Biology subjects

Bernasconi, N.

Publications and source records attributed to Bernasconi, N..

33 records · Page 2Linked to original sources

bioRxiv2023

Atypical connectome topography and signal flow in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is one of the most common pharmaco-resistant epilepsies in adults. While hippocampal pathology is the hallmark of this condition, emerging evidence indicates that brain alterations extend beyond the mesiotemporal epicenter and affect macroscale brain function and cognition. We studied macroscale functional reorganization in TLE, explored structural substrates, and examined cognitive associations. We investigated a multisite cohort of 95 patients with pharmaco-resistant TLE and 95 healthy controls using state-of-the-art multimodal 3T magnetic resonance imaging (MRI). We quantified macroscale functional topographic organization using connectome dimensionality reduction techniques and estimated directional functional flow using generative models of effective connectivity. We observed atypical functional topographies in patients with TLE relative to controls, manifesting as reduced functional differentiation between sensory/motor networks and transmodal systems such as the default mode network, with peak alterations in bilateral temporal and ventromedial prefrontal cortices. TLE-related topographic changes were consistent in all three included sites and reflected reductions in hierarchical flow patterns between cortical systems. Integration of parallel multimodal MRI data indicated that these findings were independent of TLE-related cortical grey matter atrophy, but mediated by microstructural alterations in the superficial white matter immediately beneath the cortex. The magnitude of functional perturbations was robustly associated with behavioral markers of memory function. Overall, this work provides converging evidence for macroscale functional imbalances, contributing microstructural alterations, and their associations with cognitive dysfunction in TLE.

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bioRxiv2023

Hippocampal subfield CA1-3 shows differential structural and functional network plasticity after stress-reducing socio-affective mental training

The hippocampus is a central modulator of the HPA-axis, impacting the regulation of stress on brain structure, function, and behavior. The current study assessed whether three different types of 3-months mental Training Modules geared towards nurturing a) attention-based mindfulness, b) socio-affective or c) socio-cognitive skills may impact hippocampal organization by reducing stress. We evaluated mental training-induced changes in hippocampal subfield volume and intrinsic functional connectivity, by combining longitudinal structural and resting-state fMRI connectivity analysis in 332 healthy adults. We related these changes to changes in diurnal and chronic cortisol levels. We observed increases in bilateral cornu ammonis volume (CA1-3) following the 3-months compassion-based module targeting socio-affective skills (Affect module), as compared to socio-cognitive skills (Perspective module) or a waitlist cohort with no training intervention. Structural changes were paralleled by relative increases in functional connectivity of CA1-3 when fostering socio-affective as compared to socio-cognitive skills. Furthermore, training-induced changes in CA1-3 structure and function consistently correlated with reductions in cortisol output. Notably, using a multivariate approach, we found that other subfields that did not show group-level changes also contributed to changes in cortisol levels. Overall, we provide a link between a socio-emotional behavioural intervention, changes in hippocampal subfield structure and function, and reductions in cortisol in healthy adults.

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bioRxiv2022

DIFFERENTIAL MEMORY IMPAIRMENT ACROSS RELATIONAL DOMAINS IN TEMPORAL LOBE EPILEPSY

BO_SCPLOWACKGROUNDC_SCPLOWTemporal lobe epilepsy (TLE) is typically associated with pathology of the hippocampus, a key structure involved in relational memory processes, including episodic, semantic, and spatial memory. While it is widely accepted that TLE-associated hippocampal alterations may underlie global deficits in memory, it remains poorly understood whether TLE may present with shared or unique impairment across distinct relational memory domains. MO_SCPLOWETHODSC_SCPLOWWe administered a recently validated behavioral paradigm to evaluate episodic, semantic, and spatial memory in 20 pharmacoresistant TLE patients and 53 age- and sex-matched healthy controls. We implemented linear mixed effects models to identify memory deficits in individuals with TLE relative to controls, and used partial least squares analysis to identify factors contributing to overall variations in relational memory performance across both cohorts. RO_SCPLOWESULTSC_SCPLOWTLE patients showed marked impairment in episodic memory compared to controls, while spatial and semantic memory remained relatively intact. Findings were robust, with slight decreases in effect sizes after controlling for performance on executive function tests. Via partial least squares analysis, we identified group, age, and bilateral hippocampal volumes as important variables relating to relational memory impairment. CO_SCPLOWONCLUSIONC_SCPLOWOur behavioral framework provides a granular approach for assessing relational memory deficits in people with TLE and may inform future prognostic strategies in patients with hippocampal pathology. Our work warrants further investigations into the underlying neural substrates of relational memory.

