Psychiatry - Research Publications

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    Brain charts for the human lifespan (vol 604, pg 525, 2022)
    Bethlehem, RAI ; Seidlitz, J ; White, SR ; Vogel, JW ; Anderson, KM ; Adamson, C ; Adler, S ; Alexopoulos, GS ; Anagnostou, E ; Areces-Gonzalez, A ; Astle, DE ; Auyeung, B ; Ayub, M ; Bae, J ; Ball, G ; Baron-Cohen, S ; Beare, R ; Bedford, SA ; Benegal, V ; Beyer, F ; Blangero, J ; Blesa Cabez, M ; Boardman, JP ; Borzage, M ; Bosch-Bayard, JF ; Bourke, N ; Calhoun, VD ; Chakravarty, MM ; Chen, C ; Chertavian, C ; Chetelat, G ; Chong, YS ; Cole, JH ; Corvin, A ; Costantino, M ; Courchesne, E ; Crivello, F ; Cropley, VL ; Crosbie, J ; Crossley, N ; Delarue, M ; Delorme, R ; Desrivieres, S ; Devenyi, GA ; Di Biase, MA ; Dolan, R ; Donald, KA ; Donohoe, G ; Dunlop, K ; Edwards, AD ; Elison, JT ; Ellis, CT ; Elman, JA ; Eyler, L ; Fair, DA ; Feczko, E ; Fletcher, PC ; Fonagy, P ; Franz, CE ; Galan-Garcia, L ; Gholipour, A ; Giedd, J ; Gilmore, JH ; Glahn, DC ; Goodyer, IM ; Grant, PE ; Groenewold, NA ; Gunning, FM ; Gur, RE ; Gur, RC ; Hammill, CF ; Hansson, O ; Hedden, T ; Heinz, A ; Henson, RN ; Heuer, K ; Hoare, J ; Holla, B ; Holmes, AJ ; Holt, R ; Huang, H ; Im, K ; Ipser, J ; Jack, CR ; Jackowski, AP ; Jia, T ; Johnson, KA ; Jones, PB ; Jones, DT ; Kahn, RS ; Karlsson, H ; Karlsson, L ; Kawashima, R ; Kelley, EA ; Kern, S ; Kim, KW ; Kitzbichler, MG ; Kremen, WS ; Lalonde, F ; Landeau, B ; Lee, S ; Lerch, J ; Lewis, JD ; Li, J ; Liao, W ; Liston, C ; Lombardo, MV ; Lv, J ; Lynch, C ; Mallard, TT ; Marcelis, M ; Markello, RD ; Mathias, SR ; Mazoyer, B ; McGuire, P ; Meaney, MJ ; Mechelli, A ; Medic, N ; Misic, B ; Morgan, SE ; Mothersill, D ; Nigg, J ; Ong, MQW ; Ortinau, C ; Ossenkoppele, R ; Ouyang, M ; Palaniyappan, L ; Paly, L ; Pan, PM ; Pantelis, C ; Park, MM ; Paus, T ; Pausova, Z ; Paz-Linares, D ; Pichet Binette, A ; Pierce, K ; Qian, X ; Qiu, J ; Qiu, A ; Raznahan, A ; Rittman, T ; Rodrigue, A ; Rollins, CK ; Romero-Garcia, R ; Ronan, L ; Rosenberg, MD ; Rowitch, DH ; Salum, GA ; Satterthwaite, TD ; Schaare, HL ; Schachar, RJ ; Schultz, AP ; Schumann, G ; Scholl, M ; Sharp, D ; Shinohara, RT ; Skoog, I ; Smyser, CD ; Sperling, RA ; Stein, DJ ; Stolicyn, A ; Suckling, J ; Sullivan, G ; Taki, Y ; Thyreau, B ; Toro, R ; Traut, N ; Tsvetanov, KA ; Turk-Browne, NB ; Tuulari, JJ ; Tzourio, C ; Vachon-Presseau, E ; Valdes-Sosa, MJ ; Valdes-Sosa, PA ; Valk, SL ; van Amelsvoort, T ; Vandekar, SN ; Vasung, L ; Victoria, LW ; Villeneuve, S ; Villringer, A ; Vertes, PE ; Wagstyl, K ; Wang, YS ; Warfield, SK ; Warrier, V ; Westman, E ; Westwater, ML ; Whalley, HC ; Witte, AV ; Yang, N ; Yeo, B ; Yun, H ; Zalesky, A ; Zar, HJ ; Zettergren, A ; Zhou, JH ; Ziauddeen, H ; Zugman, A ; Zuo, XN ; Bullmore, ET ; Alexander-Bloch, AF (NATURE PORTFOLIO, 2022-10-13)
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    Brain charts for the human lifespan
