Brain communications最新文献

Previous genome-wide association studies (GWAS) have identified several risk genes for stroke; however, it remains unclear how they confer risk for the disease. We conducted an integrative analysis to identify candidate genes for stroke and stroke subtypes by integrating blood-derived multi-omics data with genetic data. We systematically integrated the latest stroke GWAS database with human plasma proteomes and performed proteome-wide association studies, Mendelian randomization (MR), Bayesian colocalization analysis and transcriptome-wide association study to prioritize genes that associate the risk of stroke and its subtypes with their expression and protein abundance in plasma. The target genes were verified by performing tissue and cell type specificity, and functional analysis using the Genotype-Tissue Expression database, single-cell RNA sequencing and Gene Ontology databases. A two-step MR analysis was followed to explore the potential mechanisms. We found that the protein abundance of seven genes (MMP12, F11, SH3BGRL3, ENGASE, SCARA5, SWAP70 and SPATA20) in the plasma was associated with stroke and its subtypes, and six genes (MMP12, F11, SH3BGRL3, SCARA5, SWAP70 and SPATA20) causally related with stroke and its subtypes. The effect of F11, SH3BGRL3, SPATA20 and SWAP70 on each subtype was mediated by Factor XI inhibitors, atrial fibrillation, type 2 diabetes and systolic blood pressure, respectively (P < 0.05). We also found that SCARA5 and SWAP70 were related to stroke and ischemic stroke at the transcriptome level. Our present proteomic findings may offer potential future therapeutic targets for stroke prevention.

Epilepsy with myoclonic-atonic seizures, formerly myoclonic-astatic epilepsy or Doose syndrome, accounts for 1-2.2% of childhood-onset epilepsies. We investigated genetic determinants, long-term clinical outcomes and prognostic indicators in a large cohort using homogeneous inclusion criteria. We studied 60 patients (26.7% female), mean age 14.5 years (±9.1, range 3.2-41), followed between 1986 and 2024 at two paediatric neurology centres. Average follow-up was 11.7 years. Inclusion criteria were seizure onset between 6 months and 8 years, generalized 2-6 Hz spike-wave discharges and video-EEG documented myoclonic-atonic, myoclonic seizures or both. We analysed clinical, EEG, neuroimaging, neuropsychological and genetic data obtained with next-generation sequencing. We used χ² test, t-test, Log-rank test, Cox regression, population-averaged logistic models and Benjamini-Yekutieli procedure to identify predictors of seizure outcome, intellectual disability and other neurodevelopmental comorbidities. We observed myoclonic-atonic seizures in 55/60 (91.7%), tonic-vibratory seizures in 44/60 (73.4%), absence seizures in 30/60 (50%), myoclonic seizures without post-myoclonic atonia in 25/60 (42%) and non-convulsive status epilepticus in 13/60 (21.7%). A 'stormy' onset occurred in 26/60 patients (43.3%). The most effective drugs were valproate, ethosuximide, benzodiazepines and phenobarbital, used in different combinations, whereas the newer drugs offered no benefit. Long-term outcomes were variable. Thirty-seven patients (61.7%) achieved seizure freedom after 5.1 years on average. We observed drug resistance in 23/60 patients (38.3%) and intellectual disability in 35/60 (58.3%). One adult patient died (mortality rate 1.80/1000-person-years). Attention deficit hyperactivity disorder was the most common comorbidity (24/60, 40%). 'Stormy' onset did not predict a worse prognosis. Global developmental delay at epilepsy onset was associated with drug resistance (P = 0.004, Q = 0.064) and with intellectual disability (P = 0.003, Q = 0.048). We found pathogenic variants in 15/39 (38.5%) patients undergoing next-generation sequencing, including four genes novel for this syndrome (KMT2E; POGZ; SHANK3; YWHAG), with exome sequencing yielding higher diagnostic rates than gene panels. Epilepsy with myoclonic-atonic seizures is a complex syndrome with diverse genetic causes and variable seizure severity and outcomes. Our findings expand its genetic landscape and highlight the prognostic value of prompt overall neurodevelopmental assessment at clinical onset. Whole exome sequencing should be prioritized for early diagnosis and counselling.

