Understanding sex differences in stress regulation has important implications for understanding basic physiological differences in the male and female brain and their impact on vulnerability to sex differences in chronic medical disorders associated with stress response circuitry. In this functional magnetic resonance imaging study, we demonstrated that significant sex differences in brain activity in stress response circuitry were dependent on women's menstrual cycle phase. Twelve healthy Caucasian premenopausal women were compared to a group of healthy men from the same population, based on age, ethnicity, education, and right handedness. Subjects were scanned using negative valence/high arousal versus neutral visual stimuli that we demonstrated activated stress response circuitry [amygdala, hypothalamus, hippocampus, brainstem, orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and anterior cingulate gyrus (ACG)]. Women were scanned twice based on normal variation in menstrual cycle hormones [i.e., early follicular (EF) compared with late follicular-midcycle (LF/MC) menstrual phases]. Using SPM8b, there were few significant differences in blood oxygenation leveldependent (BOLD) signal changes in men compared to EF women, except ventromedial nucleus (VMN), lateral hypothalamic area (LHA), left amygdala, and ACG. In contrast, men exhibited significantly greater BOLD signal changes compared to LF/MC women on bilateral ACG and OFC, mPFC, LHA, VMN, hippocampus, and periaqueductal gray, with largest effect sizes in mPFC and OFC. Findings suggest that sex differences in stress response circuitry are hormonally regulated via the impact of subcortical brain activity on the cortical control of arousal, and demonstrate that females have been endowed with a natural hormonal capacity to regulate the stress response that differs from males.
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.
Functional imaging studies of sex effects in working memory (WMEM) are few, despite significant normal sex differences in brain regions implicated in WMEM. This functional MRI (fMRI) study tested for sex effects in an auditory verbal WMEM task in prefrontal, parietal, cingulate, and insula regions. Fourteen healthy, right-handed community subjects were comparable between the sexes, including on WMEM performance. Per statistical parametric mapping, women exhibited greater signal intensity changes in middle, inferior, and orbital prefrontal cortices than men (corrected for multiple comparisons). A test of mixed-sex groups, comparable on performance, showed no significant differences in the hypothesized regions, providing evidence for discriminant validity for significant sex differences. The findings suggest that combining men and women in fMRI studies of cognition may obscure or bias results.
Although cerebellar volumes are disproportionately small in individuals with DS, they do not diminish significantly with age and do not undergo age-related atrophy that is different from that of normal controls. Volume reduction in the cerebellum does not appear to be specifically responsible for the age-related decline in fine-motor control that is observed in adults with DS.
The Iowa Gambling Task (IGT) is assumed to measure executive functioning, but this has not been empirically tested by means of both convergent and discriminant validity. We used structural equation modeling (SEM) to test whether the IGT is an executive function (EF) task (convergent validity) and whether it is not related to other neuropsychological domains (discriminant validity). Healthy community-dwelling participants (N = 214) completed a comprehensive neuropsychological battery. We analyzed the conventional IGT metric and three alternative metrics based on the overall difference of advantageous minus disadvantageous choices made during the last 60 IGT responses and advantageous minus disadvantageous choices based on two specific decks of cards (D minus A). An a priori six-factor hierarchical model of neuropsychological functioning was confirmed with SEM. Attention and processing speed were grouped as "non-associative" factors. Fluency, executive functioning, visual learning/memory, and verbal learning/memory were grouped as higher-level "associative" factors. Of the non-associative factors, attention, but not speed, predicted IGT performance. When each associative factor was entered along with attention, only EF improved the model fit and that was only for metrics based on trials 41-100. SEM indicates metrics based on trails 1-100 are influenced by attention, and metrics based on trails 41-100 are influenced by attention and EF. Its associative strength with attention is twice that of EF. Conceptually, the IGT is a multi-trait task involving novel problem-solving and attentional domains to a greater extent, and executive functioning to a lesser extent.
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