7 results
An overlapping pattern of cerebral cortical thinning is associated with both positive symptoms and aggression in schizophrenia via the ENIGMA consortium
- Ting Yat Wong, Joaquim Radua, Edith Pomarol-Clotet, Raymond Salvador, Anton Albajes-Eizagirre, Aleix Solanes, Erick J. Canales-Rodriguez, Amalia Guerrero-Pedraza, Salvador Sarro, Tilo Kircher, Igor Nenadic, Axel Krug, Dominik Grotegerd, Udo Dannlowski, Stefan Borgwardt, Anita Riecher-Rössler, Andre Schmidt, Christina Andreou, Christian G. Huber, Jessica Turner, Vince Calhoun, Wenhao Jiang, Sarah Clark, Esther Walton, Gianfranco Spalletta, Nerisa Banaj, Fabrizio Piras, Valentina Ciullo, Daniela Vecchio, Irina Lebedeva, Alexander S. Tomyshev, Vasily Kaleda, Tatyana Klushnik, Geraldo Busatto Filho, Marcus Vinicius Zanetti, Mauricio Henriques Serpa, Pedro Gomes Penteado Rosa, Ryota Hashimoto, Masaki Fukunaga, Anja Richter, Bernd Krämer, Oliver Gruber, Aristotle N. Voineskos, Erin W. Dickie, David Tomecek, Antonin Skoch, Filip Spaniel, Cyril Hoschl, Alessandro Bertolino, Aurora Bonvino, Annabella Di Giorgio, Laurena Holleran, Simone Ciufolini, Tiago Reis Marques, Paola Dazzan, Robin Murray, Jelle Lamsma, Wiepke Cahn, Neeltje van Haren, Ana M. Díaz-Zuluaga, Julián A. Pineda-Zapata, Cristian Vargas, Carlos López-Jaramillo, Theo G. M. van Erp, Ruben C. Gur, Thomas Nickl-Jockschat
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- Journal:
- Psychological Medicine / Volume 50 / Issue 12 / September 2020
- Published online by Cambridge University Press:
- 16 October 2019, pp. 2034-2045
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Background
Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample.
MethodTo study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls.
ResultsThe result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression.
ConclusionThese findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.
Dentate gyrus volume deficit in schizophrenia
- Soichiro Nakahara, Jessica A. Turner, Vince D. Calhoun, Kelvin O. Lim, Bryon Mueller, Juan R. Bustillo, Daniel S. O'Leary, Sarah McEwen, James Voyvodic, Aysenil Belger, Daniel H. Mathalon, Judith M. Ford, Fabio Macciardi, Mitsuyuki Matsumoto, Steven G. Potkin, Theo G. M. van Erp
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- Journal:
- Psychological Medicine / Volume 50 / Issue 8 / June 2020
- Published online by Cambridge University Press:
- 03 June 2019, pp. 1267-1277
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Background
Schizophrenia is associated with robust hippocampal volume deficits but subregion volume deficits, their associations with cognition, and contributing genes remain to be determined.
MethodsHippocampal formation (HF) subregion volumes were obtained using FreeSurfer 6.0 from individuals with schizophrenia (n = 176, mean age ± s.d. = 39.0 ± 11.5, 132 males) and healthy volunteers (n = 173, mean age ± s.d. = 37.6 ± 11.3, 123 males) with similar mean age, gender, handedness, and race distributions. Relationships between the HF subregion volume with the largest between group difference, neuropsychological performance, and single-nucleotide polymorphisms were assessed.
ResultsThis study found a significant group by region interaction on hippocampal subregion volumes. Compared to healthy volunteers, individuals with schizophrenia had significantly smaller dentate gyrus (DG) (Cohen's d = −0.57), Cornu Ammonis (CA) 4, molecular layer of the hippocampus, hippocampal tail, and CA 1 volumes, when statistically controlling for intracranial volume; DG (d = −0.43) and CA 4 volumes remained significantly smaller when statistically controlling for mean hippocampal volume. DG volume showed the largest between group difference and significant positive associations with visual memory and speed of processing in the overall sample. Genome-wide association analysis with DG volume as the quantitative phenotype identified rs56055643 (β = 10.8, p < 5 × 10−8, 95% CI 7.0–14.5) on chromosome 3 in high linkage disequilibrium with MOBP. Gene-based analyses identified associations between SLC25A38 and RPSA and DG volume.
ConclusionsThis study suggests that DG dysfunction is fundamentally involved in schizophrenia pathophysiology, that it may contribute to cognitive abnormalities in schizophrenia, and that underlying biological mechanisms may involve contributions from MOBP, SLC25A38, and RPSA.
