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. 2023 Dec 2;13(1):373.
doi: 10.1038/s41398-023-02661-6.

Extreme deviations from the normative model reveal cortical heterogeneity and associations with negative symptom severity in first-episode psychosis from the OPTiMiSE and GAP studies

Amanda Worker  1 , Pierre Berthert  2   3 , Andrew J Lawrence  1 , Seyed Mostafa Kia  4   5   6 , Celso Arango  7 , Richard Dinga  4   5 , Silvana Galderisi  8 , Birte Glenthøj  9   10 , René S Kahn  11 , Anoushka Leslie  12 , Robin M Murray  13 , Carmine M Pariante  14   15 , Christos Pantelis  16 , Mark Weiser  17   18 , Inge Winter-van Rossum  11   19 , Philip McGuire  13 , Paola Dazzan #  1   14 , Andre F Marquand #  20   21
Affiliations

Extreme deviations from the normative model reveal cortical heterogeneity and associations with negative symptom severity in first-episode psychosis from the OPTiMiSE and GAP studies

Amanda Worker et al. Transl Psychiatry. .

Abstract

There is currently no quantifiable method to predict long-term clinical outcomes in patients presenting with a first episode of psychosis. A major barrier to developing useful markers for this is biological heterogeneity, where many different pathological mechanisms may underly the same set of symptoms in different individuals. Normative modelling has been used to quantify this heterogeneity in established psychotic disorders by identifying regions of the cortex which are thinner than expected based on a normative healthy population range. These brain atypicalities are measured at the individual level and therefore potentially useful in a clinical setting. However, it is still unclear whether alterations in individual brain structure can be detected at the time of the first psychotic episode, and whether they are associated with subsequent clinical outcomes. We applied normative modelling of cortical thickness to a sample of first-episode psychosis patients, with the aim of quantifying heterogeneity and to use any pattern of cortical atypicality to predict symptoms and response to antipsychotic medication at timepoints from baseline up to 95 weeks (median follow-ups = 4). T1-weighted brain magnetic resonance images from the GAP and OPTiMiSE samples were processed with Freesurfer V6.0.0 yielding 148 cortical thickness features. An existing normative model of cortical thickness (n = 37,126) was adapted to integrate data from each clinical site and account for effects of gender and site. Our test sample consisted of control participants (n = 149, mean age = 26, SD = 6.7) and patient data (n = 295, mean age = 26, SD = 6.7), this sample was used for estimating deviations from the normative model and subsequent statistical analysis. For each individual, the 148 cortical thickness features were mapped to centiles of the normative distribution and converted to z-scores reflecting the distance from the population mean. Individual cortical thickness metrics of +/- 2.6 standard deviations from the mean were considered extreme deviations from the norm. We found that no more than 6.4% of psychosis patients had extreme deviations in a single brain region (regional overlap) demonstrating a high degree of heterogeneity. Mann-Whitney U tests were run on z-scores for each region and significantly lower z-scores were observed in FEP patients in the frontal, temporal, parietal and occipital lobes. Finally, linear mixed-effects modelling showed that negative deviations in cortical thickness in parietal and temporal regions at baseline are related to more severe negative symptoms over the medium-term. This study shows that even at the early stage of symptom onset normative modelling provides a framework to identify individualised cortical markers which can be used for early personalised intervention and stratification.

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Conflict of interest statement

Dr. Glenthøj has been the leader of a Lundbeck Foundation Centre of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS) (January 2009 – December 2021), which was partially financed by an independent grant from the Lundbeck Foundation based on international review and partially financed by the Mental Health Services in the Capital Region of Denmark, the University of Copenhagen, and other foundations. All grants are the property of the Mental Health Services in the Capital Region of Denmark and administrated by them. She has no other conflicts to disclose. Dr. Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda.

Figures

Fig. 1
Fig. 1. Participant inclusion workflow.
Flowchart showing final sample selection.
Fig. 2
Fig. 2. Regional overlap of extreme negative deviations from the normative models in first episode psychosis patients relative to controls.
Percentage overlap, in first-episode psychosis patients and control participants, of extreme negative deviations from the normative model for each brain region (Destrieux atlas) (p < 0.01).
Fig. 3
Fig. 3. Regional overlap of extreme positive deviations from the normative model in first episode psychosis patients relative to controls.
Percentage overlap, in first-episode psychosis patients and control participants, of extreme positive deviations from the normative model for each brain region (Destrieux atlas) (p < 0.01).
Fig. 4
Fig. 4. Regional distribution of differences in median deviations in patients relative to controls.
Results from regional Mann-Witney U tests comparing median z-score between FEP patients and healthy participants. a regional standardised effect sizes overlaid on glass brain, b violin plots displaying regional z-score distributions and significant regions after Benjamin-Hochberg correction for multiple comparisons (p < 0.05).
Fig. 5
Fig. 5. Prediction of symptoms at medium term follow-up from deviations from the normative models at baseline.
Results from the linear mixed effects model predicting medium-term negative symptoms from weeks from baseline and regional z-scores. Significant regions are overlaid on a glass brain (FDR corrected).
See this image and copyright information in PMC

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