    Bethlehem, RAI ; Seidlitz, J ; White, SR ; Vogel, JW ; Anderson, KM ; Adamson, C ; Adler, S ; Alexopoulos, GS ; Anagnostou, E ; Areces-Gonzalez, A ; Astle, DE ; Auyeung, B ; Ayub, M ; Bae, J ; Ball, G ; Baron-Cohen, S ; Beare, R ; Bedford, SA ; Benegal, V ; Beyer, F ; Blangero, J ; Blesa Cabez, M ; Boardman, JP ; Borzage, M ; Bosch-Bayard, JF ; Bourke, N ; Calhoun, VD ; Chakravarty, MM ; Chen, C ; Chertavian, C ; Chetelat, G ; Chong, YS ; Cole, JH ; Corvin, A ; Costantino, M ; Courchesne, E ; Crivello, F ; Cropley, VL ; Crosbie, J ; Crossley, N ; Delarue, M ; Delorme, R ; Desrivieres, S ; Devenyi, GA ; Di Biase, MA ; Dolan, R ; Donald, KA ; Donohoe, G ; Dunlop, K ; Edwards, AD ; Elison, JT ; Ellis, CT ; Elman, JA ; Eyler, L ; Fair, DA ; Feczko, E ; Fletcher, PC ; Fonagy, P ; Franz, CE ; Galan-Garcia, L ; Gholipour, A ; Giedd, J ; Gilmore, JH ; Glahn, DC ; Goodyer, IM ; Grant, PE ; Groenewold, NA ; Gunning, FM ; Gur, RE ; Gur, RC ; Hammill, CF ; Hansson, O ; Hedden, T ; Heinz, A ; Henson, RN ; Heuer, K ; Hoare, J ; Holla, B ; Holmes, AJ ; Holt, R ; Huang, H ; Im, K ; Ipser, J ; Jack, CR ; Jackowski, AP ; Jia, T ; Johnson, KA ; Jones, PB ; Jones, DT ; Kahn, RS ; Karlsson, H ; Karlsson, L ; Kawashima, R ; Kelley, EA ; Kern, S ; Kim, KW ; Kitzbichler, MG ; Kremen, WS ; Lalonde, F ; Landeau, B ; Lee, S ; Lerch, J ; Lewis, JD ; Li, J ; Liao, W ; Liston, C ; Lombardo, MV ; Lv, J ; Lynch, C ; Mallard, TT ; Marcelis, M ; Markello, RD ; Mathias, SR ; Mazoyer, B ; McGuire, P ; Meaney, MJ ; Mechelli, A ; Medic, N ; Misic, B ; Morgan, SE ; Mothersill, D ; Nigg, J ; Ong, MQW ; Ortinau, C ; Ossenkoppele, R ; Ouyang, M ; Palaniyappan, L ; Paly, L ; Pan, PM ; Pantelis, C ; Park, MM ; Paus, T ; Pausova, Z ; Paz-Linares, D ; Pichet Binette, A ; Pierce, K ; Qian, X ; Qiu, J ; Qiu, A ; Raznahan, A ; Rittman, T ; Rodrigue, A ; Rollins, CK ; Romero-Garcia, R ; Ronan, L ; Rosenberg, MD ; Rowitch, DH ; Salum, GA ; Satterthwaite, TD ; Schaare, HL ; Schachar, RJ ; Schultz, AP ; Schumann, G ; Scholl, M ; Sharp, D ; Shinohara, RT ; Skoog, I ; Smyser, CD ; Sperling, RA ; Stein, DJ ; Stolicyn, A ; Suckling, J ; Sullivan, G ; Taki, Y ; Thyreau, B ; Toro, R ; Traut, N ; Tsvetanov, KA ; Turk-Browne, NB ; Tuulari, JJ ; Tzourio, C ; Vachon-Presseau, E ; Valdes-Sosa, MJ ; Valdes-Sosa, PA ; Valk, SL ; van Amelsvoort, T ; Vandekar, SN ; Vasung, L ; Victoria, LW ; Villeneuve, S ; Villringer, A ; Vertes, PE ; Wagstyl, K ; Wang, YS ; Warfield, SK ; Warrier, V ; Westman, E ; Westwater, ML ; Whalley, HC ; Witte, AV ; Yang, N ; Yeo, B ; Yun, H ; Zalesky, A ; Zar, HJ ; Zettergren, A ; Zhou, JH ; Ziauddeen, H ; Zugman, A ; Zuo, XN ; Bullmore, ET ; Alexander-Bloch, AF (NATURE PORTFOLIO, 2022-04-21)
    Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
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    Cell type-specific manifestations of cortical thickness heterogeneity in schizophrenia
    Di Biase, MA ; Geaghan, MP ; Reay, WR ; Seidlitz, J ; Weickert, CS ; Pebay, A ; Green, MJ ; Quide, Y ; Atkins, JR ; Coleman, MJ ; Bouix, S ; Knyazhanskaya, EE ; Lyall, AE ; Pasternak, O ; Kubicki, M ; Rathi, Y ; Visco, A ; Gaunnac, M ; Lv, J ; Mesholam-Gately, R ; Lewandowski, KE ; Holt, DJ ; Keshavan, MS ; Pantelis, C ; Ongur, D ; Breier, A ; Cairns, MJ ; Shenton, ME ; Zalesky, A (SPRINGERNATURE, 2022-04)
    Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor cells (OPCs); (4) excitatory neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells (r = -0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes (r = -0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.
