Biology subjects

Alvim, M. K. M.

Publications and source records attributed to Alvim, M. K. M..

8 recordsLinked to original sources

bioRxiv2026

Sex-related structural alterations across common epilepsies: a worldwide ENIGMA study

Epilepsy is characterized by widespread structural brain alterations extending beyond the epileptic zone, involving both cortical and subcortical regions. Importantly, the clinical manifestation of epilepsy, including seizure types, psychiatric comorbidities, and treatment responses, has been shown to differ between sexes. However, sex differences in structural alterations in epilepsy have been seldomly reported in neuroimaging studies, partly due to limited sample sizes and single-center designs. Here, we systematically investigated sex differences in common epilepsies and their related clinical variables using structural neuroimaging biomarkers in an international multi-center cohort of 1,253 epilepsy patients and 1,077 healthy controls. We studied cortical thickness and subcortical volume in two types of epilepsy: temporal lobe epilepsy (TLE) and genetic generalized epilepsy (GGE). Both male and female patients with TLE showed widespread cortical and subcortical thinning compared with controls. In GGE, when compared separately to controls, male patients showed only subtle structural alterations, whereas female patients exhibited more widespread structural alterations. Sex-stratified analyses revealed some variation in the extent and distribution of cortical thickness and subcortical volume alterations between male and female patients in both epilepsy cohorts. Yet, we did not find significant sex-by-diagnosis interaction effects in TLE and GGE. Similarly, no significant interaction effects were observed between sex and age of onset or disease duration in either patient group. Overall, although we observed some differences in regional cortical thickness and subcortical volume between male and female patients with epilepsy, we did not find significant sex-by-diagnosis interactions. Our findings indicate that sex differences in behavioral and clinical outcomes of epilepsy may involve biological or functional processes that require further investigation.

neuroscience↗

bioRxiv2024

Cell type mapping of mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy using single-nucleus multiomics

ObjectiveMild malformations of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) are brain lesions associated with focal epilepsy and characterized by increased oligodendroglial density, heterotopic neurons, and hypomyelination in the white matter. While previous studies have implicated somatic mutations in the SLC35A2 gene, the cellular and molecular mechanisms underlying MOGHE pathogenesis remain elusive. To address this gap, this study aimed to systematically characterize the cell type composition and molecular alterations of MOGHE lesions at cellular resolution using single-nucleus multiomics profiling. MethodsWe performed single-nucleus multiomics sequencing to obtain paired gene expression and chromatin accessibility profiles of > 31,000 nuclei from gray matter and white matter regions of MOGHE lesions, and compared the results with publicly available neurotypical control datasets. ResultsThe analysis of gray and white matter regions from two MOGHE patients revealed significant cellular composition alterations, including the presence of heterotopic neurons and disease-specific oligodendrocytes populations within the subcortical white matter. MOGHE-specific oligodendrocytes were characterized by the upregulation of synaptic functions and enhanced neuron communication, denoting a possible role in synaptic support and the mediation of glial-neuron interactions in the disease. On the other hand, MOGHE heterotopic neurons were characterized by the upregulation of genes associated with neuronal migration and the Wnt signaling pathway, suggesting a mechanism underlying their atypical localization. SignificanceThis high-resolution cell type mapping of MOGHE lesions in clinical samples unveils neuronal and glial populations affected by the disease, and provides novel insights into the pathophysiological mechanisms of MOGHE. Key PointsO_LIWe provide a multimodal cellular atlas of the human cortical and subcortical regions affected in MOGHE C_LIO_LIMOGHE-associated oligodendrocytes showed upregulation of synaptic functions and enhanced neuron communication C_LIO_LINeuronal migration and Wnt signaling are upregulated in MOGHE heterotopic neurons C_LI

neuroscience↗

bioRxiv2024

EPILEPTOGENESIS INHIBITS THE CIRCADIAN CLOCK AND RESHAPES THE DIURNAL TRANSCRIPTOMIC RHYTHMICITY IN THE MOUSE HIPPOCAMPUS

