M. Mallar Chakravarty

McGill University | McGill · Douglas Mental Health University Institute

The cortex and cerebellum are densely connected through reciprocal input/output projections that form segregated circuits. These circuits are shown to differentially connect anterior lobules of the cerebellum to sensorimotor regions, and lobules Crus I and II to prefrontal regions. This differential connectivity pattern leads to the hypothesis that...

Background Alzheimer’s disease (AD) is thought to result from a complex cascade of events involving several pathological processes. Recent studies have reported alterations in white matter (WM) microstructure in the early phase of AD, but WM remains understudied. We used a multivariate approach to capture the complexity and heterogeneity of WM path...

Background Alzheimer’s disease (AD) is thought to result from a complex cascade of events involving several pathological processes. Recent studies have reported alterations in white matter (WM) microstructure in the early phase of AD, but WM remains understudied. We used a multivariate approach to capture the complexity and heterogeneity of WM path...

Neuroanatomical sex differences estimated in neuroimaging studies are confounded by total intracranial volume (TIV) as a major biological factor. Employing a matching approach widely used for causal modeling, we disentangled the effect of TIV from sex to study sex-differentiated brain aging trajectories, their relation to functional networks and cy...

Background Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential tre...

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...

Psychotic disorders are a class of heterogeneous disorders for which there is evidence of numerous structural and functional brain abnormalities. One proposed neural marker for psychosis is a disruption in white matter, the structural architecture for connectivity throughout the brain. The role of white matter integrity, often measured via Fraction...

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 electr...

Background and objectives White matter hyperintensities (WMHs) are radiological abnormalities indicative of cerebrovascular dysfunction associated with increased risk for cognitive decline and increase in prevalence in older age. However, there are known sex-differences as older females harbour higher WMH burden than males. Some have hypothesized t...

Adolescents and young adults born with a complex congenital heart defect (CHD) are at risk for executive function (ExF) impairments, which contribute to the psychological and everyday burden of CHD. Cortical dysmaturation has been well described in fetuses and neonates with CHD and early evidence suggests that cortical alterations in thickness, sur...

Recent human magnetic resonance imaging (MRI) studies continually push the boundaries of spatial resolution as a means to enhance levels of neuroanatomical detail and increase the accuracy and sensitivity of derived brain morphometry measures. However, acquisitions required to achieve these resolutions have a higher noise floor, potentially impacti...

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon)...

Amyloid accumulation in Alzheimer’s disease (AD) is associated with synaptic damage and altered connectivity in brain networks. While measures of amyloid accumulation and biochemical changes in mouse models have utility for translational studies of certain therapeutics, preclinical analysis of altered brain connectivity using clinically relevant fM...

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. Post-mortem MRIs can provide complementary anatomical and microstructural information to in vivo imaging and ex vivo neuropathological assessments without compromising the sa...

Functional Magnetic Resonance Imaging (fMRI) in rodents is pivotal for understanding the mechanisms underlying Blood Oxygen Level-Dependent (BOLD) signals and phenotyping animal models of disorders, amongst other applications. Despite its growing use, comparing rodent fMRI results across different research sites remains challenging due to variation...

Ageing is a biological process associated with the natural degeneration of various regions of the brain. Alteration of neural tissue in the hippocampus with ageing typically results in cognitive decline that may serve as a risk factor for dementia and other neurodegenerative diseases. Modifiable lifestyle factors may help preserve hippocampal neura...

Schizophrenia and related psychoses are characterized by significant reductions in hippocampal volume and morphometric hippocampal-cortical connectivity. No study to date has addressed the temporal relationship between deviations in volume and connectivity across the heterogeneous spectrum of psychosis. To explore this relationship, we sampled cros...

Coincident with the legalisation of cannabis in many nations, rates of cannabis use during pregnancy have increased. Like prior investigations on smoking and alcohol, understanding how prenatal cannabis exposure (PCE) impacts offspring outcomes across the lifespan will be critical for informing choices for pregnant people, clinicians, and policy ma...

INTRODUCTION: White matter (WM) alterations are among the earliest changes in Alzheimer's disease (AD), yet limited work has comprehensively characterized the effects of AD risk factors on WM. METHODS: In older adults with a family history of AD, we investigated the sex-specific and APOE genotype-related relationships between WM microstructure and...

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. We performed GWAS meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and, for the first time, the ventral diencephalon) in 74,898...

Morphometric measures in humans derived from magnetic resonance imaging (MRI) have provided important insights into brain differences and changes associated with development and disease in vivo. Deformation-based morphometry (DBM) is a registration-based technique that has been shown to be useful in detecting local volume differences and longitudin...

Functional magnetic resonance imaging in rodents holds great potential for advancing our understanding of brain networks. Unlike the human community, there remains no standardized resource in rodents for image processing, analysis and quality control, posing significant reproducibility limitations. Our software platform, Rodent Automated Bold Impro...

Partial least squares (PLS) is actively leveraged in neuroimaging work, typically to map latent variables (LVs) representing brain-behaviour associations. Canonically, 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 permut...

