Biology subjects

Bender, B.

Publications and source records attributed to Bender, B..

12 recordsLinked to original sources

bioRxiv2026

Multi-Parametric Phase-Cycled Balanced Steady-State Free Precession Brain Tissue Characterization in Relapsing-Remitting Multiple Sclerosis

Quantitative MRI enables the detection of subtle microstructural alterations in normal-appearing white matter (NAWM) associated with pathological conditions such as multiple sclerosis. Quantitative metrics including R1, R2, and the bSSFP asymmetry index (AI) were evaluated in the WM of 20 relapsing-remitting multiple sclerosis (RRMS) patients and 10 healthy controls (HC). A multi-parametric frame-work based on a phase-cycled balanced steady-state free precession (pc-bSSFP) sequence was used. Diffusion tensor imaging-derived measures, including fiber-to-field angle, number of fiber orientations, and fractional anisotropy, were incorporated to assess parameter anisotropy. Statistical analysis was performed using linear mixed-effects models to test for group, ROI, and group-by-ROI effects for each metric, with ROI-specific group comparisons derived from the model. Significant main effects of group, ROI, and group-by-ROI interaction were observed for both R1 and R2, whereas for AI only the ROI effect reached significance (group p= 0.462; group-by-ROI p = 0.786). Fourteen of sixteen ROIs demonstrated significantly lower R1 and R2 values in RRMS compared with HC. No ROI showed significant differences in AI. In conclusion, pc-bSSFP-based relaxometry reveals predominantly white matter alterations in RRMS, while enabling a comprehensive whole-brain assessment that also encompasses gray matter.

neuroscience↗

bioRxiv2025

From stomach to striatum: Ghrelin infusions increase work for rewards

Preclinical evidence demonstrates that gut signals influence motivated behavior through the dopaminergic system. However, translational research in humans is scarce, and it is not known if surges of the stomach-derived hormone ghrelin acutely boost motivation via dopamine transmission. To close this gap, we investigated the effects of acyl ghrelin infusions (vs. saline) on instrumental work for rewards, brain responses, and dopamine transmission in healthy adults in a double-blind, randomized and placebo-controlled crossover study with [11C]raclopride PET-fMRI. In line with preclinical findings, ghrelin enhanced hunger sensations (p = .007), and effort for food and small rewards. Crucially, ghrelin enhanced functional connectivity between the hypothalamus and the striatum (NAcc: pSVC = .016), as well as within the striatum (NAcc<>Putamen: pSVC = .001), pointing to an enhanced coupling between homeostatic and motivational circuits. However, ghrelin did not alter dopamine binding potential (reflecting changes in endogenous tone), but boosted task-free phasic pulses of the NAcc BOLD signal (p = .020), which were negatively associated with binding potential (p = .034). During the task, ghrelin increased cue- (precentral gyrus: pFWE = .003) and effort-evoked brain responses (e.g., VTA/SN: psvc = .002) in accordance with increases in motivation. Together, these findings recapitulate preclinical work that ghrelin primarily boosts phasic dopamine release, reflecting enhanced incentive salience of food and smaller rewards. This highlights the potential of targeting gut-brain interactions to improve motivational symptoms, such as loss of appetite or anhedonia. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/691596v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@4321e6org.highwire.dtl.DTLVardef@166bda5org.highwire.dtl.DTLVardef@2ca69dorg.highwire.dtl.DTLVardef@16e93a9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

A Core Pattern of Cerebellar and Brainstem Degeneration and Reduced Cerebrocerebellar Structural Covariance in Spinocerebellar Ataxia Type 3 (SCA3): MRI Volumetrics from ENIGMA-Ataxia

