Biology subjects

Chakravarty, M.

Publications and source records attributed to Chakravarty, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Algorithmic Geometry Shapes the Biological Meaning of Thalamocortical Structural Covariance

Neuroimaging studies often derive and discuss structural covariance (SC) as a representation of underlying brain circuitry that reflects coordinated maturation, anatomical connectivity, transcriptional similarity, and shared genetic influences. These associations motivate its use to study brain organization across development, aging, and disease. However, the algorithms used to derive SC networks impose constraints that may shape their biological interpretation. To understand the impact of algorithm choice, we used the thalamocortical system as an example and compared five common representations of voxelwise SC, namely, principal component analysis (PCA), independent component analysis (ICA), non-negative matrix factorization (NMF), orthogonal projective NMF (OPNMF), and \textit{k}-means clustering, in 755 participants aged 8--22 years from the Philadelphia Neurodevelopmental Cohort (PNC). SC networks derived from deformation-based morphometry (DBM) were evaluated against three complementary biological benchmarks: age-related individual differences, fractional-anisotropy (FA)-based microstructural connectivity of regionally-specific thalamocortical connections, and Allen Human Brain Atlas gene expression. Each algorithm demonstrated underlying sensitivity to differing aspects of neurobiology: PCA and OPNMF showed the strongest associations between participant-level component weights and age. NMF, OPNMF, and \textit{k}-means showed greater spatial overlap between positive cortical SC and tractography-derived projections. ICA and PCA showed stronger correspondence between thalamic and cortical gene-expression profiles across the transcriptome, whereas NMF, OPNMF, and \textit{k}-means more often identified thalamic components with relatively high core-matrix gene expression. This study emphasizes that algorithmic constraints effectively act as biological priors and decomposition methods do not provide neutral compression of the data. We conclude that it is critical to consider whether the algorithmic objective matches the representational geometry of the neurobiology being studied. Overall, our findings suggest that SC studies should select and justify algorithms according to the biological question, explicitly considering whether their constraints favour distributed gradients, overlapping regional parts, or discrete clusters. Meanwhile, interpretations of SC findings could also be informed by the specific algorithmic constraints used to derive them.

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bioRxiv2026

Sex Differences in Human Subcortical Anatomy are Robust and Replicable in Adulthood, Already Evident Prepubertally, and Aligned with Sex Chromosomal and Gonadal Influences

The existence and mechanistic bases of sex effects on human subcortical anatomy remain unclear. To address these gaps, we combined structural neuroimaging of sex differences in subcortical volume and shape across three independent cohorts (combined N=2,886) with neuroimaging maps of sex chromosomal and endocrine effects from three clinical cohorts (combined N=313, including sex chromosome aneuploidies and isolated gonadotropin-releasing hormone deficiency). We found that human subcortical anatomy shows focal sex differences of moderate-strong effect size during young adulthood (male-biased surface area overlying lateral/ventral putamen and pallidum, nucleus accumbens, ventral posterior complex of thalamus, anterior hippocampus, and medial and central nuclei of amygdala; female-biased surface area overlying caudate head, posterior/dorsal pallidum, mediodorsal, lateral dorsal, lateral geniculate, and medial geniculate nuclei of thalamus, posterior hippocampus, and basolateral and lateral nuclei of amygdala). These regional sex differences show strong within-sample reproducibility at modest sample sizes (N[≥]200) and are replicable in a fully independent mid-adulthood cohort. Adult subcortical sex differences are already evident in nascent form by pre/early puberty (age 9 years), and the same holds for cortical sex differences. Comparison with neuroimaging data from rare disorder cohorts reveals a statistically significant spatial and directional congruence of subcortical sex differences with the anatomical effects of X-chromosome dosage in the striatum and effects of testicular hormones in the amygdala. Our findings provide a reference map for the fine-grained spatial patterning of sex differences in adult subcortical shape, demonstrating its replicability, establishment before pubertal progression, and spatial concordance with potentially causal sex chromosomal and gonadal effects.