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 als...

Functional networks often guide our interpretation of spatial maps of brain–phenotype associations. However, methods for assessing enrichment of associations within networks of interest have varied in terms of both scientific rigor and underlying assumptions. While some approaches have relied on subjective interpretations, others have made unrealis...

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 imagin...

Alpha-synuclein (aSyn) pathology has been extensively studied in mouse models harbouring human mutations. In spite of the known sex differences in age of onset, prevalence and disease presentation in human synucleinopathies, the impact of sex on aSyn propagation has received very little attention. To address this need, we examined sex differences i...

Elevated hippocampal perfusion has been observed in people at clinical high risk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that peripubertal treatment with diazepam can prevent the development of psychosis-relevant phenotypes. The present experimental medi...

Multiscale neuroscience conceptualizes mental illness as arising from aberrant interactions across and within multiple biopsychosocial scales. We leverage this framework to propose a multiscale disease progression model of psychosis, in which hippocampal-cortical dysconnectivity precedes impairments in episodic memory and social cognition, which le...

In the past, the cerebellum has been best known for its crucial role in motor function. However, increasingly more findings highlight the importance of cerebellar contributions in cognitive functions and neurodevelopment. Using a total of 7240 neuroimaging scans from 4862 individuals, we describe and provide detailed, openly available models of cer...

Although brain cholinergic denervation has been largely associated with cognitive decline in patients with Parkinson’s disease (PD), new evidence suggests that cholinergic upregulation occurs in the hippocampus of PD patients without cognitive deficits. The specific hippocampal sectors and potential mechanisms of this cholinergic compensatory proce...

Adolescence is a sensitive developmental period for neural sex/gender differentiation. The present study used multiparametric mapping to better characterize adolescent white matter (WM) microstructure. WM microstructure was investigated using diffusion tensor indices (fractional anisotropy; mean, radial, and axial diffusivity [AD]) and quantitative...

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of...

The occurrence of suicidal behaviors increases during adolescence. Hypersensitivity to negative social signals and deficits in cognitive control are putative mechanisms of suicidal behaviors, which necessitate confirmation in youths. Multidomain functional neuroimaging could enhance the identification of patients at suicidal risk beyond standard cl...

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 sam...

Elevated iron deposition in the brain has been observed in older adult humans and persons with Alzheimer's disease (AD), and has been associated with lower cognitive performance. We investigated the impact of iron deposition, and its topographical distribution across hippocampal subfields and segments (anterior, posterior) measured along its longit...

Background Enlarged pituitary gland volume could be a marker of psychotic disorders. However, previous studies report conflicting results. To better understand the role of the pituitary gland in psychosis, we examined a large transdiagnostic sample of individuals with psychotic disorders. Methods The study included 751 participants (174 with schiz...

Alzheimer’s disease (AD) is primarily characterized by the accumulation of amyloid and tau pathologies. However, alterations in the detailed organization and composition of neural tissue also contribute to the disease’s early stages. Here, we sought to explore whether hippocampal and cortical microstructural changes, such as myelin alterations and...

Background Elevated hippocampal perfusion has been observed in people at clinical high-risk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that prophylactic treatment with diazepam during adolescence can prevent the development of psychosis-relevant phenotypes....

Large-scale functional networks have been characterized in both rodent and human brains, typically by analyzing fMRI-BOLD signals. However, the relationship between fMRI-BOLD and underlying neural activity is complex and incompletely understood, which poses challenges to interpreting network organization obtained using this technique. Additionally,...

Background Growing evidence suggests Alzheimer’s disease (AD) develops from a complex cascade of events that vary between individuals. Multivariate approaches have the potential to capture the complexity and heterogeneity of pathologies underlying AD in a more holistic manner compared to univariate approaches. Method The MRI data of 105 older adul...

Background The sources of inter‐ and intra‐individual variability in age‐related cognitive decline remain poorly understood. We examined the association between 20‐year trajectories of cognitive decline and multimodal brain structure and morphology in older age. Method We used the Whitehall II Study, an extensively characterised cohort with 3T bra...

Background Age‐related memory decline is well associated with hippocampal atrophy, although the specific role of hippocampal subfields in memory function has not been thoroughly investigated yet. In this study, we investigated the associations between hippocampal subfield volumes and free recall and recognition performances in verbal and visual mem...

Background Growing evidence suggests Alzheimer’s disease (AD) develops from a complex cascade of events that vary between individuals. Multivariate approaches have the potential to capture the complexity and heterogeneity of pathologies underlying AD in a more holistic manner compared to univariate approaches. Method The MRI data of 105 older adul...

Background Age‐related memory decline is well associated with hippocampal atrophy, although the specific role of hippocampal subfields in memory function has not been thoroughly investigated yet. In this study, we investigated the associations between hippocampal subfield volumes and free recall and recognition performances in verbal and visual mem...

