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1. Neurostructural subgroup in 4291 individuals with schizophrenia identified using the subtype and stage inference algorithm.

Author

Jiang, Yuchao, Luo, Cheng, Wang, Jijun, Palaniyappan, Lena, Chang, Xiao, Xiang, Shitong, Zhang, Jie, Duan, Mingjun, Huang, Huan, Gaser, Christian, Nemoto, Kiyotaka, Miura, Kenichiro, Hashimoto, Ryota, Westlye, Lars, Richard, Genevieve, Fernandez-Cabello, Sara, Parker, Nadine, Andreassen, Ole, Kircher, Tilo, Nenadić, Igor, Stein, Frederike, Thomas-Odenthal, Florian, Teutenberg, Lea, Usemann, Paula, Dannlowski, Udo, Hahn, Tim, Grotegerd, Dominik, Meinert, Susanne, Lencer, Rebekka, Tang, Yingying, Zhang, Tianhong, Li, Chunbo, Yue, Weihua, Zhang, Yuyanan, Yu, Xin, Zhou, Enpeng, Lin, Ching-Po, Tsai, Shih-Jen, Rodrigue, Amanda, Glahn, David, Pearlson, Godfrey, Blangero, John, Karuk, Andriana, Pomarol-Clotet, Edith, Salvador, Raymond, Fuentes-Claramonte, Paola, Garcia-León, María, Spalletta, Gianfranco, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Cheng, Jingliang, Liu, Zhening, Yang, Jie, Gonul, Ali, Uslu, Ozgul, Burhanoglu, Birce, Uyar Demir, Aslihan, Rootes-Murdy, Kelly, Calhoun, Vince, Sim, Kang, Green, Melissa, Quidé, Yann, Chung, Young, Kim, Woo-Sung, Sponheim, Scott, Demro, Caroline, Ramsay, Ian, Iasevoli, Felice, de Bartolomeis, Andrea, Barone, Annarita, Ciccarelli, Mariateresa, Brunetti, Arturo, Cocozza, Sirio, Pontillo, Giuseppe, Tranfa, Mario, Park, Min, Kirschner, Matthias, Georgiadis, Foivos, Kaiser, Stefan, Van Rheenen, Tamsyn, Rossell, Susan, Hughes, Matthew, Woods, William, Carruthers, Sean, Sumner, Philip, Ringin, Elysha, Spaniel, Filip, Skoch, Antonin, Tomecek, David, Homan, Philipp, Homan, Stephanie, Omlor, Wolfgang, Cecere, Giacomo, Nguyen, Dana, Preda, Adrian, Thomopoulos, Sophia, Jahanshad, Neda, Cui, Long-Biao, and Yao, Dezhong

Subjects
Humans, Schizophrenia, Male, Female, Adult, Algorithms, Magnetic Resonance Imaging, Gray Matter, Machine Learning, Middle Aged, Brain, Cross-Sectional Studies, Europe, Neuroimaging, Reproducibility of Results, North America, Hippocampus
Abstract

Machine learning can be used to define subtypes of psychiatric conditions based on shared biological foundations of mental disorders. Here we analyzed cross-sectional brain images from 4,222 individuals with schizophrenia and 7038 healthy subjects pooled across 41 international cohorts from the ENIGMA, non-ENIGMA cohorts and public datasets. Using the Subtype and Stage Inference (SuStaIn) algorithm, we identify two distinct neurostructural subgroups by mapping the spatial and temporal trajectory of gray matter change in schizophrenia. Subgroup 1 was characterized by an early cortical-predominant loss with enlarged striatum, whereas subgroup 2 displayed an early subcortical-predominant loss in the hippocampus, striatum and other subcortical regions. We confirmed the reproducibility of the two neurostructural subtypes across various sample sites, including Europe, North America and East Asia. This imaging-based taxonomy holds the potential to identify individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors.

Published
2024

2. Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.

Author

Georgiadis, Foivos, Larivière, Sara, Glahn, David, Hong, L, Kochunov, Peter, Mowry, Bryan, Loughland, Carmel, Pantelis, Christos, Henskens, Frans, Green, Melissa, Cairns, Murray, Michie, Patricia, Rasser, Paul, Catts, Stanley, Tooney, Paul, Scott, Rodney, Schall, Ulrich, Carr, Vaughan, Quidé, Yann, Krug, Axel, Stein, Frederike, Nenadić, Igor, Brosch, Katharina, Kircher, Tilo, Gur, Raquel, Gur, Ruben, Satterthwaite, Theodore, Karuk, Andriana, Pomarol-Clotet, Edith, Radua, Joaquim, Fuentes-Claramonte, Paola, Salvador, Raymond, Spalletta, Gianfranco, Voineskos, Aristotle, Sim, Kang, Crespo-Facorro, Benedicto, Tordesillas Gutiérrez, Diana, Ehrlich, Stefan, Crossley, Nicolas, Grotegerd, Dominik, Repple, Jonathan, Lencer, Rebekka, Dannlowski, Udo, Calhoun, Vince, Rootes-Murdy, Kelly, Demro, Caroline, Ramsay, Ian, Sponheim, Scott, Schmidt, Andre, Borgwardt, Stefan, Tomyshev, Alexander, Lebedeva, Irina, Höschl, Cyril, Spaniel, Filip, Preda, Adrian, Nguyen, Dana, Uhlmann, Anne, Stein, Dan, Howells, Fleur, Temmingh, Henk, Diaz Zuluaga, Ana, López Jaramillo, Carlos, Iasevoli, Felice, Ji, Ellen, Homan, Stephanie, Omlor, Wolfgang, Homan, Philipp, Kaiser, Stefan, Seifritz, Erich, Misic, Bratislav, Valk, Sofie, Thompson, Paul, Van Erp, Theodorus, Turner, Jessica, Bernhardt, Boris, and Kirschner, Matthias

Subjects
Humans, Schizophrenia, Connectome, Adult, Female, Male, Magnetic Resonance Imaging, Cerebral Cortex, Nerve Net, Brain, Middle Aged, Neural Pathways, Young Adult
Abstract

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenias alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

Published
2024

3. Differences in the neural correlates of schizophrenia with positive and negative formal thought disorder in patients with schizophrenia in the ENIGMA dataset

Author

Sharkey, Rachel J., Bacon, Chelsea, Peterson, Zeru, Rootes-Murdy, Kelly, Salvador, Raymond, Pomarol-Clotet, Edith, Karuk, Andriana, Homan, Philipp, Ji, Ellen, Omlor, Wolfgang, Homan, Stephanie, Georgiadis, Foivos, Kaiser, Stefan, Kirschner, Matthias, Ehrlich, Stefan, Dannlowski, Udo, Grotegerd, Dominik, Goltermann, Janik, Meinert, Susanne, Kircher, Tilo, Stein, Frederike, Brosch, Katharina, Krug, Axel, Nenadic, Igor, Sim, Kang, Spalletta, Gianfranco, Banaj, Nerisa, Sponheim, Scott R., Demro, Caroline, Ramsay, Ian S., King, Margaret, Quidé, Yann, Green, Melissa Jane, Nguyen, Dana, Preda, Adrian, Calhoun, Vince, Turner, Jessica, van Erp, Theo, and Nickl-Jockschat, Thomas

Published
2024
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4. Structural brain abnormalities and aggressive behaviour in schizophrenia: Mega-analysis of data from 2095 patients and 2861 healthy controls via the ENIGMA consortium

Author

Lamsma, Jelle, Raine, Adrian, Kia, Seyed M, Cahn, Wiepke, Arold, Dominic, Banaj, Nerisa, Barone, Annarita, Brosch, Katharina, Brouwer, Rachel, Brunetti, Arturo, Calhoun, Vince D, Chew, Qian H, Choi, Sunah, Chung, Young-Chul, Ciccarelli, Mariateresa, Cobia, Derin, Cocozza, Sirio, Dannlowski, Udo, Dazzan, Paola, de Bartolomeis, Andrea, Di Forti, Marta, Dumais, Alexandre, Edmond, Jesse T, Ehrlich, Stefan, Evermann, Ulrika, Flinkenflügel, Kira, Georgiadis, Foivos, Glahn, David C, Goltermann, Janik, Green, Melissa J, Grotegerd, Dominik, Guerrero-Pedraza, Amalia, Ha, Minji, Hong, Elliot L, Pol, Hilleke Hulshoff, Iasevoli, Felice, Kaiser, Stefan, Kaleda, Vasily, Karuk, Andriana, Kim, Minah, Kircher, Tilo, Kirschner, Matthias, Kochunov, Peter, Kwon, Jun Soo, Lebedeva, Irina, Lencer, Rebekka, Marques, Tiago R, Meinert, Susanne, Murray, Robin, Nenadić, Igor, Nguyen, Dana, Pearlson, Godfrey, Piras, Fabrizio, Pomarol-Clotet, Edith, Pontillo, Giuseppe, Potvin, Stéphane, Preda, Adrian, Quidé, Yann, Rodrigue, Amanda, Rootes-Murdy, Kelly, Salvador, Raymond, Skoch, Antonin, Sim, Kang, Spalletta, Gianfranco, Spaniel, Filip, Stein, Frederike, Thomas-Odenthal, Florian, Tikàsz, Andràs, Tomecek, David, Tomyshev, Alexander, Tranfa, Mario, Tsogt, Uyanga, Turner, Jessica A, van Erp, Theo GM, van Haren, Neeltje EM, van Os, Jim, Vecchio, Daniela, Wang, Lei, Wroblewski, Adrian, and Nickl-Jockschat, Thomas

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Schizophrenia, Brain Disorders, Neurosciences, Biomedical Imaging, Serious Mental Illness, Mental Health, Mental Illness, Mental health
Abstract

BACKGROUND: Schizophrenia is associated with an increased risk of aggressive behaviour, which may partly be explained by illness-related changes in brain structure. However, previous studies have been limited by group-level analyses, small and selective samples of inpatients and long time lags between exposure and outcome. METHODS: This cross-sectional study pooled data from 20 sites participating in the international ENIGMA-Schizophrenia Working Group. Sites acquired T1-weighted and diffusion-weighted magnetic resonance imaging scans in a total of 2095 patients with schizophrenia and 2861 healthy controls. Measures of grey matter volume and white matter microstructural integrity were extracted from the scans using harmonised protocols. For each measure, normative modelling was used to calculate how much patients deviated (in z-scores) from healthy controls at the individual level. Ordinal regression models were used to estimate the associations of these deviations with concurrent aggressive behaviour (as odds ratios [ORs] with 99% confidence intervals [CIs]). Mediation analyses were performed for positive symptoms (i.e., delusions, hallucinations and disorganised thinking), impulse control and illness insight. Aggression and potential mediators were assessed with the Positive and Negative Syndrome Scale, Scale for the Assessment of Positive Symptoms or Brief Psychiatric Rating Scale. RESULTS: Aggressive behaviour was significantly associated with reductions in total cortical volume (OR [99% CI] = 0.88 [0.78, 0.98], p = .003) and global white matter integrity (OR [99% CI] = 0.72 [0.59, 0.88], p = 3.50 × 10-5) and additional reductions in dorsolateral prefrontal cortex volume (OR [99% CI] = 0.85 [0.74, 0.97], p =.002), inferior parietal lobule volume (OR [99% CI] = 0.76 [0.66, 0.87], p = 2.20 × 10-7) and internal capsule integrity (OR [99% CI] = 0.76 [0.63, 0.92], p = 2.90 × 10-4). Except for inferior parietal lobule volume, these associations were largely mediated by increased severity of positive symptoms and reduced impulse control. CONCLUSIONS: This study provides evidence that the co-occurrence of positive symptoms, poor impulse control and aggressive behaviour in schizophrenia has a neurobiological basis, which may inform the development of therapeutic interventions.

Published
2024

5. Two neurostructural subtypes: results of machine learning on brain images from 4,291 individuals with schizophrenia

Author

Jiang, Yuchao, Luo, Cheng, Wang, Jijun, Palaniyappan, Lena, Chang, Xiao, Xiang, Shitong, Zhang, Jie, Duan, Mingjun, Huang, Huan, Gaser, Christian, Nemoto, Kiyotaka, Miura, Kenichiro, Hashimoto, Ryota, Westlye, Lars T, Richard, Genevieve, Fernandez-Cabello, Sara, Parker, Nadine, Andreassen, Ole A, Kircher, Tilo, Nenadić, Igor, Stein, Frederike, Thomas-Odenthal, Florian, Teutenberg, Lea, Usemann, Paula, Dannlowski, Udo, Hahn, Tim, Grotegerd, Dominik, Meinert, Susanne, Lencer, Rebekka, Tang, Yingying, Zhang, Tianhong, Li, Chunbo, Yue, Weihua, Zhang, Yuyanan, Yu, Xin, Zhou, Enpeng, Lin, Ching-Po, Tsai, Shih-Jen, Rodrigue, Amanda L, Glahn, David, Pearlson, Godfrey, Blangero, John, Karuk, Andriana, Pomarol-Clotet, Edith, Salvador, Raymond, Fuentes-Claramonte, Paola, Garcia-León, María Ángeles, Spalletta, Gianfranco, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Cheng, Jingliang, Liu, Zhening, Yang, Jie, Gonul, Ali Saffet, Uslu, Ozgul, Burhanoglu, Birce Begum, Demir, Aslihan Uyar, Rootes-Murdy, Kelly, Calhoun, Vince D, Sim, Kang, Green, Melissa, Quidé, Yann, Chung, Young Chul, Kim, Woo-Sung, Sponheim, Scott R, Demro, Caroline, Ramsay, Ian S, Iasevoli, Felice, de Bartolomeis, Andrea, Barone, Annarita, Ciccarelli, Mariateresa, Brunetti, Arturo, Cocozza, Sirio, Pontillo, Giuseppe, Tranfa, Mario, Park, Min Tae M, Kirschner, Matthias, Georgiadis, Foivos, Kaiser, Stefan, Van Rheenen, Tamsyn E, Rossell, Susan L, Hughes, Matthew, Woods, William, Carruthers, Sean P, Sumner, Philip, Ringin, Elysha, Spaniel, Filip, Skoch, Antonin, Tomecek, David, Homan, Philipp, Homan, Stephanie, Omlor, Wolfgang, Cecere, Giacomo, Nguyen, Dana D, Preda, Adrian, Thomopoulos, Sophia, Jahanshad, Neda, Cui, Long-Biao, and Yao, Dezhong