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bioRxiv2026

Phosphorylated -Synuclein shapes changes in brain structure, task-related activity and functional connectivity in M83 mice

Phosphorylated -synuclein at S129 (pS129) is the predominant form of -synuclein in the aggregates known as Lewy bodies (LB) and Lewy neurites (LN), the pathological hallmarks of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), collectively known as synucleinopathies. The toxic nature of these inclusions remains contentious. To improve our understanding of these aggregates and their role in the structural and functional changes observed in synucleinopathies, we combined non-invasive structural and functional MRI in awake head-fixed M83 mice with whole-brain light-sheet fluorescence microscopy (LSFM) in the same animals following a unilateral injection of either human preformed fibrils of -synuclein (PFF) or PBS into the dorsal striatum. We developed a multimodal framework integrating the non-invasive, mesoscopic nature of MRI with the cellular-level details of LSFM to further our understanding of the underlying pathology of synucleinopathies. Using this framework, we show that four months after injection, animals injected with PFFs showed ubiquitous spread of pS129 pathology throughout the whole brain and spinal cord consistent with anatomical connectivity from the seeding region, with some structures such as the midbrain more susceptible to pS129 accumulation. Compared to controls, PFF-injected animals showed widespread atrophy as well as a decrease in functional connectivity, while evoked activity in the somatosensory/somatomotor areas in response to spontaneous paw movements showed significant hypoactivation. These cellular, structural and functional changes were significantly associated with the proportion of pS129 accumulation determined in the same animals. Our results demonstrate the deleterious effects of pS129 accumulation and argue in favor of a toxic role played by these aggregates.

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bioRxiv2026

T2 relaxometry for myelin water fraction: an ex vivo brain imaging study

Abstract Introduction: Myelin water imaging provides a non-invasive approach for indirectly investigating myelin content of the brain by magnetic resonance Imaging (MRI). Myelin water fraction (MWF) reflects the fraction of water signal associated with water trapped between myelin layers. Postmortem imaging provides a unique opportunity to validate MWF metrics against gold-standard postmortem neuropathology. However, there is a need for validated sequences that would be applicable in postmortem settings. In this study, we validated and compared the applicability of turbo spin echo (TSE) and gradient-and-spin-echo (GRASE) techniques for myelin water imaging in formaldehyde fixed postmortem human brains. Methods: 40 postmortem human brain hemispheres were scanned with TSE and GRASE sequences. Acquired data were reconstructed using a non-parametric multicomponent T2 relaxometry approach using a consistent framework to support comparison between GRASE- and TSE-derived measures. Agreement between derived measures was quantified at both voxel and regional level. Maps derived from the full 32-echo GRASE reconstruction were compared against a truncated 14-echo reconstruction to examine the contribution of the longer echoes to the derived maps. Finally, a random forest regression model was trained based on TSE data to predict the GRASE-derived MWF maps. Results: Both sequences provided robust multicomponent T2 characterization across the brain, and the derived measures showed anatomical patterns consistent with expected differences across tissue types. TSE and GRASE derived maps had moderate to strong agreement at voxel (0.41< {rho} < 0.82, all pFDR<0.001) and regional levels (0.87< {rho} < 0.98, all pFDR<0.001), with consistently stronger agreement observed for regional metrics. Echo reduction comparisons between the full 32-echo GRASE reconstruction and a truncated 14-echo reconstruction showed minimal impact of echo truncation (all {rho} > 0.98, pFDR < 0.001). The nonlinear random forest regression model trained on TSE maps was able to accurately reproduce the MWF maps derived from GRASE (r = 0.91, RMSE = 8.87). Discussion: TSE and GRASE32 capture strongly related multicomponent T2 information in fixed postmortem human brain tissue, but with systematic and tissue-dependent quantitative differences across derived measures. These differences suggest that direct interchangeability should not be assumed and that cross-sequence mapping or calibration is required when quantitative equivalence is desired.

