Publications by authors named "Fabienne Harrisberger"

20 Publications

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Association of antidepressants with brain morphology in early stages of psychosis: an imaging genomics approach.

Sci Rep 2019 06 11;9(1):8516. Epub 2019 Jun 11.

Neuropsychiatry and Brain Imaging, Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.

Depressive symptoms in subjects at Clinical High Risk for Psychosis (CHR-P) or at first-episode psychosis (FEP) are often treated with antidepressants. Our cross-sectional study investigated whether brain morphology is altered by antidepressant medication. High-resolution T-weighted structural MRI scans of 33 CHR-P and FEP subjects treated with antidepressants, 102 CHR-P and FEP individuals without antidepressant treatment and 55 controls, were automatically segmented using Freesurfer 6.0. Linear mixed-effects modelling was applied to assess the differences in subcortical volume, surface area and cortical thickness in treated, non-treated and healthy subjects, taking into account converted dosages of antidepressants. Increasing antidepressant dose was associated with larger volume of the pallidum and the putamen, and larger surface of the left inferior temporal gyrus. In a pilot subsample of separately studied subjects of known genomic risk loci, we found that in the right postcentral gyrus, the left paracentral lobule and the precentral gyrus antidepressant dose-associated surface increase depended on polygenic schizophrenia-related-risk score. As the reported regions are linked to the symptoms of psychosis, our findings reflect the possible beneficial effects of antidepressant treatment on an emerging psychosis.
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http://dx.doi.org/10.1038/s41598-019-44903-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560086PMC
June 2019

No associations between medial temporal lobe volumes and verbal learning/memory in emerging psychosis.

Eur J Neurosci 2019 09 17;50(6):3060-3071. Epub 2019 May 17.

Center for Gender Research and Early Detection, University of Basel Psychiatric Hospital, Basel, Switzerland.

Grey matter (GM) volume alterations have been repeatedly demonstrated in patients with first episode psychosis (FEP). Some of these neuroanatomical abnormalities are already evident in the at-risk mental state (ARMS) for psychosis. Not only GM alterations but also neurocognitive impairments predate the onset of frank psychosis with verbal learning and memory (VLM) being among the most impaired domains. Yet, their interconnection with alterations in GM volumes remains ambiguous. Thus, we evaluated associations of different subcortical GM volumes in the medial temporal lobe with VLM performance in antipsychotic-naïve ARMS and FEP patients. Data from 59 ARMS and 31 FEP patients, collected within the prospective Früherkennung von Psychosen study, were analysed. Structural T1-weighted images were acquired using a 3 Tesla magnetic resonance imaging scanner. VLM was assessed using the California Verbal Learning Test and its factors Attention Span, Learning Efficiency, Delayed Memory and Inaccurate Memory. FEP patients showed significantly enlarged volumes of hippocampus, pallidum, putamen and thalamus compared to ARMS patients. A significant negative association between amygdala and pallidum volume and Attention Span was found in ARMS and FEP patients combined, which however did not withstand correction for multiple testing. Although we found significant between-group differences in subcortical volumes and VLM is among the most impaired cognitive domains in emerging psychosis, we could not demonstrate an association between low performance and subcortical GM volumes alterations in antipsychotic-naïve patients. Hence, deficits in this domain do not appear to stem from alterations in subcortical structures.
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http://dx.doi.org/10.1111/ejn.14427DOI Listing
September 2019

Impact on the Onset of Psychosis of a Polygenic Schizophrenia-Related Risk Score and Changes in White Matter Volume.

Cell Physiol Biochem 2018 25;48(3):1201-1214. Epub 2018 Jul 25.

Neuropsychiatry and Brain Imaging, Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.

Background: Reductions in the volume of brain white matter are a common feature in schizophrenia and bipolar disorder while the association between white matter and polygenic schizophrenia-related risk is unclear. To look at the intermediate state between health and the full-blown disorder, we investigated this aspect in groups of patients before and after the onset of psychosis.

