Sex Differences in Insular Cortex Gyri Responses to the Valsalva Maneuver

Abstract

Sex differences in autonomic regulation may underlie cardiovascular disease variations between females and males. One key autonomic brain region is the insular cortex, which typically consists of five main gyri in each hemisphere, and shows a topographical organization of autonomic function across those gyri. The present study aims to identify possible sex differences in organization of autonomic function in the insula. We studied brain functional magnetic resonance imaging (fMRI) responses to a series of four 18-s Valsalva maneuvers in 22 healthy females (age ± SD: 50.0 ± 7.9 years) and 36 healthy males (45.3 ± 9.2 years). Comparisons of heart rate (HR) and fMRI signals were performed with repeated measures ANOVA (threshold P < 0.05 for all findings). All subjects achieved the target 30 mmHg expiratory pressure for all challenges. Typical HR responses were elicited by the maneuver, including HR increases from ~4 s into the strain period (Phase II) and rapid declines to below baseline 5-10 s, following strain release (Phase IV). Small, but significant, sex differences in HR percent change occurred during the sympathetic-dominant Phase II (female < male) and parasympathetic-dominant Phase IV (female > male, i.e., greater undershoot in males). The insular cortices showed similar patterns in all gyri, with greater signal decreases in males than females. Both sexes exhibited an anterior-posterior topographical organization of insular responses during Phase II, with anterior gyri showing higher responses than more posterior gyri. The exception was the right anterior-most gyrus in females, which had lower responses than the four other right gyri. Responses were lateralized, with right-sided dominance during Phase II in both sexes, except the right anterior-most gyrus in females, which showed lower responses than the left. The findings confirm the anterior and right-sided sympathetic dominance of the insula. Although sex differences were prominent in response magnitude, organization differences between males and females were limited to the right anterior-most gyrus, which showed a lower fMRI response in females vs. males (and vs. other gyri in females). The sex differences suggest a possible differing baseline state of brain physiology or tonic functional activity between females and males, especially in the right anterior-most gyrus.

Keywords: autonomic; cardiovascular; fMRI; functional neuroanatomy; sympathetic.

Figure 1

Insular gyri color-coded and overlaid on average anatomical scan. The anterior region of the insula is comprised of the short gyri, including the anterior short gyrus (ASG), mid short gyrus (MSG), and posterior short gyrus (PSG). The posterior region of the insula is comprised of the long gyri, including the anterior long gyrus (ALG) and posterior long gyrus (PLG). Coordinates in MNI space are indicated for each slice, and the slice location of the axial view is shown by the dashed line on the sagittal view and vice versa.

Figure 2

Heart rate (HR) and SaO₂ changes during a series of four Valsalva maneuvers, averaged for female and male groups. (A) HR% change relative to baseline and (C) SaO₂ averaged over four challenges (mean ± SE). Timepoints of significant within-group responses indicated in blue and green *, and significant group differences in red, based on P < 0.05 with repeated measures ANOVA (RMANOVA). (B) Absolute heart rate and (D) SaO₂ over series of four Valsalva maneuvers, averaged over females and males with SE shaded.

Figure 3

Mean fMRI insula responses over four Valsalva maneuvers, averaged for female and male groups. All left and right gyri patterns are shown. Timepoints of significant within-group responses and between-group differences are indicated above the x-axis and below the graphs (RMANOVA, P < 0.05).

Figure 4

Anterior-to-posterior organization of insula fMRI responses over four Valsalva maneuvers, illustrated by timetrends relative to pattern in posterior-most gyrus (PLG). Females in top and males in bottom. Timepoints of between-gyral differences are indicated by symbols above the x-axis and below the graphs (RMANOVA, P < 0.05).

Figure 5

Lateralization of insula fMRI responses over four Valsalva maneuvers, illustrated by right–left time trends, such that a higher signal indicates a greater right-sided response. Females in left column and males in right column. Timepoints of between-hemisphere differences are indicated by a red * above the graphs (RMANOVA, P < 0.05).