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bioRxiv2026

Cerebellar influences on neocortical development in humans and mice

The cerebellum has long been considered a late-maturing structure subordinate to neocortical development, therefore its potential role as an early driver of cortical organization remains largely unexplored. Using two large longitudinal neuroimaging cohorts of developing children together with lesion experiments in mice, we show that early cerebellar morphology may drive neocortical maturation in a regionally specific manner. These cross-species findings implicate the cerebellum as a possible regulator of neocortical organization.

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bioRxiv2026

Spatiotemporal trajectories of formaldehyde fixation effects on quantitative MRI in postmortem human brains

Introduction: Postmortem human brain magnetic resonance imaging (MRI) offers a unique opportunity to study finer neuroanatomical details and enables direct correlations with gold standard histological and immunohistochemical assessments. However, to prevent tissue decay, postmortem brains are preserved in fixative solutions which can alter tissue properties and exert substantial impacts on the MRI signals. The present study investigates the impact of formalin fixation, the most commonly used solution for postmortem human brain preservation, on different quantitative MRI contrasts. Methods: 142 intact human brain hemispheres immersed in 10% formalin for a range of fixation durations (between 0 days and 20 years) were imaged in a 3T MRI scanner. A subset of 10 brains were further scanned repeatedly at days 0, 3, 10, 20, 30, 60, 90, and 120 to allow for better characterization of the initial transient effects of fixation. Voxel-wise T1 and T2* relaxation, T1/T2 ratio, and myelin water fraction (MWF) maps were generated for each specimen and timepoint, and linear and nonlinear models were used to examine the spatiotemporal changes associated with progressive fixation. Results: All investigated metrics were significantly impacted by formalin fixation, albeit at different rates and with differing regional patterns. T1 and T2* relaxation time decreased as a result of progressive fixation, whereas T1/T2 ratio and MWF measures increased. T1 relaxation and T1/T2 ratio showed nonlinear patterns with initially accelerated changes that decelerate in the first few months, whereas T2* relaxation and MWF changes followed a more linear trend. Conclusion: Formaldehyde fixation exerts systematic changes on quantitative MRI signals that can be modeled and adjusted for to allow for harmonized comparisons of MRI metrics across brains fixed for differing durations. The distinct temporal trajectories observed across metrics highlight the need to account for fixation duration in study design and downstream analyses, particularly when integrating datasets acquired under heterogeneous conditions. Our findings provide a quantitative framework for correcting fixation-induced biases, thereby improving the interpretability and reproducibility of postmortem MRI studies.

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bioRxiv2025

Fractionation of sex differences in human cortical anatomy

Humans show reproducible sex differences in regional cortical volume (CV), but it remains unclear how these arise from underlying sex-biases in the two biologically dissociable determinants of CV: surface area (SA) and cortical thickness (CT). Moreover, limited access to experimental methods in humans has hindered direct studies of the causal drivers of regional sex differences in the human cortex, although rodent models have argued for both chromosomal and gonadal contributions to sex-biased mammalian cortical development. Here, we first use structural neuroimaging data in two independent human cohorts (combined N=1,754; 967 females) to quantify and spatially resolve the differential contributions of SA and CT to observed sex differences in CV. These dissociable facets of sex-biased cortical organization are highly reproducible and align with distinct functional networks and histo-molecular signatures. We then leverage complementary neuroimaging data in clinical case-control cohorts (combined N=313) featuring variations in X and Y chromosome dosage (sex chromosome aneuploidies) and testicular hormone production (isolated GnRH deficiency) to establish that regions of sex-biased CV, SA and CT in humans are enriched for congruent anatomical effects of X-chromosome dosage (e.g., primary sensory and insular cortices) and gonadal hormones (e.g. dorsomedial frontal and temporo-parietal-occipital regions). Taken together, these findings substantially advance both the breadth and granularity of our understanding regarding sex-biased cortical organization in humans - disambiguating sex effects on regional CV, SA and CT and nominating their potential genetic and endocrine causes.