Methods: On a 3 Tesla scanner, total and regional white matter volumes were investigated by structural magnetic resonance imaging (MRI) in the following groups: 37 at-risk mental state patients (ARMS), including 30 with no transition to psychosis (ARMS-NT) and 7 with a transition to psychosis (ARMS-T) pooled with 25 first episode psychosis (FEP) patients. These T1-weighted images were automatically processed with the FreeSurfer software and compared with an odds-ratio-weighted polygenic schizophrenia-related risk score (PSRS) based on the publicly available top white matter single-nucleotide polymorphisms.

Results: We found no association, only a trend, between PSRS and white matter volume over all groups (β = 0.24, p = 0.07, 95% confidence interval = [-0.02 - 0.49]). However, a higher PSRS was significantly associated with a higher probability of being assigned to the ARMS-T + FEP group rather than to the ARMS-NT group (β = 0.70, p = 0.02, 95% confidence interval = [0.14 - 1.33]); there was no such association with white matter volume. Additionally, a positive association was found between PSRS and the Brief Psychiatric Rating Scale (BPRS) total score for the pooled ARMS-NT/ARMS-T+FEP sample and for the ARMS-T + FEP group also, but none for the ARMS-NT group only.

Conclusion: These findings suggest that at-risk mental state patients with a transition and first-episode psychosis patients have a higher genetic risk for schizophrenia than at-risk mental state patients with no transition to psychosis; this risk was associated with psychopathological symptoms. Further analyses may allow polygenic schizophrenia-related risk scores to be used as biomarkers to predict psychosis.
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http://dx.doi.org/10.1159/000491986DOI Listing
September 2018

Machine Learning for Large-Scale Quality Control of 3D Shape Models in Neuroimaging.

Mach Learn Med Imaging 2017 Sep 7;10541:371-378. Epub 2017 Sep 7.

Department of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.

As very large studies of complex neuroimaging phenotypes become more common, human quality assessment of MRI-derived data remains one of the last major bottlenecks. Few attempts have so far been made to address this issue with machine learning. In this work, we optimize predictive models of quality for meshes representing deep brain structure shapes. We use standard vertex-wise and global shape features computed homologously across 19 cohorts and over 7500 human-rated subjects, training kernelized Support Vector Machine and Gradient Boosted Decision Trees classifiers to detect meshes of failing quality. Our models generalize across datasets and diseases, reducing human workload by 30-70%, or equivalently hundreds of human rater hours for datasets of comparable size, with recall rates approaching inter-rater reliability.
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http://dx.doi.org/10.1007/978-3-319-67389-9_43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049825PMC
September 2017

Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium.

Biol Psychiatry 2018 11 14;84(9):644-654. Epub 2018 May 14.

Division of Mental Health and Addiction, NORMENT, K.G. Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway.

Background: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group.

Methods: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide.

Results: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset.

Conclusions: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.
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http://dx.doi.org/10.1016/j.biopsych.2018.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177304PMC
November 2018

Disorganized Gyrification Network Properties During the Transition to Psychosis.

JAMA Psychiatry 2018 06;75(6):613-622

Department of Psychiatry (Universitäre Psychiatrische Kliniken [UPK]), University of Basel, Basel, Switzerland.

Importance: There is urgent need to improve the limited prognostic accuracy of clinical instruments to predict psychosis onset in individuals at clinical high risk (CHR) for psychosis. As yet, no reliable biological marker has been established to delineate CHR individuals who will develop psychosis from those who will not.

Objectives: To investigate abnormalities in a graph-based gyrification connectome in the early stages of psychosis and to test the accuracy of this systems-based approach to predict a transition to psychosis among CHR individuals.

Design, Setting, And Participants: This investigation was a cross-sectional magnetic resonance imaging (MRI) study with follow-up assessment to determine the transition status of CHR individuals. Participants were recruited from a specialized clinic for the early detection of psychosis at the Department of Psychiatry (Universitäre Psychiatrische Kliniken [UPK]), University of Basel, Basel, Switzerland. Participants included individuals in the following 4 study groups: 44 healthy controls (HC group), 63 at-risk mental state (ARMS) individuals without later transition to psychosis (ARMS-NT group), 16 ARMS individuals with later transition to psychosis (ARMS-T group), and 38 antipsychotic-free patients with first-episode psychosis (FEP group). The study dates were November 2008 to November 2014. The dates of analysis were March to November 2017.

