Abstract Post-stroke depressive symptoms are common, but studies on the contributions of lesion locations to depression symptoms remain inconsistent. Bayesian statistics offer the possibility to clarify these inconsistencies by providing evidence in favor and against observed associations. We reanalyzed four previously published observational cohorts with 1,864 patients with stroke characterized for depressive symptoms from France, Korea, Germany and the USA. We performed voxel-wise Bayes factor mapping using general linear models. Lesion maps were used to test for associations of post-stroke depressive symptoms with lesion location. Network level associations were tested based on structural disconnection and functional lesion network maps estimated by reference to normative connectome data. Due to a sample size with broad lesion coverage, Bayesian inference was informative in large parts of the brain. Lesion associations were found in clusters in the right hemisphere including cortical (frontal, insular, parietal) and subcortical regions (striatum, amygdala, hippocampus) and adjacent white matter. Evidence of no contribution to post-stroke depressive symptoms was observed in large parts of the left hemisphere. Structural disconnection was linked to depressive symptoms in the bilateral frontal white matter prominently involving the corpus callosum and anterior thalamic radiation. Lesion network mapping revealed evidence of an association of post-stroke depressive symptoms with network connectivity in the left posterior cingulate cortex and precuneus, and less consistently, the bilateral anterior insula, along with widespread absence of associations in other regions. Depressive symptoms were most strongly associated with right frontal lesions and right-dominant structural disconnection in frontal cortico-subcortical circuits.
Abstract Guillain–Barré syndrome (GBS) is an acute immune-mediated neuropathy that frequently results in long-term disability. The cellular mechanisms underlying GBS and the immunomodulatory effects of intravenous immunoglobulin (IVIg) remain incompletely understood. In this prospective observational cohort study, we performed single-cell RNA sequencing with paired T cell receptor (TCR) sequencing on peripheral blood and cerebrospinal fluid (CSF) collected before and after IVIg treatment from treatment-naïve patients with GBS. Pre-treatment blood and CSF were obtained from nine and eight patients, respectively; post-treatment samples were available from six patients for blood and three patients for CSF. Previously published healthy control (HC) blood and CSF single-cell datasets were analyzed for comparison. We characterized immune cell composition, transcriptional states, TCR clonality, and clonal dynamics across peripheral and CSF compartments as well as following treatment. Individuals with GBS exhibited enrichment of T helper 1 (Th1)-polarized CD4+ T cells, activated and resident-memory CD8+ T cells, and macrophages in CSF relative to paired peripheral blood. This CSF-to-blood enrichment was greater than in healthy controls (HCs) for Th1 cells, activated effector-memory CD8+ T cells, and inflammatory macrophages, although the overall degree of T-cell clonal expansion was similar between groups. In both GBS and HCs, expanded CSF CD4+ clonotypes were predominantly Th1-polarized and largely absent from blood, whereas expanded CD8+ clonotypes showed greater overlap between compartments. Among clonotypes detected in both blood and CSF, CD4+ and CD8+ T cells exhibited more activated transcriptional states in the CSF, a shift that was particularly pronounced in GBS. Following IVIg treatment, peripheral blood showed minimal changes, whereas CSF T-cell populations exhibited more substantial alterations, including reductions in Th1-associated and activated effector-memory states, increases in T helper 2 (Th2) and regulatory T cell populations, and changes in the clonal repertoire. Expanded T cell clonotypes with sequence-based predicted specificity for pathogens associated with GBS were identified in six patients, and convergent clonotype groups were detected both within and across patients. Demyelinating GBS is characterized by compartmentalized enrichment and activation of pro-inflammatory T-cell populations within the CSF rather than an overall increase in T-cell clonal expansion. Exploratory longitudinal findings further suggest that CSF T-cell populations are altered following IVIg treatment. Integrated single-cell transcriptomic and TCR analyses provide insight into the early immune response in GBS and identify candidate cellular pathways for biomarker development and therapeutic investigation.
