Hypertension differentially impacts cognition in men and women in early midlife.

The current study aimed to understand how sex differences in the timing of hypertension onset contribute to early midlife risk for cognitive decline that may differ by sex and whether sex-dependent advantages in normotensive populations are influenced by the presence of hypertension. One hundred and ninety-five adults aged 45-55 from the New England Family Study underwent neuropsychological testing to assess attention, executive function, and memory. Physician-diagnosed hypertension status was self-reported via questionnaire. Mid-adulthood hypertension was associated with worse performance on measures of attention and memory, but the cognitive domains impacted varied by sex. Hypertension was associated with only attention in men, whereas in women it was associated with attention and associative and working memory. Sex differences in midlife cognitive performance found in normotensive adults were attenuated in those with hypertension. Our results underscore the importance of accounting for sex when assessing the impact of hypertension on midlife cognition that could be indicative of later decline and risk for cognitive impairment and dementia, given hypertension is an independent risk factor.

Stress-induced alterations in HPA-axis reactivity and mesolimbic reward activation in individuals with emotional eating.

BACKGROUND: Emotional eating has emerged as a contributing factor to overeating, potentially leading to obesity or disordered eating behaviors. However, the underlying biological mechanisms related to emotional eating remain unclear. The present study examined emotional, hormonal, and neural alterations elicited by an acute laboratory stressor in individuals with and without emotional eating. METHODS: Emotional (n = 13) and non-emotional eaters (n = 15) completed two main study visits, one week apart: one visit included a Stress version and the other a No-stress version of the Maastricht Acute Stress Task (MAST). Immediately pre- and post-MAST, blood was drawn for serum cortisol and participants rated their anxiety level. After the MAST, participants completed a Food Incentive Delay (FID) task during functional magnetic resonance imaging (fMRI), followed by an ad libitum snack period. RESULTS: Emotional eaters exhibited elevated anxiety (p = 0.037) and cortisol (p = 0.001) in response to the Stress MAST. There were no changes in anxiety or cortisol among non-emotional eaters in response to the Stress MAST or in either group in response to the No-stress MAST. In response to the Stress MAST, emotional eaters exhibited reduced activation during anticipation of food reward in mesolimbic reward regions (caudate: p = 0.014, nucleus accumbens: p = 0.022, putamen: p = 0.013), compared to non-emotional eaters. Groups did not differ in snack consumption. CONCLUSIONS: These data indicate disrupted neuroendocrine and neural responsivity to psychosocial stress amongst otherwise-healthy emotional eaters, who demonstrated hyperactive HPA-axis response coupled with hypoactivation in reward circuitry. Differential responsivity to stress may represent a risk factor in the development of maladaptive eating behaviors.

Respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) modulates brain response to stress in major depression.

BACKGROUND: Negative stress significantly impacts major depressive disorder (MDD), given the shared brain circuitry between the stress response and mood. Thus, interventions that target this circuitry will have an important impact on MDD. The aim of this study was to evaluate the acute effects of a novel respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) technique in the modulation of brain activity and connectivity in women with MDD in response to negative stressful stimuli. METHODS: Twenty premenopausal women with recurrent MDD in an active episode were included in a cross-over experimental study that included two functional MRI visits within one week, randomized to receive exhalatory- (e-RAVANS) or inhalatory-gated (i-RAVANS) at each visit. Subjects were exposed to a visual stress challenge that preceded and followed RAVANS. A Factorial analysis was used to evaluate the effects of RAVANS on brain activity and connectivity and changes in depressive and anxiety symptomatology post-stress. RESULTS: Compared with i-RAVANS, e-RAVANS was significantly associated with increased activation of subgenual anterior cingulate, orbitofrontal and ventromedial prefrontal cortices and increased connectivity between hypothalamus and dorsolateral prefrontal cortex, and from nucleus tractus solitarii to locus coeruleus and ventromedial prefrontal cortex. Changes in brain activity and connectivity after e-RAVANS were significantly associated with a reduction in depressive and anxiety symptoms. CONCLUSIONS: Our study suggests exhalatory-gated RAVANS effectively modulates brain circuitries regulating response to negative stress and is associated with significant acute reduction of depressive and anxiety symptomatology in women with recurrent MDD. Findings suggest a potential non-pharmacologic intervention for acute relief of depressive symptomatology in MDD.

Impact of BDNF and sex on maintaining intact memory function in early midlife.

Sex steroid hormones and neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), play a significant neuroprotective role in memory circuitry aging. Here, we present findings characterizing the neuroprotective effects of BDNF on memory performance, as a function of sex and reproductive status in women. Participants (N = 191; mean age = 50.03 ± 2.10) underwent clinical and cognitive testing, fMRI scanning, and hormonal assessments of menopausal staging. Memory performance was assessed with the 6-Trial Selective Reminding Test and the Face-Name Associative Memory Exam. Participants also performed a working memory (WM) N-back task during fMRI scanning. Results revealed significant interactions between menopausal status and BDNF levels. Only in postmenopausal women, lower plasma BDNF levels were associated with significantly worse memory performance and altered function in the WM circuitry. BDNF had no significant impact on memory performance or WM function in pre/perimenopausal women or men. These results suggest that in postmenopausal women, BDNF is associated with memory performance and memory circuitry function, thus providing evidence of potential sex-dependent factors of risk and resilience for early intervention.

