Psychiatry - Research Publications
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ItemNo Preview AvailableWhite matter abnormalities across the lifespan of schizophrenia: a harmonized multi-site diffusion MRI study(SPRINGERNATURE, 2020-12-01)Several prominent theories of schizophrenia suggest that structural white matter pathologies may follow a developmental, maturational, and/or degenerative process. However, a lack of lifespan studies has precluded verification of these theories. Here, we analyze the largest sample of carefully harmonized diffusion MRI data to comprehensively characterize age-related white matter trajectories, as measured by fractional anisotropy (FA), across the course of schizophrenia. Our analysis comprises diffusion scans of 600 schizophrenia patients and 492 healthy controls at different illness stages and ages (14-65 years), which were gathered from 13 sites. We determined the pattern of age-related FA changes by cross-sectionally assessing the timing of the structural neuropathology associated with schizophrenia. Quadratic curves were used to model between-group FA differences across whole-brain white matter and fiber tracts at each age; fiber tracts were then clustered according to both the effect-sizes and pattern of lifespan white matter FA differences. In whole-brain white matter, FA was significantly lower across the lifespan (up to 7%; p < 0.0033) and reached peak maturation younger in patients (27 years) compared to controls (33 years). Additionally, three distinct patterns of neuropathology emerged when investigating white matter fiber tracts in patients: (1) developmental abnormalities in limbic fibers, (2) accelerated aging and abnormal maturation in long-range association fibers, (3) severe developmental abnormalities and accelerated aging in callosal fibers. Our findings strongly suggest that white matter in schizophrenia is affected across entire stages of the disease. Perhaps most strikingly, we show that white matter changes in schizophrenia involve dynamic interactions between neuropathological processes in a tract-specific manner.
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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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ItemNo Preview AvailableIncreased extracellular free-water in adult male rats following in utero exposure to maternal immune activation(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2020-01-01)BACKGROUND: In previous work, we applied novel in vivo imaging methods to reveal that white matter pathology in patients with first-episode psychosis (FEP) is mainly characterized by excessive extracellular free-water, and to a lesser extent by cellular processes, such as demyelination. Here, we apply a back-translational approach to evaluate whether or not a rodent model of maternal immune activation (MIA) induces patterns of white matter pathology that we observed in patients with FEP. To this end, we examined free-water and tissue-specific white matter alterations in rats born to mothers exposed to the viral mimic polyriboinosinic-polyribocytidylic acid (Poly-I:C) in pregnancy, which is widely used to produce alterations relevant to schizophrenia and is characterized by a robust neuroinflammatory response. METHOD: Pregnant dams were injected on gestational day 15 with the viral mimic Poly-I:C (4 mg/kg) or saline. Diffusion-weighted magnetic resonance images were acquired from 17 male offspring (9 Poly-I:C and 8 saline) on postnatal day 90, after the emergence of brain structural and behavioral abnormalities. The free-water fraction (FW) and tissue-specific fractional anisotropy (FAT), as well as conventional fractional anisotropy (FA) were computed across voxels traversing a white matter skeleton. Voxel-wise and whole-brain averaged white matter were tested for significant microstructural alterations in immune-challenged, relative to saline-exposed offspring. RESULTS: Compared to saline-exposed offspring, those exposed to maternal Poly-I:C displayed increased extracellular FW averaged across voxels comprising a white matter skeleton (t(15) = 2.74; p = 0.01). Voxel-wise analysis ascribed these changes to white matter within the corpus callosum, external capsule and the striatum. In contrast, no significant between-group differences emerged for FAT or for conventional FA, measured across average and voxel-wise white matter. CONCLUSION: We identified excess FW across frontal white matter fibers of rats exposed to prenatal immune activation, analogous to our "bedside" observation in FEP patients. Findings from this initial experiment promote use of the MIA model to examine pathological pathways underlying FW alterations observed in patients with schizophrenia. Establishing these mechanisms has important implications for clinical studies, as free-water imaging reflects a feasible biomarker that has so far yielded consistent findings in the early stages of schizophrenia.
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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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ItemNo Preview AvailableImaging of neuroinflammation in adult Niemann-Pick type C disease: a cross-sectional study(American Academy of Neurology, 2020-04-21)Objective: To test the hypothesis that neuroinflammation is a key process in adult Niemann-Pick type C (NPC) disease, we undertook PET scanning utilizing a ligand binding activated microglia on 9 patients and 9 age- and sex-matched controls. Method: We scanned all participants with the PET radioligand 11C-(R)-PK-11195 and undertook structural MRI to measure gray matter volume and white matter fractional anisotropy (FA). Results: We found increased binding of 11C-(R)-PK-11195 in total white matter compared to controls (p < 0.01), but not in gray matter regions, and this did not correlate with illness severity or duration. Gray matter was reduced in the thalamus (p < 0.0001) in patients, who also showed widespread reductions in FA across the brain compared to controls (p < 0.001). A significant correlation between 11C-(R)-PK11195 binding and FA was shown (p = 0.002), driven by the NPC patient group. Conclusions: Our findings suggest that neuroinflammation—particularly in white matter—may underpin some structural and degenerative changes in patients with NPC.