Main Outcomes And Measures: Gyrification-based structural covariance networks (connectomes) were constructed to quantify global integration, segregation, and small-worldness. Group differences in network measures were assessed using functional data analysis across a range of network densities. The extremely randomized trees algorithm with repeated 5-fold cross-validation was used to delineate ARMS-T individuals from ARMS-NT individuals. Permutation tests were conducted to assess the significance of classification performance measures.

Results: The 4 study groups comprised 161 participants with mean (SD) ages ranging from 24.0 (4.7) to 25.9 (5.7) years. Small-worldness was reduced in the ARMS-T and FEP groups and was associated with decreased integration and increased segregation in both groups (Hedges g range, 0.666-1.050). Using the connectome properties as features, a good classification performance was obtained (accuracy, 90.49%; balanced accuracy, 81.34%; positive predictive value, 84.47%; negative predictive value, 92.18%; sensitivity, 66.11%; specificity, 96.58%; and area under the curve, 88.30%).

Conclusions And Relevance: These findings suggest that there is poor integration in the coordinated development of cortical folding in patients who develop psychosis. These results further suggest that gyrification-based connectomes might be a promising means to generate systems-based measures from anatomical data to improve individual prediction of a transition to psychosis in CHR individuals.
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http://dx.doi.org/10.1001/jamapsychiatry.2018.0391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137528PMC
June 2018

Sexually dimorphic subcortical brain volumes in emerging psychosis.

Schizophr Res 2018 09 28;199:257-265. Epub 2018 Mar 28.

University of Basel Psychiatric Hospital, Department of Psychiatry, Basel, Switzerland. Electronic address:

Background: In schizophrenic psychoses, the normal sexual dimorphism of the brain has been shown to be disrupted or even reversed. Little is known, however, at what time point in emerging psychosis this occurs. We have therefore examined, if these alterations are already present in the at-risk mental state (ARMS) for psychosis and in first episode psychosis (FEP) patients.

Methods: Data from 65 ARMS (48 (73.8%) male; age=25.1±6.32) and 50 FEP (37 (74%) male; age=27±6.56) patients were compared to those of 70 healthy controls (HC; 27 (38.6%) male; age=26±4.97). Structural T1-weighted images were acquired using a 3 Tesla magnetic resonance imaging (MRI) scanner. Linear mixed effects models were used to investigate whether subcortical brain volumes are dependent on sex.

Results: We found men to have larger total brain volumes (p<0.001), and smaller bilateral caudate (p=0.008) and hippocampus volume (p<0.001) than women across all three groups. Older subjects had more GM and WM volume than younger subjects. No significant sex×group interaction was found.

Conclusions: In emerging psychosis there still seem to exist patterns of normal sexual dimorphism in total brain and caudate volume. The only structure affected by reversed sexual dimorphism was the hippocampus, with women showing larger volumes than men even in HC. Thus, we conclude that subcortical volumes may not be primarily affected by disrupted sexual dimorphism in emerging psychosis.
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http://dx.doi.org/10.1016/j.schres.2018.03.034DOI Listing
September 2018

Age-related brain structural alterations as an intermediate phenotype of psychosis.

J Psychiatry Neurosci 2017 Sep;42(5):307-319

From the F. Hoffmann-La Roche, Pharma Research Early Development, Roche Innovation Centre Basel, Basel, Switzerland (Dukart); the Department of Psychiatry (UPK), University of Basel, Basel, Switzerland (Dukart, Smieskova, Lenz, Schmidt, Walter, Huber, Riecher-Rössler, Lang, Borgwardt); the University Hospital of Psychiatry, University Hospital of Bern, Bern, Switzerland, and Specialized Early Psychosis Outpatient Service for Adolescents and Young Adults, Department of Psychiatry, Bruderholz, Switzerland (Simon); and the Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience IoPPN), King's College London, London, UK (Schmidt, Borgwardt).

Background: There is only limited agreement with respect to location, directionality and functional implications of brain structural alterations observed in patients with schizophrenia. Additionally, their link to occurrence of psychotic symptoms remains unclear. A viable way of addressing these questions is to examine populations in an at-risk mental state (ARMS) before the transition to psychosis.

