WITHDRAWN: Progressive brain structural changes mapped as psychosis develops in ‘at risk' individuals

Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Parkville, Victoria, Australia.
Schizophrenia Research (Impact Factor: 3.92). 02/2009; 108(1-3):85-92. DOI: 10.1016/j.schres.2008.11.026
Source: PubMed


Schizophrenia and related psychoses are associated with brain structural abnormalities. Recent findings in 'at risk' populations have identified progressive changes in various brain regions preceding illness onset, while changes especially in prefrontal and superior temporal regions have been demonstrated in first-episode schizophrenia patients. However, the timing of the cortical changes and their regional extent, relative to the emergence of psychosis, has not been clarified. We followed individuals at high-risk for psychosis to determine whether structural changes in the cerebral cortex occur with the onset of psychosis. We hypothesized that progressive volume loss occurs in prefrontal regions during the transition to psychosis.
35 individuals at ultra-high risk (UHR) for developing psychosis, of whom 12 experienced psychotic onset by 1-year follow-up ('converters'), participated in a longitudinal structural MRI study. Baseline and follow-up T1-weighted MR images were acquired and longitudinal brain surface contractions were assessed using Cortical Pattern Matching.
Significantly greater brain contraction was found in the right prefrontal region in the 'converters' compared with UHR cases who did not develop psychosis ('non-converters').
These findings show cortical volume loss is associated with the onset of psychosis, indicating ongoing pathological processes during the transition stage to illness. The prefrontal volume loss is in line with structural and functional abnormalities in schizophrenia, suggesting a critical role for this change in the development of psychosis.

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    • "icate the specific subgroup differences assessed with TukeyHSD post - hoc analyses between people who later became ill ( Ill ) , who later developed symptoms ( Symptoms ) and those who remained well ( Well ) . Middle horizontal lines in the boxes represent the median of the distributions . mostly in the prefrontal cortex in high risk individuals ( Sun et al . , 2009 ) and / or liability for schizophrenia ( Cannon et al . , 2002 ) . Within our high risk group , people who later became ill showed a trend of decreased clustering in the left anterior cingulate , a cortical area that has been con - sistently reported to be implicated in the development of schizophrenia ( Fusar - Poli et al . , 2011b ; J"
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    ABSTRACT: Grey matter brain networks are disrupted in schizophrenia, but it is still unclear at which point during the development of the illness these disruptions arise and whether these can be associated with behavioural predictors of schizophrenia. We investigated if single-subject grey matter networks were disrupted in a sample of people at familial risk of schizophrenia. Single-subject grey matter networks were extracted from structural MRI scans of 144 high risk subjects, 32 recent-onset patients and 36 healthy controls. The following network properties were calculated: size, connectivity density, degree, path length, clustering coefficient, betweenness centrality and small world properties. People at risk of schizophrenia showed decreased path length and clustering in mostly prefrontal and temporal areas. Within the high risk sample, the path length of the posterior cingulate cortex and the betweenness centrality of the left inferior frontal operculum explained 81% of the variance in schizotypal cognitions, which was previously shown to be the strongest behavioural predictor of schizophrenia in the study. In contrast, local grey matter volume measurements explained 48% of variance in schizotypy. The present results suggest that single-subject grey matter networks can quantify behaviourally relevant biological alterations in people at increased risk for schizophrenia before disease onset. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 08/2015; 168(1). DOI:10.1016/j.schres.2015.08.025 · 3.92 Impact Factor
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    • "Indeed, some studies investigating these structures in high risk cohorts have found that alterations precede disorder onset, suggesting that they are not caused by secondary confounding effects of the illness itself (Sun et al., 2009; Cannon et al., 2015; Bois et al., 2015). "
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    ABSTRACT: It is unknown whether brain changes occur prior to onset of schizophrenia or after it develops. Prospective familial high risk studies provide a good method to investigate this. In the Edinburgh High Risk Study, structural MRI scans of 150 young individuals at familial high risk of schizophrenia, 34 patients with first-episode schizophrenia and 36 matched controls were obtained. Of the high risk participants with scans suitable for analysis, 17 developed schizophrenia after the scans were taken, whilst 57 experienced isolated or sub-clinical psychotic symptoms, and 70 remained well. We used Freesurfer to extract volumetric measurements of the hippocampus, amygdala and nucleus accumbens with the aim of assessing whether any alterations found were present in all those at high risk, or selectively in the high risk cohort based on future clinical outcome, or only in those experiencing their first-episode of psychosis. We found no significant differences in any examined regions between controls and those at high risk, or between those at high risk who later developed schizophrenia and those who remained well. However, patients with first-episode schizophrenia demonstrated significant volumetric reductions in the bilateral hippocampus, left amygdala, and right nucleus accumbens compared to high risk individuals and healthy controls, which were not significantly associated with the intake of anti-psychotic medication or duration of illness. We found that patients had significantly smaller left amygdalae and bilateral hippocampus compared to HR[ill]. Our findings suggest that volumetric reductions of the hippocampus, amygdala and nucleus accumbens occur early in the first-episode of psychosis. The apparent absence of high risk versus control differences we found using Freesurfer is at odds with our previous studies conducted on the same sample, and possible methodological reasons for these apparent discrepancies are discussed.
    Schizophrenia Research 04/2015; 165(1). DOI:10.1016/j.schres.2015.03.024 · 3.92 Impact Factor
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    • "Clinical HR studies have found a similar pattern of results, with HR-NT showing some alterations compared to controls, and HR-T showing further alterations that distinguish them from HR-NT (Pantelis et al., 2005; Wood et al., 2008). However, not all clinical and high risk studies have found more changes in HR-T compared to HR-NT, and the direction of these abnormalities is somewhat inconsistent, with some studies showing increases in the hippocampus , and others decreases (Phillips et al., 2002; Sun et al., 2009; McIntosh et al., 2011). "
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    ABSTRACT: Schizophrenia is associated with structural brain abnormalities that are likely to be present before disease onset. It remains unclear to what extent these represent general vulnerability indicators or are associated with the developing clinical state itself. It also remains unclear whether such state or trait alterations may be evident at any given time-point, or whether they progress over time. To investigate this, structural brain scans were acquired at two time-points (mean scan-interval 1.87years) in a cohort of young unaffected individuals at high familial risk of schizophrenia (baseline, n=142; follow-up, n=64) and healthy controls (baseline, n=36; follow-up, n=18). Sub-cortical reconstructions of the hippocampus and amygdala were generated using the longitudinal pipeline available with Freesurfer. The high risk cohort was subdivided into individuals that remained well during the study (HR[well], baseline, n=68; follow-up, n=30), transient and/or partial symptoms that were insufficient to support a formal diagnosis (HR[symp], baseline, n=57; follow-up, n=26) and individuals that subsequently developed schizophrenia according to ICD-10 criteria (HR[ill], baseline, n=17; follow-up, n=8). Longitudinal change in the hippocampus and amygdala was compared, focusing first on overall differences between high-risk individuals and controls and then on sub-group differences within the high-risk cohort. We found a significantly altered developmental trajectory for all high risk individuals compared to controls, with controls showing a significant increase in hippocampal volume over time compared to those at high risk. We did not find evidence of altered longitudinal trajectories based on clinical outcome within the high risk cohort. These results suggest that an altered developmental trajectory of hippocampal volume is associated with a general familial predisposition to develop schizophrenia, as this alteration was not related to subsequent clinical outcome.
    Schizophrenia Research 12/2014; DOI:10.1016/j.schres.2014.12.003 · 3.92 Impact Factor
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