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Machine Learning and Artificial Intelligence, Mental Illness, Clinical Research, Brain Disorders, Serious Mental Illness, Neurosciences, Schizophrenia, Mental Health, Behavioral and Social Science, Biomedical Imaging, Mental health, Good Health and Well Being, ENIGMA, artificial intelligence, brain gray matter, schizophrenia, structural MRI, subtype
Abstract

Machine learning can be used to define subtypes of psychiatric conditions based on shared clinical and biological foundations, presenting a crucial step toward establishing biologically based subtypes of mental disorders. With the goal of identifying subtypes of disease progression in schizophrenia, here we analyzed cross-sectional brain structural magnetic resonance imaging (MRI) data from 4,291 individuals with schizophrenia (1,709 females, age=32.5 years±11.9) and 7,078 healthy controls (3,461 females, age=33.0 years±12.7) pooled across 41 international cohorts from the ENIGMA Schizophrenia Working Group, non-ENIGMA cohorts and public datasets. Using a machine learning approach known as Subtype and Stage Inference (SuStaIn), we implemented a brain imaging-driven classification that identifies two distinct neurostructural subgroups by mapping the spatial and temporal trajectory of gray matter (GM) loss in schizophrenia. Subgroup 1 (n=2,622) was characterized by an early cortical-predominant loss (ECL) with enlarged striatum, whereas subgroup 2 (n=1,600) displayed an early subcortical-predominant loss (ESL) in the hippocampus, amygdala, thalamus, brain stem and striatum. These reconstructed trajectories suggest that the GM volume reduction originates in the Broca's area/adjacent fronto-insular cortex for ECL and in the hippocampus/adjacent medial temporal structures for ESL. With longer disease duration, the ECL subtype exhibited a gradual worsening of negative symptoms and depression/anxiety, and less of a decline in positive symptoms. We confirmed the reproducibility of these imaging-based subtypes across various sample sites, independent of macroeconomic and ethnic factors that differed across these geographic locations, which include Europe, North America and East Asia. These findings underscore the presence of distinct pathobiological foundations underlying schizophrenia. This new imaging-based taxonomy holds the potential to identify a more homogeneous sub-population of individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors.

Published
2023

6. Neurostructural subgroup in 4291 individuals with schizophrenia identified using the subtype and stage inference algorithm

Author

Yuchao Jiang, Cheng Luo, Jijun Wang, Lena Palaniyappan, Xiao Chang, Shitong Xiang, Jie Zhang, Mingjun Duan, Huan Huang, Christian Gaser, Kiyotaka Nemoto, Kenichiro Miura, Ryota Hashimoto, Lars T. Westlye, Genevieve Richard, Sara Fernandez-Cabello, Nadine Parker, Ole A. Andreassen, Tilo Kircher, Igor Nenadić, Frederike Stein, Florian Thomas-Odenthal, Lea Teutenberg, Paula Usemann, Udo Dannlowski, Tim Hahn, Dominik Grotegerd, Susanne Meinert, Rebekka Lencer, Yingying Tang, Tianhong Zhang, Chunbo Li, Weihua Yue, Yuyanan Zhang, Xin Yu, Enpeng Zhou, Ching-Po Lin, Shih-Jen Tsai, Amanda L. Rodrigue, David Glahn, Godfrey Pearlson, John Blangero, Andriana Karuk, Edith Pomarol-Clotet, Raymond Salvador, Paola Fuentes-Claramonte, María Ángeles Garcia-León, Gianfranco Spalletta, Fabrizio Piras, Daniela Vecchio, Nerisa Banaj, Jingliang Cheng, Zhening Liu, Jie Yang, Ali Saffet Gonul, Ozgul Uslu, Birce Begum Burhanoglu, Aslihan Uyar Demir, Kelly Rootes-Murdy, Vince D. Calhoun, Kang Sim, Melissa Green, Yann Quidé, Young Chul Chung, Woo-Sung Kim, Scott R. Sponheim, Caroline Demro, Ian S. Ramsay, Felice Iasevoli, Andrea de Bartolomeis, Annarita Barone, Mariateresa Ciccarelli, Arturo Brunetti, Sirio Cocozza, Giuseppe Pontillo, Mario Tranfa, Min Tae M. Park, Matthias Kirschner, Foivos Georgiadis, Stefan Kaiser, Tamsyn E. Van Rheenen, Susan L. Rossell, Matthew Hughes, William Woods, Sean P. Carruthers, Philip Sumner, Elysha Ringin, Filip Spaniel, Antonin Skoch, David Tomecek, Philipp Homan, Stephanie Homan, Wolfgang Omlor, Giacomo Cecere, Dana D. Nguyen, Adrian Preda, Sophia I. Thomopoulos, Neda Jahanshad, Long-Biao Cui, Dezhong Yao, Paul M. Thompson, Jessica A. Turner, Theo G. M. van Erp, Wei Cheng, ENIGMA Schizophrenia Consortium, Jianfeng Feng, and ZIB Consortium

Subjects
Science
Abstract

Abstract Machine learning can be used to define subtypes of psychiatric conditions based on shared biological foundations of mental disorders. Here we analyzed cross-sectional brain images from 4,222 individuals with schizophrenia and 7038 healthy subjects pooled across 41 international cohorts from the ENIGMA, non-ENIGMA cohorts and public datasets. Using the Subtype and Stage Inference (SuStaIn) algorithm, we identify two distinct neurostructural subgroups by mapping the spatial and temporal ‘trajectory’ of gray matter change in schizophrenia. Subgroup 1 was characterized by an early cortical-predominant loss with enlarged striatum, whereas subgroup 2 displayed an early subcortical-predominant loss in the hippocampus, striatum and other subcortical regions. We confirmed the reproducibility of the two neurostructural subtypes across various sample sites, including Europe, North America and East Asia. This imaging-based taxonomy holds the potential to identify individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors.

Published
2024
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7. Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium.

Author

Constantinides, Constantinos, Han, Laura KM, Alloza, Clara, Antonucci, Linda Antonella, Arango, Celso, Ayesa-Arriola, Rosa, Banaj, Nerisa, Bertolino, Alessandro, Borgwardt, Stefan, Bruggemann, Jason, Bustillo, Juan, Bykhovski, Oleg, Calhoun, Vince, Carr, Vaughan, Catts, Stanley, Chung, Young-Chul, Crespo-Facorro, Benedicto, Díaz-Caneja, Covadonga M, Donohoe, Gary, Plessis, Stefan Du, Edmond, Jesse, Ehrlich, Stefan, Emsley, Robin, Eyler, Lisa T, Fuentes-Claramonte, Paola, Georgiadis, Foivos, Green, Melissa, Guerrero-Pedraza, Amalia, Ha, Minji, Hahn, Tim, Henskens, Frans A, Holleran, Laurena, Homan, Stephanie, Homan, Philipp, Jahanshad, Neda, Janssen, Joost, Ji, Ellen, Kaiser, Stefan, Kaleda, Vasily, Kim, Minah, Kim, Woo-Sung, Kirschner, Matthias, Kochunov, Peter, Kwak, Yoo Bin, Kwon, Jun Soo, Lebedeva, Irina, Liu, Jingyu, Mitchie, Patricia, Michielse, Stijn, Mothersill, David, Mowry, Bryan, de la Foz, Víctor Ortiz-García, Pantelis, Christos, Pergola, Giulio, Piras, Fabrizio, Pomarol-Clotet, Edith, Preda, Adrian, Quidé, Yann, Rasser, Paul E, Rootes-Murdy, Kelly, Salvador, Raymond, Sangiuliano, Marina, Sarró, Salvador, Schall, Ulrich, Schmidt, André, Scott, Rodney J, Selvaggi, Pierluigi, Sim, Kang, Skoch, Antonin, Spalletta, Gianfranco, Spaniel, Filip, Thomopoulos, Sophia I, Tomecek, David, Tomyshev, Alexander S, Tordesillas-Gutiérrez, Diana, van Amelsvoort, Therese, Vázquez-Bourgon, Javier, Vecchio, Daniela, Voineskos, Aristotle, Weickert, Cynthia S, Weickert, Thomas, Thompson, Paul M, Schmaal, Lianne, van Erp, Theo GM, Turner, Jessica, Cole, James H, ENIGMA Schizophrenia Consortium, Dima, Danai, and Walton, Esther

Subjects
ENIGMA Schizophrenia Consortium, Brain, Humans, Magnetic Resonance Imaging, Prospective Studies, Schizophrenia, Aging, Adolescent, Adult, Aged, Middle Aged, Female, Male, Young Adult, Mental Health, Serious Mental Illness, Brain Disorders, Neurosciences, Biomedical Imaging, Clinical Research, Behavioral and Social Science, Neurological, Mental health, Good Health and Well Being, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Published
2023

12. Structural brain abnormalities and aggressive behaviour in schizophrenia: Mega-analysis of data from 2095 patients and 2861 healthy controls via the ENIGMA consortium

Author

Lamsma, Jelle, primary, Raine, Adrian, additional, Kia, Seyed M., additional, Cahn, Wiepke, additional, Arold, Dominic, additional, Banaj, Nerisa, additional, Barone, Annarita, additional, Brosch, Katharina, additional, Brouwer, Rachel, additional, Brunetti, Arturo, additional, Calhoun, Vince D., additional, Chew, Qian H., additional, Choi, Sunah, additional, Chung, Young-Chul, additional, Ciccarelli, Mariateresa, additional, Cobia, Derin, additional, Cocozza, Sirio, additional, Dannlowski, Udo, additional, Dazzan, Paola, additional, de Bartolomeis, Andrea, additional, Forti, Marta Di, additional, Dumais, Alexandre, additional, Edmond, Jesse T., additional, Ehrlich, Stefan, additional, Evermann, Ulrika, additional, Flinkenflügel, Kira, additional, Georgiadis, Foivos, additional, Glahn, David C., additional, Goltermann, Janik, additional, Green, Melissa J., additional, Grotegerd, Dominik, additional, Guerrero-Pedraza, Amalia, additional, Ha, Minji, additional, Hong, Elliot L., additional, Pol, Hilleke Hulshoff, additional, Iasevoli, Felice, additional, Kaiser, Stefan, additional, Kaleda, Vasily, additional, Karuk, Andriana, additional, Kim, Minah, additional, Kircher, Tilo, additional, Kirschner, Matthias, additional, Kochunov, Peter, additional, Kwon, Jun Soo, additional, Lebedeva, Irina, additional, Lencer, Rebekka, additional, Marques, Tiago R., additional, Meinert, Susanne, additional, Murray, Robin, additional, Nenadić, Igor, additional, Nguyen, Dana, additional, Pearlson, Godfrey, additional, Piras, Fabrizio, additional, Pomarol-Clotet, Edith, additional, Pontillo, Giuseppe, additional, Potvin, Stéphane, additional, Preda, Adrian, additional, Quidé, Yann, additional, Rodrigue, Amanda, additional, Rootes-Murdy, Kelly, additional, Salvador, Raymond, additional, Skoch, Antonin, additional, Sim, Kang, additional, Spalletta, Gianfranco, additional, Spaniel, Filip, additional, Stein, Frederike, additional, Thomas-Odenthal, Florian, additional, Tikàsz, Andràs, additional, Tomecek, David, additional, Tomyshev, Alexander, additional, Tranfa, Mario, additional, Tsogt, Uyanga, additional, Turner, Jessica A., additional, van Erp, Theo G. M., additional, van Haren, Neeltje E. M., additional, van Os, Jim, additional, Vecchio, Daniela, additional, Wang, Lei, additional, Wroblewski, Adrian, additional, and Nickl-Jockschat, Thomas, additional

Published
2024
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13. Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study

Author

Georgiadis, Foivos; https://orcid.org/0000-0001-8784-9653, Larivière, Sara, Glahn, David, Hong, L Elliot, Kochunov, Peter, Mowry, Bryan; https://orcid.org/0000-0002-4115-5645, Loughland, Carmel, Pantelis, Christos; https://orcid.org/0000-0002-9565-0238, Henskens, Frans A; https://orcid.org/0000-0003-2358-5630, Green, Melissa J; https://orcid.org/0000-0002-9361-4874, Cairns, Murray J; https://orcid.org/0000-0003-2490-2538, Michie, Patricia T; https://orcid.org/0000-0002-4169-8519, Rasser, Paul E, Catts, Stanley, Tooney, Paul; https://orcid.org/0000-0003-3745-4367, Scott, Rodney J; https://orcid.org/0000-0001-7724-3404, Schall, Ulrich, Carr, Vaughan; https://orcid.org/0000-0002-8907-5804, Quidé, Yann; https://orcid.org/0000-0002-8569-7139, Krug, Axel; https://orcid.org/0000-0002-0564-2497, Stein, Frederike, Nenadić, Igor; https://orcid.org/0000-0002-0749-7473, Brosch, Katharina; https://orcid.org/0000-0002-0526-8095, Ji, Ellen; https://orcid.org/0000-0003-1527-8868, Homan, Stephanie; https://orcid.org/0000-0003-1449-7508, Omlor, Wolfgang, Homan, Philipp; https://orcid.org/0000-0001-9034-148X, Seifritz, Erich; https://orcid.org/0000-0002-7311-4426, ENIGMA Schizophrenia Consortium, Kirschner, Matthias; https://orcid.org/0000-0002-9486-1439, et al, Georgiadis, Foivos; https://orcid.org/0000-0001-8784-9653, Larivière, Sara, Glahn, David, Hong, L Elliot, Kochunov, Peter, Mowry, Bryan; https://orcid.org/0000-0002-4115-5645, Loughland, Carmel, Pantelis, Christos; https://orcid.org/0000-0002-9565-0238, Henskens, Frans A; https://orcid.org/0000-0003-2358-5630, Green, Melissa J; https://orcid.org/0000-0002-9361-4874, Cairns, Murray J; https://orcid.org/0000-0003-2490-2538, Michie, Patricia T; https://orcid.org/0000-0002-4169-8519, Rasser, Paul E, Catts, Stanley, Tooney, Paul; https://orcid.org/0000-0003-3745-4367, Scott, Rodney J; https://orcid.org/0000-0001-7724-3404, Schall, Ulrich, Carr, Vaughan; https://orcid.org/0000-0002-8907-5804, Quidé, Yann; https://orcid.org/0000-0002-8569-7139, Krug, Axel; https://orcid.org/0000-0002-0564-2497, Stein, Frederike, Nenadić, Igor; https://orcid.org/0000-0002-0749-7473, Brosch, Katharina; https://orcid.org/0000-0002-0526-8095, Ji, Ellen; https://orcid.org/0000-0003-1527-8868, Homan, Stephanie; https://orcid.org/0000-0003-1449-7508, Omlor, Wolfgang, Homan, Philipp; https://orcid.org/0000-0001-9034-148X, Seifritz, Erich; https://orcid.org/0000-0002-7311-4426, ENIGMA Schizophrenia Consortium, Kirschner, Matthias; https://orcid.org/0000-0002-9486-1439, and et al