Methods: We tested for structural brain alterations in individuals in an ARMS compared with healthy controls and patients with first-episode psychosis (FEP) using voxel-based morphometry and measures of cortical thickness. Furthermore, we evaluated if these alterations were modified by age and whether they were linked to the observed clinical symptoms.

Results: Our sample included 59 individuals with ARMS, 26 healthy controls and 59 patients with FEP. We found increased grey matter volume and cortical thickness in individuals with ARMS and a similar pattern of structural alterations in patients with FEP. We further found stronger age-related reductions in grey matter volume and cortical thickness in both patients with FEP and individuals with ARMS, linking these alterations to observed clinical symptoms.

Limitations: The ARMS group comprised subgroups with heterogeneous levels of psychosis risk and medication status. Furthermore, the cross-sectional nature of our study and the reduced number of older patients limit conclusions with respect to observed interactions with age.

Conclusion: Our findings on consistent structural alterations in individuals with ARMS and patients with FEP and their link to clinical symptoms have major implications for understanding their time of occurrence and relevance to psychotic symptoms. Interactions with age found for these alterations may explain the heterogeneity of findings reported in the literature.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573573PMC
http://dx.doi.org/10.1503/jpn.160179DOI Listing
September 2017

Altered Insular Function during Aberrant Salience Processing in Relation to the Severity of Psychotic Symptoms.

Front Psychiatry 2016 23;7:189. Epub 2016 Nov 23.

Department of Psychiatry (UPK), University of Basel , Basel , Switzerland.

There is strong evidence for abnormal salience processing in patients with psychotic experiences. In particular, there are indications that the degree of aberrant salience processing increases with the severity of positive symptoms. The aim of the present study was to elucidate this relationship by means of brain imaging. Functional magnetic resonance imaging was acquired to assess hemodynamic responses during the Salience Attribution Test, a paradigm for reaction time that measures aberrant salience to irrelevant stimulus features. We included 42 patients who were diagnosed as having a psychotic disorder and divided them into two groups according to the severity of their positive symptoms. Whole brain analysis was performed using Statistical Parametric Mapping. We found no significant behavioral differences with respect to task performance. Patients with more positive symptoms showed increased hemodynamic responses in the left insula corresponding to aberrant salience than in patients with less positive symptoms. In addition, left insula activation correlated negatively with cumulative antipsychotic medication. Aberrant salience processing in the insula may be increased in psychosis, depending on the severity of positive symptoms. This study indicates that clinically similar psychosis manifestations share the same functional characteristics. In addition, our results suggest that antipsychotic medication can modulate insular function.
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http://dx.doi.org/10.3389/fpsyt.2016.00189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120113PMC
November 2016

Hippocampal volume in subjects at clinical high-risk for psychosis: A systematic review and meta-analysis.

Neurosci Biobehav Rev 2016 Dec 20;71:680-690. Epub 2016 Oct 20.

Psychiatric University Clinics (UPK) Basel, Basel, Switzerland.

Several magnetic resonance imaging studies have reported reductions in hippocampal volume in patients with psychosis. It is unclear whether structural abnormalities predate illness onset. We conducted a detailed, systematic literature search for studies reporting hippocampal volume in subjects with clinical high-risk, compared to healthy controls. The overall sample size comprised 1429 subjects. Meta-analysis revealed no difference for left, but a small, albeit significant, difference for right hippocampal volume, such that clinical high-risk patients had slightly smaller hippocampal volume than healthy controls (g=0.24, p=0.0418). Meta-regression indicated a moderating effect of manual tracing approach, due to one outlying site. The small difference on the right side did not remain significant (g=0.14, 95%CI=[-0.03-0.32], p=0.11) after removal of this outlier. This meta-analysis suggests that there is no reduction in hippocampal volume before transition to psychosis and hippocampal volume cannot be used as a biomarker in clinical high-risk individuals.
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http://dx.doi.org/10.1016/j.neubiorev.2016.10.007DOI Listing
December 2016

Alterations in the hippocampus and thalamus in individuals at high risk for psychosis.

NPJ Schizophr 2016 28;2:16033. Epub 2016 Sep 28.

