Striatal connectopic maps link to functional domains across psychiatric disorders

Abstract

Transdiagnostic approaches to psychiatry have significant potential in overcoming the limitations of conventional diagnostic paradigms. However, while frameworks such as the Research Domain Criteria have garnered significant enthusiasm among researchers and clinicians from a theoretical angle, examples of how such an approach might translate in practice to understand the biological mechanisms underlying complex patterns of behaviors in realistic and heterogeneous populations have been sparse. In a richly phenotyped clinical sample (n = 186) specifically designed to capture the complex nature of heterogeneity and comorbidity within- and between stress- and neurodevelopmental disorders, we use exploratory factor analysis on a wide range of clinical questionnaires to identify four stable functional domains that transcend diagnosis and relate to negative valence, cognition, social functioning and inhibition/arousal before replicating them in an independent dataset (n = 188). We then use connectopic mapping to map inter-individual variation in fine-grained topographical organization of functional connectivity in the striatum—a central hub in motor, cognitive, affective and reward-related brain circuits—and use multivariate machine learning (canonical correlation analysis) to show that these individualized topographic representations predict transdiagnostic functional domains out of sample (r = 0.20, p = 0.026). We propose that investigating psychiatric symptoms across disorders is a promising path to linking them to underlying biology, and can help bridge the gap between neuroscience and clinical psychiatry.

Multi‐polygenic scores in psychiatry: From disorder specific to transdiagnostic perspectives

“…Consistent with the previous factor analysis results from a smaller overlapping sample (Mulders et al, 2022), we observed four transdiagnostic domains (i.e., negative valence, social, and arousal/regulatory systems) among a broad battery of psychiatric, personality, and psychological assessments, which together explained up to 81% of individuals' subjective experience of their functioning and disability. Importantly, the finding that DEP‐PRS was selectively linked to the functioning of the negative valence system points to the direction of a shared domain of functioning that underlies its associations with multiple disorders.…”

“…Converging a wide array of psychopathology assessments into cross‐disorder constructs, the factor analysis of 31 (sub)scales of psychiatric, personality, and psychological traits measured in MIND‐SET (Table S3) yielded four factors, which together explained 67.3% of the variance (KMO = 0.948, Bartlett's test p < 0.001). These four factors matched the previous finding using a subsample of the same cohort with a highly similar component matrix (Mulders et al, 2022), in which the interpretation of the factors roughly corresponded to previously defined RDoC domains (Cuthbert & Insel, 2013; Kozak & Cuthbert, 2016; Figure 3a): the first factor related to negative thinking, emotions, and poor self‐concept across instruments (i.e., RDoC negative valence systems); the second factor summarized difficulties in social functioning (i.e., RDoC social processes); the third factor described cognitive abilities (i.e., RDoC cognitive systems); the last factor related to the ability in regulation and inhibition (i.e., RDoC arousal/regulatory systems). To evaluate the relevance of the derived factors to individuals' functioning and disabilities, we assessed their relationship with self‐rated quality of life measured using OQ‐45 and WHODAS 2.0 scales.…”

“…Converging a wide array of psychopathology assessments into crossdisorder constructs, the factor analysis of 31 (sub)scales of psychiatric, personality, and psychological traits measured in MIND-SET (Table S3) yielded four factors, which together explained 67.3% of the variance (KMO = 0.948, Bartlett's test p < 0.001). These four factors matched the previous finding using a subsample of the same cohort with a highly similar component matrix (Mulders et al, 2022), in which the interpretation of the factors roughly corresponded to previously defined RDoC domains (Cuthbert & Insel, 2013;Kozak & Cuthbert, 2016; Figure 3a): S11); together, they explained the outcomes with an adjusted R 2 of 0.81 and 0.65, respectively. Different disorder categories were represented by distinct factor profiles, which resembled their clinical presentations (Figure S5).…”

“…To derive transdiagnostic dimensions measured by the scales in Table S3, exploratory factor analysis (maximum likelihood estimation, oblique rotation) was performed based on 387 participants (327 patients) who had completed the entire test battery. The same analysis was previously conducted in a subset of participants from the same cohort, as described before (Mulders et al, 2022). A four‐factor solution outperformed the simulated eigenvectors in the parallel analysis (Figure S1; Horn, 1965), which was in line with the scree‐plot.…”

Unpacking the functional heterogeneity of the Emotional Face Matching Task: a normative modelling approach

“…The clinical relevance of our models can also be tested in the context of transdiagnostic symptom domains; a conceptualisation of mental functioning that transcends diagnostic boundaries and allows for nuanced brain-behaviour interpretations. As such, for 217 (of our 236) patients for whom all required data was available, we repeated a previously validated factor analysis method (performed in SPSS v24.0, oblique rotation) [26] to obtain individual factor loadings on 4 functional domains: (1) negative valence, (2) cognitive function, (3) social processes and (4) arousal/inhibition.…”