FMRI response to acute psychological stress differentiates patients with psychogenic non-epileptic seizures from healthy controls - A biochemical and neuroimaging biomarker study

Abstract

We investigated psychological stress response in the brain regions involved in emotion-motor-executive control in psychogenic non-epileptic seizures (PNES). 12 PNES patients and 12 healthy controls (HCs) underwent stress task and resting state functional MRI (fMRI), mood and quality of life (QOL) assessments, and measurements of salivary cortisol, alpha-amylase, and heart rate. Group differences were assessed, and we correlated beta values from a priori selected brain regions showing stress task fMRI group differences with other stress response measures. We also used the regions showing stress task fMRI group differences as seeds for resting state functional connectivity (rs-FC) analysis. Mood and QOL were worse in PNES versus HCs. Physiological and assessment measures were similar except 'Planful Problem Solving' coping that was greater for HCs (p = .043). Perceived stress associated negatively with heart rate change (r_s = -0.74, p = .0063). There was stress fMRI hyporeactivity in left/right amygdala and left hippocampus in PNES versus HCs (corrected p < .05). PNES exhibited a positive association between alpha-amylase change and right amygdala activation (r_s = 0.71, p = .010). PNES versus HCs exhibited greater right amygdala rs-FC to left precentral and inferior/middle frontal gyri (corrected p < .05). Our findings of fMRI hyporeactivity to psychological stress, along with greater emotion-motor-executive control network rs-FC in PNES when compared to HCs suggest a dysregulation in stress response circuitry in PNES.

Keywords: Alpha-amylase; Cortisol; Emotion; Psychogenic non-epileptic seizures (PNES); Psychological stress; fMRI.

Fig. 1

CONSORT flow diagram outlining recruitment of the 12 patients with psychogenic non-epileptic seizures (PNES) and 12 age-/sex-/education-matched healthy control participants.

Fig. 2

Pre- and post-stress performance on assessments and physiological measures of stress reactivity during the study session for the 12 patients with psychogenic non-epileptic seizures (PNES) and 12 healthy control (HC) participants. PNES and HC groups exhibit parallel trajectories for (A) positive affect, (B) negative affect, (C) state-related STAI scores, and (D) the distress subscale of the DSSQ. Graphs indicate mean +/− SEM at each time point for each assessment. (E) Heart rate was recorded following each of the 8 positive feedback messages (p1-p8) during the Control Math Task, and following each of the 8 negative feedback messages (n1-n8) during the Stress Math Task. Change in average heart rate between tasks was calculated for each group. (F) Salivary cortisol levels and (G) alpha-amylase levels are shown for samples collected at 60, 45 and 30 min before MRI preparation and scanning (s1, s2, and s3, respectively) and then immediately after completion of stress fMRI (s4) and another 4 samples at 15-min intervals (s5-s8). We regarded cortisol and alpha-amylase levels at s8 to be the recovery baseline in order to calculate percent change in cortisol reduction (dCORT) and alpha-amylase reduction (dAA) from the sample immediately post-stress (s4). Graphs indicate mean +/− SEM at each time point for each measure.

Fig. 3

Statistical maps of significant clusters showing PNES and HC group differences in stress-related task activation and resting state functional connectivity. (A) We defined seven a priori regions of interest: (1) amygdala, (2) hippocampus, and (3) insula involved in emotion; (4) anterior cingulate and (5) inferior frontal gyrus involved in executive function; (6) precentral gyrus and (7) postcentral gyrus involved in motor control. (B1) Compared to HC, PNES exhibited decreased response (in blue) to stress fMRI (hard versus easy math) in the bilateral amygdala and left hippocampus (corrected p < .05). (B2) The bar graph below of beta-weight values (mean +/− SEM) for each significant region illustrates an opposite response between groups. (B3) The scatter plot illustrates the significant association between stress task fMRI response in the right amygdala and stress-related change in alpha-amylase (dAA) in patients with PNES. (C1) Compared to HC, PNES exhibited increased resting state functional connectivity (corrected p < .05) between the right amygdala seed region to both the left inferior/middle frontal gyrus (L. IFG/MFG) and the left precentral gyrus (L. PCG). (C2) To the right, the bar graph of z-scores (mean +/− SEM) for each region illustrates that the group differences in functional connectivity are due to an opposing pattern of connectivity. L. = left hemisphere; R. = right hemisphere.