Department of Psychiatry, University of Basel, Basel, Switzerland; Medical Image Analysis Centre, University of Basel, Basel, Switzerland; Department of Psychosis Studies, King's College London, Institute of Psychiatry Psychology and Neuroscience, London, UK.

Reduction in hippocampal volume is a hallmark of schizophrenia and already present in the clinical high-risk state. Nevertheless, other subcortical structures, such as the thalamus, amygdala and pallidum can differentiate schizophrenia patients from controls. We studied the role of hippocampal and subcortical structures in clinical high-risk individuals from two cohorts. High-resolution T-weighted structural MRI brain scans of a total of 91 clinical high-risk individuals and 64 healthy controls were collected in two centers. The bilateral volume of the hippocampus, the thalamus, the caudate, the putamen, the pallidum, the amygdala, and the accumbens were automatically segmented using FSL-FIRST. A linear mixed-effects model and a prospective meta-analysis were applied to assess group-related volumetric differences. We report reduced hippocampal and thalamic volumes in clinical high-risk individuals compared to healthy controls. No volumetric alterations were detected for the caudate, the putamen, the pallidum, the amygdala, or the accumbens. Moreover, we found comparable medium effect sizes for group-related comparison of the thalamus in the two analytical methods. These findings underline the relevance of specific alterations in the hippocampal and subcortical volumes in the high-risk state. Further analyses may allow hippocampal and thalamic volumes to be used as biomarkers to predict psychosis.
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http://dx.doi.org/10.1038/npjschz.2016.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5040554PMC
September 2016

Structural Network Disorganization in Subjects at Clinical High Risk for Psychosis.

Schizophr Bull 2017 05;43(3):583-591

Department of Psychosis Studies, King's College London, Institute of Psychiatry, Psychology and Neuroscience, PO63 De Crespigny Park, London, UK.

Previous network studies in chronic schizophrenia patients revealed impaired structural organization of the brain's rich-club members, a set of highly interconnected hub regions that play an important integrative role for global brain communication. Moreover, impaired rich-club connectivity has also been found in unaffected siblings of schizophrenia patients, suggesting that abnormal rich-club connectivity is related to familiar, possibly reflecting genetic, vulnerability for schizophrenia. However, no study has yet investigated whether structural rich-club organization is also impaired in individuals with a clinical risk syndrome for psychosis. Diffusion tensor imaging and probabilistic tractography was used to construct structural whole-brain networks in 24 healthy controls and 24 subjects with an at-risk mental state (ARMS). Graph theory was applied to quantify the structural rich-club organization and global network properties. ARMS subjects revealed a significantly altered structural rich-club organization compared with the control group. The disruption of rich-club organization was associated with the severity of negative psychotic symptoms and led to an elevated level of modularity in ARMS subjects. This study shows that abnormal structural rich-club organization is already evident in clinical high-risk subjects for psychosis and further demonstrates the impact of rich-club disorganization on global network communication. Together with previous evidence in chronic schizophrenia patients and unaffected siblings, our findings suggest that abnormal structural rich-club organization may reflect an endophenotypic marker of psychosis.
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http://dx.doi.org/10.1093/schbul/sbw110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464048PMC
May 2017

Increased superior frontal gyrus activation during working memory processing in psychosis: Significant relation to cumulative antipsychotic medication and to negative symptoms.

Schizophr Res 2016 08 18;175(1-3):20-26. Epub 2016 Apr 18.

Psychiatric University Clinics (UPK) Basel, Wilhelm Klein-Strasse 27, Basel, Switzerland; Medical Image Analysis Center, University Hospital Basel, Switzerland; Neurobiology Laboratory for Brain Aging and Mental Health, Psychiatric Clinics of the University of Basel, Basel, Switzerland; Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Transfacultary Research Platform, Molecular & Cognitive Neuroscience, University of Basel, Basel, Switzerland. Electronic address:

Objectives: Impairment in working memory (WM) is a core symptom in schizophrenia. However, little is known about how clinical features influence functional brain activity specific to WM processing during the development of first-episode psychosis (FEP) to schizophrenia (SZ). We compared functional WM-specific brain activity in FEP and SZ patients, including the effects of the duration of illness, psychopathological factors and antipsychotic medication.