Abstract Social cognitive deficits manifest early in behavioral variant frontotemporal dementia (bvFTD), compromising individuals’ ability to interpret social cues, empathize, and maintain interpersonal relationships. Current neurobiological models emphasize cortical network disruption, particularly within the salience, semantic appraisal, and default mode networks, as primary contributors to social dysfunction. However, despite the increasingly recognized role of the cerebellum in higher-order cognitive and socioemotional processes, its contributions to social deficits remains underexplored in bvFTD. Here, we investigated the unique and network-level influences of cerebellar subregions on social cognition across experimental and real-world assessments in early-stage bvFTD. A total of 107 individuals with bvFTD and 100 healthy controls were evaluated across three social domains: theory of mind (ToM) (The Awareness of Social Inference Test-Social Inference-Enriched, TASIT-SIE; Cognitive Emotional Perspective Taking Test), emotion reading (Dynamic Affect Recognition Test; TASIT-Emotion Evaluation Test; Comprehensive Affect Testing System), and real-life empathy (Revised Self-Monitoring Scale; Interpersonal Reactivity Index). Using a functional cerebellar parcellation, we extracted volumes of posterior cerebellar subregions implicated in social-linguistic and multiple-demand networks from participants’ structural MRIs. To address the high collinearity between cerebellar and cortical atrophy patterns, we applied sequential regression, partial least squares correlation, and dominance analysis to characterize brain-behavior relationships. Additionally, supplementary structural equation modelling (SEM) examined whether the associations between cerebellar integrity and social cognition was mediated by executive functioning. Our results showed that cerebellar subregional integrity contributed to social cognitive deficits in individuals with early-stage bvFTD. Cerebellar subregions, particularly right Crus I and II, showed the strongest and most selective contribution to high-level inferential Theory of Mind performance. Tasks involving dynamic emotion stimuli exhibited a more distributed pattern of cerebello-cerebral involvement. By contrast, questionnaire-based measures of real-world social functioning were less prominently represented in the latent covariance structure. SEM further showed that cerebellar integrity remained directly associated with social cognition after accounting for executive functioning, whereas the indirect association through executive functioning was not significant. These findings highlight the task-dependent nature of cerebellar involvement in social cognition, and demonstrate that time-limited experimental tasks, particularly those involving inferential reasoning about beliefs and affect, are likely to be especially valuable in detecting subtle cerebello-cerebral network dysfunction that questionnaire-based measures may overlook. Our results extend cortex-centric models of social dysfunction in bvFTD by demonstrating that cerebellar subregions contribute to distributed cerebello-cerebral systems associated with social cognitive performance. These findings provide a foundation for future longitudinal and mechanistic studies of cerebello-cerebral dysfunction in neurodegenerative disease.
Abstract The amygdaloid complex is one of the most structurally and functionally heterogeneous regions of the mammalian brain, acting as an integrative node between sensory, mnemonic and visceral systems. It comprises a set of subnuclei whose cytoarchitectural differentiation, neurochemical profiles and anatomical boundaries have been debated since the earliest descriptions. This heterogeneity is established during ontogenetic development, assembling progenitors from pallial and subpallial domains, and preoptic and hypothalamic territories, resulting in a highly connected network. Maturation is not complete at birth, the amygdala changes through childhood and adolescence, leaving a protracted window of environmental sensitivity. Single-nucleus RNA sequencing and spatial transcriptomics have added a molecular layer to this framework, resolving populations that no single marker separates, and set explicit limits on the resolution at which rodent-derived subdivisions can be transferred to the human amygdala. Together these levels of description provide a structural framework for understanding its functions, which include emotional regulation and conditioned fear, social and sexual behaviours, decision-making, reward and punishment processing, empathy and memory modulation. Cross-species comparison reveals further variation, particularly the expansion of the basolateral complex in primates and the redistribution of neurons towards the lateral nucleus in humans. In summary, the amygdala acts as a densely connected hub with a broad role not only in physiological and psychological health but also in disease states; indeed, the amygdala is affected early in several neurodegenerative disorders, and in some (notably limbic-predominant age-related TDP-43 encephalopathy and argyrophilic grain disease) it is among the first regions in which pathology is detected.