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bioRxiv2025

Accurate spatial localization of Allen Human Brain Atlas gene expression data for human neuroimaging

The Allen Human Brain Atlas has been a tremendously impactful resource in neuroimaging. The usefulness of this resource in neuroimaging arises from spatial coordinates of dissected tissue samples being provided in relation to a Montreal Neurological Institute (MNI)-space standard brain template, thereby allowing for the integration of gene expression and spatially standardized neuroimaging data. In fact, two previous sets of spatial coordinates exist, and surprisingly, the accuracy of these coordinates in placing dissected tissue samples in correct anatomical locations within MNI-space have not been examined. Here, we show that there are significant inaccuracies in the two previous sets of coordinates, and provide a refined set of coordinates as a resource to the neuroscience community. We show (through analyses of meta-analytic data and a re-analysis of real study data) that using previous inaccurate coordinates can result in dramatically different genes being identified, which could compromise further downstream analyses.

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bioRxiv2025

Evidence-based guidelines for improving network detectability in rodent fMRI

Mouse resting-state functional magnetic resonance imaging (rs-fMRI) is an increasingly popular tool for probing brain activity under experimental manipulations; however, there remains considerable variability in data quality throughout the field. There is a need for an accessible set of acquisition guidelines such that a baseline level of data quality can be attained regardless of domain expertise or specialized equipment (i.e. in anesthetized, free-breathing mice). In particular, there is a gap in the literature regarding the interpretation of physiological parameters as markers of anesthetic depth, and ultimately, data quality. To this end, we developed a set of acquisition guidelines after examining whether continuous physiological variables predict network detectability above and beyond categorical external variables (anesthetic dose, session, time) in C57Bl/7 and C3HeB/FeJ mice anesthetized with isoflurane-dexmedetomidine. Standard physiological metrics (respiration rate and heart rate) did not predict network detectability above and beyond anesthetic dose but instead depended strongly on strain and subject, thus we advise against tuning anesthesia based on respiration or heart rate when the goal is obtaining clear resting-state networks. The most important predictor of improved network detectability was a low isoflurane dose of 0.23%, hence we recommend that researchers prioritize piloting the minimal possible isoflurane dose for their mouse model. In summary, our work examines the contributions from sources of variability that impact rs-fMRI data quality and synthesizes the findings into practical guidelines to help experimenters adapt their acquisition protocols and improve data quality.

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bioRxiv2025

Whole brain dimensional approach identifies shared and sex-specific networks of stress susceptibility in male and female mice.

Stress is a major risk factor for depression and anxiety, two highly comorbid disorders with sex differences in symptom presentation and prevalence. Accumulating evidence on the chronic variable stress (CVS) mouse model has revealed that stress susceptibility is sex-specific, as females require less stress exposure (6 days) compared to males (21-28 days) to develop comparable adaptations in depressive- and anxiety-like behaviors. However, the neuroanatomical changes associated with stress susceptibility remain unclear in each sex. Given this differential susceptibility, elucidating these mechanisms requires a phenotype-matched approach in which stress duration is titrated in a sex-specific manner to induce comparable behavioral adaptations. Here, we used a multi-variate brain-behavior and connectomic analysis to examine signatures of stress susceptibility in female and male mice. Using structural magnetic resonance imaging (MRI), we investigate whole-brain neuroanatomical changes associated with behavioral susceptibility within each sex. We then examined the structural connectome underlying neuroanatomical changes associated with behavioral susceptibility within each sex, and putative molecular basis for behaviorally-relevant changes using spatial gene expression analyses. CVS induced significant neuroanatomical changes in regions commonly implicated in anxiety- and depressive-like phenotypes in both sexes (e.g. nucleus accumbens and hippocampus); however qualitative differences between sexes in the direction of change were observed. In addition to these changes, in females stress-induced neuroanatomical changes were associated with both depressive- and anxiety-like behavior, whereas in males we observed two orthogonal dimensions of neuroanatomical changes associated with anxiety-like behavior or social preference. The connectomic topology underlying these brain-behavior dimensions revealed the cortical hub regions for females and subcortical hub regions for males. In females, neuroanatomical changes were associated with genes enriched for protein localization to the cell surface, suggesting alterations in cholinergic signaling By implementing a phenotype-matched CVS protocol, our findings indicate that the neuroanatomical signature of stress susceptibility encompasses similar brain regions across both sexes, however the direction of change, association to behavior and connectomic properties may differ in each sex.