Methods: Cross-sectional study of male FEP (n=22) and SZ (n=20) patients performing an n-back task when undergoing functional magnetic resonance imaging (fMRI). Clinical features were collected by semi-structured interviews and medical records.

Results: The SZ group performed significantly worse than the FEP group in the 2-back condition. The SZ group also showed significantly higher activation in the left superior frontal gyrus in the 2-back versus 0-back condition (2-back>0-back). This frontal activation correlated positively with negative symptoms and with cumulative antipsychotic medication during the year before the fMRI examination. There were no significant correlations between activation and duration of illness.

Conclusion: There was greater frontal neural activation in SZ than in FEP. This indicated differences in WM processing, and was significantly related to cumulative antipsychotic exposure and negative symptoms, but not to the duration of illness.
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http://dx.doi.org/10.1016/j.schres.2016.03.033DOI Listing
August 2016

Brain Diffusion Changes in Emerging Psychosis and the Impact of State-Dependent Psychopathology.

Neurosignals 2015 19;23(1):71-83. Epub 2015 Dec 19.

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience King's College London, London, UK.

Background/aims: Previous diffusion tensor imaging (DTI) studies have shown microstructural changes in the brain white matter of at-risk mental state (ARMS) subjects for psychosis and patients with first-episode psychosis (FEP). However, only a few studies have been conducted in clinical high-risk samples and findings in both groups are inconsistent, in particular along the superior longitudinal fasciculus (SLF).

Methods: This DTI study used tract-based spatial statistics (TBSS) to compare fractional anisotropy (FA) and mean diffusivity (MD) between ARMS subjects, untreated and antipsychotic-treated FEP patients and healthy controls (HC) across the whole brain and the SLF.

Results: Compared to HC, ARMS and FEP patients showed increased FA and decreased MD in diverse regions across the whole brain including the SLF. FA in the SLF was positively correlated with positive psychotic symptoms in ARMS and FEP individuals. Furthermore, untreated but not treated FEP patients showed increased FA in the left inferior longitudinal fasciculus and right SLF.

Conclusion: This study revealed increased FA and decreased MD in early stages of psychosis in widespread white matter tracts including the SLF. Our findings further suggest that microstructural changes in the SLF are probably related to state-dependent psychopathology.
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http://dx.doi.org/10.1159/000442605DOI Listing
October 2016

Classifying individuals at high-risk for psychosis based on functional brain activity during working memory processing.

Neuroimage Clin 2015 30;9:555-63. Epub 2015 Sep 30.

Medical Image Analysis Centre, University Hospital Basel, Mittlere Strasse 83, Basel 4031, Switzerland ; Department of Psychiatry, University of Basel, Wilhelm Klein-Strasse, 27, Basel 4056, Switzerland ; Department of Psychosis Studies, King's College London, Institute of Psychiatry, De Crespigny Park 16, London SE58AF, UK.

The psychosis high-risk state is accompanied by alterations in functional brain activity during working memory processing. We used binary automatic pattern-classification to discriminate between the at-risk mental state (ARMS), first episode psychosis (FEP) and healthy controls (HCs) based on n-back WM-induced brain activity. Linear support vector machines and leave-one-out-cross-validation were applied to fMRI data of matched ARMS, FEP and HC (19 subjects/group). The HC and ARMS were correctly classified, with an accuracy of 76.2% (sensitivity 89.5%, specificity 63.2%, p = 0.01) using a verbal working memory network mask. Only 50% and 47.4% of individuals were classified correctly for HC vs. FEP (p = 0.46) or ARMS vs. FEP (p = 0.62), respectively. Without mask, accuracy was 65.8% for HC vs. ARMS (p = 0.03) and 65.8% for HC vs. FEP (p = 0.0047), and 57.9% for ARMS vs. FEP (p = 0.18). Regions in the medial frontal, paracingulate, cingulate, inferior frontal and superior frontal gyri, inferior and superior parietal lobules, and precuneus were particularly important for group separation. These results suggest that FEP and HC or FEP and ARMS cannot be accurately separated in small samples under these conditions. However, ARMS can be identified with very high sensitivity in comparison to HC. This might aid classification and help to predict transition in the ARMS.
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http://dx.doi.org/10.1016/j.nicl.2015.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625212PMC
July 2016

Hippocampal volume correlates with attenuated negative psychotic symptoms irrespective of antidepressant medication.