Abstract

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network ar

Published
2024

14. Impact of language proficiency on mental health service use, treatment and outcomes: 'Lost in Translation'

Author

Dimitrina Miteva, Foivos Georgiadis, Lorna McBroom, Vanessa Noboa, Boris B. Quednow, Erich Seifritz, Stefan Vetter, and Stephan T. Egger

Subjects
Language Proficiency, Mental Health, Treatment Outcomes, Coercive Treatment, Psychiatry, RC435-571
Abstract

Background: Mastery of a language is bound to place of origin; low language proficiency is thus related to migration and cultural differences, all of which influence access to mental health care, treatment and outcomes. Switzerland, being multilingual, allows the disentangling of language proficiency from migration and, to some extent, culture. This study uses propensity score matching to explore how language proficiency relates to help-seeking behaviour, service use, treatment and outcomes in patients with mental health disorders. Methods: We used the first admission of patients admitted to and discharged from an academic psychiatric hospital in Switzerland between January 1st, 2013 and December 31st, 2019, with an observation period of one-year post-discharge (until December 31st, 2020). We paired 2101 patients with low language proficiency to 2101 language proficient patients, balancing baseline sociodemographic and clinical characteristics using propensity score matching. Results: Patients with low language proficiency had a higher probability of compulsory admission (OR: 1.79, 99%CI: 1.60–2.02); which remained after adjustment for confounders (OR: 1.51; 99%CI: 1.21–1.89). Whilst in treatment, they had higher rates of compulsory medication (OR: 1.73, 99%CI: 1.16–2.59) and seclusion/restraint (OR: 1.87, 99%CI: 1.25–2.79). Furthermore, patients initially admitted voluntarily had a higher probability of being compulsorily retained (OR: 1.74, 99%CI: 1.24–2.46). Both groups showed similar clinical improvement rates and service use parameters. Conclusions: Our results demonstrate that low language proficiency constitutes a risk factor for coercive measures throughout hospitalisation. The results demonstrate the need for an increase in language sensitivity in psychiatric care.

Published
2022
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15. From genetics to systems biology of stress-related mental disorders

Author

Shareefa Dalvie, Chris Chatzinakos, Obada Al Zoubi, Foivos Georgiadis, Lee Lancashire, and Nikolaos P. Daskalakis

Subjects
Stress disorders, Traumatic, Genetics, Systems biology, Transcriptome, Epigenomics, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429, Neurophysiology and neuropsychology, QP351-495
Abstract

Many individuals will be exposed to some form of traumatic stress in their lifetime which, in turn, increases the likelihood of developing stress-related disorders such as post-traumatic stress disorder (PTSD), major depressive disorder (MDD) and anxiety disorders (ANX). The development of these disorders is also influenced by genetics and have heritability estimates ranging between ∼30 and 70%. In this review, we provide an overview of the findings of genome-wide association studies for PTSD, depression and ANX, and we observe a clear genetic overlap between these three diagnostic categories. We go on to highlight the results from transcriptomic and epigenomic studies, and, given the multifactorial nature of stress-related disorders, we provide an overview of the gene-environment studies that have been conducted to date. Finally, we discuss systems biology approaches that are now seeing wider utility in determining a more holistic view of these complex disorders.

Published
2021
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16. Gene expression in the dorsolateral and ventromedial prefrontal cortices implicates immune-related gene networks in PTSD

Author

Mark W. Logue, Zhenwei Zhou, Filomene G. Morrison, Erika J. Wolf, Nikolaos P. Daskalakis, Christos Chatzinakos, Foivos Georgiadis, Adam T. Labadorf, Matthew J. Girgenti, Keith A. Young, Douglas E. Williamson, Xiang Zhao, Jaclyn Garza Grenier, Bertrand Russell Huber, and Mark W. Miller

Subjects
PTSD, RNAseq, vmPFC, dlPFC, Expression, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429, Neurophysiology and neuropsychology, QP351-495
Abstract

Studies evaluating neuroimaging, genetically predicted gene expression, and pre-clinical genetic models of PTSD, have identified PTSD-related abnormalities in the prefrontal cortex (PFC) of the brain, particularly in dorsolateral and ventromedial PFC (dlPFC and vmPFC). In this study, RNA sequencing was used to examine gene expression in the dlPFC and vmPFC using tissue from the VA National PTSD Brain Bank in donors with histories of PTSD with or without depression (dlPFC n = 38, vmPFC n = 35), depression cases without PTSD (n = 32), and psychopathology-free controls (dlPFC n = 24, vmPFC n = 20). Analyses compared PTSD cases to controls. Follow-up analyses contrasted depression cases to controls. Twenty-one genes were differentially expressed in PTSD after strict multiple testing correction. PTSD-associated genes with roles in learning and memory (FOS, NR4A1), immune regulation (CFH, KPNA1) and myelination (MBP, MOBP, ERMN) were identified. PTSD-associated genes partially overlapped depression-associated genes. Co-expression network analyses identified PTSD-associated networks enriched for immune-related genes across the two brain regions. However, the immune-related genes and association patterns were distinct. The immune gene IL1B was significantly associated with PTSD in candidate-gene analysis and was an upstream regulator of PTSD-associated genes in both regions. There was evidence of replication of dlPFC associations in an independent cohort from a recent study, and a strong correlation between the dlPFC PTSD effect sizes for significant genes in the two studies (r = 0.66, p

Published
2021
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17. Two neurostructural subtypes: results of machine learning on brain images from 4,291 individuals with schizophrenia

Author

Jiang, Yuchao, primary, Luo, Cheng, additional, Wang, Jijun, additional, Palaniyappan, Lena, additional, Chang, Xiao, additional, Xiang, Shitong, additional, Zhang, Jie, additional, Duan, Mingjun, additional, Huang, Huan, additional, Gaser, Christian, additional, Nemoto, Kiyotaka, additional, Miura, Kenichiro, additional, Hashimoto, Ryota, additional, Westlye, Lars T., additional, Richard, Genevieve, additional, Fernandez-Cabello, Sara, additional, Parker, Nadine, additional, Andreassen, Ole A., additional, Kircher, Tilo, additional, Nenadi?, Igor, additional, Stein, Frederike, additional, Thomas-Odenthal, Florian, additional, Teutenberg, Lea, additional, Usemann, Paula, additional, Dannlowski, Udo, additional, Hahn, Tim, additional, Grotegerd, Dominik, additional, Meinert, Susanne, additional, Lencer, Rebekka, additional, Tang, Yingying, additional, Zhang, Tianhong, additional, Li, Chunbo, additional, Yue, Weihua, additional, Zhang, Yuyanan, additional, Yu, Xin, additional, Zhou, Enpeng, additional, Lin, Ching-Po, additional, Tsai, Shih-Jen, additional, Rodrigue, Amanda L., additional, Glahn, David, additional, Pearlson, Godfrey, additional, Blangero, John, additional, Karuk, Andriana, additional, pomarol-Clotet, Edith, additional, Salvador, Raymond, additional, Fuentes-Claramonte, Paola, additional, angeles, Maria, additional, Spalletta, Gianfranco, additional, Piras, Fabrizio, additional, Vecchio, Daniela, additional, Banaj, Nerisa, additional, Cheng, Jingliang, additional, Liu, Zhening, additional, Yang, Jie, additional, Gonul, Ali Saffet, additional, Uslu, Ozgul, additional, Burhanoglu, Birce Begum, additional, Demir, Aslihan Uyar, additional, Rootes-Murdy, Kelly, additional, Calhoun, Vince D., additional, Sim, Kang, additional, Green, Melissa, additional, Quide, Yann, additional, Chung, Young Chul, additional, Kim, Woo-Sung, additional, Sponheim, Scott R., additional, Demro, Caroline, additional, Ramsay, Ian S., additional, Iasevoli, Felice, additional, Bartolomeis, Andrea de, additional, Barone, Annarita, additional, Ciccarelli, Mariateresa, additional, Brunetti, Arturo, additional, Cocozza, Sirio, additional, Pontillo, Giuseppe, additional, Tranfa, Mario, additional, Park, Min Tae M., additional, Kirschner, Matthias, additional, Georgiadis, Foivos, additional, Kaiser, Stefan, additional, Rheenen, Tamsyn Van, additional, Rossell, Susan, additional, Hughes, Matthew, additional, Woods, William, additional, Carruthers, Sean, additional, Sumner, Philip, additional, Ringin, Elysha, additional, Spaniel, Filip, additional, Skoch, Antonin, additional, Tomecek, David, additional, Homan, Philipp, additional, Homan, Stephanie, additional, Omlor, Wolfgang, additional, Cecere, Giacomo, additional, Nguyen, Dana D, additional, Preda, Adrian, additional, Thomopoulos, Sophia, additional, Jahanshad, Neda, additional, Cui, Long-Biao, additional, Yao, Dezhong, additional, Thompson, Paul M., additional, Turner, Jessica A., additional, van Erp, Theo G.M., additional, Cheng, Wei, additional, and Feng, Jianfeng, additional

Published
2023
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18. Neural Correlates of Positive and Negative Formal Thought Disorder in Individuals with Schizophrenia: An ENIGMA Schizophrenia Working Group Study

Author

Nickl-Jockschat, Thomas, primary, Sharkey, Rachel, additional, Bacon, Chelsea, additional, Peterson, Zeru, additional, Rootes-Murdy, Kelly, additional, Salvador, Raymond, additional, Pomarol, Edith, additional, Karuk, Andriana, additional, Homan, Philipp, additional, Ji, Ellen, additional, Omlor, Wolfgang, additional, Homan, Stephanie, additional, Georgiadis, Foivos, additional, Kaiser, Stefan, additional, Kirschner, Matthias, additional, Ehrlich, Stefan, additional, Dannlowski, Udo, additional, Grotegerd, Dominik, additional, Goltermann, Janik, additional, Meinert, Susanne, additional, Kircher, Tilo, additional, Stein, Frederike, additional, Brosch, Katharina, additional, Krug, Axel, additional, Nenadic, Igor, additional, Sim, Kang, additional, Piras, Fabrizio, additional, Banaj, Nerisa, additional, Sponheim, Scott, additional, Demro, Caroline, additional, Ramsay, Ian, additional, King, Margaret, additional, Quidé, Yann, additional, Green, Melissa, additional, Nguyen, Dana, additional, Preda, Adrian, additional, Calhoun, Vince, additional, Turner, Jessica, additional, Erp, Theo van, additional, and Spalletta, Gianfranco, additional

Published
2023
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19. Estimating multimodal brain variability in schizophrenia spectrum disorders: A worldwide ENIGMA study

Author

Omlor, Wolfgang, primary, Rabe, Finn, additional, Fuchs, Simon, additional, Cecere, Giacomo, additional, Homan, Stephanie, additional, Surbeck, Werner, additional, Kallen, Nils, additional, Georgiadis, Foivos, additional, Spiller, Tobias, additional, Seifritz, Erich, additional, Weickert, Thomas, additional, Bruggemann, Jason, additional, Weickert, Cynthia, additional, Potkin, Steven, additional, Hashimoto, Ryota, additional, Sim, Kang, additional, Rootes-Murdy, Kelly, additional, Quide, Yann, additional, Houenou, Josselin, additional, Banaj, Nerisa, additional, Vecchio, Daniela, additional, Piras, Fabrizio, additional, Piras, Federica, additional, Spalletta, Gianfranco, additional, Salvador, Raymond, additional, Karuk, Andriana, additional, Pomarol-Clotet, Edith, additional, Rodrigue, Amanda, additional, Pearlson, Godfrey, additional, Glahn, David, additional, Tomecek, David, additional, Spaniel, Filip, additional, Skoch, Antonin, additional, Kirschner, Matthias, additional, Kaiser, Stefan, additional, Kochunov, Peter, additional, Fan, Feng-Mei, additional, Andreassen, Ole A., additional, Westlye, Lars T., additional, Berthet, Pierre, additional, Calhoun, Vince D, additional, Howells, Fleur, additional, Uhlmann, Anne, additional, Scheffler, Freda, additional, Stein, Dan, additional, Iasevoli, Felice, additional, Cairns, Murray J., additional, Carr, Vaughan J., additional, Catts, Stanley V., additional, Di Biase, Maria A., additional, Jablensky, Assen, additional, Green, Melissa J., additional, Henskens, Frans A., additional, Klauser, Paul, additional, Loughland, Carmel, additional, Michie, Patricia T., additional, Mowry, Bryan, additional, Pantelis, Christos, additional, Rasser, Paul E., additional, Schall, Ulrich, additional, Scott, Rodney, additional, Zalesky, Andrew, additional, de Bartolomeis, Andrea, additional, Barone, Annarita, additional, Ciccarelli, Mariateresa, additional, Brunetti, Arturo, additional, Cocozza, Sirio, additional, Pontillo, Giuseppe, additional, Tranfa, Mario, additional, Di Giorgio, Annabella, additional, Thomopoulos, Sophia I., additional, Jahanshad, Neda, additional, Thompson, Paul M., additional, van Erp, Theo, additional, Turner, Jessica, additional, and Homan, Philipp, additional

Published
2023
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21. Neural Correlates of Positive and Negative Formal Thought Disorder in Individuals with Schizophrenia: An ENIGMA Schizophrenia Working Group Study

