Dissecting Heterogeneity in Functional Network Connectivity Aberrations in Antipsychotic Medication-Naïve First Episode Psychosis Patients – A Normative Modeling Study
Authors: Thukral Rhea A. , Maximo Jose O. , Lahti Adrienne C. , Rutherford Saige E. , Larson Jordan S. , Zhang Hui , Marquand Andre F. , Kraguljac Nina V. 
Published: August 2024

ABSTRACTImportanceWhile there is a general consensus that functional connectome pathology is a key mechanism underlying psychosis spectrum disorders, the literature is plagued with inconsistencies and translation into clinical practice is non-existent. This is perhaps because group-level findings may not be accurate reflections of pathology at the individual patient level.ObjectiveTo characterize inter-individual heterogeneity in functional networks and investigate if normative values can be leveraged to identify biologically less heterogeneous subgroups of patients.Design, Setting, and ParticipantsWe used data collected in a case-control study conducted at the University of Alabama at Birmingham (UAB). We recruited antipsychotic medication-naïve first-episode psychosis patients from UAB outpatient, inpatient, and emergency room settings.Main Outcome(s) and Measure(s)Individual-level patterns of deviations from a normative reference range in resting-state functional networks using the Yeo-17 atlas for parcellations.ResultsStatistical analyses included 108 medication-naïve first-episode psychosis patients. We found that there is a high level of inter-individual heterogeneity in resting-state network connectivity deviations from the normative reference range. Interestingly 48% of patients did not have any functional connectivity deviations, and no more than 11.1% of patients shared functional deviations between the same regions of interest. In apost hocanalysis, we grouped patients based on deviations into four theoretically possible groups. We discovered that all four groups do exist in our experimental data and showed that subgroups based on deviation profiles were significantly less heterogeneous compared to the overall group (positive deviation group: z= -2.88, p = 0.002; negative deviation group: z= -3.36, p<0.001).Conclusions and RelevanceOur findings experimentally demonstrate that there is a high level of inter-individual heterogeneity in resting-state network pathology in first-episode psychosis patients which support the idea that group-level findings are not accurate reflections of pathology at the individual level. We also demonstrated that normative functional connectivity deviations may have utility for identifying biologically less heterogeneous subgroups of patients, even though they are not distinguishable clinically. Our findings constitute a significant step towards making precision psychiatry a reality, where patients are selected for treatments based on their individual biological characteristics.KEY POINTSQuestionHow heterogeneous is individual-level resting-state functional network pathology in patients suffering from a first psychotic episode? Can normative reference values in functional network connectivity be leveraged to identify biologically more homogenous subgroups of patients?FindingsWe report that functional network pathology is highly heterogeneous, with no more than 11% of patients sharing functional deviations between the same regions of interest.MeaningNormative modeling is a tool that can map individual neurobiological differences and enables the classification of a clinically heterogenous patient group into subgroups that are neurobiologically less heterogenous.