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bioRxiv2022

Cortical microstructural gradients capture memory network reorganization in temporal lobe epilepsy

Temporal lobe epilepsy (TLE), one of the most common pharmaco-resistant epilepsies, is associated with pathology of paralimbic brain regions, particularly in the mesiotemporal lobe. Cognitive dysfunction in TLE is frequent, and particularly affects episodic memory. Crucially, these difficulties challenge the quality of life of patients, sometimes more than seizures, underscoring the need to assess neural processes of cognitive dysfunction in TLE to improve patient management. Our work harnessed a novel conceptual and analytical approach to assess spatial gradients of microstructural differentiation between cortical areas based on high-resolution MRI analysis. Gradients track region-to-region variations in intracortical lamination and myeloarchitecture, serving as a system-level measure of structural and functional reorganization. Comparing cortex-wide microstructural gradients between 21 patients and 35 healthy controls, we observed a contracted gradient in TLE driven by reduced microstructural differentiation between paralimbic cortices and the remaining cortex with marked abnormalities in ipsilateral temporopolar and dorsolateral prefrontal regions. Findings were replicated in an independent cohort. Using an independent post mortem dataset, we observed that in vivo findings reflected topographical variations in cortical lamination patterns, confirming that TLE-related changes in the microstructural gradient reflected increased proximity of regions with more dissimilar laminar structure. Disease-related transcriptomics could furthermore show specificity of our findings to TLE over other common epilepsy syndromes. Finally, microstructural dedifferentiation was associated with cognitive network reorganization seen during an episodic memory functional MRI paradigm, and correlated with inter-individual differences in task accuracy. Collectively, our findings showing a pattern of reduced microarchitectural differentiation between paralimbic regions and the remaining cortex provide a parsimonious explanation for functional network reorganization and cognitive dysfunction characteristic of TLE.

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bioRxiv2022

Atypical intrinsic neural timescales in temporal lobe epilepsy

ObjectiveTemporal lobe epilepsy (TLE) is the most common drug-resistant epilepsy in adults. Here, we aimed to profile local neural function in TLE in vivo, building on prior evidence that has identified widespread structural alterations. Using multimodal MRI, we mapped intrinsic neural timescales (INT) at rest, examined associations to TLE-related structural compromise, and evaluated the clinical utility of INT. MethodsWe studied 46 TLE patients and 44 healthy controls from two independent sites, and mapped INT changes in patients relative to controls across hippocampal, subcortical, and neocortical regions. We examined region-specific associations to structural alterations and explored effects of age and epilepsy duration. A supervised machine learning paradigm assessed utility of INT for classifying patients-vs-controls and seizure focus lateralization. ResultsRelative to controls, TLE showed marked INT reductions across multiple regions bilaterally, indexing faster changing resting activity, with strongest effects in ipsilateral medial and lateral temporal regions, and sensorimotor cortices. Findings were consistent in each site and robust, albeit with reduced effect sizes, when correcting for structural alterations. TLE-related INT reductions increased with advancing disease duration, yet findings differed from aging effects seen in controls. Classifiers based on INT distinguished patients-vs-controls (balanced accuracy, 5-fold: 76{+/-}2.65%; cross-site, 72-83%) and lateralized the focus in TLE (balanced accuracy, 5-fold: 96{+/-}2.10%; cross-site, 95-97%) with high accuracies and generalization. ConclusionsOur findings robustly demonstrate atypical macroscale function in TLE in a topography that extends beyond mesiotemporal epicenters. INT measurements can assist in TLE diagnosis, seizure focus lateralization, and monitoring of disease progression, which suggests clinical utility.