Author

Sharkey, Rachel J., primary, Bacon, Chelsea, additional, Peterson, Zeru, additional, Rootes-Murdy, Kelly, additional, Salvador, Raymond, additional, Pomarol-Clotet, Edith, additional, Karuk, Andriana, additional, Homan, Philipp, additional, Ji, Ellen, additional, Omlor, Wolfgang, additional, Homan, Stephanie, additional, Georgiadis, Foivos, additional, Kaiser, Stefan, additional, Kirschner, Matthias, additional, Ehrlich, Stefan, additional, Dannlowski, Udo, additional, Grotegerd, Dominik, additional, Goltermann, Janik, additional, Meinert, Susanne, additional, Kircher, Tilo, additional, Stein, Frederike, additional, Brosch, Katharina, additional, Krug, Axel, additional, Nenadić, Igor, additional, Sim, Kang, additional, Spalletta, Gianfranco, additional, Piras, Fabrizio, additional, Banaj, Nerisa, additional, Sponheim, Scott R, additional, Demro, Caroline, additional, Ramsay, Ian S, additional, King, Margaret, additional, Quidé, Yann, additional, Green, Melissa J., additional, Nguyen, Dana, additional, Preda, Adrian, additional, Calhoun, Vince D., additional, Turner, Jessica A., additional, van Erp, Theo G.M., additional, and Nickl-Jockschat, Thomas, additional

Published
2023
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22. Neural Correlates of Positive and Negative Formal Thought Disorder in Individuals with Schizophrenia: An ENIGMA Schizophrenia Working Group Study

Author

Sharkey, Rachel J., Bacon, Chelsea, Peterson, Zeru, Rootes-Murdy, Kelly, Salvador, Raymond, Pomarol-Clotet, Edith, Karuk, Andriana, Homan, Philipp, Ji, Ellen, Omlor, Wolfgang, Homan, Stephanie, Georgiadis, Foivos, Kaiser, Stefan, Kirschner, Matthias, Ehrlich, Stefan, Dannlowski, Udo, Grotegerd, Dominik, Goltermann, Janik, Meinert, Susanne, Kircher, Tilo, Stein, Frederike, Brosch, Katharina, Krug, Axel, Nenadić, Igor, Sim, Kang, Spalletta, Gianfranco, Piras, Fabrizio, Banaj, Nerisa, Sponheim, Scott R, Demro, Caroline, Ramsay, Ian S, King, Margaret, Quidé, Yann, Green, Melissa J., Nguyen, Dana, Preda, Adrian, Calhoun, Vince D., Turner, Jessica A., van Erp, Theo G.M., and Nickl-Jockschat, Thomas

Subjects
Article
Abstract

Formal thought disorder (FTD) is a key clinical factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, relationship between FTD symptom dimensions and patterns of regional brain volume deficiencies in schizophrenia remain to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles based on a large multi-site cohort through the ENIGMA Schizophrenia Working Group (752 individuals with schizophrenia and 1256 controls), to unravel the neuroanatomy of positive, negative and total FTD in schizophrenia and their cellular bases. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks for positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD was also linked to microglial cell types. These findings relate different dimensions of FTD to distinct brain structural changes and their cellular underpinnings, improve our mechanistic understanding of these key psychotic symptoms.

Published
2023

24. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author

Schijven, Dick, primary, Postema, Merel C., additional, Fukunaga, Masaki, additional, Matsumoto, Junya, additional, Miura, Kenichiro, additional, de Zwarte, Sonja M. C., additional, van Haren, Neeltje E. M., additional, Cahn, Wiepke, additional, Hulshoff Pol, Hilleke E., additional, Kahn, René S., additional, Ayesa-Arriola, Rosa, additional, Ortiz-García de la Foz, Víctor, additional, Tordesillas-Gutierrez, Diana, additional, Vázquez-Bourgon, Javier, additional, Crespo-Facorro, Benedicto, additional, Alnæs, Dag, additional, Dahl, Andreas, additional, Westlye, Lars T., additional, Agartz, Ingrid, additional, Andreassen, Ole A., additional, Jönsson, Erik G., additional, Kochunov, Peter, additional, Bruggemann, Jason M., additional, Catts, Stanley V., additional, Michie, Patricia T., additional, Mowry, Bryan J., additional, Quidé, Yann, additional, Rasser, Paul E., additional, Schall, Ulrich, additional, Scott, Rodney J., additional, Carr, Vaughan J., additional, Green, Melissa J., additional, Henskens, Frans A., additional, Loughland, Carmel M., additional, Pantelis, Christos, additional, Weickert, Cynthia Shannon, additional, Weickert, Thomas W., additional, de Haan, Lieuwe, additional, Brosch, Katharina, additional, Pfarr, Julia-Katharina, additional, Ringwald, Kai G., additional, Stein, Frederike, additional, Jansen, Andreas, additional, Kircher, Tilo T. J., additional, Nenadić, Igor, additional, Krämer, Bernd, additional, Gruber, Oliver, additional, Satterthwaite, Theodore D., additional, Bustillo, Juan, additional, Mathalon, Daniel H., additional, Preda, Adrian, additional, Calhoun, Vince D., additional, Ford, Judith M., additional, Potkin, Steven G., additional, Chen, Jingxu, additional, Tan, Yunlong, additional, Wang, Zhiren, additional, Xiang, Hong, additional, Fan, Fengmei, additional, Bernardoni, Fabio, additional, Ehrlich, Stefan, additional, Fuentes-Claramonte, Paola, additional, Garcia-Leon, Maria Angeles, additional, Guerrero-Pedraza, Amalia, additional, Salvador, Raymond, additional, Sarró, Salvador, additional, Pomarol-Clotet, Edith, additional, Ciullo, Valentina, additional, Piras, Fabrizio, additional, Vecchio, Daniela, additional, Banaj, Nerisa, additional, Spalletta, Gianfranco, additional, Michielse, Stijn, additional, van Amelsvoort, Therese, additional, Dickie, Erin W., additional, Voineskos, Aristotle N., additional, Sim, Kang, additional, Ciufolini, Simone, additional, Dazzan, Paola, additional, Murray, Robin M., additional, Kim, Woo-Sung, additional, Chung, Young-Chul, additional, Andreou, Christina, additional, Schmidt, André, additional, Borgwardt, Stefan, additional, McIntosh, Andrew M., additional, Whalley, Heather C., additional, Lawrie, Stephen M., additional, du Plessis, Stefan, additional, Luckhoff, Hilmar K., additional, Scheffler, Freda, additional, Emsley, Robin, additional, Grotegerd, Dominik, additional, Lencer, Rebekka, additional, Dannlowski, Udo, additional, Edmond, Jesse T., additional, Rootes-Murdy, Kelly, additional, Stephen, Julia M., additional, Mayer, Andrew R., additional, Antonucci, Linda A., additional, Fazio, Leonardo, additional, Pergola, Giulio, additional, Bertolino, Alessandro, additional, Díaz-Caneja, Covadonga M., additional, Janssen, Joost, additional, Lois, Noemi G., additional, Arango, Celso, additional, Tomyshev, Alexander S., additional, Lebedeva, Irina, additional, Cervenka, Simon, additional, Sellgren, Carl M., additional, Georgiadis, Foivos, additional, Kirschner, Matthias, additional, Kaiser, Stefan, additional, Hajek, Tomas, additional, Skoch, Antonin, additional, Spaniel, Filip, additional, Kim, Minah, additional, Kwak, Yoo Bin, additional, Oh, Sanghoon, additional, Kwon, Jun Soo, additional, James, Anthony, additional, Bakker, Geor, additional, Knöchel, Christian, additional, Stäblein, Michael, additional, Oertel, Viola, additional, Uhlmann, Anne, additional, Howells, Fleur M., additional, Stein, Dan J., additional, Temmingh, Henk S., additional, Diaz-Zuluaga, Ana M., additional, Pineda-Zapata, Julian A., additional, López-Jaramillo, Carlos, additional, Homan, Stephanie, additional, Ji, Ellen, additional, Surbeck, Werner, additional, Homan, Philipp, additional, Fisher, Simon E., additional, Franke, Barbara, additional, Glahn, David C., additional, Gur, Ruben C., additional, Hashimoto, Ryota, additional, Jahanshad, Neda, additional, Luders, Eileen, additional, Medland, Sarah E., additional, Thompson, Paul M., additional, Turner, Jessica A., additional, van Erp, Theo G. M., additional, and Francks, Clyde, additional

Published
2023
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25. Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study

Author

Georgiadis, Foivos, primary, Larivière, Sara, additional, Glahn, David, additional, Hong, L. Elliot, additional, Kochunov, Peter, additional, Mowry, Bryan, additional, Loughland, Carmel, additional, Pantelis, Christos, additional, Henskens, Frans A., additional, Green, Melissa J., additional, Cairns, Murray J., additional, Michie, Patricia T, additional, Rasser, Paul E., additional, Tooney, Paul, additional, Scott, Rodney J., additional, Catts, Stanley, additional, Schall, Ulrich, additional, Carr, Vaughan, additional, Quidé, Yann, additional, Krug, Axel, additional, Stein, Frederike, additional, Nenadić, Igor, additional, Brosch, Katharina, additional, Kircher, Tilo, additional, Gur, Raquel, additional, Gur, Ruben, additional, Satterthwaite, Theodore D., additional, Karuk, Andriana, additional, Clotet, Edith Pomarol-, additional, Radua, Joaquim, additional, Fuentes-Claramonte, Paola, additional, Salvador, Raymond, additional, Spalletta, Gianfranco, additional, Voineskos, Aristotle, additional, Sim, Kang, additional, Crespo-Facorro, Benedicto, additional, Gutiérrez, Diana Tordesillas, additional, Ehrlich, Stefan, additional, Crossley, Nicolas, additional, Grotegerd, Dominik, additional, Repple, Jonathan, additional, Lencer, Rebekka, additional, Dannlowski, Udo, additional, Calhoun, Vince, additional, Demro, Caroline, additional, Ramsay, Ian S., additional, Sponheim, Scott R., additional, Schmidt, Andre, additional, Borgwardt, Stefan, additional, Tomyshev, Alexander S., additional, Lebedeva, Irina, additional, Hoschl, Cyril, additional, Spaniel, Filip, additional, Preda, Adrian, additional, Nguyen, Dana, additional, Uhlmann, Anne, additional, Stein, Dan J, additional, Howells, Fleur M, additional, Temmingh, Henk S., additional, Diaz Zuluaga, Ana M., additional, Jaramillo, Carlos López, additional, Iasevoli, Felice, additional, Ji, Ellen, additional, Homan, Stephanie, additional, Omlor, Wolfgang, additional, Homan, Philipp, additional, Kaiser, Stefan, additional, Seifritz, Erich, additional, Misic, Bratislav, additional, Valk, Sofie L., additional, Thompson, Paul, additional, van Erp, Theo G.M., additional, Turner, Jessica, additional, Bernhardt, Boris, additional, and Kirschner, Matthias, additional

Published
2023
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26. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author

Schijven, Dick, Postema, Merel C., Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja M. C., van Haren, Neeltje E. M., Cahn, Wiepke, Hulshoff Pol, Hilleke E., Kahn, René S., Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T., Agartz, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Kochunov, Peter, Bruggemann, Jason M., Catts, Stanley V., Michie, Patricia T., Mowry, Bryan J., Quidé, Yann, Rasser, Paul E., Schall, Ulrich, Scott, Rodney J., Carr, Vaughan J., Green, Melissa J., Henskens, Frans A., Loughland, Carmel M., Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W., de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia-Katharina, Ringwald, Kai G., Stein, Frederike, Jansen, Andreas, Kircher, Tilo T. J., Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D., Bustillo, Juan, Mathalon, Daniel H., Preda, Adrian, Calhoun, Vince D., Ford, Judith M., Potkin, Steven G., Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W., Voineskos, Aristotle N., Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M., Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., du Plessis, Stefan, Luckhoff, Hilmar K., Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T., Rootes-Murdy, Kelly, Stephen, Julia M., Mayer, Andrew R., Antonucci, Linda A., Fazio, Leonardo, Pergola, Giulio, Bertolino, Alessandro, Díaz-Caneja, Covadonga M., Janssen, Joost, Lois, Noemi G., Arango, Celso, Tomyshev, Alexander S., Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M., Georgiadis, Foivos, Kirschner, Matthias, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin, Spaniel, Filip, Kim, Minah, Kwak, Yoo Bin, Oh, Sanghoon, Kwon, Jun Soo, James, Anthony, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne, Howells, Fleur M., Stein, Dan J., Temmingh, Henk S., Diaz-Zuluaga, Ana M., Pineda-Zapata, Julian A., López-Jaramillo, Carlos, Homan, Stephanie, Ji, Ellen, Surbeck, Werner, Homan, Philipp, Fisher, Simon E., Franke, Barbara, Glahn, David C., Gur, Ruben C., Hashimoto, Ryota, Jahanshad, Neda, Lueders, Eileen, Medland, Sarah E., Thompson, Paul M., Turner, Jessica A., van Erp, Theo G. M., Francks, Clyde, Schijven, Dick, Postema, Merel C., Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja M. C., van Haren, Neeltje E. M., Cahn, Wiepke, Hulshoff Pol, Hilleke E., Kahn, René S., Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T., Agartz, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Kochunov, Peter, Bruggemann, Jason M., Catts, Stanley V., Michie, Patricia T., Mowry, Bryan J., Quidé, Yann, Rasser, Paul E., Schall, Ulrich, Scott, Rodney J., Carr, Vaughan J., Green, Melissa J., Henskens, Frans A., Loughland, Carmel M., Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W., de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia-Katharina, Ringwald, Kai G., Stein, Frederike, Jansen, Andreas, Kircher, Tilo T. J., Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D., Bustillo, Juan, Mathalon, Daniel H., Preda, Adrian, Calhoun, Vince D., Ford, Judith M., Potkin, Steven G., Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W., Voineskos, Aristotle N., Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M., Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., du Plessis, Stefan, Luckhoff, Hilmar K., Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T., Rootes-Murdy, Kelly, Stephen, Julia M., Mayer, Andrew R., Antonucci, Linda A., Fazio, Leonardo, Pergola, Giulio, Bertolino, Alessandro, Díaz-Caneja, Covadonga M., Janssen, Joost, Lois, Noemi G., Arango, Celso, Tomyshev, Alexander S., Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M., Georgiadis, Foivos, Kirschner, Matthias, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin, Spaniel, Filip, Kim, Minah, Kwak, Yoo Bin, Oh, Sanghoon, Kwon, Jun Soo, James, Anthony, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne, Howells, Fleur M., Stein, Dan J., Temmingh, Henk S., Diaz-Zuluaga, Ana M., Pineda-Zapata, Julian A., López-Jaramillo, Carlos, Homan, Stephanie, Ji, Ellen, Surbeck, Werner, Homan, Philipp, Fisher, Simon E., Franke, Barbara, Glahn, David C., Gur, Ruben C., Hashimoto, Ryota, Jahanshad, Neda, Lueders, Eileen, Medland, Sarah E., Thompson, Paul M., Turner, Jessica A., van Erp, Theo G. M., and Francks, Clyde

