Early-life trauma endophenotypes and brain circuit-gene expression relationships in functional neurological (conversion) disorder
Open accessAbstract
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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All of these ACEs implicate stress-system activation-and priming-from early in life, via a complex web of processes.
“All of these ACEs implicate stress-system activation—and priming—from early in life, via a complex web of processes (see Chung et al. for a comprehensive discussion pertaining to FND) [38,41,116].”
From Illness-Promoting Psychological Processes in Children and Adolescents with Functional Neurological Disorder (2023) · cites this paper as [116]
The Introduction links early-life maltreatment to altered brain circuits and discusses genes involved in stress-response systems. The Discussion suggests stress-related neuroplasticity following physical abuse in patients with FND. These passages support a connection between some childhood adversity and later stress-related changes, but do not establish stress-system activation and priming from early life for all the ACEs in the claim. (LLM, conf=0.84)
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Paredes-Echeverri, S., Maggio, J., Bègue, I., Pick, S., Nicholson, T. R., & Perez, D. L. (2022) · The Journal of Neuropsychiatry and Clinical Neurosciences · doi:10.1176/appi.neuropsych.21010025 · Cited by 62 · see citing works
Self-citationIdentification of biopsychological trait markers in functional neurological disorders
Weber, S., Bühler, J., Vanini, G., Loukas, S., Bruckmaier, R., & Aybek, S. (2023) · Brain · doi:10.1093/brain/awac442 · Cited by 63 · see citing works
Sojka, P., Diez, I., Bareš, M., & Perez, D. L. (2021) · Human Brain Mapping · doi:10.1002/hbm.25304 · Cited by 43 · see citing works
Self-citationAsadi-Pooya, A. A., Brigo, F., Kozlowska, K., Perez, D. L., Pretorius, C., Sawchuk, T., Saxena, A., Tolchin, B., & Valente, K. D. (2021) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2021.107903 · Cited by 40 · see citing works
Self-citationRai, S., Foster, S., Griffiths, K. R., Breukelaar, I. A., Kozlowska, K., & Korgaonkar, M. S. (2022) · NeuroImage Clinical · doi:10.1016/j.nicl.2022.103110 · Cited by 35 · see citing works
Activation of Functional Brain Networks in Children With Psychogenic Non-epileptic Seizures
Radmanesh, M., Jalili, M., & Kozlowska, K. (2020) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2020.00339 · Cited by 35 · see citing works
Chung, J., Mukerji, S., & Kozlowska, K. (2023) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/00048674221082520 · Cited by 27 · see citing works
Jungilligens, J., Wellmer, J., Kowoll, A., Schlegel, U., Axmacher, N., & Popkirov, S. (2021) · Seizure · doi:10.1016/j.seizure.2020.11.021 · Cited by 25 · see citing works
A dimensional approach to functional movement disorders: Heresy or opportunity
Spagnolo, P. A., Garvey, M., & Hallett, M. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.04.005 · Cited by 23 · see citing works
Fobian, A. D., & Szaflarski, J. P. (2021) · Epilepsy & Behavior Reports · doi:10.1016/j.ebr.2021.100479 · Cited by 21 · see citing works
Kozlowska, K., Schollar-Root, O., Savage, B., Hawkes, C., Chudleigh, C., Raghunandan, J., Scher, S., & Helgeland, H. (2023) · Children · doi:10.3390/children10111724 · Cited by 14 · see citing works
“All of these ACEs implicate stress-system activation—and priming—from early in life, via a complex web of processes (see Chung et al. for a comprehensive discussion pertaining to FND) [38,41,116].”
Background
- Authors
- Diez, I., Larson, A. G., Nakhate, V., Dunn, E. C., Fricchione, G. L., Nicholson, T. R., Sepulcre, J., & Perez, D. L.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- King's College London (GB)
- Corresponding author
- Perez, David L.
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2020-02-12
- Volume
- 26
- Issue
- 8
- Pages
- 3817-3828
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC7423688
- OpenAlex
- W3006600978
- Semantic Scholar
- 6f466382621f0e684a86bec6fd1cd251a7877149
- Cited by
- 100
- References
- 76
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 18 · 2023: 11 · 2022: 23 · 2021: 13 · 2020: 9
- FWCI
- 10.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- TECNALIA Publications (Fundación TECNALIA Research & Innovation) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Funders
- Sidney R. Baer, Jr. Foundation
- Massachusetts General Hospital
- National Institute for Health and Care Research (CS-2014-14-016)
- National Institutes of Health (1s10rr023043-01)
- National Institute of Mental Health (K23MH111983)
- National Center for Research Resources (S10-RR-023043)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Psychosomatic Disorders and Their Treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Keywords
- conversion disorder, child physical abuse, physical neglect, endophenotypes, resting-state functional connectivity, brain network architecture, gene expression, Allen Human Brain Atlas, amygdala, insula, sensorimotor cortex, hemispheric lateralization, neuronal morphogenesis, synaptic transmission, locomotory behavior, brain development
- MeSH terms
- Brain, Child, Conversion Disorder, Humans, Magnetic Resonance Imaging, Gene Expression, Endophenotypes, Neuroimaging
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