Visual snow syndrome is a neurological disorder characterized by persistent visual disturbances and associated symptoms. Although the neural basis of the visual snow syndrome remains poorly understood, it may involve increased neuronal excitability and/or altered neuroplasticity in the visual cortex, which could, in turn, affect visual gamma oscillations. An altered excitation-inhibition balance is hypothesized to alter the modulation of gamma power and frequency by stimulation intensity, while maladaptive neuroplasticity may impact time-dependent changes in gamma power during repeated stimulation. To investigate potential alterations in the excitation-inhibition balance and neuroplasticity in visual snow syndrome, we used magnetoencephalography to record visual gamma oscillations in 26 patients with this disorder and 27 healthy controls. Participants were exposed to repeatedly presented high-contrast annular gratings, which were either static or drifting at varying speeds to systematically manipulate stimulation intensity. We also assessed heart rate variability during rest and repetitive visual stimulation to explore the relationship between time-dependent gamma changes and parasympathetic activation, which is known to promote activity-dependent plasticity. Our results showed no significant group differences in gamma power or frequency, nor in their modulation by drift rate, suggesting that the excitation-inhibition balance in the V1 area remains largely intact in visual snow syndrome. Both groups exhibited an initial brief decrease in gamma power followed by a sustained linear increase with stimulus repetition, likely reflecting activity-dependent plasticity. Heart rate variability parameters were comparable across groups, with the parasympathetic-sympathetic balance index correlating with repetition-related increase in gamma power, further supporting the link between time-dependent gamma changes and neuroplasticity. Notably, patients with visual snow syndrome exhibited a steeper repetition-related increase in gamma power, indicating atypically heightened activity-dependent plasticity in this group. These findings provide the first experimental evidence suggesting that altered activity-dependent neuroplasticity plays a role in the pathophysiology of the visual snow syndrome. Furthermore, they identify repetition-related increases in gamma power as a potential biomarker of aberrant neuroplasticity, offering novel insights into the pathophysiology of the visual snow syndrome and potential avenues for targeted therapeutic interventions.

Restless limbs syndrome (RLS) is a neurological disorder characterized by an uncontrollable urge to move the limbs. Although it affects up to 10% of the general population, its underlying mechanisms remain poorly understood. Neurophysiological excitability testing may help elucidate mechanisms related to sensorimotor integration, axonal ion channel dysfunction and impaired neural inhibition. This study aimed to assess both CNS and PNS function by examining cortical, spinal and peripheral nerve excitability within the same individuals for the first time. To investigate potential widespread excitability changes in RLS, we specifically analysed hand muscles, offering new insights into the extent of neural involvement beyond the lower limbs. The study included 56 RLS patients, divided into treated and untreated groups, along with 32 healthy controls. Notably, none of the patients experienced symptoms in their hands. Cortical excitability was assessed via threshold-tracking transcranial magnetic stimulation (TMS) to evaluate intracortical inhibition and facilitation. Sensory-motor integration was measured via long-latency reflexes (LLRs), while spinal cord excitability was assessed using F-waves, H-reflexes and RIII-reflexes. Axonal excitability was examined using the extended TRONDNF protocol. TMS revealed a significant reduction in short-interval intracortical inhibition (SICI) in patients, particularly at inter-stimulus intervals (ISIs) of 2.5 and 3 ms. When averaging across ISIs from 1 to 7 ms, patients on medication exhibited significantly less inhibition compared to healthy controls. Long-interval intracortical inhibition (LICI) was also reduced at ISIs of 150 and 200 ms, while facilitation parameters remained within normal ranges. Patients exhibited increased amplitude of the second component of the LLR recorded from the abductor pollicis brevis, whereas RIII reflex measurements showed no significant differences. Axonal excitability testing revealed a graded increase in hyperpolarization-activated currents in patients with more severe symptoms. The observed reductions in SICI and LICI suggest impaired intracortical inhibition in the M1 hand area, offering indirect evidence of cortical dysfunction in regions clinically unaffected by the disease. The increased LLR amplitudes further indicate altered sensorimotor integration at the cortical level, whereas the absence of significant changes in RIII reflexes suggests that segmental spinal dysfunction within the pain pathway of the upper limbs is unlikely. Finally, axonal excitability findings point to a potential role of hyperpolarization-activated currents in either contributing to or predisposing individuals to RLS symptoms.