Abstract

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Published
2023
Full Text
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27. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author

Schijven, Dick; https://orcid.org/0000-0001-5190-7241, Postema, Merel C; https://orcid.org/0000-0002-1536-7062, Fukunaga, Masaki; https://orcid.org/0000-0003-1010-2644, Matsumoto, Junya; https://orcid.org/0000-0003-4228-3208, Miura, Kenichiro, de Zwarte, Sonja M C, van Haren, Neeltje E M, Cahn, Wiepke, Hulshoff Pol, Hilleke E, Kahn, René S, Ayesa-Arriola, Rosa; https://orcid.org/0000-0003-0570-5352, de la Foz, Víctor Ortiz-García; https://orcid.org/0000-0002-0627-1827, Tordesillas-Gutierrez, Diana; https://orcid.org/0000-0003-1458-3932, Vázquez-Bourgon, Javier; https://orcid.org/0000-0002-5478-3376, Crespo-Facorro, Benedicto, Alnæs, Dag; https://orcid.org/0000-0001-7361-5418, Dahl, Andreas; https://orcid.org/0000-0002-2668-8371, Westlye, Lars T; https://orcid.org/0000-0001-8644-956X, Agartz, Ingrid, Andreassen, Ole A; https://orcid.org/0000-0002-4461-3568, Jönsson, Erik G, Kochunov, Peter, Bruggemann, Jason M, Catts, Stanley V, Michie, Patricia T, Mowry, Bryan J, Quidé, Yann, Rasser, Paul E; https://orcid.org/0000-0003-3482-721X, Schall, Ulrich; https://orcid.org/0000-0001-9041-4562, Scott, Rodney J; https://orcid.org/0000-0001-7724-3404, Carr, Vaughan J; https://orcid.org/0000-0002-8907-5804, Green, Melissa J; https://orcid.org/0000-0002-9361-4874, Henskens, Frans A; https://orcid.org/0000-0003-2358-5630, Loughland, Carmel M, Pantelis, Christos; https://orcid.org/0000-0002-9565-0238, Weickert, Cynthia Shannon, Weickert, Thomas W, de Haan, Lieuwe, Brosch, Katharina; https://orcid.org/0000-0002-0526-8095, Pfarr, Julia-Katharina, Ringwald, Kai G, Stein, Frederike, Jansen, Andreas, Kircher, Tilo T J, Nenadić, Igor, Krämer, Bernd; https://orcid.org/0000-0002-1145-9103, Gruber, Oliver; https://orcid.org/0000-0003-1841-7413, Satterthwaite, Theodore D; https://orcid.org/0000-0001-7072-9399, Bustillo, Juan; https://orcid.org/0000-0001-8730-8152, Mathalon, Daniel H, Preda, Adrian, Calhoun, Vince D; https://orcid.org/0000-0001-9058-0747, Ford, Judith M; https://orcid.org/0000-0002-6500-6548, Potkin, Steven G, Chen, Jingxu, Tan, Yunlong; https://orcid.org/0000-0002-3522-3912, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan; https://orcid.org/0000-0003-2132-4445, Fuentes-Claramonte, Paola; https://orcid.org/0000-0002-1428-7976, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond; https://orcid.org/0000-0001-5557-1562, Sarró, Salvador; https://orcid.org/0000-0003-1835-2189, Pomarol-Clotet, Edith, Ciullo, Valentina; https://orcid.org/0000-0002-6870-6259, Piras, Fabrizio; https://orcid.org/0000-0003-3566-5494, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco; https://orcid.org/0000-0002-7432-4249, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W, Voineskos, Aristotle N; https://orcid.org/0000-0003-0156-0395, Sim, Kang; https://orcid.org/0000-0003-3209-9626, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M; https://orcid.org/0000-0003-0829-0519, Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André; https://orcid.org/0000-0001-6055-8397, Borgwardt, Stefan; https://orcid.org/0000-0002-5792-3987, McIntosh, Andrew M, Whalley, Heather C, Lawrie, Stephen M; https://orcid.org/0000-0002-2444-5675, du Plessis, Stefan, Luckhoff, Hilmar K, Scheffler, Freda; https://orcid.org/0000-0002-8898-8599, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo; https://orcid.org/0000-0002-0623-3759, Edmond, Jesse T, Rootes-Murdy, Kelly, Stephen, Julia M, Mayer, Andrew R, Antonucci, Linda A, Fazio, Leonardo; https://orcid.org/0000-0003-4000-974X, Pergola, Giulio; https://orcid.org/0000-0002-9193-1841, Bertolino, Alessandro, Díaz-Caneja, Covadonga M; https://orcid.org/0000-0001-8538-3175, Janssen, Joost, Lois, Noemi G; https://orcid.org/0000-0002-6600-072X, Arango, Celso; https://orcid.org/0000-0003-3382-4754, Tomyshev, Alexander S, Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M, Georgiadis, Foivos, Kirschner, Matthias; https://orcid.org/0000-0002-9486-1439, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin; https://orcid.org/0000-0002-1739-3256, Spaniel, Filip, Kim, Minah; https://orcid.org/0000-0001-8668-0817, Kwak, Yoo Bin, Oh, Sanghoon; https://orcid.org/0000-0002-7394-5211, Kwon, Jun Soo; https://orcid.org/0000-0002-1060-1462, James, Anthony; https://orcid.org/0000-0002-2742-8328, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne; https://orcid.org/0000-0002-1753-7811, Howells, Fleur M, Stein, Dan J; https://orcid.org/0000-0001-7218-7810, Temmingh, Henk S; https://orcid.org/0000-0002-7688-0759, Diaz-Zuluaga, Ana M, Pineda-Zapata, Julian A, López-Jaramillo, Carlos, Homan, Stephanie; https://orcid.org/0000-0003-1449-7508, Ji, Ellen; https://orcid.org/0000-0003-1527-8868, Surbeck, Werner; https://orcid.org/0000-0002-4733-795X, Homan, Philipp; https://orcid.org/0000-0001-9034-148X, Fisher, Simon E; https://orcid.org/0000-0002-3132-1996, Franke, Barbara; https://orcid.org/0000-0003-4375-6572, Glahn, David C; https://orcid.org/0000-0002-4749-6977, Gur, Ruben C; https://orcid.org/0000-0002-9657-1996, Hashimoto, Ryota, Jahanshad, Neda, Luders, Eileen; https://orcid.org/0000-0001-5659-992X, Medland, Sarah E, Thompson, Paul M; https://orcid.org/0000-0002-4720-8867, Turner, Jessica A, van Erp, Theo G M, Francks, Clyde; https://orcid.org/0000-0002-9098-890X, Schijven, Dick; https://orcid.org/0000-0001-5190-7241, Postema, Merel C; https://orcid.org/0000-0002-1536-7062, Fukunaga, Masaki; https://orcid.org/0000-0003-1010-2644, Matsumoto, Junya; https://orcid.org/0000-0003-4228-3208, Miura, Kenichiro, de Zwarte, Sonja M C, van Haren, Neeltje E M, Cahn, Wiepke, Hulshoff Pol, Hilleke E, Kahn, René S, Ayesa-Arriola, Rosa; https://orcid.org/0000-0003-0570-5352, de la Foz, Víctor Ortiz-García; https://orcid.org/0000-0002-0627-1827, Tordesillas-Gutierrez, Diana; https://orcid.org/0000-0003-1458-3932, Vázquez-Bourgon, Javier; https://orcid.org/0000-0002-5478-3376, Crespo-Facorro, Benedicto, Alnæs, Dag; https://orcid.org/0000-0001-7361-5418, Dahl, Andreas; https://orcid.org/0000-0002-2668-8371, Westlye, Lars T; https://orcid.org/0000-0001-8644-956X, Agartz, Ingrid, Andreassen, Ole A; https://orcid.org/0000-0002-4461-3568, Jönsson, Erik G, Kochunov, Peter, Bruggemann, Jason M, Catts, Stanley V, Michie, Patricia T, Mowry, Bryan J, Quidé, Yann, Rasser, Paul E; https://orcid.org/0000-0003-3482-721X, Schall, Ulrich; https://orcid.org/0000-0001-9041-4562, Scott, Rodney J; https://orcid.org/0000-0001-7724-3404, Carr, Vaughan J; https://orcid.org/0000-0002-8907-5804, Green, Melissa J; https://orcid.org/0000-0002-9361-4874, Henskens, Frans A; https://orcid.org/0000-0003-2358-5630, Loughland, Carmel M, Pantelis, Christos; https://orcid.org/0000-0002-9565-0238, Weickert, Cynthia Shannon, Weickert, Thomas W, de Haan, Lieuwe, Brosch, Katharina; https://orcid.org/0000-0002-0526-8095, Pfarr, Julia-Katharina, Ringwald, Kai G, Stein, Frederike, Jansen, Andreas, Kircher, Tilo T J, Nenadić, Igor, Krämer, Bernd; https://orcid.org/0000-0002-1145-9103, Gruber, Oliver; https://orcid.org/0000-0003-1841-7413, Satterthwaite, Theodore D; https://orcid.org/0000-0001-7072-9399, Bustillo, Juan; https://orcid.org/0000-0001-8730-8152, Mathalon, Daniel H, Preda, Adrian, Calhoun, Vince D; https://orcid.org/0000-0001-9058-0747, Ford, Judith M; https://orcid.org/0000-0002-6500-6548, Potkin, Steven G, Chen, Jingxu, Tan, Yunlong; https://orcid.org/0000-0002-3522-3912, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan; https://orcid.org/0000-0003-2132-4445, Fuentes-Claramonte, Paola; https://orcid.org/0000-0002-1428-7976, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond; https://orcid.org/0000-0001-5557-1562, Sarró, Salvador; https://orcid.org/0000-0003-1835-2189, Pomarol-Clotet, Edith, Ciullo, Valentina; https://orcid.org/0000-0002-6870-6259, Piras, Fabrizio; https://orcid.org/0000-0003-3566-5494, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco; https://orcid.org/0000-0002-7432-4249, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W, Voineskos, Aristotle N; https://orcid.org/0000-0003-0156-0395, Sim, Kang; https://orcid.org/0000-0003-3209-9626, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M; https://orcid.org/0000-0003-0829-0519, Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André; https://orcid.org/0000-0001-6055-8397, Borgwardt, Stefan; https://orcid.org/0000-0002-5792-3987, McIntosh, Andrew M, Whalley, Heather C, Lawrie, Stephen M; https://orcid.org/0000-0002-2444-5675, du Plessis, Stefan, Luckhoff, Hilmar K, Scheffler, Freda; https://orcid.org/0000-0002-8898-8599, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo; https://orcid.org/0000-0002-0623-3759, Edmond, Jesse T, Rootes-Murdy, Kelly, Stephen, Julia M, Mayer, Andrew R, Antonucci, Linda A, Fazio, Leonardo; https://orcid.org/0000-0003-4000-974X, Pergola, Giulio; https://orcid.org/0000-0002-9193-1841, Bertolino, Alessandro, Díaz-Caneja, Covadonga M; https://orcid.org/0000-0001-8538-3175, Janssen, Joost, Lois, Noemi G; https://orcid.org/0000-0002-6600-072X, Arango, Celso; https://orcid.org/0000-0003-3382-4754, Tomyshev, Alexander S, Lebedeva, Irina, Cervenka, Simon, Sellgren, Carl M, Georgiadis, Foivos, Kirschner, Matthias; https://orcid.org/0000-0002-9486-1439, Kaiser, Stefan, Hajek, Tomas, Skoch, Antonin; https://orcid.org/0000-0002-1739-3256, Spaniel, Filip, Kim, Minah; https://orcid.org/0000-0001-8668-0817, Kwak, Yoo Bin, Oh, Sanghoon; https://orcid.org/0000-0002-7394-5211, Kwon, Jun Soo; https://orcid.org/0000-0002-1060-1462, James, Anthony; https://orcid.org/0000-0002-2742-8328, Bakker, Geor, Knöchel, Christian, Stäblein, Michael, Oertel, Viola, Uhlmann, Anne; https://orcid.org/0000-0002-1753-7811, Howells, Fleur M, Stein, Dan J; https://orcid.org/0000-0001-7218-7810, Temmingh, Henk S; https://orcid.org/0000-0002-7688-0759, Diaz-Zuluaga, Ana M, Pineda-Zapata, Julian A, López-Jaramillo, Carlos, Homan, Stephanie; https://orcid.org/0000-0003-1449-7508, Ji, Ellen; https://orcid.org/0000-0003-1527-8868, Surbeck, Werner; https://orcid.org/0000-0002-4733-795X, Homan, Philipp; https://orcid.org/0000-0001-9034-148X, Fisher, Simon E; https://orcid.org/0000-0002-3132-1996, Franke, Barbara; https://orcid.org/0000-0003-4375-6572, Glahn, David C; https://orcid.org/0000-0002-4749-6977, Gur, Ruben C; https://orcid.org/0000-0002-9657-1996, Hashimoto, Ryota, Jahanshad, Neda, Luders, Eileen; https://orcid.org/0000-0001-5659-992X, Medland, Sarah E, Thompson, Paul M; https://orcid.org/0000-0002-4720-8867, Turner, Jessica A, van Erp, Theo G M, and Francks, Clyde; https://orcid.org/0000-0002-9098-890X

Abstract

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, using MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets in the ENIGMA consortium, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macro-structural asymmetry may reflect differences at the molecular, cytoarchitectonic or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Published
2023

28. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author

Dick Schijven, Merel C. Postema, Masaki Fukunaga, Junya Matsumoto, Kenichiro Miura, Sonja M. C. de Zwarte, Neeltje E. M. van Haren, Wiepke Cahn, Hilleke E. Hulshoff Pol, René S. Kahn, Rosa Ayesa-Arriola, Víctor Ortiz-García de la Foz, Diana Tordesillas-Gutierrez, Javier Vázquez-Bourgon, Benedicto Crespo-Facorro, Dag Alnæs, Andreas Dahl, Lars T. Westlye, Ingrid Agartz, Ole A. Andreassen, Erik G. Jönsson, Peter Kochunov, Jason M. Bruggemann, Stanley V. Catts, Patricia T. Michie, Bryan J. Mowry, Yann Quidé, Paul E. Rasser, Ulrich Schall, Rodney J. Scott, Vaughan J. Carr, Melissa J. Green, Frans A. Henskens, Carmel M. Loughland, Christos Pantelis, Cynthia Shannon Weickert, Thomas W. Weickert, Lieuwe de Haan, Katharina Brosch, Julia-Katharina Pfarr, Kai G. Ringwald, Frederike Stein, Andreas Jansen, Tilo T. J. Kircher, Igor Nenadić, Bernd Krämer, Oliver Gruber, Theodore D. Satterthwaite, Juan Bustillo, Daniel H. Mathalon, Adrian Preda, Vince D. Calhoun, Judith M. Ford, Steven G. Potkin, Jingxu Chen, Yunlong Tan, Zhiren Wang, Hong Xiang, Fengmei Fan, Fabio Bernardoni, Stefan Ehrlich, Paola Fuentes-Claramonte, Maria Angeles Garcia-Leon, Amalia Guerrero-Pedraza, Raymond Salvador, Salvador Sarró, Edith Pomarol-Clotet, Valentina Ciullo, Fabrizio Piras, Daniela Vecchio, Nerisa Banaj, Gianfranco Spalletta, Stijn Michielse, Therese van Amelsvoort, Erin W. Dickie, Aristotle N. Voineskos, Kang Sim, Simone Ciufolini, Paola Dazzan, Robin M. Murray, Woo-Sung Kim, Young-Chul Chung, Christina Andreou, André Schmidt, Stefan Borgwardt, Andrew M. McIntosh, Heather C. Whalley, Stephen M. Lawrie, Stefan du Plessis, Hilmar K. Luckhoff, Freda Scheffler, Robin Emsley, Dominik Grotegerd, Rebekka Lencer, Udo Dannlowski, Jesse T. Edmond, Kelly Rootes-Murdy, Julia M. Stephen, Andrew R. Mayer, Linda A. Antonucci, Leonardo Fazio, Giulio Pergola, Alessandro Bertolino, Covadonga M. Díaz-Caneja, Joost Janssen, Noemi G. Lois, Celso Arango, Alexander S. Tomyshev, Irina Lebedeva, Simon Cervenka, Carl M. Sellgren, Foivos Georgiadis, Matthias Kirschner, Stefan Kaiser, Tomas Hajek, Antonin Skoch, Filip Spaniel, Minah Kim, Yoo Bin Kwak, Sanghoon Oh, Jun Soo Kwon, Anthony James, Geor Bakker, Christian Knöchel, Michael Stäblein, Viola Oertel, Anne Uhlmann, Fleur M. Howells, Dan J. Stein, Henk S. Temmingh, Ana M. Diaz-Zuluaga, Julian A. Pineda-Zapata, Carlos López-Jaramillo, Stephanie Homan, Ellen Ji, Werner Surbeck, Philipp Homan, Simon E. Fisher, Barbara Franke, David C. Glahn, Ruben C. Gur, Ryota Hashimoto, Neda Jahanshad, Eileen Luders, Sarah E. Medland, Paul M. Thompson, Jessica A. Turner, Theo G. M. van Erp, Clyde Francks, Neurology, and Child and Adolescent Psychiatry / Psychology

Subjects
subcortical, Neuroinformatics, Multidisciplinary, All institutes and research themes of the Radboud University Medical Center, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Schizophrenia, brain imaging, cortical, asymmetry
Abstract

Contains fulltext : 291574.pdf (Publisher’s version ) (Open Access) Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Published
2023

29. Brain ageing in schizophrenia:evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Author

Constantinides, Constantinos, Han, Laura K. M., Alloza, Clara, Antonucci, Linda Antonella, Arango, Celso, Ayesa-Arriola, Rosa, Banaj, Nerisa, Bertolino, Alessandro, Borgwardt, Stefan, Bruggemann, Jason, Bustillo, Juan, Bykhovski, Oleg, Calhoun, Vince, Carr, Vaughan, Catts, Stanley, Chung, Young-Chul, Crespo-Facorro, Benedicto, Díaz-Caneja, Covadonga M., Donohoe, Gary, Plessis, Stefan Du, Edmond, Jesse, Ehrlich, Stefan, Emsley, Robin, Eyler, Lisa T., Fuentes-Claramonte, Paola, Georgiadis, Foivos, Green, Melissa, Guerrero-Pedraza, Amalia, Ha, Minji, Hahn, Tim, Henskens, Frans A., Holleran, Laurena, Homan, Stephanie, Homan, Philipp, Jahanshad, Neda, Janssen, Joost, Ji, Ellen, Kaiser, Stefan, Kaleda, Vasily, Kim, Minah, Kim, Woo-Sung, Kirschner, Matthias, Kochunov, Peter, Kwak, Yoo Bin, Kwon, Jun Soo, Lebedeva, Irina, Liu, Jingyu, Mitchie, Patricia, Michielse, Stijn, Mothersill, David, Mowry, Bryan, de la Foz, Víctor Ortiz-García, Pantelis, Christos, Pergola, Giulio, Piras, Fabrizio, Pomarol-Clotet, Edith, Preda, Adrian, Quidé, Yann, Rasser, Paul E., Rootes-Murdy, Kelly, Salvador, Raymond, Sangiuliano, Marina, Sarró, Salvador, Schall, Ulrich, Schmidt, André, Scott, Rodney J., Selvaggi, Pierluigi, Sim, Kang, Skoch, Antonin, Spalletta, Gianfranco, Spaniel, Filip, Thomopoulos, Sophia I., Tomecek, David, Tomyshev, Alexander S., Tordesillas-Gutiérrez, Diana, van Amelsvoort, Therese, Vázquez-Bourgon, Javier, Vecchio, Daniela, Voineskos, Aristotle, Weickert, Cynthia S., Weickert, Thomas, Thompson, Paul M., Schmaal, Lianne, van Erp, Theo G. M., Turner, Jessica, Cole, James H., Du Plessis, Stefan, Bin Kwak, Yoo, Dima, Danai, Walton, Esther, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Neurochirurgie, RS: MHeNs - R3 - Neuroscience, MUMC+: MA Med Staf Spec Psychiatrie (9), RS: MHeNs - R2 - Mental Health, and Psychiatry 3

Subjects
Cellular and Molecular Neuroscience, Psychiatry and Mental health, SDG 3 - Good Health and Well-being, Molecular Biology
Abstract

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18–72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18–73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen’s d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Published
2023

30. Connectome architecture shapes large-scale cortical reorganization in schizophrenia: a worldwide ENIGMA study

Author

Foivos Georgiadis, Sara Larivière, David Glahn, L. Elliot Hong, Peter Kochunov, Bryan Mowry, Carmel Loughland, Christos Pantelis, Frans A. Henskens, Melissa J. Green, Murray J. Cairns, Patricia T Michie, Paul E. Rasser, Paul Tooney, Rodney J. Scott, Stanley Catts, Ulrich Schall, Vaughan Carr, Yann Quidé, Axel Krug, Frederike Stein, Igor Nenadić, Katharina Brosch, Tilo Kircher, Raquel Gur, Ruben Gur, Theodore D. Satterthwaite, Andriana Karuk, Edith Pomarol-Clotet, Joaquim Radua, Paola Fuentes-Claramonte, Raymond Salvador, Gianfranco Spalletta, Aristotle Voineskos, Kang Sim, Benedicto Crespo-Facorro, Diana Tordesillas Gutiérrez, Stefan Ehrlich, Nicolas Crossley, Dominik Grotegerd, Jonathan Repple, Rebekka Lencer, Udo Dannlowski, Vince Calhoun, Caroline Demro, Ian S. Ramsay, Scott. Sponheim, Andre Schmidt, Stefan Borgwardt, Alexander S. Tomyshev, Irina Lebedeva, Cyril Hoschl, Filip Spaniel, Adrian Preda, Dana Nguyen, Anne Uhlmann, Dan J Stein, Fleur M Howells, Henk S. Temmingh, Ana M. Diaz Zuluaga, Carlos López Jaramillo, Felice Iasevoli, Ellen Ji, Stephanie Homan, Wolfgang Omlor, Philipp Homan, Stefan Kaiser, Erich Seifritz, Bratislav Misic, Paul Thompson, Theo G.M. van Erp, Jessica Turner, Boris Bernhardt, and Matthias Kirschner

Abstract

ObjectiveSchizophrenia is associated with widespread brain-morphological alterations, believed to be shaped by the underlying connectome architecture. This study tests whether large-scale structural reorganization in schizophrenia relates to normative network architecture, in particular regional centrality/hubness and connectivity patterns. We examine network effects in schizophrenia across different disease stages, and transdiagnostically explore consistency of such relationships in patients with bipolar and major depressive disorder.MethodsWe studied anatomical MRI scans from 2,439 adults with schizophrenia and 2,867 healthy controls from 26 ENIGMA sites. Case-control patterns of structural alterations were evaluated against two network susceptibility models: 1) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; 2) epicenter models, which identify regions whose typical connectivity profile most closely resembles the disease-related morphological alteration patterns. Both susceptibility models were tested across schizophrenia disease stages and compared to meta-analytic bipolar and major depressive disorder case-control maps.ResultsIn schizophrenia, regional gray matter reductions co-localized with interconnected hubs, in both the functional (r=0.58, pspinspin=0.01). Epicenters were identified in temporo-paralimbic regions, extending to frontal areas. We found unique epicenters for first-episode and early stages, and a shift from occipital to temporal-frontal epicenters in chronic stages. Transdiagnostic comparisons revealed shared epicenters in schizophrenia and bipolar, but not major depressive disorders.ConclusionsCortical reorganization over the course of schizophrenia closely reflects brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters. The observed overlapping epicenters for schizophrenia and bipolar disorder furthermore suggest shared pathophysiological processes within the schizophrenia-bipolar-spectrum.

Published
2023

31. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author

Schijven, Dick, primary, Postema, Merel C., additional, Fukunaga, Masaki, additional, Matsumoto, Junya, additional, Miura, Kenichiro, additional, de Zwarte, Sonja M.C., additional, van Haren, Neeltje E.M., additional, Cahn, Wiepke, additional, Hulshoff Pol, Hilleke E., additional, Kahn, René S., additional, Ayesa-Arriola, Rosa, additional, Ortiz-García de la Foz, Víctor, additional, Tordesillas-Gutierrez, Diana, additional, Vázquez-Bourgon, Javier, additional, Crespo-Facorro, Benedicto, additional, Alnæs, Dag, additional, Dahl, Andreas, additional, Westlye, Lars T., additional, Agartz, Ingrid, additional, Andreassen, Ole A., additional, Jönsson, Erik G., additional, Kochunov, Peter, additional, Bruggemann, Jason M., additional, Catts, Stanley V., additional, Michie, Patricia T., additional, Mowry, Bryan J., additional, Quidé, Yann, additional, Rasser, Paul E., additional, Schall, Ulrich, additional, Scott, Rodney J., additional, Carr, Vaughan J., additional, Green, Melissa J., additional, Henskens, Frans A., additional, Loughland, Carmel M., additional, Pantelis, Christos, additional, Weickert, Cynthia Shannon, additional, Weickert, Thomas W., additional, de Haan, Lieuwe, additional, Brosch, Katharina, additional, Pfarr, Julia-Katharina, additional, Ringwald, Kai G., additional, Stein, Frederike, additional, Jansen, Andreas, additional, Kircher, Tilo T.J., additional, Nenadic, Igor, additional, Krämer, Bernd, additional, Gruber, Oliver, additional, Satterthwaite, Theodore D., additional, Bustillo, Juan, additional, Mathalon, Daniel H., additional, Preda, Adrian, additional, Calhoun, Vince D., additional, Ford, Judith M., additional, Potkin, Steven G., additional, Chen, Jingxu, additional, Tan, Yunlong, additional, Wang, Zhiren, additional, Xiang, Hong, additional, Fan, Fengmei, additional, Bernardoni, Fabio, additional, Ehrlich, Stefan, additional, Fuentes-Claramonte, Paola, additional, Garcia-Leon, Maria Angeles, additional, Guerrero-Pedraza, Amalia, additional, Salvador, Raymond, additional, Sarró, Salvador, additional, Pomarol-Clotet, Edith, additional, Ciullo, Valentina, additional, Piras, Fabrizio, additional, Vecchio, Daniela, additional, Banaj, Nerisa, additional, Spalletta, Gianfranco, additional, Michielse, Stijn, additional, van Amelsvoort, Therese, additional, Dickie, Erin W., additional, Voineskos, Aristotle N., additional, Sim, Kang, additional, Ciufolini, Simone, additional, Dazzan, Paola, additional, Murray, Robin M., additional, Kim, Woo-Sung, additional, Chung, Young-Chul, additional, Andreou, Christina, additional, Schmidt, André, additional, Borgwardt, Stefan, additional, McIntosh, Andrew M., additional, Whalley, Heather C., additional, Lawrie, Stephen M., additional, du Plessis, Stefan, additional, Luckhoff, Hilmar K., additional, Scheffler, Freda, additional, Emsley, Robin, additional, Grotegerd, Dominik, additional, Lencer, Rebekka, additional, Dannlowski, Udo, additional, Edmond, Jesse T., additional, Rootes-Murdy, Kelly, additional, Stephen, Julia M., additional, Mayer, Andrew R., additional, Antonucci, Linda A., additional, Fazio, Leonardo, additional, Pergola, Giulio, additional, Bertolino, Alessandro, additional, Díaz-Caneja, Covadonga M., additional, Janssen, Joost, additional, Lois, Noemi G., additional, Arango, Celso, additional, Tomyshev, Alexander S., additional, Lebedeva, Irina, additional, Cervenka, Simon, additional, Sellgren, Carl M., additional, Georgiadis, Foivos, additional, Kirschner, Matthias, additional, Kaiser, Stefan, additional, Hajek, Tomas, additional, Skoch, Antonin, additional, Spaniel, Filip, additional, Kim, Minah, additional, Kwak, Yoo Bin, additional, Oh, Sanghoon, additional, Kwon, Jun Soo, additional, James, Anthony, additional, Bakker, Geor, additional, Knöchel, Christian, additional, Stäblein, Michael, additional, Oertel, Viola, additional, Uhlmann, Anne, additional, Howells, Fleur M., additional, Stein, Dan J., additional, Temmingh, Henk S., additional, Diaz-Zuluaga, Ana M., additional, Pineda-Zapata, Julian A., additional, López-Jaramillo, Carlos, additional, Homan, Stephanie, additional, Ji, Ellen, additional, Surbeck, Werner, additional, Homan, Philipp, additional, Fisher, Simon E., additional, Franke, Barbara, additional, Glahn, David C., additional, Gur, Ruben C., additional, Hashimoto, Ryota, additional, Jahanshad, Neda, additional, Luders, Eileen, additional, Medland, Sarah E., additional, Thompson, Paul M., additional, Turner, Jessica A., additional, van Erp, Theo G.M., additional, and Francks, Clyde, additional

