maas) was associated with reduced activation in the right inferior frontal gyrus during comprehension and increased activation in the precuneus. Regression analysis also showed that a measure of social cognition (TASIT) was associated with cerebellar activation, supporting its emerging role in mentalizing and social prediction. These findings demonstrate that narrative generation relies on dynamic interactions among DMN, language, and cerebellar systems, with comprehension and production sharing a common representational foundation but diverging in their linguistic, memory, and social-cognitive demands. Regression results highlight potential neural mechanisms linking individual differences in lexical and social processing to narrative performance.
This study aims to investigate the fatigue-attenuating effects of anodal high-definition transcranial direct current stimulation (HD-tDCS) on the forearm flexor muscles during isometric contractions and clarify whether these effects are mediated by enhanced corticomuscular coherence (CMC) in beta and gamma frequency bands. Twenty healthy young male participants underwent anodal HD-tDCS intervention on the contralateral motor cortex (left hemisphere) of the forearm flexor muscles at 2 mA for 20 min, prior to performing a 30% maximal voluntary contraction (MVC) isometric endurance task. This study employed a crossover sham-controlled design, with participants receiving either anodal stimulation (HD-tDCS) or sham stimulation prior to the task. During the task, electroencephalography (EEG) and surface electromyography (sEMG) of the forearm flexor muscles signals were recorded. CMC areas in EEG beta and gamma bands, as well as the frequency of the maximal peak of the coherence (Cohmax) in the beta and gamma bands, were calculated. The time to failure (TTF) was significantly greater in the anodal HD-tDCS group compared to the baseline and sham groups (P < 0.05). Subjective perception of fatigue assessed by the Borg Rating of Perceived Exertion (RPE) was also significantly lower in the anodal HD-tDCS group compared to the baseline and sham groups (P < 0.05). The anodal HD-tDCS group exhibited significantly higher beta-band (13-30 Hz) CMC during fatigue compared to both the baseline and sham groups (P < 0.05), especially in terms of the frequency of Cohmax in the beta band. There were no significant differences in gamma-band (31-50 Hz) CMC. Correlation analysis showed that TTF was negatively correlated with RPE (r=-0.58, P = 0.0073) and positively correlated with beta-band CMC area (r = 0.54, P = 0.015). Anodal HD-tDCS applied to the contralateral motor cortex (M1) can effectively prolong the TTF of the forearm flexor muscles and reduce perception of fatigue. This may be attributed to the enhancement of synchronized activity between the brain and muscles induced by anodal HD-tDCS, resulting in improved muscle function.
Following subarachnoid hemorrhage (SAH), long-lasting inflammation triggered by activated glial cells has adverse effects on neurological recovery. As an α2 adrenoceptor agonist commonly utilized for sedative purposes, dexmedetomidine (DEX) has demonstrated the ability to confer neuroprotective effects across diverse physiological or pathological conditions. This study was designed to determine whether DEX protects against SAH by altering astrocytic reactivity. Eight-week-old male C57BL/6 mice were subjected to experimental SAH. They were treated with DEX in the presence or absence of the α2 adrenoceptor antagonist atipamezole (ATI) via intraperitoneal injection. Neurological function was evaluated on the basis of a modified Garcia score and beam balance test. TUNEL staining was conducted to assess neuronal apoptosis. Western blotting was carried out to determine the expression of Bcl-2, Bax, and cleaved caspase-3 in the hippocampus and ZO-1 and occludin in the cortex, and ELISA was conducted to measure TNF-α, IL-6, IL-1β, and HMGB1 expression. The wet‒dry method was employed to measure the water content in the brain tissue. The permeability of the blood‒brain barrier (BBB) was assessed via Evans blue staining. Primary astrocytes were treated with S100A4 and/or DEX. The expression levels of GFAP, C3, GBP2, Serping 1, PTX3, S100A10, S100A4, and the NF-κB pathway were also determined. DEX improved early neurological deficits in SAH mice, mitigated the permeability of the BBB, and reduced the brain water content. DEX attenuated neuronal apoptosis and proinflammatory cytokine (TNF-α, IL-6, IL-1β and HMGB1) expression in the cortex. However, DEX-mediated protective effects were attenuated by ATI administration. Additionally, DEX attenuated GFAP, C3, Serping1, S100A4, and NF-κB pathway activation in the brain and in S100A4-treated primary astrocytes, whereas ATI reversed the effects of DEX. DEX has neuroprotective and anti-inflammatory effects in SAH through the inhibition of S100A4-mediated astrocytic "A1" polarization via the activation of the α2A adrenoceptor.