Epileptogenesis is the process that leads the brain into epileptic activity. Clinical evidence shows that [~]90% of people with epilepsy present rhythmicity in the timing of their seizures presentation. However, whether the circadian clock is a key player during epileptogenesis remains unknown. Here, we triggered epileptogenesis in mice by the intra-amygdala injection of kainic acid and profiled by RNA sequencing their hippocampal diurnal mRNA rhythmicity. We show that epileptogenesis largely reshapes the hippocampal transcriptomic rhythmicity and that the molecular clock machinery is inhibited due to the disruption of the core clock gene Bmal1. We identified relevant dysregulated pathways and their dynamics in epileptogenesis, predicting a key role for microglial-driven neuroinflammation. We predicted the genes that Bmal1 is directly controlling over time. Finally, we sought for translational relevance evidence by performing RNA sequencing in hippocampal samples resected from patients with mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) and cross-analyzing datasets.

neuroscience↗

bioRxiv2024

Multimodal single-cell sequencing of the human cortex reveals neuronal vulnerability and activated glial cell states in focal cortical dysplasia

Focal Cortical Dysplasia (FCD) is a neurodevelopmental condition characterized by malformations of the cerebral cortex that often cause drug-resistant epilepsy. In this study, we performed multi-omics single-cell profiling to map the chromatin accessibility and transcriptome landscapes of FCD type II, generating a comprehensive multimodal single-cell dataset comprising 61,525 cells from 11 clinical samples of lesions and controls. Our findings revealed profound chromatin, transcriptomic, and cellular alterations affecting neuronal and glial cells in FCD lesions, including the selective loss of upper-layer excitatory neurons, significant expansion of oligodendrocytes and immature astrocytic populations, and a unique neuronal subpopulation harboring dysmorphic neurons. Furthermore, we uncovered activated microglia subsets, particularly in FCD IIb cases. This comprehensive study unveils neuronal and glial cell states driving FCD development and epileptogenicity, enhancing our understanding of FCD and offering new directions for targeted therapy development.

neuroscience↗

bioRxiv2024

A worldwide ENIGMA study on epilepsy-related gray and white matter compromise across the adult lifespan

ObjectivesTemporal lobe epilepsy (TLE) is commonly associated with mesiotemporal pathology and widespread alterations of grey and white matter structures. Evidence supports a progressive condition although the temporal evolution of TLE is poorly defined. This ENIGMA-Epilepsy study utilized multimodal magnetic resonance imaging (MRI) data to investigate structural alterations in TLE patients across the adult lifespan. We charted both grey and white matter changes and explored the covariance of age-related alterations in both compartments. MethodsWe studied 769 TLE patients and 885 healthy controls across an age range of 17-73 years, from multiple international sites. To assess potentially non-linear lifespan changes in TLE, we harmonized data and combined median split assessments with cross-sectional sliding window analyses of grey and white matter age-related changes. Covariance analyses examined the coupling of grey and white matter lifespan curves. ResultsIn TLE, age was associated with a robust grey matter thickness/volume decline across a broad cortico-subcortical territory, extending beyond the mesiotemporal disease epicentre. White matter changes were also widespread across multiple tracts with peak effects in temporo-limbic fibers. While changes spanned the adult time window, changes accelerated in cortical thickness, subcortical volume, and fractional anisotropy (all decreased), and mean diffusivity (increased) after age 55 years. Covariance analyses revealed strong limbic associations between white matter tracts and subcortical structures with cortical regions. ConclusionsThis study highlights the profound impact of TLE on lifespan changes in grey and white matter structures, with an acceleration of aging-related processes in later decades of life. Our findings motivate future longitudinal studies across the lifespan and emphasize the importance of prompt diagnosis as well as intervention in patients.