In Disorders of Consciousness, ¹⁸F-fluorodeoxyglucose PET (FDG-PET) is known to be effective in distinguishing vegetative state/unresponsive wakefulness syndrome from minimally conscious state, and when combined with MRI techniques, the risk of misdiagnosis decreases. However, FDG-PET studies on chronic patients with different etiologies (traumatic, vascular, and anoxic brain injury) are limited, and the association between metabolic activity and resting-state functional MRI (fMRI) networks remains unclear. This study combined FDG-PET with resting-state functional MRI and MRI to assess: i) the diagnostic accuracy of FDG-PET metabolism in different etiological groups of patients; ii) whether resting-state fMRI networks presence or absence was associated with higher versus lower FDG-PET metabolism. A group of 84 chronic patients underwent FDG-PET (47 vegetative state/unresponsive wakefulness syndrome, 31 minimally conscious state, and six emerged from a minimally conscious state), equally distributed in traumatic, vascular, and anoxic etiologies. Eight cases of covert cortical processing were identified. A subgroup of 68 patients also underwent resting-state fMRI. Standardized uptake values were calculated for these areas of interest: 10 resting-state fMRI networks, the precuneus, and a whole-brain mask. Patients in a vegetative state/unresponsive wakefulness syndrome exhibited a significant decrease in metabolism compared to patients in a minimally conscious state across all areas of interest. Patients with covert cortical processing showed intermediate metabolic levels between the two diagnostic categories. The anoxic group displayed a severe decrease in metabolism compared to patients with traumatic and vascular etiologies. The highest diagnostic accuracy among the areas of interest was reached in the precuneus and medial visual network (Area Under the Curve, AUC = 0.82-0.83). However, when anoxic patients were excluded, the diagnostic accuracy did not reach statistical significance, although the medial visual network and precuneus retained a trend of gradually increasing metabolism as clinical conditions improved. Identification of resting-state functional MRI networks was associated with increased metabolism in all networks at the group level, even excluding patients with severe structural damage. FDG-PET proves to be a technique capable of distinguishing vegetative state/unresponsive wakefulness syndrome from minimally conscious state even in chronic patients, although its diagnostic accuracy can be significantly affected by the etiology. There is a concordance between the metabolism level and the presence of resting-state fMRI networks.

Although traditionally viewed as relatively spared in Alzheimer's disease (Ad), the cerebellum is increasingly recognized for its contribution to cognitive and behavioural dysfunction. However, longitudinal data delineating subregional cerebellar involvement across the Ad continuum remain limited. In this study, we investigated longitudinal cerebellar atrophy and its clinical correlates in 259 older adults classified via amyloid PET into four biomarker-defined groups: cognitively normal controls, preclinical Ad, Ad-related mild cognitive impairment and Ad dementia. Structural MRI data were analysed using the Spatially Unbiased Infratentorial Template (SUIT), and longitudinal changes in 28 cerebellar subregions were assessed via generalized estimating equations, controlling for demographic and biological covariates. Across longitudinal analyses, cerebellar structural alterations in preclinical Ad were closely associated with both cognitive and behavioural measure changes. Reductions in lobule VI and Crus I/II were correlated with episodic memory decline, emphasizing the cerebellum's contributions to early cognitive deterioration. The same regions were involved in associations with apathy and behavioural dysregulation, suggesting the cerebellar contribution to emerging neuropsychiatric symptoms through disruption of motivational and executive circuits. In addition, stage-dependent cortico-cerebellar coupling was noted, with coordinated volume loss between cerebellar lobule VI and temporo-orbitofrontal cortices in the preclinical stage, but selective posterior cerebellar-posterior cingulate synchrony in dementia, indicating progressive network reorganization and eventual decoupling along the disease continuum. This study provides the first biomarker-defined longitudinal mapping of cerebellar subregional atrophy in Ad. The findings demonstrate that cerebellar degeneration is not confined to advanced stages but emerges early and dynamically interacts with cortical networks, influencing both cognitive decline and neuropsychiatric symptoms. The distinct atrophy patterns and cortico-cerebellar decoupling underscore the cerebellum's potential as a disease-stage-specific biomarker and therapeutic target in Ad.

