Transition to Psychosis Associated With Prefrontal and Subcortical Dysfunction in Ultra High-Risk Individuals

Allen, Paul; Luigjes, Judy; Howes, Oliver; Egerton, Alice; Hirao, Kazuyuki; Valli, Isabel; Kambeitz, Joseph; Fusar‐Poli, Paolo; Broome, Matthew R.; McGuire, Philip

doi:10.1093/schbul/sbr194

Cited by 124 publications

(135 citation statements)

References 38 publications

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“…2 There are additional studies that have focused on the early changes in schizophrenia, including. 6,12,15,[29][30][31][32] Another important factor in the heterogeneity of the findings may be that many studies have focused on functional connectivity between regions specified a priori, rather than adopting a whole-brain analysis. Consequently the reported findings are influenced by choice of the regions of interest, and may not cover the most significantly different areas that may reflect the core pathological changes in schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Brain-Wide Analysis of Functional Connectivity in First-Episode and Chronic Stages of Schizophrenia

Wang

Zhang

et al. 2016

SCHBUL

130

132

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Published reports of functional abnormalities in schizophrenia remain divergent due to lack of staging point-of-view and whole-brain analysis. To identify key functional-connectivity differences of first-episode (FE) and chronic patients from controls using resting-state functional MRI, and determine changes that are specifically associated with disease onset, a clinical staging model is adopted. We analyze functionalconnectivity differences in prodromal, FE (mostly drug naïve), and chronic patients from their matched controls from 6 independent datasets involving a total of 789 participants (343 patients). Brain-wide functional-connectivity analysis was performed in different datasets and the results from the datasets of the same stage were then integrated by meta-analysis, with Bonferroni correction for multiple comparisons. Prodromal patients differed from controls in their pattern of functionalconnectivity involving the inferior frontal gyri (Broca's area). In FE patients, 90% of the functional-connectivity changes involved the frontal lobes, mostly the inferior frontal gyrus including Broca's area, and these changes were correlated with delusions/blunted affect. For chronic patients, functionalconnectivity differences extended to wider areas of the brain, including reduced thalamo-frontal connectivity, and increased thalamo-temporal and thalamo-sensorimoter connectivity that were correlated with the positive, negative, and general symptoms, respectively. Thalamic changes became prominent at the chronic stage. These results provide evidence for distinct patterns of functional-dysconnectivity across FE and chronic stages of schizophrenia. Importantly, abnormalities in the frontal language networks appear early, at the time of disease onset. The identification of stage-specific pathological processes may help to understand the disease course of schizophrenia and identify neurobiological markers crucial for early diagnosis.

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Section: Introductionmentioning

confidence: 99%

Brain-Wide Analysis of Functional Connectivity in First-Episode and Chronic Stages of Schizophrenia

Wang

Zhang

et al. 2016

SCHBUL

130

132

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“…. Neuroimaging studies of the UHR population have implicated increased functional abnormalities in the prefrontal cortex (PFC), midbrain and medial temporal lobe (MTL) 15 , structural abnormalities involving the PFC 16 17 and MTL…”

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confidence: 99%

“…, elevated dopaminergic activity in the striatum 19 and midbrain 15 , and abnormalities in levels of glutamate 20 and GABA 21 . In general, these abnormalities are qualitatively similar but less severe than those seen in patients with psychotic disorders 5 .…”