Amyloid accumulation in Alzheimer's disease (AD) is associated with synaptic damage and altered connectivity in brain networks. While measures of amyloid accumulation and biochemical changes in mouse models have utility for translational studies of certain therapeutics, preclinical analysis of altered brain connectivity using clinically relevant fM...

Background and Hypothesis Schizophrenia is associated with widespread cortical thinning and abnormality in the structural covariance network, which may reflect connectome alterations due to treatment effect or disease progression. Notably, patients with treatment-resistant schizophrenia (TRS) have stronger and more widespread cortical thinning, but...

Functional networks often guide our interpretation of spatial maps of brain-phenotype associations. However, methods for assessing enrichment of associations within networks of interest have varied in terms of both scientific rigor and underlying assumptions. While some approaches have relied on subjective interpretations, others have made unrealis...

The menopause transition has been repeatedly associated with decreased cognitive performance and increased incidence of Alzheimer’s Disease (AD), particularly when it is induced surgically 1,2 or takes place at a younger age 3,4 . However, there are very few studies that use neuroimaging techniques to examine the effects of these variables in aggre...

The menopause transition has been repeatedly associated with decreased cognitive performance and increased incidence of Alzheimer’s Disease (AD), particularly when it is induced surgically 1,2 or takes place at a younger age 3,4 . However, there are very few studies that use neuroimaging techniques to examine the effects of these variables in aggre...

Significant evidence suggests that misfolded alpha‐synuclein (aSyn), a major component of Lewy bodies, propagates in a prion‐like manner contributing to disease progression in Parkinson's disease (PD) and other synucleinopathies. In fact, timed inoculation of M83 hemizygous mice with recombinant human aSyn preformed fibrils (PFF) has shown symptoma...

The cortex and cerebellum are densely connected through reciprocal input/output projections that form segregated loop circuits. Anatomical studies in primates and imaging studies in humans show that anterior lobules of the cerebellum exhibit denser connections to sensorimotor and parietal cortical regions, while lobules Crus I and II are more heavi...

Structural magnetic resonance imaging (MRI) quality is known to impact and bias neuroanatomical estimates and downstream analysis, including case-control comparisons, and a growing body of work has demonstrated the importance of careful quality control (QC) and evaluated the impact of image and image-processing quality. However, the growing size of...

Autism presents with significant phenotypic and neuroanatomical heterogeneity, and neuroimaging studies of the thalamus, globus pallidus and striatum in autism have produced inconsistent and contradictory results. These structures are critical mediators of functions known to be atypical in autism, including sensory gating and motor function. We exa...

Polypharmacy is relatively common in early psychosis, but little attention has been paid to the anticholinergic burden of medication use (cumulative effect of medications that block the cholinergic system). Evidence suggests that anticholinergic burden is associated with cognitive deficits and that hippocampal dysfunction may be involved in those i...

Schizophrenia is associated with widespread cortical thinning and abnormality in the structural covariance network, which may reflect connectome alterations due to treatment effect or disease progression. Notably, patients with treatment-resistant schizophrenia (TRS) have stronger and more widespread cortical thinning, but it remains unclear whethe...

Psychosis represents a heterogeneous collection of biological and behavioural alterations that evolve over time. We propose a multiscale disease progression model of psychosis, in which hippocampal-cortical dysconnectivity precedes impaired episodic memory and social cognition, worsening negative symptoms and lowering functional outcome. In two cro...

Background and purpose: While brain iron dysregulation has been observed in several neurodegenerative disorders, its association with the progressive neurodegeneration in Niemann-Pick type C is unknown. Systemic iron abnormalities have been reported in patients with Niemann-Pick type C and in animal models of Niemann-Pick type C. In this study, we...

Recent research found that the combination of masculine gender identity and gynephilia was associated with cortical T1 relaxation time, which is considered to reflect gray matter density. We hypothesized that mean diffusivity (MD), a diffusion tensor imaging metric that reflects the degree to which water movement is free versus constrained, in comb...

Background Sleep dysfunction is common in neurodegenerative disorders, however, its neural correlates, remain poorly characterized in genetic frontotemporal dementia (FTD). Atrophy in two hypothalamic nuclei, the suprachiasmatic nucleus and the lateral hypothalamic area, important for sleep regulation, may be related to this dysfunction. Thus, we e...

Recent human neuroimaging studies tend to have increased magnetic resonance image (MRI) acquisition resolutions, seeking finer levels of detail and more accurate brain morphometry. However, higher-resolution images inherently contain greater amounts of noise contamination, leading to poorer quality brain morphometry if not addressed adequately. Thi...

Objectives: Antipsychotics are widely used to treat first-episode psychosis but may have an anticholinergic burden, that is, a cumulative effect of medications that block the cholinergic system. Studies suggest that a high anticholinergic burden negatively affects memory in psychosis, where cognitive deficits, particularly those in verbal memory,...

Understanding the relationship between the structural and functional architecture of the human brain remains a key question in neuroscience. In this regard variation in cortical myelin may provide key insights into the functional organization. Previous findings have demonstrated that regions sharing myeloarchitectonic features are also likely to be...