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bioRxiv2025

The effect of chronic stress and chronic alcohol intake on behavior, brain structure, and functional connectivity in a rat model

Pathological chronic stress is stress exceeding the organisms ability to cope physiologically, which may act as a risk factor in the onset and relapse of alcohol use disorder. Chronic- restraint stress (CRS) and ethanol intake are independently known to induce changes in brain structure and function, however, their combined effects on neurodevelopment over long periods of time remains largely unexplored. We conducted an in vivo longitudinal rat model with three main goals. 1) to determine if chronic stress increases ethanol intake; 2) to determine the effect of chronic- stress and ethanol intake in behavioral measures, brain structure, and function; and 3) to investigate the effect of sex. This observational study included Wistar rats assigned to four groups: 1) ethanol consumption (EtOH+/CRS-), 2) stress exposure (EtOH-/CRS+), 3) both ethanol and stress exposure (EtOH+/CRS+), and 4) control group (EtOH-/CRS-). Our results showed that chronic stress did not affect ethanol intake but led to reduced body weight gain, elevated corticosterone levels, and impaired recognition memory. Structural MRI revealed that both exposures produced additive brain volume changes in regions such as the olfactory bulb, orbitofrontal cortex, caudate-putamen, hippocampus, and cerebellum. Functional connectivity analysis using network-based statistics identified disrupted cortical-subcortical connections. Results found here were sex-dependent in terms of volumetric changes (higher effects on males) and functional connectivity (higher effects on females). Findings suggest sex-dependent mechanisms where both chronic- ethanol intake and stress affect brain plasticity during neurodevelopment. Understanding these region-specific vulnerabilities is crucial for addressing alcohol use disorders and stress-related neuropathology. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/638122v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@27094dorg.highwire.dtl.DTLVardef@d3b8faorg.highwire.dtl.DTLVardef@155deeorg.highwire.dtl.DTLVardef@c9bb7b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO Created with bioRender C_FIG

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bioRxiv2024

Impact of prenatal delta-9-tetrahydrocannabinol exposure on mouse brain development: a fetal-to-adulthood magnetic resonance imaging study

While cannabis use during pregnancy is often perceived as harmless, little is known about its consequences on offspring neurodevelopment. There is an urgent need to map the effects of prenatal cannabis exposure on the brain through the course of the lifespan. We used magnetic resonance imaging spanning nine timepoints, behavioral assays, and electron microscopy to build a trajectory from gestation to adulthood in mice exposed prenatally to delta-9-tetrahydrocannabinol (THC). Our results demonstrate a spatio-temporal patterning, with ventriculomegaly in THC-exposed embryos followed by a deceleration of brain growth in neonates that is sustained until adulthood, especially in females. We observed consistently impacted regions in both the cortex and subcortex, aligned with sex-dependent changes to social behavior in neonates and increased anxiety-like behavior in adolescents. Our results suggest prenatal THC exposure has a sustained sex-dependent impact on neurodevelopment that may persist into early adulthood.