Obesity and binge eating disorder (BED) are global health concerns that share overlapping neural mechanisms. These include alterations in the brain's reward and control systems leading to heightened sensitivity to food cues and impaired self-regulation, which underpin overeating. Identifying neuroimaging-based biomarkers that index these mechanisms could advance individualised treatments. This scoping review examined evidence on fMRI food cue reactivity as a potential approach for developing predictive and response biomarkers relevant to the treatment of obesity and BED. A systematic search of MEDLINE, Scopus, PsycINFO, and Embase (to July 2025) identified 57 eligible studies incorporating fMRI cue reactivity measures in the context of pharmacological, surgical, psychological, and lifestyle interventions. Of these, 7 reported predictive outcomes only (6 for adults with obesity and 1 for children and adolescents with obesity), 41 reported response outcomes only (36 for adults with obesity, 3 for children and adolescents with obesity and 2 for adults with binge eating), and 9 reported both predictive and response outcomes (8 for adults with obesity and 1 for adults with binge eating). Across paradigms and intervention modalities, there was consistent involvement of reward (striatum, insula, orbitofrontal and ventromedial prefrontal cortex) and cognitive control regions (dorsolateral and dorsomedial prefrontal cortex) as response outcomes from successful treatment. Reductions in reward-system reactivity following interventions were consistently associated with improved clinical outcomes, supporting the potential of fMRI food cue reactivity as a candidate biomarker of treatment response. However, this finding is highly skewed towards obesity, given the limited number of studies that report results for BED (3 studies). Furthermore, consistent evidence for reliable predictive biomarkers was also limited, likely due to methodological variability and small sample sizes. Overall, this review supports the potential of response outcomes from fMRI food cue reactivity as an indicator of treatment efficacy in obesity and highlights the limited evidence in BED. We also emphasise the need for further standardisation of paradigms and biomarker validation efforts.
Focal cortical dysplasia (FCD) is a common neurodevelopmental disorder characterised by cortical malformations and is a major cause of drug-resistant epilepsy. FCD type I (FCDI) presents with architectural abnormalities of the neocortex but without cytological abnormalities. Currently, FCDI remains a significant clinical challenge. Epileptogenic cortical tissues from three FCDI patients and three relatively normal neocortical tissues as controls were analysed using single-nucleus RNA sequencing and spatial transcriptomic for multi-omics integration. This study constructed a single-cell spatial transcriptomic atlas of the epileptogenic cortex from FCDI patients. Excitatory neurons (ENs) and astrocytes (Ast) exhibited the most prominent alterations in FCDI. Hub genes associated with FCDI were identified in ENs, and a transcription factor (TF)‒hub gene regulatory network was constructed. Notably, CBLN2highEx-1 was identified as being potentially involved in processes related to neuronal hyperexcitability and cortical development in FCDI. Western blot and immunofluorescence assays validated the altered expression of selected key genes and TFs at the protein level. Additionally, Ast exhibited increased heterogeneity, impaired differentiation and a higher proportion of immature Ast in FCDI, with predicted TFs regulating this process. Further analysis revealed aberrant signalling pathways and ligand‒receptor interactions between ENs and Ast in FCDI, with spatial co-localisation patterns that may contribute to disease progression. This study highlights the specific dysregulation of ENs and Ast, along with aberrant cellular communication, which may play a critical role in the pathogenesis of FCDI. These findings provide novel insights into the molecular mechanisms underlying FCDI and offer potential therapeutic targets for precision treatment and drug development.