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bioRxiv2022

A whole-brain 3D myeloarchitectonic atlas: mapping the Vogt-Vogt legacy to the cortical surface

Building precise and detailed parcellations of anatomically and functionally distinct brain areas has been a major focus in Neuroscience. Pioneer anatomists parcellated the cortical manifold based on extensive histological studies of post-mortem brain, harnessing local variations in cortical cyto- and myeloarchitecture to define areal boundaries. Compared to the cytoarchitectonic field, where multiple neuroimaging studies have recently translated this old legacy data into useful analytical resources, myeloarchitectonics, which parcellate the cortex based on the organization of myelinated fibers, has received less attention. Here, we present the neocortical surface-based myeloarchitectonic atlas based on the histology-derived maps of the Vogt-Vogt school and its 2D translation by Nieuwenhuys. In addition to a myeloarchitectonic parcellation, our package includes intracortical laminar profiles of myelin content based on Vogt-Vogt-Hopf original publications. Histology-derived myelin density mapped on our atlas demonstrate close overlap with in vivo quantitative MRI markers for myelin and relates to cytoarchitectural features. Complementing the existing battery of approaches for digital cartography, the whole-brain myeloarchitectonic atlas offers an opportunity to validate imaging surrogate markers of myelin in both health and disease. HighlightsO_LIOur myeloarchitectonic atlas builds on extensive meta-analyses-derived and ground-truth histological data. C_LIO_LIOur atlas provides qualitative and quantitative 3D information on cortical myelin architecture. C_LIO_LIMRI surrogate markers of myelin demonstrate close overlap with histological cortical parcellations, supporting biological validity of non-invasive metrics. C_LIO_LIThis atlas can be seamlessly integrated into widely used neuroimaging analysis software to inform studies in health and disease. C_LI

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bioRxiv2021

Heritability of hippocampal functional and microstructural organisation

The hippocampus is a uniquely infolded allocortical structure in the medial temporal lobe that consists of the microstructurally and functionally distinct subregions: subiculum, cornu ammonis, and dentate gyrus. The hippocampus is a remarkably plastic region that is implicated in learning and memory. At the same time it has been shown that hippocampal subregion volumes are heritable, and that genetic expression varies along a posterior to anterior axis. Here, we studied how a heritable, stable, hippocampal organisation may support its flexible function in healthy adults. Leveraging the twin set-up of the Human Connectome Project with multimodal neuroimaging, we observed that the functional connectivity between hippocampus and cortex was heritable and that microstructure of the hippocampus genetically correlated with cortical microstructure. Moreover, both functional and microstructural organisation could be consistently captured by anterior-to-posterior and medial-to-lateral axes across individuals. However, heritability of functional, relative to microstructural, organisation was found reduced, suggesting individual variation in functional organisation of subfields is under low genetic control. Last, we demonstrate that structure and function couple along its genetic axes, suggesting an interplay of stability and plasticity within the hippocampus. Our study provides new insights on the heritability of the hippocampal formation and illustrates how genetic axes may scaffold hippocampal structure and function.

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bioRxiv2021

An open MRI dataset for multiscale neuroscience

AO_SCPLOWBSTRACTC_SCPLOWMultimodal neuroimaging grants a powerful window into the structure and function of the human brain at multiple scales. Recent methodological and conceptual advances have enabled investigations of the interplay between large-scale spatial trends (also referred to as gradients) in brain microstructure and connectivity, offering an integrative framework to study multiscale brain organization. Here, we share a multimodal MRI dataset for Microstructure-Informed Connectomics (MICA-MICs) acquired in 50 healthy adults (23 women; 29.54{+/-}5.62 years) who underwent high-resolution T1-weighted MRI, myelin-sensitive quantitative T1 relaxometry, diffusion-weighted MRI, and resting-state functional MRI at 3 Tesla. In addition to raw anonymized MRI data, this release includes brain-wide connectomes derived from i) resting-state functional imaging, ii) diffusion tractography, iii) microstructure covariance analysis, and iv) geodesic cortical distance, gathered across multiple parcellation scales. Alongside, we share large-scale gradients estimated from each modality and parcellation scale. Our dataset will facilitate future research examining the coupling between brain microstructure, connectivity, and macroscale function. MICA-MICs is available on the Canadian Open Neuroscience Platforms data portal (https://portal.conp.ca).

