Kimberly Albert

Estradiol levels modulate brain activity and negative responses to psychosocial stress across the menstrual cycle

Although ovarian hormones are thought to have a potential role in the well-known sex difference in mood and anxiety disorders, the mechanisms through which ovarian hormone changes contribute to stress regulation are not well understood. One mechanism by which ovarian hormones might impact mood regulation is by mediating the effect of psychosocial stress, which often precedes depressive episodes and may have mood consequences that are particularly relevant in women. In the current study, brain activity and mood response to psychosocial stress was examined in healthy, normally cycling women at either the high or low estradiol phase of the menstrual cycle. Twenty eight women were exposed to the Montreal Imaging Stress Task (MIST), with brain activity determined through functional magnetic resonance imaging, and behavioral response assessed with subjective mood and stress measures. Brain activity responses to psychosocial stress differed between women in the low versus high estrogen phase of the menstrual cycle: women with high estradiol levels showed significantly less deactivation in limbic regions during psychosocial stress compared to women with low estradiol levels. Additionally, women with higher estradiol levels also had less subjective distress in response to the MIST than women with lower estradiol levels. The results of this study suggest that, in normally cycling premenopausal women, high estradiol levels attenuate the brain activation changes and negative mood response to psychosocial stress. Normal ovarian hormone fluctuations may alter the impact of psychosocially stressful events by presenting periods of increased vulnerability to psychosocial stress during low estradiol phases of the menstrual cycle. This menstrual cycle-related fluctuation in stress vulnerability may be relevant to the greater risk for affective disorder or post-traumatic stress disorder in women.

Tamoxifen Improves Cholinergically Modulated Cognitive Performance in Postmenopausal Women

Tamoxifen (TMX) is a selective estrogen receptor modulator that is used as an estrogen receptor antagonist for the treatment and prevention of breast cancer. Whether TMX has antagonist activities in the human brain is less clear and its effects on cognitive function have not been experimentally explored. This study examined how TMX affected cognitive performance in older women using a model of anticholinergic drug-induced cognitive dysfunction. Twenty-one postmenopausal women were administered 20 mg of oral TMX or placebo for 3 months. Participants then took part in five drug challenges using the anticholinergic antinicotinic agent mecamylamine (MECA) and antimuscarinic agent scopolamine (SCOP) and were tested on a comprehensive battery including tasks of attention and psychomotor function, verbal episodic memory, and spatial navigation. After a 3-month placebo washout, participants were then crossed over to the alternate treatment and repeated the drug challenges after 3 months. Compared with placebo treatment, TMX significantly attenuated the impairment from cholinergic blockade on tasks of verbal episodic memory and spatial navigation, but effects on attentional/psychomotor tasks were more variable. Analysis by APOE genotype showed that APO ɛ4+ women showed a greater beneficial effect of TMX on reversing the cholinergic impairment than APO ɛ4− women on most tasks. This study provides evidence that TMX may act as an estrogen-like agonist to enhance cholinergic system activity and hippocampally mediated learning.

The Effects of Age and Estrogen on Stress Responsivity in Older Women

OBJECTIVE The current study examined whether age after menopause impacted the effect of estradiol (E2) on mood after a psychosocial stress manipulation. BACKGROUND Previous studies have shown that E2 improves mood in women around the menopause transition but does not improve mood for older postmenopausal women. We have previously shown that E2 treatment in nondepressed women resulted in increased negative mood after psychosocial stress. DESIGN Participants were 22 postmenopausal women placed on either oral placebo or 17β-estradiol (1 mg/day for 1 month, then 2 mg/day for 2 months). METHOD At the end of the 3-month treatment phase, the participants performed the Trier Social Stress Test followed by mood ratings. To examine the effects of age on the estrogen-stress interaction, we performed a median split on age and created four groups of participants: younger-placebo (mean age: 55.5 years), younger-E2 (mean age: 55.5 years), older-placebo (mean age: 73.0 years), and older-E2 (mean age: 76.8 years). RESULTS : The results showed that both older and younger E2-treated participants exhibited a significant and similar increase in negative mood after psychosocial stress compared with placebo-treated women. CONCLUSIONS These results suggest that E2 may play a significant role in modulating emotional reactivity to stressful events and that this effect persists in older women. Furthermore, responsivity to E2 effects on emotional processing appears to be intact even years after menopause in contrast with other cognitive and behavioral effects of E2, which may be limited to the early postmenopausal years.

Estrogen, Stress, and Depression: A Neurocognitive Model

The stress exposure model of depression suggests that depression is the result of biological vulnerability combined with the trigger of stressful life events. Altered function of brain regions important to the stress response have been consistently found in individuals with depression and include hypothalamic-pituitaryadrenal axis hyperactivity and insensitivity to negative feedback effects of cortisol. The cortisol response to stress shows sex differences and decreases during high-estradiol phases of the menstrual cycle. Women remain more sensitive than men to lower levels of cortisol following repeated stressors; thus, women may be more sensitive to mood dysregulation following psychosocial stress because of changing ovarian hormone effects on the hypothalamicpituitary-adrenal axis and brain circuits important for the stress response. Depressive symptoms and the risk of recurrent and new-onset depression increase during perimenopause. Studies with large multiethnic cohorts and long follow-up periods support the hypothesis that change in menopausal status is associated with increased risk of depressive symptoms independent of other factors. Studies of the menopause transition suggest that alterations in estradiol levels are associated with changes in cognition and mood regulatory disturbances and that early (or surgical) menopause may be particularly associated with a risk for depression. The menopause transition may present a period of vulnerability for emotional dysregulation, similar to other well-known vulnerability phases such as the premenstrual and the immediate postpartum periods. If the loss of normal estradiol cycling increases the risk of depression and/or stressinduced hypothalamic-pituitary-adrenal axis disruption, does replacing estradiol reduce the risk of mood dysfunction? While large prospective studies in major depression after menopause have not shown benefit of estradiol treatment, perimenopausal depression appears to benefit from such therapy. Thus, responses of depression in perimenopausal and postmenopausal women to estradiol may be different.

