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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.

SUBMITTER: Diez I

PROVIDER: S-EPMC7423688 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Heterogeneity in attention-deficit/hyperactivity disorder (ADHD), with complex interactive operations of genetic and environmental factors, is expressed in a variety of disorder manifestations: severity, co-morbidities of symptoms, and the effects of genes on phenotypes. Neurodevelopmental influences of genomic imprinting have set the stage for the structural-physiological variations that modulate the cognitive, affective, and pathophysiological domains of ADHD. The relative contributions of genetic and environmental factors provide rapidly proliferating insights into the developmental trajectory of the condition, both structurally and functionally. Parent-of-origin effects seem to support the notion that genetic risks for disease process debut often interact with the social environment, i.e., the parental environment in infants and young children. The notion of endophenotypes, markers of an underlying liability to the disorder, may facilitate detection of genetic risks relative to a complex clinical disorder. Simple genetic association has proven insufficient to explain the spectrum of ADHD. At a primary level of analysis, the consideration of epigenetic regulation of brain signalling mechanisms, dopamine, serotonin, and noradrenaline is examined. Neurotrophic factors that participate in the neurogenesis, survival, and functional maintenance of brain systems, are involved in neuroplasticity alterations underlying brain disorders, and are implicated in the genetic predisposition to ADHD, but not obviously, nor in a simple or straightforward fashion. In the context of intervention, genetic linkage studies of ADHD pharmacological intervention have demonstrated that associations have fitted the "drug response phenotype," rather than the disorder diagnosis. Despite conflicting evidence for the existence, or not, of genetic associations between disorder diagnosis and genes regulating the structure and function of neurotransmitters and brain-derived neurotrophic factor (BDNF), associations between symptoms-profiles endophenotypes and single nucleotide polymorphisms appear reassuring.

Project description:BackgroundPast research has examined the health outcomes of early sexual trauma in reproductive age women, but little is known about potential long-term effects in older age.ObjectiveTo examine associations between early life sexual trauma and later life sexual/genitourinary dysfunction and general functional disability in women.DesignCross-sectional analysis of nationally representative observational data from the National Social Life, Health, and Aging Project (2010-2011) PARTICIPANTS: One thousand seven hundred forty-five US women aged ≥ 50 years MAIN MEASURES: Two forms of early life sexual trauma (childhood sexual abuse and unwanted first sexual experience), sexual/genitourinary dysfunction (pain during sex, lack of pleasure during sex, urinary incontinence, other urinary symptoms), and general functional disability (difficulty performing 7 activities of daily living (ADLs) or 8 instrumental activities of daily living (IADLs)), assessed by interview and questionnaire.Key resultsOf 1745 women, 11% reported a history of childhood sexual abuse and 39% an unwanted first sexual experience. Childhood sexual abuse was associated with later life sexual/genitourinary dysfunction (pain during sex [OR 1.9, 95% CI 1.1-3.3], other urinary problems [OR 1.9, 95% CI 1.2-3.1]), and difficulty with multiple ADLs/IADLs (walking across the room [OR 1.9, 95% CI 1.2-3.1], getting in or out of bed [OR 2.0, 95% CI 1.2-3.3], bathing [OR 2.0, 95% CI 1.2-3.5], prepping meals [OR 2.4, 95% CI 1.5-3.8], shopping for food [OR 1.6, 95% CI 1.0-2.4], and completing light work [OR 1.6, 95% CI 1.0-2.4]), after adjusting for age, race, and education. Unwanted first sexual experience was associated with later life lack of pleasure with sex (OR 1.7, 95% CI 1.1-2.5) and difficulty with ADLs/IADLs (walking one block [OR 1.5, 95% CI 1.1-2.1], completing light work [OR 1.6, 95% CI 1.1-2.1]) in adjusted analyses.ConclusionsEarly sexual trauma may be an under-recognized marker of risk of aging-related functional decline in women. Findings underline the importance of providing trauma-informed care for women across the aging spectrum.

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

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