Interactive impact of childhood maltreatment, depression, and age on cortical brain structure: mega-analytic findings from a large multi-site cohort
- Leonardo Tozzi, Lisa Garczarek, Deborah Janowitz, Dan J. Stein, Katharina Wittfeld, Henrik Dobrowolny, Jim Lagopoulos, Sean N. Hatton, Ian B. Hickie, Angela Carballedo, Samantha J. Brooks, Daniella Vuletic, Anne Uhlmann, Ilya M. Veer, Henrik Walter, Robin Bülow, Henry Völzke, Johanna Klinger-König, Knut Schnell, Dieter Schoepf, Dominik Grotegerd, Nils Opel, Udo Dannlowski, Harald Kugel, Elisabeth Schramm, Carsten Konrad, Tilo Kircher, Dilara Jüksel, Igor Nenadić, Axel Krug, Tim Hahn, Olaf Steinsträter, Ronny Redlich, Dario Zaremba, Bartosz Zurowski, Cynthia H.Y. Fu, Danai Dima, James Cole, Hans J. Grabe, Colm G. Connolly, Tony T. Yang, Tiffany C. Ho, Kaja Z. LeWinn, Meng Li, Nynke A. Groenewold, Lauren E. Salminen, Martin Walter, Alan N Simmons, Theo G.M. van Erp, Neda Jahanshad, Bernhard T. Baune, Nic J.A. van der Wee, Marie-Jose van Tol, Brenda W.J.H. Penninx, Derrek P. Hibar, Paul M. Thompson, Dick J. Veltman, Lianne Schmaal, Thomas Frodl, ‘for the ENIGMA-MDD Consortium’
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- Journal:
- Psychological Medicine / Volume 50 / Issue 6 / April 2020
- Published online by Cambridge University Press:
- 14 May 2019, pp. 1020-1031
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Background
Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.
MethodsWithin the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.
ResultsCM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.
ConclusionsSeverity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.
D2 receptor occupancy following lurasidone treatment in patients with schizophrenia or schizoaffective disorder
- Steven G. Potkin, David B. Keator, Marilyn L. Kesler-West, Dana D. Nguyen, Theo. G. M. van Erp, Jogeshwar Mukherjee, Nikunj Shah, Adrian Preda
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- Journal:
- CNS Spectrums / Volume 19 / Issue 2 / April 2014
- Published online by Cambridge University Press:
- 30 September 2013, pp. 176-181
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Objective/Introduction
Lurasidone is an atypical antipsychotic medication approved for the treatment of schizophrenia over a dose range of 40–160 mg/day. This study examined D2 receptor occupancy and its association with clinical improvement and side effects in patients with schizophrenia or schizoaffective disorder following repeated doses of 80, 120, or 160 mg/day of lurasidone.
MethodsTwenty-five patients with The Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnoses of schizophrenia or schizoaffective disorder were washed out of their antipsychotic medications (5 half-lives) and randomly assigned to 80, 120, or 160 mg/day of lurasidone. Subjects were imaged with 18F-fallypride at baseline and at steady-state lurasidone treatment to determine D2 receptor occupancy.
ResultsBlood lurasidone concentration (plus major metabolite), but not dose, significantly correlated with D2 receptor occupancy. D2 receptor occupancy in several subcortical structures is associated with positive but not negative symptom improvement or the presence of movement symptoms.
DiscussionBlood concentrations greater than 70 ng/mL may be required to achieve a 65% occupancy level in subcortical areas. Intersubject blood concentrations at fixed dose were highly variable and may account for the lack of dose correlations.
ConclusionsPositron emission tomography (PET) occupancy data suggest that greater than 65% occupancy can be achieved across the dose range of 80–160 mg/day and that some patients require higher doses to achieve antipsychotic efficacy; this finding supports prior randomized clinical trial results.
