Identification of biopsychological trait markers in functional neurological disorders

Abstract

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.

Keywords: conversion disorders; cortisol; emotional neglect; hypothalamic–pituitary–adrenal axis; partial least squares correlation; voxel-based morphometry.

Figure 1

Traumatic life events. (A) For visualization purposes, means and confidence intervals of overall number of experienced traumata (ranging from 0 to 29). (B) Means and confidence intervals of six trauma severity scores (determined by subjective impact and age of trauma, ranging from 0 to 13 for emotional neglect, emotional abuse, physical abuse, sexual harassment and sexual abuse or from 0 to 24 for bodily threat). (C) Means and confidence intervals of developmental composite scores (across trauma subscores). (D) Means and confidence intervals of duration of trauma. ***P < 0.001, **P < 0.01, *P < 0.05. Results are FDR-corrected.

Figure 2

Cortisol profile of FND patients and healthy controls. Mean and confidence intervals of daytime cortisol profile in FND patients and HC. *P < 0.05.

Figure 3

Results of voxel-based morphometry analysis. (A) Differential effect of voxel-wise comparison (HC > FND) with smaller grey-matter volume in FND in the hippocampus, parahippocampal gyri, amygdala and dorsolateral frontal gyri. (B) Differential effect of mean region-of-interest volume using a hippocampal mask (upper panel) and amygdala mask (lower panel) with smaller grey-matter volume in FND. For both analyses, total intracranial volume (TIV), age, sex, depression (BDI) and anxiety (STAI) were added as covariates, thresholded on whole-brain level at P_FWE < 0.05. ***P < 0.001, **P < 0.01, *P < 0.05. A model corrected only for TIV, age and sex can be found in Supplementary Fig. 3 and Supplementary Table 3.

Figure 4

PLSC results of the different cortisol measures (CARi, PACC, DBCC) in FND patients and healthy controls. The outcome (A) and cortisol saliences (B) of the significant PLSC component (P = 0.033) are presented. Fifth to 95th percentiles of bootstrapping are indicated in the error bars and highlighted bars indicate robustness. The height of the bar corresponds to the salience weight to the multivariate correlation pattern and can be interpreted similarly to correlation coefficients as the data were standardized. The permutation null distribution and the bootstrap mean percentiles are reported in Supplementary Fig. 4 and Supplementary Table 4. EN = emotional neglect; EA = emotional abuse; PA = physical abuse; SH = sexual harassment; SA = sexual abuse; BT = bodily threat.

Figure 5

PLSC results of the imaging data (hippocampal and amygdalar volumes) in FND patients and healthy controls. The outcome (A) and imaging saliences (B) of the significant PLSC component (P = 0.021) are presented. Fifth to 95th percentiles of bootstrapping are indicated in the error bars and highlighted bars indicate robustness. The height of the bar corresponds to the salience weight to the multivariate correlation pattern and can be interpreted similarly to correlation coefficients as the data were standardized. The permutation null distribution and the bootstrap mean percentiles are reported in Supplementary Fig. 5 and Supplementary Table 5.

Figure 6

The stress–diathesis model in functional neurological disorders. The aetiology of FND is multifactorial and depends on predisposing, precipitating, and perpetuating risk factors. Long-term exposure to stress can exert neurotoxic effects on regions particularly sensitive to cortisol. Moreover, it can alter the HPA axis in terms of a maladaptive habituation. Distinct predisposing factors, i.e. ‘trait’ markers might influence the individual resilience to stress and the later development of psychopathology. CRF = corticotropin-releasing factor; ACTH = adrenocorticotropic hormone.