Hormonal cycle modulates arousal circuitry in women using functional magnetic resonance imaging

Abstract

Sex-specific behaviors are in part based on hormonal regulation of brain physiology. This functional magnetic resonance imaging (fMRI) study demonstrated significant differences in activation of hypothalamic-pituitary-adrenal (HPA) circuitry in adult women with attenuation during ovulation and increased activation during early follicular phase. Twelve normal premenopausal women were scanned twice during the early follicular menstrual cycle phase compared with late follicular/midcycle, using negative valence/high arousal versus neutral visual stimuli, validated by concomitant electrodermal activity (EDA). Significantly greater magnitude of blood oxygenation level-dependent signal changes were found during early follicular compared with midcycle timing in central amygdala, paraventricular and ventromedial hypothalamic nuclei, hippocampus, orbitofrontal cortex (OFC), anterior cingulate gyrus (aCING), and peripeduncular nucleus of the brainstem, a network of regions implicated in the stress response. Arousal (EDA) correlated positively with brain activity in amygdala, OFC, and aCING during midcycle but not in early follicular, suggesting less cortical control of amygdala during early follicular, when arousal was increased. This is the first evidence suggesting that estrogen may likely attenuate arousal in women via cortical-subcortical control within HPA circuitry. Findings have important implications for normal sex-specific physiological functioning and may contribute to understanding higher rates of mood and anxiety disorders in women and differential sensitivity to trauma than men.

Figure 1.

fMRI localization of significant differences in signal change within women comparing early follicular with midcycle menstrual phases during aversive arousal versus neutral visual stimuli. Images are derived from contrasts estimated by SPM of significant BOLD signal changes comparing aversive affective arousal stimuli versus neutral stimuli at early follicular versus midcycle menstrual timing, four-voxel minimum, controlled for multiple comparisons. R., Right; L., left; Amyg., amygdala; Med., medial; Lat., lateral; Ant., anterior.

Figure 2.

Three-dimensional images of anatomic localization of significant differences in signal change within women comparing early follicular with midcycle menstrual phases during aversive arousal versus neutral visual stimuli. Images represent the significant differences in BOLD signal intensity changes localized within anatomic regions (in red), corrected for multiple comparisons, comparing aversive affective stimuli versus neutral stimuli at two points in a woman's menstrual cycle (i.e., early follicular compared with midcycle menstrual phases). Regions of interest are shown within the mesh brain to illustrate the full context (i.e., whole brain) within which our brain regions of interest lie. L Cent. Amyg., Left central amygdala; Med. OFC, medial orbitofrontal cortex; R Ant. Cing., right anterior cingulate; R PPN, right peripeduncular nucleus; R VMN, right ventromedial hypothalamic nuclei.

Figure 3.

Signal intensity changes in BOLD activations comparing aversive affective with neutral stimuli in regions of interest at early follicular and late follicular/midcycle peak menstrual phases. Values indicate the degree of change in magnetic resonance signal detected between experimental condition and fixation and reported as percentage signal change. Comparison-to-fixation value of neutral valence/low arousal condition was subtracted from comparison-to-fixation value of negative valence/high arousal condition. Signal change values within each region of interest were averaged. Effect sizes presented in SD units represent differences between negative versus neutral signal intensity changes at early follicular and midcycle conditions. r, Right; Ant. Cing, anterior cingulate; lcAmyg, left central amygdala; Lat., lateral; Med., medial.