Neuroimage Clin 2015 29;8:230-7. Epub 2015 Apr 29.

Department of Psychiatry (UPK), Wilhelm Klein-Strasse 27, Basel, Switzerland ; Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK ; Medical Image Analysis Centre, University Hospital, Basel, Switzerland.

Background: Individuals with at-risk mental state for psychosis (ARMS) often suffer from depressive and anxiety symptoms, which are clinically similar to the negative symptomatology described for psychosis. Thus, many ARMS individuals are already being treated with antidepressant medication.

Objectives: To investigate clinical and structural differences between psychosis high-risk individuals with or without antidepressants.

Methods: We compared ARMS individuals currently receiving antidepressants (ARMS-AD; n = 18), ARMS individuals not receiving antidepressants (ARMS-nonAD; n = 31) and healthy subjects (HC; n = 24), in terms of brain structure abnormalities, using voxel-based morphometry. We also performed region of interest analysis for the hippocampus, anterior cingulate cortex, amygdala and precuneus.

Results: The ARMS-AD had higher 'depression' and lower 'motor hyperactivity' scores than the ARMS-nonAD. Compared to HC, there was significantly less GMV in the middle frontal gyrus in the whole ARMS cohort and in the superior frontal gyrus in the ARMS-AD subgroup. Compared to ARMS-nonAD, the ARMS-AD group showed more gray matter volume (GMV) in the left superior parietal lobe, but less GMV in the left hippocampus and the right precuneus. We found a significant negative correlation between attenuated negative symptoms and hippocampal volume in the whole ARMS cohort.

Conclusion: Reduced GMV in the hippocampus and precuneus is associated with short-term antidepressant medication and more severe depressive symptoms. Hippocampal volume is further negatively correlated with attenuated negative psychotic symptoms. Longitudinal studies are needed to distinguish whether hippocampal volume deficits in the ARMS are related to attenuated negative psychotic symptoms or to antidepressant action.
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http://dx.doi.org/10.1016/j.nicl.2015.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4473852PMC
April 2016

Modulation of motivational salience processing during the early stages of psychosis.

Schizophr Res 2015 Aug 18;166(1-3):17-23. Epub 2015 May 18.

Psychiatric University Clinics (UPK) Basel, Wilhelm Klein-Strasse 27, Basel, Switzerland; Medical Image Analysis Center, University Hospital Basel, Switzerland; Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK.

Background: Deficits in motivational salience processing have been related to psychotic symptoms and disturbances in dopaminergic neurotransmission. We aimed at exploring changes in salience processing and brain activity during different stages of psychosis and antipsychotic medication effect.

Methods: We used fMRI during the Salience Attribution Task to investigate hemodynamic differences between 19 healthy controls (HCs), 34 at-risk mental state (ARMS) individuals and 29 individuals with first-episode psychosis (FEP), including a subgroup of 17 FEP without antipsychotic medication (FEP-UM) and 12 FEP with antipsychotic medication (FEP-M). Motivational salience processing was operationalized by brain activity in response to high-probability rewarding cues (adaptive salience) and in response to low-probability rewarding cues (aberrant salience).

Results: Behaviorally, adaptive salience response was not accelerated in FEP, although they correctly distinguished between trials with low and high reward probability. In comparison to HC, ARMS exhibited a lower hemodynamic response during adaptive salience in the right inferior parietal lobule and FEP-UM in the left dorsal cingulate gyrus. The FEP-M group exhibited a lower adaptive salience response than HC in the right insula and than ARMS in the anterior cingulate gyrus. In unmedicated individuals, the severity of hallucinations and delusions correlated negatively with the insular- and anterior cingulate hemodynamic response during adaptive salience. We found no differences in aberrant salience processing associated with behavior or medication.

Conclusion: The changes in adaptive motivational salience processing during psychosis development reveal neurofunctional abnormalities in the somatosensory and premotor cortex. Antipsychotic medication seems to modify hemodynamic responses in the anterior cingulate and insula.
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http://dx.doi.org/10.1016/j.schres.2015.04.036DOI Listing
August 2015

Approaching a network connectivity-driven classification of the psychosis continuum: a selective review and suggestions for future research.