Published
2022
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32. Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Author

Constantinos Constantinides, Laura KM Han, Clara Alloza, Linda Antonucci, Celso Arango, Rosa Ayesa-Arriola, Nerisa Banaj, Alessandro Bertolino, Stefan Borgwardt, Jason Bruggemann, Juan Bustillo, Oleg Bykhovski, Vaughan Carr, Stanley Catts, Young-Chul Chung, Benedicto Crespo-Facorro, Covadonga M Díaz-Caneja, Gary Donohoe, Stefan Du Plessis, Jesse Edmond, Stefan Ehrlich, Robin Emsley, Lisa T Eyler, Paola Fuentes-Claramonte, Foivos Georgiadis, Melissa Green, Amalia Guerrero-Pedraza, Minji Ha, Tim Hahn, Frans A Henskens, Laurena Holleran, Stephanie Homan, Philipp Homan, Neda Jahanshad, Joost Janssen, Ellen Ji, Stefan Kaiser, Vasily Kaleda, Minah Kim, Woo-Sung Kim, Matthias Kirschner, Peter Kochunov, Yoo Bin Kwak, Jun Soo Kwon, Irina Lebedeva, Jingyu Liu, Patricia Mitchie, Stijn Michielse, David Mothersill, Bryan Mowry, Víctor Ortiz-García de la Foz, Christos Pantelis, Giulio Pergola, Fabrizio Piras, Edith Pomarol-Clotet, Adrian Preda, Yann Quidé, Paul E Rasser, Kelly Rootes-Murdy, Raymond Salvador, Marina Sangiuliano, Salvador Sarró, Ulrich Schall, André Schmidt, Rodney J Scott, Pierluigi Selvaggi, Kang Sim, Antonin Skoch, Gianfranco Spalletta, Filip Spaniel, Sophia I. Thomopoulos, David Tomecek, Alexander S Tomyshev, Diana Tordesillas-Gutiérrez, Therese van Amelsvoort, Javier Vázquez-Bourgon, Daniela Vecchio, Aristotle Voineskos, Cynthia S Weickert, Thomas Weickert, Paul M Thompson, Lianne Schmaal, Theo GM van Erp, Jessica Turner, James H Cole, Danai Dima, and Esther Walton

Abstract

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.64 years (95% CI: 3.01, 4.26; I2 = 55.28%) compared to controls, after adjusting for age and sex (Cohen’s d = 0.50). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Published
2022

33. From genetics to systems biology of stress-related mental disorders

Author

Lee Lancashire, Nikolaos P. Daskalakis, Shareefa Dalvie, Foivos Georgiadis, Chris Chatzinakos, and Obada Al Zoubi

Subjects
Traumatic, Epigenomics, Neurophysiology and neuropsychology, Physiology, Systems biology, Neurosciences. Biological psychiatry. Neuropsychiatry, Biochemistry, Cellular and Molecular Neuroscience, Endocrinology, Stress (linguistics), medicine, Genetics, Original Research Article, RC346-429, Molecular Biology, Depression (differential diagnoses), Genetic association, Endocrine and Autonomic Systems, QP351-495, Traumatic stress, medicine.disease, Stress disorders, Major depressive disorder, Anxiety, Neurology. Diseases of the nervous system, medicine.symptom, Psychology, Transcriptome, RC321-571
Abstract

Many individuals will be exposed to some form of traumatic stress in their lifetime which, in turn, increases the likelihood of developing stress-related disorders such as post-traumatic stress disorder (PTSD), major depressive disorder (MDD) and anxiety disorders (ANX). The development of these disorders is also influenced by genetics and have heritability estimates ranging between ∼30 and 70%. In this review, we provide an overview of the findings of genome-wide association studies for PTSD, depression and ANX, and we observe a clear genetic overlap between these three diagnostic categories. We go on to highlight the results from transcriptomic and epigenomic studies, and, given the multifactorial nature of stress-related disorders, we provide an overview of the gene-environment studies that have been conducted to date. Finally, we discuss systems biology approaches that are now seeing wider utility in determining a more holistic view of these complex disorders.

Published
2021

34. Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Author

Constantinides, Constantinos, primary, Han, Laura KM, additional, Alloza, Clara, additional, Antonucci, Linda, additional, Arango, Celso, additional, Ayesa-Arriola, Rosa, additional, Banaj, Nerisa, additional, Bertolino, Alessandro, additional, Borgwardt, Stefan, additional, Bruggemann, Jason, additional, Bustillo, Juan, additional, Bykhovski, Oleg, additional, Carr, Vaughan, additional, Catts, Stanley, additional, Chung, Young-Chul, additional, Crespo-Facorro, Benedicto, additional, Díaz-Caneja, Covadonga M, additional, Donohoe, Gary, additional, Plessis, Stefan Du, additional, Edmond, Jesse, additional, Ehrlich, Stefan, additional, Emsley, Robin, additional, Eyler, Lisa T, additional, Fuentes-Claramonte, Paola, additional, Georgiadis, Foivos, additional, Green, Melissa, additional, Guerrero-Pedraza, Amalia, additional, Ha, Minji, additional, Hahn, Tim, additional, Henskens, Frans A, additional, Holleran, Laurena, additional, Homan, Stephanie, additional, Homan, Philipp, additional, Jahanshad, Neda, additional, Janssen, Joost, additional, Ji, Ellen, additional, Kaiser, Stefan, additional, Kaleda, Vasily, additional, Kim, Minah, additional, Kim, Woo-Sung, additional, Kirschner, Matthias, additional, Kochunov, Peter, additional, Kwak, Yoo Bin, additional, Kwon, Jun Soo, additional, Lebedeva, Irina, additional, Liu, Jingyu, additional, Mitchie, Patricia, additional, Michielse, Stijn, additional, Mothersill, David, additional, Mowry, Bryan, additional, de la Foz, Víctor Ortiz-García, additional, Pantelis, Christos, additional, Pergola, Giulio, additional, Piras, Fabrizio, additional, Pomarol-Clotet, Edith, additional, Preda, Adrian, additional, Quidé, Yann, additional, Rasser, Paul E, additional, Rootes-Murdy, Kelly, additional, Salvador, Raymond, additional, Sangiuliano, Marina, additional, Sarró, Salvador, additional, Schall, Ulrich, additional, Schmidt, André, additional, Scott, Rodney J, additional, Selvaggi, Pierluigi, additional, Sim, Kang, additional, Skoch, Antonin, additional, Spalletta, Gianfranco, additional, Spaniel, Filip, additional, Thomopoulos, Sophia I., additional, Tomecek, David, additional, Tomyshev, Alexander S, additional, Tordesillas-Gutiérrez, Diana, additional, van Amelsvoort, Therese, additional, Vázquez-Bourgon, Javier, additional, Vecchio, Daniela, additional, Voineskos, Aristotle, additional, Weickert, Cynthia S, additional, Weickert, Thomas, additional, Thompson, Paul M, additional, Schmaal, Lianne, additional, van Erp, Theo GM, additional, Turner, Jessica, additional, Cole, James H, additional, Dima, Danai, additional, and Walton, Esther, additional

Published
2022
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35. Gene expression in the dorsolateral and ventromedial prefrontal cortices implicates immune-related gene networks in PTSD

Author

Logue, Mark W., primary, Zhou, Zhenwei, additional, Morrison, Filomene G., additional, Wolf, Erika J., additional, Daskalakis, Nikolaos P., additional, Chatzinakos, Christos, additional, Georgiadis, Foivos, additional, Labadorf, Adam T., additional, Girgenti, Matthew J., additional, Young, Keith A., additional, Williamson, Douglas E., additional, Zhao, Xiang, additional, Grenier, Jaclyn Garza, additional, Huber, Bertrand Russell, additional, and Miller, Mark W., additional

Published
2021
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37. Schizophrenia polygenic risk during typical development reflects multiscale cortical organization

Author

Kirschner, Matthias, primary, Paquola, Casey, additional, Khundrakpam, Budhachandra S., additional, Vainik, Uku, additional, Bhutani, Neha, additional, Hodzic-Santor, Benazir, additional, Georgiadis, Foivos, additional, Al-Sharif, Noor B., additional, Misic, Bratislav, additional, Bernhardt, Boris, additional, Evans, Alan C., additional, and Dagher, Alain, additional

Published
2021
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38. Brain Network Architecture Intricately Linked to Morphological Abnormalities in Major Psychiatric Disorders

Author

Georgiadis, Foivos, primary, Lariviere, Sara, additional, Carr, Vaughan, additional, Catts, Stanley, additional, Green, Melissa, additional, Henskens, Frans, additional, Jablensky, Assen, additional, Mowry, Bryan, additional, Michie, Patricia, additional, Pantelis, Christos, additional, Quidé, Yann, additional, Krug, Alex, additional, Kircher, Tilo, additional, Salvador, Raymond, additional, Pomarol-Clotet, Edith, additional, Spalletta, Gianfranco, additional, Piras, Fabrizio, additional, Banaj, Nerisa, additional, Ciullo, Valentina, additional, Voineskos, Aristotle, additional, Sim, Kang, additional, Crespo-Facorro, Benedicto, additional, Tordesillas-Gutiérrez, Diana, additional, Crossley, Nicolas, additional, Undurraga, Juan, additional, Gonzalez-Valderrama, Alfonso, additional, Calhoun, Vince, additional, Borgwardt, Stefan, additional, Schmidt, Andre, additional, Andreou, Christina, additional, Kaiser, Stefan, additional, Seifritz, Erich, additional, Ji, Ellen, additional, Homan, Stephanie, additional, Homan, Philipp, additional, Turner, Jessica A., additional, van Erp, Theo, additional, Thompson, Paul M., additional, Bernhardt, Boris, additional, and Kirschner, Matthias, additional

Published
2021
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39. Schizophrenia polygenic risk during typical development reflects multiscale cortical organization

Author

Matthias Kirschner, Casey Paquola, Budhachandra S. Khundrakpam, Uku Vainik, Neha Bhutani, Benazir Hodzic-Santor, Foivos Georgiadis, Noor B. Al-Sharif, Bratislav Misic, Boris Bernhardt, Alan C. Evans, and Alain Dagher

Subjects
business.industry, General Medicine, medicine.disease, Neurodevelopmental disorder, medicine.anatomical_structure, Cortical abnormalities, Schizophrenia, Cortex (anatomy), Medicine, Polygenic risk score, Bipolar disorder, business, Neurocognitive, Neuroscience, Depression (differential diagnoses)
Abstract

Schizophrenia is widely recognized as a neurodevelopmental disorder, but determining neurodevelopmental features of schizophrenia requires a departure from classic case-control designs. Polygenic risk scoring for schizophrenia (PRS-SCZ) enables investigation of the influence of genetic risk for schizophrenia on cortical anatomy during neurodevelopment and prior to disease onset. PRS-SCZ and cortical morphometry were assessed in typically developing children (3 - 21 years) using T1-weighted MRI and whole genome genotyping (n=390) from the Pediatric Imaging, Neurocognition and Genetics (PING) cohort. Then, we sought to contextualise the findings using (i) age-matched transcriptomics, (ii) gradients of cortical differentiation and (iii) case-control differences of major psychiatric disorders. Higher PRS-SCZ was associated with greater cortical thickness in typically developing children, while surface area and cortical volume showed only subtle associations. Greater cortical thickness was most prominent in areas with heightened gene expression for dendrites and synapses. The pattern of PRS-SCZ associations with cortical thickness reflected functional specialisation in the cortex and was spatially related to cortical abnormalities of patient populations of schizophrenia, bipolar disorder, and major depression. Finally, age interaction models indicated PRS-SCZ effects on cortical thickness were most pronounced between ages 3 and 6, suggesting an influence of PRS-SCZ on cortical maturation early in life. Integrating imaging-genetics with multi-scale mapping of cortical organization, our work contributes to an emerging understanding of how risk for schizophrenia and related disorders manifest in early life.