Impact of adrenal hormones, reproductive aging, and major depression on memory circuitry decline in early midlife.

Dehydroepiandrosterone-sulfate (DHEAS) is an adrenal androgen that is, in part, aromatized to estradiol. It continues to be produced after menopause and provides estrogenicity after depletion of ovarian hormones. Estradiol depletion contributes to memory circuitry changes over menopause, including changes in hippocampal (HIPP) and dorsolateral- and ventrolateral-prefrontal cortex (DLPFC; VLPFC) function. Further, major depressive disorder (MDD) patients have, in general, lower levels of estradiol and lower DHEAS than healthy controls, thus potentially a higher risk of adverse menopausal outcomes. We investigated whether higher DHEAS levels after menopause is associated with better memory circuitry function, especially in women with MDD. 212 adults (ages 45-55, 50% women) underwent clinical and fMRI testing. Participants performed a working memory (WM) N-back task and an episodic memory verbal encoding (VE) task during fMRI scanning. DHEAS levels were significantly associated with memory circuitry function, specifically in MDD postmenopausal women. On the WM task, lower DHEAS levels were associated with increased HIPP activity. On the VE task, lower DHEAS levels were associated with decreased activity in the HIPP and VLPFC. In contrast, there was no association between DHEAS levels and memory circuitry function in MDD pre/perimenopausal women, men, and non-MDD participants regardless of sex and reproductive status. In fact, MDD postmenopausal women with higher levels of DHEAS were similar to MDD pre/perimenopausal women and men. Thus, memory circuitry deficits associated with MDD and a lower ability of the adrenal gland to produce DHEAS after menopause may contribute to a lower ability to maintain intact memory function with age.

Sex differences in episodic memory in early midlife: impact of reproductive aging.

OBJECTIVE: Few have characterized cognitive changes with age as a function of menopausal stage relative to men, or sex differences in components of memory in early midlife. The study aim was to investigate variation in memory function in early midlife as a function of sex, sex steroid hormones, and reproductive status. METHODS: A total of 212 men and women aged 45 to 55 were selected for this cross-sectional study from a prenatal cohort of pregnancies whose mothers were originally recruited in 1959 to 1966. They underwent clinical and cognitive testing and hormonal assessments of menopause status. Multivariate general linear models for multiple memory outcomes were used to test hypotheses controlling for potential confounders. Episodic memory, executive function, semantic processing, and estimated verbal intelligence were assessed. Associative memory and episodic verbal memory were assessed using Face-Name Associative Memory Exam (FNAME) and Selective Reminding Test (SRT), given increased sensitivity to detecting early cognitive decline. Impacts of sex and reproductive stage on performance were tested. RESULTS: Women outperformed men on all memory measures including FNAME (ß = -0.30, P < 0.0001) and SRT (ß = -0.29, P < 0.0001). Furthermore, premenopausal and perimenopausal women outperformed postmenopausal women on FNAME (initial learning, ß= 0.32, P = 0.01) and SRT (recall, ß= 2.39, P = 0.02). Across all women, higher estradiol was associated with better SRT performance (recall, ß = 1.96, P = 0.01) and marginally associated with FNAME (initial learning, ß = 0.19, P = 0.06). CONCLUSIONS: This study demonstrated that, in early midlife, women outperformed age-matched men across all memory measures, but sex differences were attenuated for postmenopausal women. Initial learning and memory retrieval were particularly vulnerable, whereas memory consolidation and storage were preserved. Findings underscore the significance of the decline in ovarian estradiol production in midlife and its role in shaping memory function.

Striatal Hypersensitivity During Stress in Remitted Individuals with Recurrent Depression.

BACKGROUND: Increased sensitivity to stress and dysfunctional reward processing are two primary characteristics of major depressive disorder (MDD) that may persist after remission. Preclinical work has established the pivotal role of the striatum in mediating both stress and reward responses. Human neuroimaging studies have corroborated these preclinical findings and highlighted striatal dysfunction in MDD in response to reward but have yet to investigate striatal function during stress, in particular in individuals with recurrent depression. METHODS: A validated mild psychological stress task involving viewing of negative stimuli during functional magnetic resonance imaging was conducted in 33 remitted individuals with a history of recurrent major depressive disorder (rMDD) and 35 matched healthy control subjects. Cortisol and anxiety levels were assessed throughout scanning. Stress-related activation was investigated in three striatal regions: caudate, nucleus accumbens, and putamen. Psychophysiologic interaction analyses probed connectivity of regions with central structures of the neural stress circuitry, such as the amygdala and hippocampus. RESULTS: The task increased cortisol and anxiety levels, although to a greater extent in rMDD individuals than healthy control subjects. In response to the negative stimuli, rMDD individuals, but not controls, also exhibited significantly potentiated caudate, nucleus accumbens, and putamen activations and increased caudate-amygdala and caudate-hippocampus connectivity. CONCLUSIONS: The findings highlight striatal hypersensitivity in response to a mild psychological stress in rMDD, as manifested by hyperactivation and hyperconnectivity with the amygdala and hippocampus. Striatal hypersensitivity during stress might thus constitute a trait mark of depression, providing a potential neural substrate for the interaction between stress and reward dysfunction in MDD.