Psychiatry - Research Publications
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ItemRich club and reward network connectivity as endophenotypes for alcohol dependence: a diffusion tensor imaging study(WILEY, 2019-03)We aimed to examine the whole-brain white matter connectivity and local topology of reward system nodes in patients with alcohol use disorder (AUD) and unaffected siblings, relative to healthy comparison individuals. Diffusion-weighted magnetic resonance imaging scans were acquired from 18 patients with AUD, 15 unaffected siblings of AUD patients and 15 healthy controls. Structural networks were examined using network-based statistic and connectomic analysis. Connectomic analysis showed a significant ordered difference in normalized rich club organization (AUD < Siblings < Controls). We also found rank ordered differences (Control > Sibling > AUD) for both nodal clustering coefficient and nodal local efficiency in reward system nodes, particularly left caudate, right putamen and left hippocampus. Network-based statistic analyses showed that AUD group had significantly weaker connectivity than controls in the right hemisphere, mostly in the edges connecting putamen and hippocampus with other brain regions. Our results suggest that reward system network abnormalities, especially in subcortical structures, and impairments in rich-club organization might be related to the familial predisposition for AUD.
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ItemNo Preview AvailableWhite matter pathology in schizophrenia(Springer Nature, 2020-01-01)Significant effort has been devoted to characterizing white matter pathology in patients with schizophrenia and its impact on brain connectivity (Samartzis et al., J Neuroimaging 24(2):101-10, 2014; Fusar-Poli et al., Neurosci Biobehav Rev 37(8):1680-91, 2013; Bora et al., Schizophr Res 127(1):46-57, 2011). This is particularly important in light of the disconnection hypothesis-a key etiological theory of schizophrenia suggesting that symptoms arise from a failure of integration between distinct brain regions (Friston, Schizophr Res 30(2):115-25, 1998). In this chapter, we focus on neuroimaging evidence demonstrating structural white matter alterations in schizophrenia. Key questions addressed include: what methods are sensitive to the pathophysiology of schizophrenia? What is the evidence that white matter pathology emerges prior to or near to the onset of psychosis? Is the trajectory of white matter pathology stable or, alternatively, a dynamic process, with progressive changes evident over the course of illness? What are the limitations of these studies? How does neuroimaging evidence relate to micro- and meso-structural white matter findings?.
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ItemAdvanced Diffusion Imaging in Psychosis Risk: a cross-sectional and longitudinal study of white matter development(Oxford University Press, 2020-04-01)Background: Studies in individuals at clinical high risk (CHR) for psychosis provide a powerful means to predict outcomes and inform putative mechanisms underlying conversion to psychosis. In previous work, we applied advanced diffusion imaging methods to reveal that white matter pathology in a CHR population is characterized by cellular-specific changes in white matter, suggesting a preexisting neurodevelopmental anomaly. However, it remains unknown whether these deficits relate to clinical symptoms and/or conversion to frank psychosis. To address this gap, we examined cross-sectional and longitudinal white matter maturation in the largest imaging population of CHR individuals to date, obtained from the North American Prodrome Longitudinal Study (NAPLS-3). Methods: Multi-shell diffusion magnetic resonance imaging (MRI) data were collected across multiple timepoints (1–6 at ~2 month intervals) in 286 subjects (age range=12–32 years). These were 230 unmedicated CHR subjects, including 11% (n=25) who transitioned to psychosis (CHR-converters), as well as 56 age and sex-matched healthy controls. Raw diffusion signals were harmonized to remove scanner/site-induced effects, yielding a unified imaging dataset. Fractional anisotropy of cellular tissue (FAt) and the volume fraction of extracellular free-water (FW) were assessed in 12 major tracts from the IIT Human Brain Atlas (v.5.0). Linear mixed effects (LME) models were fitted to infer developmental trajectories of FAt and FW across age for CHR-converters, CHR-nonconverters and control groups, while accounting for the repeated measurements on each individual. Results: The rate at which FAt changed with age significantly differed between the three groups across commissural and association tracts (5 in total; p<0.05). In these tracts, FAt increased with age in controls (0.002% change per year) and in CHR-nonconverters, albeit at a slower rate (0.00074% per year). In contrast, FAt declined with age in CHR-converters at a rate that was significantly faster (-3.944% per year) than the rate of increase in the other two groups. By 25 years of age, FAt was significantly lower in both CHR groups compared to controls (p<0.05). With regard to FW, the rate of change significantly differed between CHR-converters and controls across the forceps major and the left inferior longitudinal and fronto‐occipital fasciculi (IFOF; 3 tracts in total; p<0.05). This was due to increased FW with age in the CHR-converters (0.0024% change per year) relative to controls (-0.0002% per year). Consequently, FW was significantly higher in CHR-converters compared to controls by 20 years of age (p<.05). With regard to symptoms, there was a significant impact of IFOF FW on positive symptom severity across CHR subjects, regardless of conversion status (t=2.37, p<0.05). Discussion: Our results revealed that clinical high-risk for psychosis is associated with cellular-specific alterations in white matter, regardless of conversion status. Only converters showed excess extracellular free-water, which involved tracts connecting occipital, posterior temporal, and orbito-frontal areas. We also demonstrate a direct impact of free-water on positive symptomatology, collectively, suggesting that excess free-water may signal acute psychosis and its onset. This marker may be useful for patient selection for clinical trials and assessment of individuals with prodromal psychosis.