Published
2021
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40. Brain Network Architecture Intricately Linked to Morphological Abnormalities in Major Psychiatric Disorders

Author

Vince D. Calhoun, Edith Pomarol-Clotet, Erich Seifritz, Vaughan J. Carr, Stanley V. Catts, Alfonso Gonzalez-Valderrama, Juan Undurraga, Raymond Salvador, André Schmidt, Ellen Ji, Christos Pantelis, Diana Tordesillas-Gutiérrez, Tilo Kircher, Valentina Ciullo, Assen Jablensky, Stefan Kaiser, Stefan Borgwardt, Yann Quidé, Bryan J. Mowry, Kang Sim, Melissa J. Green, Sara Larivière, Theo G.M. van Erp, Foivos Georgiadis, Aristotle N. Voineskos, Stephanie Homan, A Krug, Boris C. Bernhardt, Patricia T. Michie, Christina Andreou, Philipp Homan, Benedicto Crespo-Facorro, Matthias Kirschner, Gianfranco Spalletta, Fabrizio Piras, Nicolas Crossley, Paul M. Thompson, Nerisa Banaj, Jessica A. Turner, and Frans Henskens

Subjects
Brain network, medicine.medical_specialty, Human Connectome Project, Schizophrenia (object-oriented programming), medicine, Mega analysis, Bipolar disorder, Architecture, Psychology, medicine.disease, Psychiatry, Biological Psychiatry
Published
2021

42. TWAS pathway method greatly enhances the number of leads for uncovering the molecular underpinnings of psychiatric disorders

Author

Donghyung Lee, Vladimir I. Vladimirov, Silviu-Alin Bacanu, Kenneth S. Kendler, Foivos Georgiadis, Chris Chatzinakos, Bradley T. Webb, Nikolaos P. Daskalakis, Na Cai, Jonathan Flint, Brien P. Riley, and Anna R. Docherty

Subjects
Genetic Markers, Linkage disequilibrium, medicine.medical_specialty, Multifactorial Inheritance, Quantitative Trait Loci, TWAS, Single-nucleotide polymorphism, Genome-wide association study, Gene Expression, Genetics, Gwas, Pathway, Twas, Biology, Polymorphism, Single Nucleotide, Cellular and Molecular Neuroscience, Risk Factors, medicine, SNP, Humans, GWAS, Genetic Predisposition to Disease, genetics, Psychiatry, Gene, Genetics (clinical), Psychiatric genetics, Genetic association, pathway, Gene Expression Profiling, Computational Biology, Original Articles, Prognosis, Psychiatry and Mental health, Phenotype, Psychotic Disorders, Expression quantitative trait loci, gene expression, Original Article, Transcriptome, Software, Genome-Wide Association Study, Signal Transduction
Abstract

Genetic signal detection in genome‐wide association studies (GWAS) is enhanced by pooling small signals from multiple Single Nucleotide Polymorphism (SNP), for example, across genes and pathways. Because genes are believed to influence traits via gene expression, it is of interest to combine information from expression Quantitative Trait Loci (eQTLs) in a gene or genes in the same pathway. Such methods, widely referred to as transcriptomic wide association studies (TWAS), already exist for gene analysis. Due to the possibility of eliminating most of the confounding effects of linkage disequilibrium (LD) from TWAS gene statistics, pathway TWAS methods would be very useful in uncovering the true molecular basis of psychiatric disorders. However, such methods are not yet available for arbitrarily large pathways/gene sets. This is possibly due to the quadratic (as a function of the number of SNPs) computational burden for computing LD across large chromosomal regions. To overcome this obstacle, we propose JEPEGMIX2‐P, a novel TWAS pathway method that (a) has a linear computational burden, (b) uses a large and diverse reference panel (33 K subjects), (c) is competitive (adjusts for background enrichment in gene TWAS statistics), and (d) is applicable as‐is to ethnically mixed‐cohorts. To underline its potential for increasing the power to uncover genetic signals over the commonly used nontranscriptomics methods, for example, MAGMA, we applied JEPEGMIX2‐P to summary statistics of most large meta‐analyses from Psychiatric Genetics Consortium (PGC). While our work is just the very first step toward clinical translation of psychiatric disorders, PGC anorexia results suggest a possible avenue for treatment.

Published
2020

43. TWAS pathway method greatly enhances the number of leads for uncovering the molecular underpinnings of psychiatric disorders

Author

Chatzinakos, Chris, primary, Georgiadis, Foivos, additional, Lee, Donghyung, additional, Cai, Na, additional, Vladimirov, Vladimir I., additional, Docherty, Anna, additional, Webb, Bradley T., additional, Riley, Brien P., additional, Flint, Jonathan, additional, Kendler, Kenneth S., additional, Daskalakis, Nikolaos P., additional, and Bacanu, Silviu‐Alin, additional

Published
2020
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45. TWASpathway method greatly enhances the number of leads for uncovering the molecular underpinnings of psychiatric disorders

Author

Chatzinakos, Chris, Georgiadis, Foivos, Lee, Donghyung, Cai, Na, Vladimirov, Vladimir I., Docherty, Anna, Webb, Bradley T., Riley, Brien P., Flint, Jonathan, Kendler, Kenneth S., Daskalakis, Nikolaos P., and Bacanu, Silviu‐Alin

Abstract

Genetic signal detection in genome‐wide association studies (GWAS) is enhanced by pooling small signals from multiple Single Nucleotide Polymorphism (SNP), for example, across genes and pathways. Because genes are believed to influence traits via gene expression, it is of interest to combine information from expression Quantitative Trait Loci (eQTLs) in a gene or genes in the same pathway. Such methods, widely referred to as transcriptomic wide association studies (TWAS), already exist for gene analysis. Due to the possibility of eliminating most of the confounding effects of linkage disequilibrium (LD) from TWAS gene statistics, pathway TWAS methods would be very useful in uncovering the true molecular basis of psychiatric disorders. However, such methods are not yet available for arbitrarily large pathways/gene sets. This is possibly due to the quadratic (as a function of the number of SNPs) computational burden for computing LD across large chromosomal regions. To overcome this obstacle, we propose JEPEGMIX2‐P, a novel TWAS pathway method that (a) has a linear computational burden, (b) uses a large and diverse reference panel (33 K subjects), (c) is competitive (adjusts for background enrichment in gene TWAS statistics), and (d) is applicable as‐is to ethnically mixed‐cohorts. To underline its potential for increasing the power to uncover genetic signals over the commonly used nontranscriptomics methods, for example, MAGMA, we applied JEPEGMIX2‐P to summary statistics of most large meta‐analyses from Psychiatric Genetics Consortium (PGC). While our work is just the very first step toward clinical translation of psychiatric disorders, PGC anorexia results suggest a possible avenue for treatment.

Published
2020
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46. Schizophrenia Polygenic Risk During Typical Development Reflects Multiscale Cortical Organization

Author

Kirschner, Matthias, Paquola, Casey, Khundrakpam, Budhachandra S., Vainik, Uku, Bhutani, Neha, Hodzic-Santor, Benazir, Georgiadis, Foivos, Al-Sharif, Noor B., Misic, Bratislav, Bernhardt, Boris C., Evans, Alan C., and Dagher, Alain

Abstract

Schizophrenia is widely recognized as a neurodevelopmental disorder. Abnormal cortical development in otherwise typically developing children and adolescents may be revealed using polygenic risk scores for schizophrenia (PRS-SCZ).

Published
2022
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47. Genetic susceptibility to schizophrenia through neuroinflammatory pathways is associated with retinal thinning: Findings from the UK-Biobank.

Author

Rabe F, Smigielski L, Georgiadis F, Kallen N, Omlor W, Kirschner M, Cathomas F, Grünblatt E, Silverstein S, Blose B, Barthelmes D, Schaal K, Rubio J, Lencz T, and Homan P

Abstract

The human retina is part of the central nervous system and can be easily and non-invasively imaged with optical coherence tomography. While imaging the retina may provide insights on central nervous system-related disorders such as schizophrenia, a typical challenge are confounders often present in schizophrenia which may negatively impact retinal health. Here, we therefore aimed to investigate retinal changes in the context of common genetic variations conveying a risk of schizophrenia as measured by polygenic risk scores. We used population data from the UK Biobank, including White British and Irish individuals without diagnosed schizophrenia, and estimated a polygenic risk score for schizophrenia based on the newest genome-wide association study (PGC release 2022). We hypothesized that greater genetic susceptibility to schizophrenia is associated with retinal thinning, especially within the macula. To gain additional mechanistic insights, we conducted pathway-specific polygenic risk score associations analyses, focusing on gene pathways that are related to schizophrenia. Of 65484 individuals recruited, 48208 participants with available matching imaging-genetic data were included in the analysis of whom 22427 (53.48%) were female and 25781 (46.52%) were male. Our robust principal component regression results showed that polygenic risk scores for schizophrenia were associated with retinal thinning while controlling for confounding factors (b = -0.03, p = 0.007, pFWER = 0.01). Similarly, we found that polygenic risk for schizophrenia specific to neuroinflammation gene sets revealed significant associations with retinal thinning (b = -0.03, self-contained p = 0.041 (reflecting the level of association), competitive p = 0.05 (reflecting the level of enrichment)). These results go beyond previous studies suggesting a relationship between manifested schizophrenia and retinal phenotypes. They indicate that the retina is a mirror reflecting the genetic complexities of schizophrenia and that alterations observed in the retina of individuals with schizophrenia may be connected to an inherent genetic predisposition to neurodegenerative aspects of the condition. These associations also suggest the potential involvement of the neuroinflammatory pathway, with indications of genetic overlap with specific retinal phenotypes. The findings further indicate that this gene pathway in individuals with a high polygenic risk for schizophrenia could contribute through acute-phase proteins to structural changes in the retina., Competing Interests: PH has received grants and honoraria from Novartis, Lundbeck, Mepha, Janssen, Boehringer Ingelheim, Neurolite outside of this work. No other disclosures were reported.

Published
2024
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48. Estimating multimodal brain variability in schizophrenia spectrum disorders: A worldwide ENIGMA study.

Author

Omlor W, Rabe F, Fuchs S, Cecere G, Homan S, Surbeck W, Kallen N, Georgiadis F, Spiller T, Seifritz E, Weickert T, Bruggemann J, Weickert C, Potkin S, Hashimoto R, Sim K, Rootes-Murdy K, Quide Y, Houenou J, Banaj N, Vecchio D, Piras F, Piras F, Spalletta G, Salvador R, Karuk A, Pomarol-Clotet E, Rodrigue A, Pearlson G, Glahn D, Tomecek D, Spaniel F, Skoch A, Kirschner M, Kaiser S, Kochunov P, Fan FM, Andreassen OA, Westlye LT, Berthet P, Calhoun VD, Howells F, Uhlmann A, Scheffler F, Stein D, Iasevoli F, Cairns MJ, Carr VJ, Catts SV, Di Biase MA, Jablensky A, Green MJ, Henskens FA, Klauser P, Loughland C, Michie PT, Mowry B, Pantelis C, Rasser PE, Schall U, Scott R, Zalesky A, de Bartolomeis A, Barone A, Ciccarelli M, Brunetti A, Cocozza S, Pontillo G, Tranfa M, Di Giorgio A, Thomopoulos SI, Jahanshad N, Thompson PM, van Erp T, Turner J, and Homan P

Abstract

Objective: Schizophrenia is a multifaceted disorder associated with structural brain heterogeneity. Despite its relevance for identifying illness subtypes and informative biomarkers, structural brain heterogeneity in schizophrenia remains incompletely understood. Therefore, the objective of this study was to provide a comprehensive insight into the structural brain heterogeneity associated with schizophrenia., Methods: This meta- and mega-analysis investigated the variability of multimodal structural brain measures of white and gray matter in individuals with schizophrenia versus healthy controls. Using the ENIGMA dataset of MRI-based brain measures from 22 international sites with up to 6139 individuals for a given brain measure, we examined variability in cortical thickness, surface area, folding index, subcortical volume and fractional anisotropy., Results: We found that individuals with schizophrenia are distinguished by higher heterogeneity in the frontotemporal network with regard to multimodal structural measures. Moreover, individuals with schizophrenia showed higher homogeneity of the folding index, especially in the left parahippocampal region., Conclusions: Higher multimodal heterogeneity in frontotemporal regions potentially implies different subtypes of schizophrenia that converge on impaired frontotemporal interaction as a core feature of the disorder. Conversely, more homogeneous folding patterns in the left parahippocampal region might signify a consistent characteristic of schizophrenia shared across subtypes. These findings underscore the importance of structural brain variability in advancing our neurobiological understanding of schizophrenia, and aid in identifying illness subtypes as well as informative biomarkers.

Published
2023
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49. Neural Correlates of Positive and Negative Formal Thought Disorder in Individuals with Schizophrenia: An ENIGMA Schizophrenia Working Group Study.

Author

Nickl-Jockschat T, Sharkey R, Bacon C, Peterson Z, Rootes-Murdy K, Salvador R, Pomarol E, Karuk A, Homan P, Ji E, Omlor W, Homan S, Georgiadis F, Kaiser S, Kirschner M, Ehrlich S, Dannlowski U, Grotegerd D, Goltermann J, Meinert S, Kircher T, Stein F, Brosch K, Krug A, Nenadic I, Sim K, Piras F, Banaj N, Sponheim S, Demro C, Ramsay I, King M, Quidé Y, Green M, Nguyen D, Preda A, Calhoun V, Turner J, van Erp T, and Spalletta G

Abstract

Formal thought disorder (FTD) is a key clinical factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, relationship between FTD symptom dimensions and patterns of regional brain volume deficiencies in schizophrenia remain to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles based on a large multi-site cohort through the ENIGMA Schizophrenia Working Group (752 individuals with schizophrenia and 1256 controls), to unravel the neuroanatomy of positive, negative and total FTD in schizophrenia and their cellular bases. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks for positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD was also linked to microglial cell types. These findings relate different dimensions of FTD to distinct brain structural changes and their cellular underpinnings, improve our mechanistic understanding of these key psychotic symptoms., Competing Interests: Confiicts of Interest The authors declare that there is no conflict of interest.

Published
2023
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50. Neural Correlates of Positive and Negative Formal Thought Disorder in Individuals with Schizophrenia: An ENIGMA Schizophrenia Working Group Study.

Author

Sharkey RJ, Bacon C, Peterson Z, Rootes-Murdy K, Salvador R, Pomarol-Clotet E, Karuk A, Homan P, Ji E, Omlor W, Homan S, Georgiadis F, Kaiser S, Kirschner M, Ehrlich S, Dannlowski U, Grotegerd D, Goltermann J, Meinert S, Kircher T, Stein F, Brosch K, Krug A, Nenadić I, Sim K, Spalletta G, Piras F, Banaj N, Sponheim SR, Demro C, Ramsay IS, King M, Quidé Y, Green MJ, Nguyen D, Preda A, Calhoun VD, Turner JA, van Erp TGM, and Nickl-Jockschat T

Abstract

Formal thought disorder (FTD) is a key clinical factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, relationship between FTD symptom dimensions and patterns of regional brain volume deficiencies in schizophrenia remain to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles based on a large multi-site cohort through the ENIGMA Schizophrenia Working Group (752 individuals with schizophrenia and 1256 controls), to unravel the neuroanatomy of positive, negative and total FTD in schizophrenia and their cellular bases. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks for positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD was also linked to microglial cell types. These findings relate different dimensions of FTD to distinct brain structural changes and their cellular underpinnings, improve our mechanistic understanding of these key psychotic symptoms.

Published
2023
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