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bioRxiv2020

A structure-function substrate of memory for spatial configurations in medial and lateral temporal cortices

AO_SCPLOWBSTRACTC_SCPLOWPrior research has shown that structures of the mesiotemporal lobe, particularly the hippocampal-parahippocampal complex, are engaged in different forms of spatial cognition. Here, we developed a new paradigm, the Conformational Shift Spatial task (CSST), which examines the ability to encode and retrieve spatial relations between three unrelated items. This task is short, uses symbolic cues, and incorporates two difficulty levels and can be administered inside and outside the scanner. A cohort of 48 healthy young adults underwent the CSST, together with a set of validated behavioral measures and multimodal magnetic resonance imaging (MRI). Interindividual differences in CSST performance correlated with scores on an established spatial memory paradigm, but neither with episodic memory nor pattern separation performance, highlighting the specificity of the new measure. Analyzing high resolution structural MRI data, individuals with better spatial memory showed thicker medial as well as lateral temporal cortices. Functional relevance of these findings was supported by task-based functional MRI analysis in the same participants and ad hoc meta-analysis. Exploratory resting-state functional MRI analyses centered on clusters of morphological effects revealed additional modulation of intrinsic network integration, particularly between lateral and medial temporal structures. Our work presents a novel spatial memory paradigm and supports an integrated structure-function substrate in the human temporal lobe. Task paradigms are programmed in python and made open access.

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bioRxiv2020

Topographic profiling of memory-related pattern separation processes in humans

AO_SCPLOWBSTRACTC_SCPLOWEpisodic memory is our ability to remember past events accurately. Pattern separation, the process of of orthogonalizing similar aspects of external information into nonoverlapping representations, is one of its mechanisms. Converging evidence suggests a pivotal role of the hippocampus, in concert with neocortical areas, in this process. The current study aimed to identify principal dimensions of functional activation associated with pattern separation in hippocampal and neocortical areas, in both healthy individuals and patients with lesions to the hippocampus. Administering a pattern separation fMRI paradigm to a group of healthy adults, we detected task-related activation in bilateral hippocampal and distributed neocortical areas. Capitalizing on manifold learning techniques applied to parallel resting-state fMRI data, we could identify that hippocampal and neocortical activity patterns were efficiently captured by their principal gradients of intrinsic functional connectivity, which follows the hippocampal long axis and sensory-fugal cortical organization. Functional activation patterns and their alignment with these principal dimensions were altered in patients. Notably, inter-individual differences in the concordance between task-related activity and intrinsic functional gradients were correlated with pattern separation performance in both patients and controls. Our work outlines a parsimonious approach to capture the functional underpinnings of episodic memory processes at the systems level, and to decode functional reorganization in clinical populations.

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bioRxiv2020

Convergence of cortical types and functional motifs in the mesiotemporal lobe

AO_SCPLOWBSTRACTC_SCPLOWThe parahippocampus-hippocampus complex in the mesiotemporal lobe (MTL) is implicated in many different cognitive processes, is compromised in numerous disorders, and exhibits a unique cytoarchitectural transition from six-layered isocortex to three-layered allocortex. Our study leveraged an ultra-high-resolution histological reconstruction of a human brain to (i) develop a continuous surface model of the MTL iso-to-allocortex transition and (ii) quantitatively characterise the regions cytoarchitecture. We projected the model into the native space of in vivo functional magnetic resonance imaging of healthy adults to (iii) construct a generative model of its intrinsic circuitry and (iv) determine its relationship with distributed functional dynamics of macroscale isocortical fluctuations. We provide evidence that the most prominent axis of cytoarchitectural differentiation of the MTL follows infolding from iso-to-allocortex and is defined by depth-specific variations in neuron density. Intrinsic effective connectivity exhibited a more complex relationship to MTL geometry, varying across both iso-to-allocortical and anterior-posterior axes. Variation along the long axis of the MTL was associated with differentiation between transmodal and unimodal systems, with anterior regions linked to transmodal cortex. In contrast, the iso-to-allocortical gradient was associated with the multiple demand system, with isocortex linked to regions activated when task demands prohibit the use of prior knowledge. Our findings establish a novel model of the MTL, in which its broad influence on neural function emerges through the combination micro- and macro-scale structural features. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/148643v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@48dbc7org.highwire.dtl.DTLVardef@15500a2org.highwire.dtl.DTLVardef@19c99b2org.highwire.dtl.DTLVardef@2eab49_HPS_FORMAT_FIGEXP M_FIG C_FIG