Heritability of Multivariate Gray Matter Measures in Schizophrenia
- Jessica A. Turner, Vince D. Calhoun, Andrew Michael, Theo G. M. van Erp, Stefan Ehrlich, Judith M. Segall, Randy L. Gollub, John Csernansky, Steven G. Potkin, Beng-Choon Ho, Juan Bustillo, S. Charles Schulz, FBIRN, Lei Wang
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- Journal:
- Twin Research and Human Genetics / Volume 15 / Issue 3 / June 2012
- Published online by Cambridge University Press:
- 15 June 2012, pp. 324-335
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Structural brain measures are employed as endophenotypes in the search for schizophrenia susceptibility genes. We analyzed two independent structural imaging datasets with voxel-based morphometry and with source-based morphometry, a multivariate, independent components analysis, to determine the stability and heritability of regional gray matter concentration abnormalities in schizophrenia. The samples comprised 209 and 102 patients with schizophrenia and 208 and 96 healthy volunteers, respectively. The second sample additionally included non-ill siblings of participants with and without schizophrenia. A standard voxel-based analysis showed reproducible regional gray matter deficits in the affected participants compared with unrelated, unaffected controls in both datasets: patients showed significant gray matter concentration deficits in cortical frontal, temporal, and insular lobes. Source-based morphometry (SBM) was applied to the gray matter images of the entire sample to determine the effects of diagnosis on networks of covarying structures. The SBM analysis extracted 24 significant sets of covarying regions (components). Four of these components showed significantly lower gray matter concentrations in patients (p < .05). We determined the familiality of the observed SBM components based on 66 sibling pairs (25 discordant for schizophrenia). Two components, one including the medial frontal, insular, inferior frontal, and temporal lobes, and the other including the posterior occipital lobe, showed significant familiality (p < .05). We conclude that structural brain deficits in schizophrenia are replicable, and that SBM can extract unique familial and likely heritable components. SBM provides a useful data reduction technique that can provide measures that may serve as endophenotypes for schizophrenia.
Developmental disruptions in neural connectivity in the pathophysiology of schizophrenia
- Katherine H. Karlsgodt, Daqiang Sun, Amy M. Jimenez, Evan S. Lutkenhoff, Rachael Willhite, Theo G. M. van Erp, Tyrone D. Cannon
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- Development and Psychopathology / Volume 20 / Issue 4 / Fall 2008
- Published online by Cambridge University Press:
- 07 October 2008, pp. 1297-1327
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Schizophrenia has been thought of as a disorder of reduced functional and structural connectivity. Recent advances in neuroimaging techniques such as functional magnetic resonance imaging, structural magnetic resonance imaging, diffusion tensor imaging, and small animal imaging have advanced our ability to investigate this hypothesis. Moreover, the power of longitudinal designs possible with these noninvasive techniques enable the study of not just how connectivity is disrupted in schizophrenia, but when this disruption emerges during development. This article reviews genetic and neurodevelopmental influences on structural and functional connectivity in human populations with or at risk for schizophrenia and in animal models of the disorder. We conclude that the weight of evidence across these diverse lines of inquiry points to a developmental disruption of neural connectivity in schizophrenia and that this disrupted connectivity likely involves susceptibility genes that affect processes involved in establishing intra- and interregional connectivity.
13 - Investigating gene–environment interaction in schizophrenia using neuroimaging
- from III - The genetic epidemiology of schizophrenia
- Edited by Robin M. Murray, Institute of Psychiatry, London, Peter B. Jones, University of Cambridge, Ezra Susser, Columbia University, New York, Jim Van Os, Universiteit Maastricht, Netherlands, Mary Cannon, Institute of Psychiatry, London
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- The Epidemiology of Schizophrenia
- Published online:
- 18 September 2009
- Print publication:
- 28 November 2002, pp 254-270
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Summary
Applications of classical epidemiological methods have led to general acceptance of a multifactorial threshold model of schizophrenia, whereby multiple genetic influences and environmental factors aggregate together, additively and/or interactively, to form a continuum of disease liability. Studies that make use of clinical diagnostic categories are limited in what they can tell us about the precise nature of the aetiological factors involved in schizophrenia because of the inherent limitations of categorical measures in reflecting a continuous liability scale. We propose that new methodologies that can represent this liability continuum on a quantitative scale are needed to aid in the search for schizophrenia susceptibility genes and in elucidating the pathophysiological mechanisms by which these genes and environmental factors act. Here we review evidence concerning structural brain abnormalities as markers of aetiological influences in schizophrenia, concluding that use of quantitative neuroanatomical measures will facilitate the detection of predisposing gene loci and help to clarify whether nongenetic influences contribute independently of or interactively with genetic factors in influences in schizophrenia, concluding that use of quantitative neuroanatomical measures will facilitate the detection of predisposing geneloci and help to clarify whether nongenetic influences contribute independently of or interactively with genetic factors in influencing disease liability. The eventual discovery of such genes will spawn a new era of epidemiological research, in which the effects of specific predisposing genotypes and specific environmental factors on schizophrenia phenomenology and pathophysiology can be studied.
Investigating gene-environment interaction in schizophrenia
Family, twin, and adoption studies have demonstrated that schizophrenia is a substantially heritable disorder. These studies are reviewed in Chapter 10. Still, attempts at isolating specific genes that confer vulnerability to schizophrenia have so far been only moderately successful (Moldin, 1997).