Front Hum Neurosci 2014 13;8:1047. Epub 2015 Jan 13.

Department of Psychiatry (UPK), University of Basel Basel, Switzerland ; Department of Psychosis Studies, Institute of Psychiatry, King's College London London, UK.

Brain changes in schizophrenia evolve along a dynamic trajectory, emerging before disease onset and proceeding with ongoing illness. Recent investigations have focused attention on functional brain interactions, with experimental imaging studies supporting the disconnection hypothesis of schizophrenia. These studies have revealed a broad spectrum of abnormalities in brain connectivity in patients, particularly for connections integrating the frontal cortex. A critical point is that brain connectivity abnormalities, including altered resting state connectivity within the fronto-parietal (FP) network, are already observed in non-help-seeking individuals with psychotic-like experiences. If we consider psychosis as a continuum, with individuals with psychotic-like experiences at the lower and psychotic patients at the upper ends, individuals with psychotic-like experiences represent a key population for investigating the validity of putative biomarkers underlying the onset of psychosis. This paper selectively addresses the role played by FP connectivity in the psychosis continuum, which includes patients with chronic psychosis, early psychosis, clinical high risk, genetic high risk, as well as the general population with psychotic experiences. We first discuss structural connectivity changes among the FP pathway in each domain in the psychosis continuum. This may provide a basis for us to gain an understanding of the subsequent changes in functional FP connectivity. We further indicate that abnormal FP connectivity may arise from glutamatergic disturbances of this pathway, in particular from abnormal NMDA receptor-mediated plasticity. In the second part of this paper we propose some concepts for further research on the use of network connectivity in the classification of the psychosis continuum. These concepts are consistent with recent efforts to enhance the role of data in driving the diagnosis of psychiatric spectrum diseases.
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http://dx.doi.org/10.3389/fnhum.2014.01047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292722PMC
January 2015

Approaching a network connectivity-driven classification of the psychosis continuum: a selective review and suggestions for future research.

Front Hum Neurosci 2014 13;8:1047. Epub 2015 Jan 13.

Department of Psychiatry (UPK), University of Basel Basel, Switzerland ; Department of Psychosis Studies, Institute of Psychiatry, King's College London London, UK.

Brain changes in schizophrenia evolve along a dynamic trajectory, emerging before disease onset and proceeding with ongoing illness. Recent investigations have focused attention on functional brain interactions, with experimental imaging studies supporting the disconnection hypothesis of schizophrenia. These studies have revealed a broad spectrum of abnormalities in brain connectivity in patients, particularly for connections integrating the frontal cortex. A critical point is that brain connectivity abnormalities, including altered resting state connectivity within the fronto-parietal (FP) network, are already observed in non-help-seeking individuals with psychotic-like experiences. If we consider psychosis as a continuum, with individuals with psychotic-like experiences at the lower and psychotic patients at the upper ends, individuals with psychotic-like experiences represent a key population for investigating the validity of putative biomarkers underlying the onset of psychosis. This paper selectively addresses the role played by FP connectivity in the psychosis continuum, which includes patients with chronic psychosis, early psychosis, clinical high risk, genetic high risk, as well as the general population with psychotic experiences. We first discuss structural connectivity changes among the FP pathway in each domain in the psychosis continuum. This may provide a basis for us to gain an understanding of the subsequent changes in functional FP connectivity. We further indicate that abnormal FP connectivity may arise from glutamatergic disturbances of this pathway, in particular from abnormal NMDA receptor-mediated plasticity. In the second part of this paper we propose some concepts for further research on the use of network connectivity in the classification of the psychosis continuum. These concepts are consistent with recent efforts to enhance the role of data in driving the diagnosis of psychiatric spectrum diseases.
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http://dx.doi.org/10.3389/fnhum.2014.01047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292722PMC
January 2015

Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations.

Schizophr Bull 2014 Jul 24;40(4):729-36. Epub 2014 May 24.

Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype.
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http://dx.doi.org/10.1093/schbul/sbu069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059449PMC
July 2014