Biology subjects

Kasprian, G.

Publications and source records attributed to Kasprian, G..

4 recordsLinked to original sources

bioRxiv2025

Beyond the Resection: Surgical White Matter Disruption alters Non-Resected Brain Anatomy

Resective neurosurgery is a cornerstone treatment for many neurological conditions. Although traditionally viewed as localised procedure, increasing evidence from advanced magnetic resonance imaging (MRI) shows that also non-resected anatomy can degenerate following surgery. The relationship between local tissue removal and these postoperative changes remains thus far speculative. Here, we investigate the hypothesis that degenerative changes to surgically preserved grey and white matter are mediated by transneuronal degeneration, a deterioration of intact neuronal populations due to lost axonal input. Using a robust structural and diffusion MRI framework, we first identify widespread postoperative atrophy: pronounced cortical thickness decreases near the resection, and extensive white matter impairments across the ipsilateral hemisphere. Importantly, we then link these alterations to surgical white matter disruption, revealing a sequential network atrophy following neurosurgery. Beyond degenerative effects, we also demonstrate often reported structural network reorganisations as an artefact of image processing, indicating limited capacity for macroscale plasticity post-resection. Key PointsO_LIResective neurosurgery can lead to postoperative atrophy of non-resected grey and white matter. Utilising a robust longitudinal neuroimaging framework, we evaluate these changes as consequences of transneuronal degeneration, demonstrating a sequential atrophy of brain anatomy following the loss of surgically disrupted white matter. C_LIO_LIThe majority of severed connections projected to atrophic cortices near the resection, indicating them to be short association fibers. Consecutive white matter atrophy however affected extensive ipsilateral pathways, highlighting a cascading network effect of resective brain surgery. C_LIO_LIWe did not find evidence to support often reported structural reorganisations of large-scale brain networks post-resection. Yet, we demonstrate that evidence typically interpreted as such can be replicated when using non-robust reconstruction methods. C_LI

neuroscience↗

bioRxiv2023

Direct interhemispheric cortical communication via thalamic commissures: a new white-matter pathway in the primate brain

Cortical neurons of eutherian mammals project to the contralateral hemisphere, crossing the midline primarily via the corpus callosum and the anterior, posterior, and hippocampal commissures. We recently reported an additional commissural pathway in rodents, termed the thalamic commissures (TCs), as another interhemispheric axonal fiber pathway that connects cortex to the contralateral thalamus. Here, we demonstrate that TCs also exist in primates and characterize the connectivity of these pathways with high-resolution diffusion-weighted magnetic resonance imaging, viral axonal tracing, and functional MRI. We present evidence of TCs in both New World (Callithrix jacchus and Cebus apella) and Old World primates (Macaca mulatta). Further, like rodents, we show that the TCs in primates develop during the embryonic period, forming anatomical and functionally active connections of the cortex with the contralateral thalamus. We also searched for TCs in the human brain, showing their presence in humans with brain malformations, although we could not identify TCs in healthy subjects. These results pose the TCs as an important fiber pathway in the primate brain, allowing for more robust interhemispheric connectivity and synchrony and serving as an alternative commissural route in developmental brain malformations. Significance statementBrain connectivity is a central topic in neuroscience. Understanding how brain areas can communicate allows for the comprehension of brain structure and function. We have described in rodents a new commissure pathway that connects the cortex to the contralateral thalamus. Here, we investigate whether this pathway exists in non-human primates and humans. The presence of these commissures poses the TCs as an important fiber pathway in the primate brain, allowing for more robust interhemispheric connectivity and synchrony and serving as an alternative commissural route in developmental brain malformations.

neuroscience↗

bioRxiv2023

ARID1B controls transcriptional programs of axon projection in the human corpus callosum

Mutations in ARID1B, a member of the mSWI/SNF complex, cause severe neurodevelopmental phenotypes with elusive mechanisms in humans. The most common structural abnormality in the brain of ARID1B patients is agenesis of the corpus callosum (ACC). This condition is characterized by a partial or complete absence of the corpus callosum (CC), an interhemispheric white matter tract that connects distant cortical regions. Using human neural organoids, we identify a vulnerability of callosal projection neurons (CPNs) to ARID1B haploinsufficiency, resulting in abnormal maturation trajectories and dysregulation of transcriptional programs of CC development. Through a novel in vitro model of the CC tract, we demonstrate that ARID1B mutations reduce the proportion of CPNs capable of forming long-range projections, leading to structural underconnectivity phenotypes. Our study uncovers new functions of the mSWI/SNF during human corticogenesis, identifying cell-autonomous defects in axonogenesis as a cause of ACC in ARID1B patients. O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/539362v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@dd4e9aorg.highwire.dtl.DTLVardef@153a081org.highwire.dtl.DTLVardef@14e884corg.highwire.dtl.DTLVardef@d64081_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO Human callosal projection neurons are vulnerable to ARID1B haploinsufficiency. (Top) During healthy development, callosal projection neurons (CPNs) project long interhemispheric axons, forming the corpus callosum (CC) tract, which can be modeled in vitro. (Bottom) In ARID1B patients, transcriptional dysregulation of genetic programs of CC development reduces the formation of long-range projections from CPNs, causing CC agenesis in vivo and underconnectivity phenotypes in vitro. C_FIG

neuroscience↗

bioRxiv2022

Single-cell brain organoid screening identifies developmental defects in autism

Development of the human brain involves processes that are not seen in many other species, but can contribute to neurodevelopmental disorders (1-4). Cerebral organoids can be used to investigate neurodevelopmental disorders in a human context but are limited by variability and low throughput. We have developed the CRISPR-human organoids-scRNA-seq (CHOOSE) system that utilizes verified pairs of gRNAs, inducible CRISPR/Cas9-based genetic disruption, and single-cell transcriptomics for pooled loss-of-function screening in mosaic organoids. Genetic perturbations of 36 high-risk autism spectrum disorder (ASD) genes related to transcriptional regulation allowed us to identify their effects on cell fate determination and discover developmental stages susceptible to ASD gene perturbations. We construct a developmental gene regulatory network (GRN) of cerebral organoids from single-cell multiomic data including transcriptome and chromatin modalities and identify ASD-associated and perturbation-enriched regulatory modules. We show that perturbing members of the BAF chromatin remodeling complex leads to an expanded population of ventral telencephalon progenitors. Specifically, the BAF subunit ARID1B controls the fate transitions of progenitors to oligodendrocyte precursor cells and interneurons, which we confirmed in patient-specific induced pluripotent stem cell (iPSC) derived organoids. Our study paves the way for phenotypically characterizing disease susceptibility genes in human organoid models with cell type, developmental trajectory, and gene regulatory network readouts.

developmental biology↗