Sex differences in brain activity during aversive visceral stimulation and its expectation in patients with chronic abdominal pain: a network analysis

Abstract

Differences in brain responses to aversive visceral stimuli may underlie previously reported sex differences in symptoms as well as perceptual and emotional responses to such stimuli in patients with irritable bowel syndrome (IBS). The goal of the current study was to identify brain networks activated by expected and delivered aversive visceral stimuli in male and female patients with chronic abdominal pain, and to test for sex differences in the effective connectivity of the circuitry comprising these networks. Network analysis was applied to assess the brain response of 46 IBS patients (22 men and 24 women) recorded using [15O] water positron emission tomography during rest/baseline and expected and delivered aversive rectal distension. Functional connectivity results from partial least squares analyses provided support for the hypothesized involvement of 3 networks corresponding to: 1) visceral afferent information processing (thalamus, insula and dorsal anterior cingulate cortex, orbital frontal cortex), 2) emotional-arousal (amygdala, rostral and subgenual cingulate regions, and locus coeruleus complex) and 3) cortical modulation (frontal and parietal cortices). Effective connectivity results obtained via structural equation modeling indicated that sex-related differences in brain response are largely due to alterations in the effective connectivity of emotional-arousal circuitry rather than visceral afferent processing circuits. Sex differences in the cortico-limbic circuitry involved in emotional-arousal, pain facilitation and autonomic responses may underlie the observed differences in symptoms, and in perceptual and emotional responses to aversive visceral stimuli.

Figure 1. Projection plot of the common thalamo-centric network

The plot depicts the network of brain regions that reliably correlated with the right thalamus (MNI, 4, 8, 4) across conditions and sex. Blue regions indicate regions with negative salience and correlated negatively with the thalamus. Red regions denote areas of positive salience that correlated positively with the thalamus. Sagittal section shows location of selected axial slices in the Z-plane plane of MNI space.

Figure 2. Projection plot of the common amygdalo-centric network

The plot shows the network of brain regions that correlated with the right and left amygdala (MNI ±20,-5,-17) similarly across conditions and sex. Red denotes regions of positive salience that correlated positively with the amygdalae whereas blue denotes regions of negative salience that correlated negatively with the bilateral amygdala activity. Sagittal section shows location of selected axial slices in the Z-plane of MNI space.

Figure 3. Projection plot of sex-related amygdalo-centric network

The plot shows the network of regions that reliably correlating with amygdalae (MNI ±20,-5,-17) across conditions. For females, blue regions indicate regions correlated negatively with the bilateral amygdala activity and yellow regions denote areas that correlated positively with the amygdalae. For men, blue regions indicate regions correlated positively with the amygdalae and yellow regions denote areas that correlated negatively. Sagittal section shows location of selected axial slices in the Z-plane of MNI space.

Figure 4. Network nodes and schematic neural circuitry underlying responses to expectation and experience of aversive visceral stimulus

The structural model for the proposed network to be tested was comprised of “emotional-arousal” (orange), “homeostatic-afferent” processing (blue) and “cortical-modulatory” circuitry (green). The table inset on the right gives MNI coordinates for network nodes shown in Fig. 4, left. Abbreviations: BA- Brodmann areas, Amyg- amygdala, iACC- infragenual cingulate cortex, INS- insula, LCC- locus coeruleus complex, mOFC- medial orbital frontal cortex, sACC- supragenual anterior cingulate cortex, Thal- thalamus, ROI- region of interest.

Figure 5. Estimated effective connectivity of the proposed network comprising the “homeostatic-afferent”, “emotional-arousal”, and “cortical-modulatory circuits”

The operation of the proposed network (as estimated by the completely unconstrained model) during BL, INF and EXP (columns) is presented for females and males (rows). The beta coefficients (effective connectivity) are depicted by the thickness and color of the arrows. Solid arrows represent a parameter estimate that was considered significantly different from zero whereas dashed lines represent nonsignificant coefficients. Red arrows represent positive coupling whereas blue arrows represent negative coupling. The legend depicts the magnitude of the coefficients associated with each thickness. Abbreviations: Amyg- amygdala, iACC- infragenual cingulate cortex, INS- insula, LCC- locus coeruleus complex, mOFC- medial orbital frontal cortex, n.s.- nonsignificant, sACC- supragenual anterior cingulate cortex, Thal- thalamus.