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bioRxiv2024

Developmental changes in hippocampal neurite colocalize with the expression of genes involved in modulating low-theta oscillations

The hippocampus is a critical brain structure supporting memory encoding and retrieval, yet the development of its microstructure in humans remains unknown. Understanding this development may provide insight into the mechanisms underlying memory and their disruption in disease. To address this, we non-invasively estimated the density and branching complexity of neurite (dendrites, axons, glial processes) using diffusion-weighted MRI in 364 participants aged 8-21. With development, we observed large increases in neurite density and branching complexity that persisted until approximately 15 years of age before stabilizing at adult-like values. Increases in neurite density were relatively homogenous across hippocampal axes, whereas increases in branching complexity were heterogeneous; increasing primarily in CA1, SRLM, subiculum, and anterior hippocampus. To assess whether this development may be attributable to specific cell-types, we tested for spatial overlap between age-related change in neurite and the cell-type composition of hippocampal tissue via cross-reference with an out-of-sample gene-expression atlas. We found age-related changes in neurite density spatially overlapped with a granule cell component; whereas age-related changes in neurite branching complexity overlapped with a pyramidal neuron component. These results provide the first glimpse at the nonlinear maturation of hippocampal microstructure and the cell-type composition of hippocampal tissue underlying these changes.

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bioRxiv2024

Sex and APOE4-specific links between cardiometabolic risk factors and white matter alterations in individuals with a family history of Alzheimer's disease

INTRODUCTIONWhite matter (WM) alterations are among the earliest changes in Alzheimers disease (AD), yet limited work has comprehensively characterized the effects of AD risk factors on WM. METHODSIn older adults with a family history of AD, we investigated the sex-specific and APOE genotype-related relationships between WM microstructure and risk factors. Multiple MRI-derived metrics were integrated using a multivariate approach based on the Mahalanobis distance (D2). The links between WM D2 and cognition were also explored. RESULTSWM D2 in several regions was associated with high systolic blood pressure, BMI, and glycated hemoglobin, and low cholesterol, in both males and females. APOE4+ displayed a distinct risk pattern, with LDL-cholesterol having a detrimental effect only in carriers, and this pattern was linked to immediate memory performance. Myelination was the main mechanism underlying WM alterations. DISCUSSIONOur findings reveal that combined exposure to multiple cardiometabolic risk factors negatively impacts microstructural health, which may subsequently affect cognition. Notably, APOE4 carriers exhibited a different risk pattern, especially in the role of LDL, suggesting distinct underlying mechanisms in this group.

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bioRxiv2024

Evaluating permutation-based inference for partial least squares analysis of neuroimaging data

Partial least squares (PLS) is actively leveraged in neuroimaging work, typically to map latent variables (LVs) representing brain-behaviour associations. LVs are considered statistically significant if they tend to capture more covariance than LVs derived from permuted data, with a Procrustes rotation applied to map each set of permuted LVs to the space defined by the originals, creating an "apples to apples" comparison. Yet, it has not been established whether applying the rotation makes the permutation test more sensitive to whether true LVs are present in a dataset, and it is unclear if significance alone is sufficient to fully characterize a PLS decomposition, given that complementary metrics like strength and split-half stability may offer non-redundant information about the LVs. Accordingly, we performed PLS analyses across a range of simulated datasets with known latent effects, observing that the Procrustes rotation systematically weakened the null distributions for the first LV. By extension, the first LV was nearly always significant, regardless of whether the effect was weak, undersampled, noisy, or simulated at all. But, if no rotation was applied, all possible LVs tended to be significant as we increased the sample size of UK Biobank datasets. Meanwhile, LV strength and stability metrics accurately tracked our confidence that effects were present in simulated data, and allowed for a more nuanced assessment of which LVs may be relevant in the UK Biobank. We end by presenting a list of considerations for researchers implementing PLS permutation testing, and by discussing promising alternative tests which may alleviate the concerns raised by our findings.