ObjectiveSpinocerebellar ataxia type 3 (SCA3) is a rare, inherited neurodegenerative disease. Here, we profile the spatial spread of atrophy across the whole brain, determine whether brain degeneration preferentially maps onto specific functional networks, and investigate the relationship between cerebellar and cerebral anatomical changes. MethodsWhole-brain grey and white matter (GM and WM) voxel-based morphometry was performed on 408 individuals with SCA3 (82 pre-ataxic) and 293 controls. The SCA3 cohort was stratified by ataxia severity to investigate disease progression, with cerebellar GM atrophy mapped onto a task-based functional atlas. Volume was correlated with disease duration and intensity. Cerebrocerebellar volumetric covariance was assessed to determine whether atrophy was coupled between infra- and supratentorial regions. ResultsThe pattern of atrophy is spatially consistent but progressive in magnitude across the disease course. The greatest atrophy was found in the pons, cerebellar WM, and cerebellar peduncles; correlations with disease severity and duration were also strongest in these regions. Cerebellar GM atrophy was greatest in functional regions associated with motor execution and planning, attention, and emotional processing. Sparse cerebral cortical atrophy appears only in the most severe disease subgroup, while striatal atrophy begins in the earliest stages. Reduced cerebrocerebellar structural covariance is observed in SCA3 participants versus controls. InterpretationWhile cerebellar and brainstem atrophy become more severe, the pattern of atrophy remains largely consistent as SCA3 progresses. Cerebellar GM degeneration occurs in regions associated with motor, cognitive, and affective control, in line with clinical presentation. Cerebellar atrophy is not directly mirrored by cerebral changes.

neuroscience↗

bioRxiv2025

Functional connectivity of thalamic nuclei during sensorimotor task-based fMRI at 9.4 Tesla

The thalamus is the brains central communication hub, playing a key role in processing and relaying sensorimotor and cognitive information between the cerebral cortex and other brain regions. It consists of specific and non-specific nuclei, each with a different role. Specific thalamic nuclei relay sensory and motor information to specific cortical and subcortical regions to ensure precise communication. In contrast, non-specific thalamic nuclei are involved in general functions such as attention or consciousness through broader and less targeted connections. In the present study, we aimed to investigate the functional connectivity patterns of the thalamic nuclei identified in our previous study as being involved in motor (finger-tapping) and sensory (finger-touch) tasks. The results of this study show that thalamic nuclei are not static hubs with a predefined role in neural signal processing, as they show different task-specific functional connectivity patterns in the anterior, middle, lateral, and posterior thalamic nuclei. Instead, they are all functional hubs that can flexibly change their connections to other brain regions in response to task demands. This work has important implications for understanding task-dependent functional connectivity between thalamic nuclei and different brain regions using task-based fMRI at 9.4 Tesla.

neuroscience↗

bioRxiv2024

The Pattern and Staging of Brain Atrophy in Spinocerebellar Ataxia Type 2 (SCA2): MRI Volumetrics from ENIGMA-Ataxia

ObjectiveSpinocerebellar ataxia type 2 (SCA2) is a rare, inherited neurodegenerative disease characterised by progressive deterioration in both motor coordination and cognitive function. Atrophy of the cerebellum, brainstem, and spinal cord are core features of SCA2, however the evolution and pattern of whole-brain atrophy in SCA2 remain unclear. We undertook a multi-site, structural magnetic resonance imaging (MRI) study to comprehensively characterize the neurodegeneration profile of SCA2. MethodsVoxel-based morphometry analyses of 110 participants with SCA2 and 128 controls were undertaken to assess groupwise differences in whole-brain volume. Correlations with clinical severity and genotype, and cross-sectional profiling of atrophy patterns at different disease stages, were also performed. ResultsAtrophy in SCA2 relative to controls was greatest (Cohens d>2.5) in the cerebellar white matter (WM), middle cerebellar peduncle, pons, and corticospinal tract. Very large effects (d>1.5) were also evident in the superior cerebellar, inferior cerebellar, and cerebral peduncles. In cerebellar grey matter (GM), large effects (d>0.8) mapped to areas related to both motor coordination and cognitive tasks. Strong correlations (|r|>0.4) between volume and disease severity largely mirrored these groupwise outcomes. Stratification by disease severity showed a degeneration pattern beginning in cerebellar and pontine WM in pre-clinical subjects; spreading to the cerebellar GM and cerebro-cerebellar/corticospinal WM tracts; then finally involving the thalamus, striatum, and cortex in severe stages. InterpretationThe magnitude and pattern of brain atrophy evolves over the course of SCA2, with widespread, non-uniform involvement across the brainstem, cerebellar tracts, and cerebellar cortex; and late involvement of the cerebral cortex and striatum.