neuroscience↗

bioRxiv2023

Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study

ObjectiveThe intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current cortico-centric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural MRI in 1,602 adults with epilepsy and 1,022 healthy controls across twenty-two sites from the global ENIGMA-Epilepsy working group. MethodsA state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in i) all epilepsies; ii) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS); iii) non-lesional temporal lobe epilepsy (TLE-NL); iv) genetic generalised epilepsy; and (v) extra-temporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness. ResultsAcross all epilepsies, reduced total cerebellar volume was observed (d=0.42). Maximum volume loss was observed in the corpus medullare (dmax=0.49) and posterior lobe grey matter regions, including bilateral lobules VIIB (dmax= 0.47), Crus I/II (dmax= 0.39), VIIIA (dmax=0.45) and VIIIB (dmax=0.40). Earlier age at seizure onset ({eta}{rho}2max=0.05) and longer epilepsy duration ({eta}{rho}2max=0.06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls. SignificanceWe provide robust evidence of deep cerebellar and posterior lobe subregional grey matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in non-motor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellum subregions into neurobiological models of epilepsy. Key pointsO_LICerebellar involvement in epilepsy is poorly understood within current cortico-centric models of this disease C_LIO_LIWe used a novel, deep learning segmentation tool to parcellate the cerebellum into 28 anatomical subunits using an international MRI dataset of 1,602 individuals with epilepsy (aged between 18 and 65 years old) including temporal lobe epilepsy with hippocampal sclerosis (TLE-HS, n=562), TLE non-lesional (TLE-NL, n=284), generalised genetic epilepsy (GGE, n=186) and extra temporal focal epilepsy (ETLE, n=251) and 1,022 controls. C_LIO_LIAcross all epilepsies (vs. controls) robust changes in the corpus medullare and posterior lobe "non-motor" regions were observed, with maximal differences in bilateral VIIB and Crus II lobules. Lower volume of these regions correlated with longer disease duration. Anterior "motor lobe" regions were relatively spared. C_LIO_LIFindings were most pronounced in TLE-HS and ETLE groups, with distinct neuroanatomical profiles observed. C_LIO_LICortical thinning was associated with pronounced cerebellar volume loss in TLE-HS epilepsy, relative to controls. C_LI ETHICAL PUBLICATION STATEMENTWe confirm that we have read the Journals position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

neuroscience↗

bioRxiv2023

Identifying cellular markers of focal cortical dysplasia type II with cell-type deconvolution and single-cell signatures

Focal cortical dysplasia (FCD) is a brain malformation that causes medically refractory epilepsy. FCD is classified into three categories based on structural and cellular abnormalities, with FCD type II being the most common and characterized by disrupted organization of the cortex and abnormal neuronal development. In this study, we employed cell-type deconvolution and single-cell signatures to analyze bulk RNA-seq from multiple transcriptomic studies, aiming to characterize the cellular composition of brain lesions in patients with FCD IIa and IIb subtypes. Our deconvolution analyses revealed specific cellular changes in FCD IIb, including neuronal loss and an increase in reactive astrocytes (astrogliosis) when compared to FCD IIa. Astrogliosis in FCD IIb was further supported by a gene signature analysis and histologically confirmed by glia fibrilla acidic protein (GAP) immunostaining. Overall, our findings demonstrate that FCD II subtypes exhibit differential neuronal and glial compositions, with astrogliosis emerging as a hallmark of FCD IIb. These observations, validated in independent patient cohorts and confirmed using immunohistochemistry, offer novel insights into the involvement of glial cells in FCD type II pathophysiology and may contribute to the development of targeted therapies for this condition.

neuroscience↗

bioRxiv2018

A systems-level analysis highlights microglial activation as a modifying factor in common forms of human epilepsy

The common human epilepsies are associated with distinct patterns of reduced cortical thickness, detectable on neuroimaging, with important clinical consequences. To explore underlying mechanisms, we layered MRI-based cortical structural maps from a large-scale epilepsy neuroimaging study onto highly spatially-resolved human brain gene expression data, identifying >2,500 genes overexpressed in regions of reduced cortical thickness, compared to relatively-protected regions. The resulting set of differentially-expressed genes shows enrichment for microglial markers, and in particular, activated microglial states. Parallel analyses of cell-specific eQTLs show enrichment in human genetic signatures of epilepsy severity, but not epilepsy causation. Post mortem brain tissue from humans with epilepsy shows excess activated microglia. In an experimental model, depletion of activated microglia prevents cortical thinning, but not the development of chronic seizures. These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

neuroscience↗