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confidence: 99%

Using neuroimaging to help predict the onset of psychosis

et al. 2017

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The aim of this review is to assess the potential for neuroimaging measures to facilitate prediction of the onset of psychosis. Research in this field has mainly involved people at 'ultra-high risk' (UHR) of psychosis, who have a very high risk of developing a psychotic disorder within a few years of presentation to mental health services.The review details the key findings and developments in this area to date, and examines the methodological and logistical challenges associated with making A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT2 predictions in an individual subject in a clinical setting. Key wordsPsychosis prediction; Ultra High-Risk of psychosis; machine learning; Support Vector Machines; multimodal neuroimaging; multicentre neuroimaging studies; graph analysis Psychosis prediction and the ultra high-risk statePsychosis describes a syndrome that includes symptoms such as hallucinations, delusions, disorganised thought, and catatonia Criteria for UHR status include attenuated psychotic symptoms and / or a brief limited intermittent psychotic episode and / or a genetically determined vulnerability, alongside deterioration in social and occupational functioning 7 8 . UHR status comes A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT3 with the caveat that those who meet UHR status are selectively those who have come into contact with clinical services. This review uses the term UHR throughout.The UHR population is strikingly heterogeneous in terms of clinical outcomes.Follow-up studies 9 10 suggest that 7 years after clinical presentation, approximately a third of UHR subjects will have developed a psychotic disorder, with most transitions occurring in the first 2 years 11. Most of those who do not develop a psychotic disorder will have persistent attenuated symptoms and / or have developed another mental health disorder, whilst 14% will have recovered (see figure 1).Clinical intervention in the UHR group may reduce the likelihood of the onset of a psychotic disorder 12. However, as most UHR subjects do not develop a psychotic disorder, providing preventative treatment to all of those at risk is clinically inefficient. Identifying biomarkers that could be used to stratify the UHR group according to clinical outcome would enable the selective delivery of preventative interventions to the subgroup that would benefit the most.It is difficult to predict clinical outcomes in an UHR subject on the basis of their clinical features at presentation. Although the clinical assessment at presentation has good diagnostic validity for ruling out a future psychotic disorder (meta analytical sensitivity of UHR assessment = 0.96) 13, it has only a modest ability to rule in a future psychotic disorder (meta-analytical specificity of UHR assessment = 0.47) 13.There is thus a need to find other forms of assessment that can improve the specificity of psychosis prediction. Fusar-Poli et al. (2015) 14 and based on data by Lin et al. (2011) 10 . A C C E P T E D M A N U S C R I P T ACCEPTED MANU...

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“…Our hypothesis that such abnormalities would be represented in conflict-related activity of the DLPFC and striatum was further grounded in (1) increasing evidence of abnormal functioning of frontostriatal loops in the prodromal phase of psychotic illness (Allen et al, 2012;Dandash et (2) prior studies implicating frontostriatal circuits in cognitive control (Marsh et al, 2009;Kerns, 2006;Rubia et al, 2006); and (3) studies pointing to the selective vulnerability of the dopaminergic system in these circuits during adolescent development (Naneix et al, 2013;Matthews et al, 2013).…”

Section: Introductionmentioning

confidence: 97%

Neural Dysfunction in Cognitive Control Circuits in Persons at Clinical High-Risk for Psychosis

Colibazzi

Horga

Wang

et al. 2015

Neuropsychopharmacol

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Cognitive control, a set of functions that develop throughout adolescence, is important in the pathogenesis of psychotic disorders. Whether cognitive control has a role in conferring vulnerability for the development of psychotic illness is still unknown. The aim of this study was to investigate the neural systems supporting cognitive control in individuals deemed to be potentially prodromal for psychotic illness. We recruited 56 participants at clinical high-risk (CHR) for psychosis based on the Structured Interview for Psychosis-Risk Syndromes (SIPS) and 49 healthy controls. Twelve of the CHR participants eventually developed psychosis. We compared functional magnetic resonance imaging (fMRI) BOLD signal during the performance of the Simon task. We tested for differences between CHR individuals and controls in conflict-related functional activity. In the CHR group when compared with controls, we detected smaller conflictrelated activations in several cortical areas, including the Dorsolateral Prefrontal Cortex (DLPFC). Furthermore, conflict-related activations in the DLPFC of those CHR individuals who ultimately developed psychosis (CHR converters) were smaller than in non-converters (CHR non-converters). Higher levels of conflict-related activation were associated with better social and role outcome. Risk for psychosis was associated at the neural level with reduced conflict-related brain activity. This neural phenotype appears correlated within the DLPFC with the development of psychosis and with functional outcome.

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Transition to Psychosis Associated With Prefrontal and Subcortical Dysfunction in Ultra High-Risk Individuals

Cited by 124 publications

References 38 publications

Brain-Wide Analysis of Functional Connectivity in First-Episode and Chronic Stages of Schizophrenia

Brain-Wide Analysis of Functional Connectivity in First-Episode and Chronic Stages of Schizophrenia

Using neuroimaging to help predict the onset of psychosis

Neural Dysfunction in Cognitive Control Circuits in Persons at Clinical High-Risk for Psychosis

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