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    White Matter Alterations Between Brain Network Hubs Underlie Processing Speed Impairment in Patients With Schizophrenia.
    Klauser, P ; Cropley, VL ; Baumann, PS ; Lv, J ; Steullet, P ; Dwir, D ; Alemán-Gómez, Y ; Bach Cuadra, M ; Cuenod, M ; Do, KQ ; Conus, P ; Pantelis, C ; Fornito, A ; Van Rheenen, TE ; Zalesky, A (Oxford University Press (OUP), 2021-01)
    Processing speed (PS) impairment is one of the most severe and common cognitive deficits in schizophrenia. Previous studies have reported correlations between PS and white matter diffusion properties, including fractional anisotropy (FA), in several fiber bundles in schizophrenia, suggesting that white matter alterations could underpin decreased PS. In schizophrenia, white matter alterations are most prevalent within inter-hub connections of the rich club. However, the spatial and topological characteristics of this association between PS and FA have not been investigated in patients. In this context, we tested whether structural connections comprising the rich club network would underlie PS impairment in 298 patients with schizophrenia or schizoaffective disorder and 190 healthy controls from the Australian Schizophrenia Research Bank. PS, measured using the digit symbol coding task, was largely (Cohen's d = 1.33) and significantly (P < .001) reduced in the patient group when compared with healthy controls. Significant associations between PS and FA were widespread in the patient group, involving all cerebral lobes. FA was not associated with other cognitive measures of phonological fluency and verbal working memory in patients, suggesting specificity to PS. A topological analysis revealed that despite being spatially widespread, associations between PS and FA were over-represented among connections forming the rich club network. These findings highlight the need to consider brain network topology when investigating high-order cognitive functions that may be spatially distributed among several brain regions. They also reinforce the evidence that brain hubs and their interconnections may be particularly vulnerable parts of the brain in schizophrenia.
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    Network Analysis of Symptom Comorbidity in Schizophrenia: Relationship to Illness Course and Brain White Matter Microstructure
    Ye, H ; Zalesky, A ; Lv, J ; Loi, SM ; Cetin-Karayumak, S ; Rathi, Y ; Tian, Y ; Pantelis, C ; Di Biase, MA (Oxford University Press (OUP), 2021-03-08)
    INTRODUCTION: Recent network-based analyses suggest that schizophrenia symptoms are intricately connected and interdependent, such that central symptoms can activate adjacent symptoms and increase global symptom burden. Here, we sought to identify key clinical and neurobiological factors that relate to symptom organization in established schizophrenia. METHODS: A symptom comorbidity network was mapped for a broad constellation of symptoms measured in 642 individuals with a schizophrenia-spectrum disorder. Centrality analyses were used to identify hub symptoms. The extent to which each patient's symptoms formed clusters in the comorbidity network was quantified with cluster analysis and used to predict (1) clinical features, including illness duration and psychosis (positive symptom) severity and (2) brain white matter microstructure, indexed by the fractional anisotropy (FA), in a subset (n = 296) of individuals with diffusion-weighted imaging (DWI) data. RESULTS: Global functioning, substance use, and blunted affect were the most central symptoms within the symptom comorbidity network. Symptom profiles for some patients formed highly interconnected clusters, whereas other patients displayed unrelated and disconnected symptoms. Stronger clustering among an individual's symptoms was significantly associated with shorter illness duration (t = 2.7; P = .0074), greater psychosis severity (ie, positive symptoms expression) (t = -5.5; P < 0.0001) and lower fractional anisotropy in fibers traversing the cortico-cerebellar-thalamic-cortical circuit (r = .59, P < 0.05). CONCLUSION: Symptom network structure varies over the course of schizophrenia: symptom interactions weaken with increasing illness duration and strengthen during periods of high positive symptom expression. Reduced white matter coherence relates to stronger symptom clustering, and thus, may underlie symptom cascades and global symptomatic burden in individuals with schizophrenia.
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    Individual deviations from normative models of brain structure in a large cross-sectional schizophrenia cohort
    Lv, J ; Di Biase, M ; Cash, RFH ; Cocchi, L ; Cropley, VL ; Klauser, P ; Tian, Y ; Bayer, J ; Schmaal, L ; Cetin-Karayumak, S ; Rathi, Y ; Pasternak, O ; Bousman, C ; Pantelis, C ; Calamante, F ; Zalesky, A (SPRINGERNATURE, 2021-07)
    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.