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ItemNo Preview AvailableQuantifying Genetic and Environmental Influence on Gray Matter Microstructure Using Diffusion MRI(OXFORD UNIV PRESS INC, 2020-12-01)Early neuroimaging work in twin studies focused on studying genetic and environmental influence on gray matter macrostructure. However, it is also important to understand how gray matter microstructure is influenced by genes and environment to facilitate future investigations of their influence in mental disorders. Advanced diffusion MRI (dMRI) measures allow more accurate assessment of gray matter microstructure compared with conventional diffusion tensor measures. To understand genetic and environmental influence on gray matter, we used diffusion and structural MRI data from a large twin and sibling study (N = 840) and computed advanced dMRI measures including return to origin probability (RTOP), which is heavily weighted toward intracellular and intra-axonal restricted spaces, and mean squared displacement (MSD), more heavily weighted to diffusion in extracellular space and large cell bodies in gray matter. We show that while macrostructural features like brain volume are mainly genetically influenced, RTOP and MSD can together tap into both genetic and environmental influence on microstructure.
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ItemWhite matter microstructure and connectivity in patients with obsessive-compulsive disorder and their unaffected siblings(WILEY, 2020-10-22)OBJECTIVE: We aimed to examine white matter microstructure and connectivity in individuals with obsessive-compulsive disorder (OCD) and their unaffected siblings, relative to healthy controls. METHODS: Diffusion-weighted magnetic resonance imaging (dMRI) scans were acquired in 30 patients with OCD, 21 unaffected siblings, and 31 controls. We examined white matter microstructure using measures of fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). Structural networks were examined using network-based statistic (NBS). RESULTS: Compared to controls, OCD patients showed significantly reduced FA and increased RD in clusters traversing the left forceps minor, inferior fronto-occipital fasciculus, anterior thalamic radiation, and cingulum. Furthermore, the OCD group displayed significantly weaker connectivity (quantified by the streamline count) compared to controls in the right hemisphere, most notably in edges connecting subcortical structures to temporo-occipital cortical regions. The sibling group showed intermediate streamline counts, FA and RD values between OCD and healthy control groups in connections found to be abnormal in patients with OCD. However, these reductions did not significantly differ compared to controls. CONCLUSION: Therefore, siblings of OCD patients display intermediate levels in dMRI measures of microstructure and connectivity, suggesting white matter abnormalities might be related to the familial predisposition for OCD.
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ItemIndividual deviations from normative models of brain structure in a large cross-sectional schizophrenia cohort(SPRINGERNATURE, 2020-09-22)The heterogeneity of schizophrenia has defied efforts to derive reproducible and definitive anatomical maps of structural brain changes associated with the disorder. We aimed to map deviations from normative ranges of brain structure for individual patients and evaluate whether the loci of individual deviations recapitulated group-average brain maps of schizophrenia pathology. For each of 48 white matter tracts and 68 cortical regions, normative percentiles of variation in fractional anisotropy (FA) and cortical thickness (CT) were established using diffusion-weighted and structural MRI from healthy adults (n = 195). Individuals with schizophrenia (n = 322) were classified as either within the normative range for healthy individuals of the same age and sex (5-95% percentiles), infra-normal (<5% percentile) or supra-normal (>95% percentile). Repeating this classification for each tract and region yielded a deviation map for each individual. Compared to the healthy comparison group, the schizophrenia group showed widespread reductions in FA and CT, involving virtually all white matter tracts and cortical regions. Paradoxically, however, no more than 15-20% of patients deviated from the normative range for any single tract or region. Furthermore, 79% of patients showed infra-normal deviations for at least one locus (healthy individuals: 59 ± 2%, p < 0.001). Thus, while infra-normal deviations were common among patients, their anatomical loci were highly inconsistent between individuals. Higher polygenic risk for schizophrenia associated with a greater number of regions with infra-normal deviations in CT (r = -0.17, p = 0.006). We conclude that anatomical loci of schizophrenia-related changes are highly heterogeneous across individuals to the extent that group-consensus pathological maps are not representative of most individual patients. Normative modeling can aid in parsing schizophrenia heterogeneity and guiding personalized interventions.
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ItemNo Preview AvailableNeuroimaging auditory verbal hallucinations in schizophrenia patient and healthy populations(CAMBRIDGE UNIV PRESS, 2020-02-01)BACKGROUND: Auditory verbal hallucinations (AVH) are a cardinal feature of schizophrenia, but they can also appear in otherwise healthy individuals. Imaging studies implicate language networks in the generation of AVH; however, it remains unclear if alterations reflect biologic substrates of AVH, irrespective of diagnostic status, age, or illness-related factors. We applied multimodal imaging to identify AVH-specific pathology, evidenced by overlapping gray or white matter deficits between schizophrenia patients and healthy voice-hearers. METHODS: Diffusion-weighted and T1-weighted magnetic resonance images were acquired in 35 schizophrenia patients with AVH (SCZ-AVH), 32 healthy voice-hearers (H-AVH), and 40 age- and sex-matched controls without AVH. White matter fractional anisotropy (FA) and gray matter thickness (GMT) were computed for each region comprising ICBM-DTI and Desikan-Killiany atlases, respectively. Regions were tested for significant alterations affecting both SCZ-AVH and H-AVH groups, relative to controls. RESULTS: Compared with controls, the SCZ-AVH showed widespread FA and GMT reductions; but no significant differences emerged between H-AVH and control groups. While no overlapping pathology appeared in the overall study groups, younger (<40 years) H-AVH and SCZ-AVH subjects displayed overlapping FA deficits across four regions (p < 0.05): the genu and splenium of the corpus callosum, as well as the anterior limbs of the internal capsule. Analyzing these regions with free-water imaging ascribed overlapping FA abnormalities to tissue-specific anisotropy changes. CONCLUSIONS: We identified white matter pathology associated with the presence of AVH, independent of diagnostic status. However, commonalities were constrained to younger and more homogenous groups, after reducing pathologic variance associated with advancing age and chronicity effects.