Huntington's disease has traditionally been considered a motor disorder, but it is currently classified as a multisystem neurodegenerative disease that involves brain regions, such as the amygdala, and causes depression. The aim of the present study was to analyse the distribution of huntingtin in the human amygdaloid basolateral complex, considering its nuclei, sex, triplet repeats and Vonsattel score, as well as to characterize the cellular relationships between huntingtin and associated copathologies. The present study included 23 human brain samples from patients (males and females) with and without Huntington's disease, Parkinson's disease and Alzheimer's disease. An unbiased stereology approach was used to quantify huntingtin deposits. Multiple immunofluorescence experiments were conducted to analyse the relationship between huntingtin and glial populations. Immunohistochemistry against pathological markers of other neurodegenerative diseases was also carried out. Quantification data did not reveal differences among different nuclei (basomedial, basolateral or lateral) in the basolateral complex or according to sex. Huntingtin deposits did not correlate with cytosine-adenine-guanine (CAG) repeats. However, these deposits were positively correlated with pathological Vonsattel grades. Additional aggregates of other pathological proteinopathies were also observed. This correlation between the human basolateral amygdaloid complex and the Vonsattel stage provides a new perspective for neuropathological diagnosis and helps in understanding nonmotor symptoms such as depression.

The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer's disease to explore the brain asymmetry within the Alzheimer's disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer's disease progression in autosomal dominant Alzheimer's disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

People with aphasia experience cognitive deficits in addition to their well-documented language impairments, with attention being a frequently affected domain. While numerous studies highlight the impact of attention deficits on language abilities in people with aphasia, research examining the neural correlates of these deficits and the influence of stimulus modality on attention performance remains limited. In this cross-sectional study, in Experiment 1, we investigated sustained attention deficits in people with aphasia using four matched tasks that varied by modality (visual versus auditory) and linguistic content (verbal versus non-verbal). In Experiment 2, we further explored whether the neural resources supporting sustained attention differ by modality. Participants included 56 people with aphasia following left-hemisphere stroke (Experiments 1 and 2), 14 individuals after right-hemisphere stroke and 23 age-matched healthy controls (only Experiment 1). Participants completed four sustained attention tasks. Structural MRI scans were obtained for stroke participants, and neural correlates of attention were explored in people with aphasia. Behavioural analyses revealed that people with aphasia, as a group and across subtypes, performed significantly worse on auditory tasks with notably slower reaction times compared to healthy controls, indicating sustained attention deficits, particularly in the auditory modality. Compared to individuals with right-hemisphere stroke, people with aphasia made significantly more errors only on the auditory verbal task, which may reflect the combined impact of language impairment and attentional demands. No significant differences were observed between non-fluent and fluent aphasia subtypes, indicating comparable sustained attention deficits across these groups. However, participants with non-fluent aphasia demonstrated slower reaction times across nearly all tasks compared to healthy individuals, while those with fluent aphasia showed slower reaction times only in the auditory modality. Lesion-symptom mapping analysis did not reveal distinct brain-behaviour associations specific to the auditory modality. However, for the visual verbal task, poorer performance was associated with lesions in the inferior and middle frontal gyri and underlying white matter fasciculi (inferior fronto-occipital fasciculus, uncinate fasciculus and corpus callosum), regions implicated in written word comprehension. Taken together, these findings suggest that people with aphasia exhibit modality-specific sustained attention deficits, particularly in the auditory domain, likely reflecting impaired processing of auditory information.

Mild traumatic brain injury can disrupt brain function and is associated with high morbidity and healthcare utilization. While many individuals recover from mild traumatic brain injury, a significant proportion experience long-term sequelae, collectively known as post-concussion syndrome. Symptoms of post-concussion syndrome include headache, dizziness, insomnia, cognitive processing difficulties and mental health disturbances. The disease burden is augmented by the current lack of objective measures to accurately predict long-term symptoms and deficits, providing an opportunity to utilize biomarkers in biofluids. A large proportion of available diagnostic clinical tools are subjective symptom scores. This review aims to explore current fluid biomarkers, grouped by clinical symptoms. With the available literature, we have discovered a wide range of fluid biomarkers that have been investigated for predicting post-traumatic headache, including neuropeptides; sleep disturbances, such as cortisol and melatonin; vestibular disturbances, including interleukin-6 and neurone-specific enolase; and vomiting, such as S100B. Along with physical symptoms, biomarkers investigated for predicting cognitive disturbances include inflammatory markers, S100B, neurofilament light chain, tau, microRNA and hormones. Biomarkers to predict mental health disturbances may include brain-derived neurotrophic factor, tau and cortisol. By utilizing such biomarkers, there is capacity to adopt a personalized medicine approach to facilitate early interventions for those most in need while also identifying individuals with a favourable prognosis who can safely return to their normal activities.