The cerebellum rapidly integrates with cerebral networks during infancy and shows consistent structural and functional alterations in Autism Spectrum Disorder (ASD), suggesting that early cerebellar development may be consequential for later behavioral and psychiatric outcomes. Yet, little is known about the effect of ASD genetic liability on cerebello-cerebral functional connectivity in infancy or whether effects may differ by biological sex. Here, we leveraged neonatal functional magnetic resonance imaging, genetic, and behavioral follow-up data from the Developing Human Connectome Project (dHCP) to examine the relationship between ASD polygenic scores (PGS) and functional connectivity of cerebellar regions associated with sensorimotor and social-cognitive functions in 198 term-born neonates (mean age: 9.7 days). We report widespread sex differences in neonatal cerebello-cerebral connectivity that are regionally specific across cerebellar subdivisions. Across the full sample, elevated ASD PGS predicted alterations in cerebello-cerebral connectivity, with hemisphere-dependent differences in sensorimotor cerebellar connectivity with temporal cortex, and hyperconnectivity between the right social-cognitive seed and posterior cingulate. Notably, elevated ASD PGS predicted opposing patterns of cerebello-cerebral connectivity in males and females, including male hyperconnectivity between the right sensorimotor cerebellum and default mode areas, and female hyperconnectivity between the right social-cognitive seed and sensorimotor cortex. Connectivity associated with elevated ASD PGS showed nominal, sex-specific associations with 18-month language ability, attention problems, and emotional reactivity. Our findings show that ASD PGS influences the functional configuration of the cerebellum at birth and suggest that underlying cerebellar connectivity profiles associated with ASD may partially underlie distinct behavioral presentations in males and females.
Early detection of renal involvement in ANCA-associated vasculitis (AAV) is crucial, as functional changes often precede anatomical damage. Current diagnostic standards, such as the measurement of serum creatinine, renal biopsy and urinary analyses have limitations due to delayed detection and lack of specifity. Functional renal MRI (fMRI) techniques, including diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), arterial spin labeling (ASL) and blood oxygenation level dependent (BOLD) offer promising non-invasive alternatives for assessing renal function in AAV. The aim of this study was to evaluate the feasibility of non-invasive assessment of renal changes associated with AAV using mpMRI (multiparametric MRI). This study evaluated 7 patients and 10 healthy controls: patients with rapidly progressive glomerulonephritis (RPGN) due to AAV (n = 3), AAV patients without clinical signs of renal involvement (n = 4), and healthy controls (n = 10). All participants underwent functional renal MRI. Key parameters, including the apparent diffusion coefficient (ADC), fractional anisotropy (FA), and ASL-based renal perfusion and T2* parameter maps, were acquired and analyzed. The following differences in renal imaging parameters were observed between RPGN patients and healthy controls: RPGN patients showed reduced ADC values in the renal medulla and increased FA values compared to controls. Additionally, ASL values in the renal cortex were lower in RPGN patients. T2* values were lower in RPGN patients compared to the healthy control group in the cortex, and higher in the medulla. Patients with AAV without confirmed renal involvement also showed alterations in ADC, T2* and FA values compared to healthy controls. Our findings indicate that mpMRI parameter might detect renal changes in AAV. Therefore, mpMRI might offer novel opportunities for non-invasive detection of disease-associated changes.
