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Early-life trauma endophenotypes and brain circuit–gene expression relationships in functional neurological (conversion) disorder

Abstract

Functional neurological (conversion) disorder (FND) is a neuropsychiatric condition whereby individuals present with sensorimotor symptoms incompatible with other neurological disorders. Early-life maltreatment (ELM) is a risk factor for developing FND, yet few studies have investigated brain network–trauma relationships in this population. In this neuroimaging–gene expression study, we used two graph theory approaches to elucidate ELM subtype effects on resting-state functional connectivity architecture in 30 patients with motor FND. Twenty-one individuals with comparable depression, anxiety, and ELM scores were used as psychiatric controls. Thereafter, we compared trauma endophenotypes in FND with regional differences in transcriptional gene expression as measured by the Allen Human Brain Atlas (AHBA). In FND patients only, we found that early-life physical abuse severity, and to a lesser extent physical neglect, correlated with corticolimbic weighted-degree functional connectivity. Connectivity profiles influenced by physical abuse occurred in limbic (amygdalar–hippocampal), paralimbic (cingulo-insular and ventromedial prefrontal), and cognitive control (ventrolateral prefrontal) areas, as well as in sensorimotor and visual cortices. These findings held adjusting for individual differences in depression/anxiety, PTSD, and motor phenotypes. In FND, physical abuse also correlated with amygdala and insula coupling to motor cortices. In exploratory analyses, physical abuse correlated connectivity maps overlapped with the AHBA spatial expression of three gene clusters: (i) neuronal morphogenesis and synaptic transmission genes in limbic/paralimbic areas; (ii) locomotory behavior and neuronal generation genes in left-lateralized structures; and (iii) nervous system development and cell motility genes in right-lateralized structures. These circuit-specific architectural profiles related to individual differences in childhood physical abuse burden advance our understanding of the pathophysiology of FND.

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Fig. 1: Physical abuse and physical neglect burden influence the corticolimbic architecture in patients with functional neurological disorder (FND).
Fig. 2: The magnitude of early-life physical abuse correlates with amygdala—precentral gyrus and insula—precentral gyrus functional connectivity strength in patients with functional neurological disorder.
Fig. 3: Clustering of gene expression profiles associated with physical abuse correlated weighted-degree functional connectivity maps in patients with functional neurological disorder.
Fig. 4: Spatial similarity between physical abuse correlated weighted-degree functional connectivity maps in patients with functional neurological disorder (FND) and regional brain-derived neurotrophic factor (BDNF) expression.

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Funding

ID was supported by postdoctoral fellowship program from the Basque Country Government. DLP was funded by the National Institute of Mental Health Grant K23MH111983-03, Massachusetts General Hospital Physician-Scientist Development Award and the Sidney R. Baer Jr. Foundation. This study was also supported by the NIH shared instrument grant S10RR023043.

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Correspondence to David L. Perez.

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TRN is funded by a UK National Institute for Health Research (NIHR) Clinician Scientist Fellowship. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. DLP has received honoraria for continuing medical education lectures in functional neurological disorder.

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Diez, I., Larson, A.G., Nakhate, V. et al. Early-life trauma endophenotypes and brain circuit–gene expression relationships in functional neurological (conversion) disorder. Mol Psychiatry 26, 3817–3828 (2021). https://doi.org/10.1038/s41380-020-0665-0

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