Identification of biopsychological trait markers in functional neurological disorders
Open accessAbstract
Stress is a well-known risk factor to develop a functional neurological disorder, a frequent neuropsychiatric medical condition in which patients experience a variety of disabling neurological symptoms. Only little is known about biological stress regulation, and how it interacts with predisposing biological and psychosocial risk factors. Dysregulation of the hypothalamic-pituitary-adrenal axis in patients with functional neurological disorders has been postulated, but its relationship to preceding psychological trauma and brain anatomical changes remains to be elucidated. We set out to study the hypothalamic-pituitary-adrenal axis analysing the cortisol awakening response and diurnal baseline cortisol in 86 patients with mixed functional neurological symptoms compared to 76 healthy controls. We then examined the association between cortisol regulation and the severity and duration of traumatic life events. Finally, we analysed volumetric brain alterations in brain regions particularly sensitive to psychosocial stress, acting on the assumption of the neurotoxic effect of prolonged cortisol exposure. Overall, patients had a significantly flatter cortisol awakening response (P < 0.001) and reported longer (P = 0.01) and more severe (P < 0.001) emotional neglect as compared to healthy controls. Moreover, volumes of the bilateral amygdala and hippocampus were found to be reduced in patients. Using a partial least squares correlation, we found that in patients, emotional neglect plays a role in the multivariate pattern between trauma history and hypothalamic-pituitary-adrenal axis dysfunction, while cortisol did not relate to reduced brain volumes. This suggests that psychological stress acts as a precipitating psychosocial risk factor, whereas a reduced brain volume rather represents a biological predisposing trait marker for the disorder. Contrarily, an inverse relationship between brain volume and cortisol was found in healthy controls, representing a potential neurotoxic effect of cortisol. These findings support the theory of reduced subcortical volumes representing a predisposing trait factor in functional neurological disorders, rather than a state effect of the illness. In summary, this study supports a stress-diathesis model for functional neurological disorders and showed an association between different attributes of trauma history and abnormalities in hypothalamus-pituitary-adrenal axis function. Moreover, we suggest that reduced hippocampal and amygdalar volumes represent a biological 'trait marker' for functional neurological disorder patients, which might contribute to a reduced resilience to stress.
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Taken together, these data suggest that ACEs are broad ranging and that activation and priming of the stress system-leading to subsequent vulnerability to FND-take place across the lifespan.
“Taken together, these data suggest that ACEs are broad ranging and that activation and priming of the stress system—leading to subsequent vulnerability to FND—take place across the lifespan [37,38,41,43,119].”
From Illness-Promoting Psychological Processes in Children and Adolescents with Functional Neurological Disorder (2023) · cites this paper as [43]
The Discussion (page unavailable) links early, prolonged emotional neglect in FND to possible long-term HPA-axis sensitization, and the Results > Trauma report several types of childhood adversity and traumatic events in adulthood. The paper does not establish that stress-system activation or priming leading to FND vulnerability takes place across the lifespan; its proposed mechanism is qualified as possible, and the Conclusion says a causal relationship remains to be discovered. (LLM, conf=0.84)
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Kanaan, R., & Craig, T. (2019) · Psychological Medicine · doi:10.1017/s0033291719000990 · Cited by 20 · see citing works
Vulnerability to psychogenic non-epileptic seizures is linked to low neuropeptide Y levels
Winterdahl, M., Miani, A., Vercoe, M., Ciovica, A., Uber-Zak, L., Rask, C. U., & Zak, P. J. (2017) · Stress · doi:10.1080/10253890.2017.1378638 · Cited by 19 · see citing works
The Role of Early Stressors in Child Health and Mental Health Outcomes
Dozier, M., & Peloso, E. D. (2006) · Archives of Pediatrics and Adolescent Medicine · doi:10.1001/archpedi.160.12.1300 · Cited by 16 · see citing works
Bridging structural and functional biomarkers in functional movement disorder using network mapping
Sojka, P., Slovák, M., Věchetová, G., Jech, R., Perez, D. L., & Serranová, T. (2022) · Brain and Behavior · doi:10.1002/brb3.2576 · Cited by 14 · see citing works
Association between brain metabolism and clinical course of motor functional neurological disorders
Conejero, I., Collombier, L., López‐Castromán, J., Mura, T., Alonso, S., Olié, É., Boudousq, V., Boulet, F., Arquizan, C., Boulet, C., et al. (2022) · Brain · doi:10.1093/brain/awac146 · Cited by 13 · see citing works
Leeds Sleep Evaluation Questionnaire (LSEQ)
Shahid, A., Wilkinson, K., Marcu, S., et al. (2011) · Springer eBooks · doi:10.1007/978-1-4419-9893-4_48 · Cited by 12 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [68]Guilliams TG, Edwards L. Chronic stress and the HPA axis: Clinical assessment and therapeutic considerations. Stand. 2010; 9: 1– 12.
Cited by
Sorted by citations
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
“Taken together, these data suggest that ACEs are broad ranging and that activation and priming of the stress system—leading to subsequent vulnerability to FND—take place across the lifespan [37,38,41,43,119].”
Background
- Authors
- Weber, S., Bühler, J., Vanini, G., Loukas, S., Bruckmaier, R., & Aybek, S.
- Affiliations
- University of Bern (CH)
- University of Geneva (CH)
- Corresponding author
- Aybek, Selma
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-11-23
- Volume
- 146
- Issue
- 6
- Pages
- 2627-2641
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC10232283
- OpenAlex
- W4309825941
- Cited by
- 63
- References
- 97
- Citations by year
- 2026: 19 · 2025: 20 · 2024: 18 · 2023: 6
- FWCI
- 6.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by-nc)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Open Access CRIS of the University of Bern
- Funders
- Swiss National Science Foundation (PP00P3_176985)
- Leenards Nested Project (3642)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Psychiatry and Mental health › Psychosomatic Disorders and Their Treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Fibromyalgia and Chronic Fatigue Syndrome Research
- Keywords
- conversion disorder, hypothalamic-pituitary-adrenal axis, cortisol awakening response, diurnal cortisol, emotional neglect, psychological trauma, amygdala volume, hippocampal volume, diathesis-stress model, stress resilience, trait markers, brain volumetry
- MeSH terms
- Brain, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Saliva, Stress, Psychological
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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