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ItemConnectome analysis with diffusion MRI in idiopathic Parkinson's disease: Evaluation using multi-shell, multi-tissue, constrained spherical deconvolution(ELSEVIER SCI LTD, 2018)Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects extensive regions of the central nervous system. In this work, we evaluated the structural connectome of patients with PD, as mapped by diffusion-weighted MRI tractography and a multi-shell, multi-tissue (MSMT) constrained spherical deconvolution (CSD) method to increase the precision of tractography at tissue interfaces. The connectome was mapped with probabilistic MSMT-CSD in 21 patients with PD and in 21 age- and gender-matched controls. Mapping was also performed by deterministic single-shell, single tissue (SSST)-CSD tracking and probabilistic SSST-CSD tracking for comparison. A support vector machine was trained to predict diagnosis based on a linear combination of graph metrics. We showed that probabilistic MSMT-CSD could detect significantly reduced global strength, efficiency, clustering, and small-worldness, and increased global path length in patients with PD relative to healthy controls; by contrast, probabilistic SSST-CSD only detected the difference in global strength and small-worldness. In patients with PD, probabilistic MSMT-CSD also detected a significant reduction in local efficiency and detected clustering in the motor, frontal temporoparietal associative, limbic, basal ganglia, and thalamic areas. The network-based statistic identified a subnetwork of reduced connectivity by MSMT-CSD and probabilistic SSST-CSD in patients with PD, involving key components of the cortico-basal ganglia-thalamocortical network. Finally, probabilistic MSMT-CSD had superior diagnostic accuracy compared with conventional probabilistic SSST-CSD and deterministic SSST-CSD tracking. In conclusion, probabilistic MSMT-CSD detected a greater extent of connectome pathology in patients with PD, including those with cortico-basal ganglia-thalamocortical network disruptions. Connectome analysis based on probabilistic MSMT-CSD may be useful when evaluating the extent of white matter connectivity disruptions in PD.
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ItemPET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia(NATURE PUBLISHING GROUP, 2017-08-29)We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide (11C-(R)-PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients recently diagnosed with schizophrenia; (iii) 15 patients chronically ill with schizophrenia; and, (iv) 27 age-matched healthy controls. Regional-binding potential (BPND) was calculated using the simplified reference-tissue model with four alternative reference inputs. The UHR, recent-onset and chronic patient groups were compared to age-matched healthy control groups to examine between-group BPND differences in 6 regions: dorsal frontal, orbital frontal, anterior cingulate, medial temporal, thalamus and insula. Correlation analysis tested for BPND associations with gray matter volume, peripheral cytokines and clinical variables. The null hypothesis of equality in BPND between patients (UHR, recent-onset and chronic) and respective healthy control groups (younger and older) was not rejected for any group comparison or region. Across all subjects, BPND was positively correlated to age in the thalamus (r=0.43, P=0.008, false discovery rate). No correlations with regional gray matter, peripheral cytokine levels or clinical symptoms were detected. We therefore found no evidence of microglial activation in groups of individuals at high risk, recently diagnosed or chronically ill with schizophrenia. While the possibility of 11C-(R)-PK11195-binding differences in certain patient subgroups remains, the patient cohorts in our study, who also displayed normal peripheral cytokine profiles, do not substantiate the assumption of microglial activation in schizophrenia as a regular and defining feature, as measured by 11C-(R)-PK11195 BPND.
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ItemMinimum spanning tree analysis of the human connectome(WILEY, 2018-06)One of the challenges of brain network analysis is to directly compare network organization between subjects, irrespective of the number or strength of connections. In this study, we used minimum spanning tree (MST; a unique, acyclic subnetwork with a fixed number of connections) analysis to characterize the human brain network to create an empirical reference network. Such a reference network could be used as a null model of connections that form the backbone structure of the human brain. We analyzed the MST in three diffusion-weighted imaging datasets of healthy adults. The MST of the group mean connectivity matrix was used as the empirical null-model. The MST of individual subjects matched this reference MST for a mean 58%-88% of connections, depending on the analysis pipeline. Hub nodes in the MST matched with previously reported locations of hub regions, including the so-called rich club nodes (a subset of high-degree, highly interconnected nodes). Although most brain network studies have focused primarily on cortical connections, cortical-subcortical connections were consistently present in the MST across subjects. Brain network efficiency was higher when these connections were included in the analysis, suggesting that these tracts may be utilized as the major neural communication routes. Finally, we confirmed that MST characteristics index the effects of brain aging. We conclude that the MST provides an elegant and straightforward approach to analyze structural brain networks, and to test network topological features of individual subjects in comparison to empirical null models.
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ItemNo Preview AvailableAbnormal white matter integrity in synthetic cannabinoid users(ELSEVIER SCIENCE BV, 2016-11)Synthetic cannabinoids have become increasingly popular in the last few years especially among adolescents and young adults. However, no previous studies have assessed the effects of synthetic cannabinoids on the structure of the human brain. Understanding the harms of synthetic cannabinoid use on brain structure is therefore crucial given its increasing use. Diffusion tensor imaging (DTI) was performed in 22 patients who used synthetic cannabinoids more than five times a week for at least 1 year and 18 healthy controls. Fractional anisotropy (FA) was significantly reduced in the cannabinoid group compared to controls in a cluster of white matter voxels spanning the left temporal lobe, subcortical structures and brainstem. This cluster was predominantly traversed by the inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, fornix, cingulum-hippocampus and corticospinal tracts. Long-term use of synthetic cannabinoids is associated with white matter abnormalities in adolescents and young adults. Disturbed brain connectivity in synthetic cannabinoid users may underlie cognitive impairment and vulnerability to psychosis.