Hyperkinetic movement disorders arise from dysfunction within cortico-basal ganglia-cerebellar loops. They frequently involve psychiatric and cognitive symptoms, reflecting impairment of both motor and non-motor domains within these loops. ADCY5 (MxMD-ADCY5) and SGCE (MYC/DYT-SGCE) related movement disorders are childhood-onset monogenic hyperkinetic conditions, both characterized by myoclonus, dystonia, and frequent psychiatric manifestations. Previous evidence suggests predominant basal ganglia involvement in MxMD-ADCY5 and cerebellar involvement in MYC/DYT-SGCE. The aim was to determine how basal ganglia and cerebellar dysfunction drives cortical dysregulation in hyperkinetic movement disorders. Resting-state functional magnetic resonance imaging (fMRI) was used to examine effective connectivity in motor and non-motor cortico-basal ganglia-cerebellar loops. Findings were validated using leave-one-out cross-validation. Microstructural properties of regions within these loops were assessed with diffusion-weighted imaging, using neurite orientation dispersion and density measures. We enrolled 21 patients with MxMD-ADCY5, 24 with MYC/DYT-SGCE, and matched healthy controls. Both patient groups exhibited elevated rates of psychiatric comorbidities. In MxMD-ADCY5, abnormal basal ganglia connectivity influenced the cerebellum, which in turn modulated cortical activity across motor and non-motor loops. Reduced neurite density was observed in the subthalamic nucleus, a relay between basal ganglia and cerebellum. In MYC/DYT-SGCE, the cerebellum showed predominant influence on cortical activity, with downstream modulation of basal ganglia activity, but no microstructural alterations were detected. Cross-validation largely confirmed the connectivity patterns' reliability. Abnormal cortical modulation in both disorders converges on a shared cerebellar-cortical pathway, with basal ganglia influences in MxMD-ADCY5 transmitted via the cerebellum to the cortex, and cerebellar contributions in MYC/DYT-SGCE directly influencing the cortex. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Internalizing disorders have been linked to alterations in default mode network (DMN) resting-state functional connectivity (RSFC). Given the increased risk of internalizing disorders in offspring of parents with a history of internalizing disorders, this study examined associations between parental depression and anxiety severity and adolescent DMN RSFC. Participants were 116 parent-adolescent dyads with youth between ages of 11-17 years. Structured diagnostic interviews and self-report questionnaires were completed by parents and adolescents to assess history and severity of internalizing disorders. Adolescents completed resting-state functional magnetic resonance imaging to determine the RSFC between regions of the DMN including the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), and bilateral lateral parietal cortices (LPC). Analyses examined region-of-interest (ROI) to ROI RSFC, with bivariate correlations and linear regressions used to assess whether child age, sex, child internalizing symptoms, and parental internalizing symptoms were associated with child RSFC alterations. After controlling for child age, sex, internalizing symptoms, and in-scanner motion, increased parental depressive severity was associated with increased child RSFC between the PCC and right LPC. Child internalizing symptoms were also linked to decreased RSFC between the right LPC and the mPFC. This study is limited by its modest sample size relative to effect sizes for functional connectivity-phenotype associations, cross-sectional design, and a relatively homogeneous sample in terms of ethnicity, socioeconomic status, and parental sex. Results suggest that, among youth with a parental history of depression or anxiety, increased severity of parental depression is associated with altered offspring DMN RSFC.
Schizophrenia spectrum disorders (SSD) feature deficits in movement intention, predictive mechanisms, and agency. While prior work characterised BOLD amplitude during movement preparation and temporal dynamics across the entire movement period, it remains unknown whether preparatory neural (BOLD) response timing and duration are selectively impaired in SSD. We analysed fMRI data from 20 SSD patients and 20 healthy controls during active and passive hand movements with video feedback (own vs. other hand). Preparatory and executory BOLD responses were modelled separately using the canonical HRF and its temporal (TD) and dispersion (DD) derivatives to evaluate timing and duration. Patients with SSD showed pronounced preparatory abnormalities under own-hand feedback, including delayed responses in right supplementary motor area during active movement preparation. Passive- and active-specific timing was reversed (earlier/later) in the left (caudate, middle temporal gyrus, superior parietal gyrus) and right (postcentral gyrus, right precentral gyrus, anterior cingulate cortex). Response duration showed reduced/reversed modulation (shorter/longer) in the right supplementary motor area, bilateral supramarginal gyrus, left inferior parietal cortex, and bilateral middle temporal gyrus. Earlier response timing in right precentral gyrus during active own-hand were negatively correlated with delusions of being controlled and formal thought disorder. No group differences emerged during execution.