neuroscience↗

bioRxiv2024

UltraCortex: Submillimeter Ultra-High Field 9.4 T Brain MR Image Collection and Manual Cortical Segmentations

The UltraCortex repository (https://www.ultracortex.org) houses magnetic resonance imaging data of the human brain obtained at an ultra-high field strength of 9.4 T. It contains 86 structural MR images with spatial resolutions ranging from 0.6 to 0.8 mm. Additionally, the repository includes segmentations of 12 brains into gray and white matter compartments. These segmentations have been independently validated by two expert neuroradiologists, thus establishing them as a reliable gold standard. This resource provides researchers with access to high-quality brain imaging data and validated segmentations, facilitating neuroimaging studies and advancing our understanding of brain structure and function. Existing repositories do not accommodate field strengths beyond 7 T, nor do they offer validated segmentations, underscoring the significance of this new resource.

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↗

bioRxiv2021

Topographic divergence of atypical cortical asymmetry and regional atrophy patterns in temporal lobe epilepsy: a worldwide enigma study

AO_SCPLOWBSTRACTC_SCPLOWTemporal lobe epilepsy (TLE), a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter pathology in TLE relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multi-site ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 TLE patients and 1,418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in TLE, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity, and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of TLE-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of TLE and may inform future discovery and validation of complementary MRI biomarkers in TLE.

neuroscience↗

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.

neuroscience↗

bioRxiv2019

RosettaGPCR: Multiple Template Homology Modeling of GPCRs with Rosetta

G-protein coupled receptors (GPCRs) represent a significant target class for pharmaceutical therapies. However, to date, only about 10% of druggable GPCRs have had their structures characterized at atomic resolution. Further, because of the flexibility of GPCRs, alternative conformations remain to be modeled, even after an experimental structure is available. Thus, computational modeling of GPCRs is a crucial component for understanding biological function and to aid development of new therapeutics. Previous single- and multi-template homology modeling protocols in Rosetta often generated non-native-like conformations of transmembrane -helices and/or extracellular loops. Here we present a new Rosetta protocol for modeling GPCRs that is improved in two critical ways: Firstly, it uses a blended sequence- and structure-based alignment that now accounts for structure conservation in extracellular loops. Secondly, by merging multiple template structures into one comparative model, the best possible template for every region of a target GPCR can be used expanding the conformational space sampled in a meaningful way. This new method allows for accurate modeling of receptors using templates as low as 20% sequence identity, which accounts for nearly the entire druggable space of GPCRs. A model database of all non-odorant GPCRs is made available at www.rosettagpcr.org. Author SummaryStructure-based drug discovery is among the new technologies driving the development of next generation therapeutics. Inherent to this process is the availability of a protein structure for virtual screening. The most heavily drugged protein family, G-protein coupled receptors (GPCRs), however suffers from a lack of experimental structures that could hinder drug development. Technical challenges prevent the determination of every protein structure, so we turn to computational modeling to predict the structures of the remaining proteins. Again, traditional techniques fail due to the high divergence of this family. Here, we build on available methods specifically for the challenge of modeling GPCRs. This new method outperforms other methods and allows for the ability to accurately model nearly 90% of the entire GPCR family. We therefore generate a model database of all GPCRs (www.rosettagpcr.org) for use in future drug development.

bioinformatics↗

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↗