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bioRxiv2019

White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA Epilepsy study

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analyzed from 1,069 non-epileptic controls and 1,249 patients: temporal lobe epilepsy with hippocampal sclerosis (N=599), temporal lobe epilepsy with normal MRI (N=275), genetic generalized epilepsy (N=182) and nonlesional extratemporal epilepsy (N=193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at p<0.001). Across "all epilepsies" lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. Less robust effects were seen with mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Those with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced differences in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and in mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of microstructural abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicentre study of epilepsy. Overall, epilepsy patients showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding new insights into pathological substrates that may be used to guide future therapeutic and genetic studies.

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bioRxiv2019

Functional connectome contractions in temporal lobe epilepsy

AO_SCPLOWBSTRACTC_SCPLOWTemporal lobe epilepsy (TLE) is the most common drug-resistant epilepsy in adults. While commonly related to hippocampal pathology, increasing evidence suggests structural changes beyond the mesiotemporal lobe. Functional anomalies and their link to underlying structural alterations, however, remain incompletely understood. We studied 30 drug-resistant TLE patients and 57 healthy controls using multimodal magnetic resonance imaging analyses. We developed a novel framework that parameterizes functional connectivity distance, consolidating functional and geometric properties of macroscale networks. Compared to controls, TLE showed connectivity distance reductions in temporo-insular and prefrontal networks, suggesting topological segregation of functional networks. Our novel approach furthermore allowed for the testing of morphological and microstructural associations, and revealed that functional connectivity contractions occurred independently from TLE-related cortical atrophy but were mediated by microstructural changes in the underlying white matter. All patients underwent a comparable resective surgery after our study and a regularized supervised machine learning paradigm with 5-fold cross-validation demonstrated that patient-specific functional anomalies predicted post-surgical seizure outcome with 74{+/-}8% accuracy, outperforming classifiers operating on clinical and structural imaging features. Our findings suggest connectivity distance contractions as a clinically relevant pathoconnectomic substrate of TLE. Functional topological isolation may represent a microstructurally mediated network mechanism that tilts the balance towards epileptogenesis.

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bioRxiv2019

Targeting age-related differences in brain and cognition with multimodal imaging and connectome topography profiling

I.AO_SCPLOWBSTRACTC_SCPLOWAging is characterised by accumulation of structural and metabolic changes in the brain. Recent studies suggest transmodal brain networks are especially sensitive to aging, which, we hypothesise, may be due to their apical position in the cortical hierarchy. Studying an open-access healthy cohort (n=102, age range = 30-89 years) with MRI and A{beta} PET data, we estimated age-related cortical thinning, hippocampal atrophy and A{beta} deposition. In addition to carrying out surface-based morphological and metabolic mapping, we stratified effects along neocortical and hippocampal resting-state functional connectome gradients derived from independent datasets. The cortical gradient depicts an axis of functional differentiation from sensory-motor regions to transmodal regions, whereas the hippocampal gradient recapitulates its long-axis. While age-related thinning and increased A{beta} deposition occurred across the entire cortical topography, increased A{beta} deposition was especially pronounced towards higher-order transmodal regions. Age-related atrophy was greater towards the posterior end of the hippocampal long-axis. No significant effect of age on A{beta} deposition in the hippocampus was observed. Imaging markers correlated with behavioural measures of fluid intelligence and episodic memory in a topography-specific manner. Our results strengthen existing evidence of structural and metabolic change in the aging brain and support the use of connectivity gradients as a compact framework to analyse and conceptualize brain-based biomarkers of aging.

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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.

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