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bioRxiv2024

Beyond brain size: disentangling the effect of sex and brain size on brain morphometry and cognitive functioning

It is imperative to study sex differences in brain morphology and function. However, there are major observable and unobservable confounding factors that can contribute to the estimated differences. Males have larger head sizes than females. Head size differences not only act as a confounding factor in studying sex differences in the brain, but also impact its anatomy and functioning. In this work, we seek to disentangle the effect of head size from sex in studying sex differentiated aging trajectories, its relation to canonical functional networks and cytoarchitectural classes, brain allometry, cognition. Using the UK Biobank (UKBB) neuroimaging data (N = 35,732 participants, 19,281 females, 44-82 years of age), we created a subsample (N = 11,294) where females (N = 5,657) and males were matched by their total intracranial volume (TIV) and age, a subsample that maintains the UKBB sample distribution, one matched only by age, and one that exaggerated the TIV difference between sexes. We then modeled the aging trajectories at both regional and vertex-wise levels in the four subsamples, and compared the estimations of the models. Our results show that when females and males have the same head size, the overall sex estimations tend towards zero, suggesting that most of the variability results from head size differences. Our approach also revealed bidirectional sex differences in brain neuroanatomy previously masked by the effect of head size. Further, the scaling relationship between regional and total brain volume remains fairly consistent across the lifespan and is not sex differentiated overall. We evaluated how the results of cognitive tests with perceived sex differences are influenced and explained by head size and found that although the correlation between TIV and cognitive scores is low, the matching process changes the direction of the effect sizes of differences between sexes in "verbal and numerical reasoning" and "working memory" cognitive domains. Taken together, employing a matching approach that is widely used in causal modeling studies, we provide new evidence for disentanglement of sex differences in the brain from head size as a biological confound.

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bioRxiv2024

Multimodal identification of the mouse brain using simultaneous Ca2+ imaging and fMRI

Individual differences in neuroimaging are of interest to clinical and cognitive neuroscientists based on their potential for guiding the personalized treatment of various heterogeneous neurological conditions and diseases. Despite many advantages, the workhorse in this arena, BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI) suffers from low spatiotemporal resolution and specificity as well as a propensity for noise and spurious signal corruption. To better understand individual differences in BOLD-fMRI data, we can use animal models where fMRI, alongside complementary but more invasive contrasts, can be accessed. Here, we apply simultaneous wide-field fluorescence calcium imaging and BOLD-fMRI in mice to interrogate individual differences using a connectome-based identification framework adopted from the human fMRI literature. This approach yields high spatiotemporal resolution cell-type specific signals (here, from glia, excitatory, as well as inhibitory interneurons) from the whole cortex. We found mouse multimodal connectome-based identification to be successful and explored various features of these data.

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bioRxiv2024

The Douglas Bell Canada Brain Bank Post-mortem Brain Imaging Protocol

Magnetic resonance imaging (MRI) is a valuable non-invasive tool that has been widely used for in vivo investigations of brain morphometry and microstructural characteristics. Postmortem MRIs can provide complementary anatomical and microstructural information to in vivo imaging and ex vivo neuropathological assessments without compromising the sample for future investigations. We have developed a postmortem MRI protocol for the brain specimens of the Douglas-Bell Canada Brain Bank (DBCBB), the largest brain bank in Canada housing over 3000 neurotypical and diseased brain specimens, that allows for acquisition of high-resolution 3T and 7T MRIs. Our protocol can be used to scan DBCBB specimens with minimal tissue manipulation, allowing for feasibly scanning large numbers of postmortem specimens while retaining the quality of the tissue for downstream histology and immunohistochemistry assessments. We demonstrate the robustness of this protocol in spite of the dependency of image quality on fixation by acquiring data on the first day of extraction and fixation, to over twenty years post fixation. The acquired images can be used to perform volumetric segmentations, cortical thickness measurements, and quantitative analyses which can be potentially used to link MRI-derived and ex vivo histological measures, assaying both the normative organization of the brain and ex vivo measures of pathology.

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