Attention bias in older women with remitted depression is associated with enhanced amygdala activity and functional connectivity

BACKGROUND Cognitive bias is a common characteristic of major depressive disorder (MDD) and is posited to remain during remission and contribute to recurrence risk. Attention bias may be related to enhanced amygdala activity or altered amygdala functional connectivity in depression. The current study examined attention bias, brain activity for emotional images, and functional connectivity in post-menopausal women with and without a history of major depression. METHODS Attention bias for emotionally valenced images was examined in 33 postmenopausal women with (n=12) and without (n=21) a history of major depression using an emotion dot probe task during fMRI. Group differences in amygdala activity and functional connectivity were assessed using fMRI and examined for correlations to attention performance. RESULTS Women with a history of MDD showed greater attentional bias for negative images and greater activity in brain areas including the amygdala for both positive and negative images (pcorr <0.001) than women without a history of MDD. In all participants, amygdala activity for negative images was correlated with attention facilitation for emotional images. Women with a history of MDD had significantly greater functional connectivity between the amygdala and hippocampal complex. In all participants amygdala-hippocampal connectivity was positively correlated with attention facilitation for negative images. LIMITATIONS Small sample with unbalanced groups. CONCLUSIONS These findings provide evidence for negative attentional bias in euthymic, remitted depressed individuals. Activity and functional connectivity in limbic and attention networks may provide a neurobiological basis for continued cognitive bias in remitted depression.

Frontocingulate cerebral blood flow and cerebrovascular reactivity associated with antidepressant response in late-life depression ☆

BACKGROUND Vascular pathology is common in late-life depression (LLD) and may contribute to alterations in cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). In turn, such hemodynamic deficits may adversely affect brain function and clinical course. The goal of this study was to examine whether altered cerebral hemodynamics in depressed elders predicted antidepressant response. METHODS 21 depressed elders completed cranial 3T MRI, including a pseudo-continuous Arterial Spin Labeling (pcASL) acquisition on both room air and during a hypercapnia challenge. Participants then completed 12 weeks of open-label sertraline. Statistical analyses examined the relationship between regional normalized CBF and CVR values and change in Montgomery-Asberg Depression Rating Scale (MADRS) and tested for differences based on remission status. RESULTS 10 participants remitted and 11 did not. After controlling for age and baseline MADRS, greater change in MADRS with treatment was associated with lower pre-treatment normalized CBF in the caudal anterior cingulate cortex (cACC) and lateral orbitofrontal cortex (OFC), as well as lower CVR with hypercapnia in the caudal medial frontal gyrus (cMFG). After controlling for age and baseline MADRS score, remitters exhibited lower CBF in the cACC and lower CVR in the cMFG. LIMITATIONS Our sample was small, did not include a placebo arm, and we examined only specific regions of interest. CONCLUSIONS Our findings suggest that increased perfusion of the OFC and the ACC is associated with a poor antidepressant response. They do not support that vascular pathology as measured by CBF and CVR negatively affects acute treatment outcomes.

Altered Brain Connectivity in Early Postmenopausal Women with Subjective Cognitive Impairment

Cognitive changes after menopause are a common complaint, especially as the loss of estradiol at menopause has been hypothesized to contribute to the higher rates of dementia in women. To explore the neural processes related to subjective cognitive complaints, this study examined resting state functional connectivity in 31 postmenopausal women (aged 50–60) in relationship to cognitive complaints following menopause. A cognitive complaint index was calculated using responses to a 120-item questionnaire. Seed regions were identified for resting state brain networks important for higher-order cognitive processes and for areas that have shown differences in volume and functional activity associated with cognitive complaints in prior studies. Results indicated a positive correlation between the executive control network and cognitive complaint score, weaker negative functional connectivity within the frontal cortex, and stronger positive connectivity within the right middle temporal gyrus in postmenopausal women who report more cognitive complaints. While longitudinal studies are needed to confirm this hypothesis, these data are consistent with previous findings suggesting that high levels of cognitive complaints may reflect changes in brain connectivity and may be a potential marker for the risk of late-life cognitive dysfunction in postmenopausal women with otherwise normal cognitive performance.

Anterior-posterior gradient differences in lobar and cingulate cortex cerebral blood flow in late-life depression

Vascular pathology is common in late-life depression, contributing to changes in cerebral function. We examined whether late-life depression was associated with differences in cerebral blood flow (CBF) and whether such differences were related to vascular risk and cerebrovascular pathology, specifically white matter hyperintensity (WMH) volumes. Twenty-three depressed elders and 20 age- and sex-matched elders with no psychiatric history completed cranial 3T MRI. MRI procedures included a pseudo-continuous Arterial Spin Labeling (pcASL) acquisition obtained while on room air and during a hypercapnia challenge allowing for calculation of cerebrovascular reactivity (CVR). Brain segmentation identified frontal, temporal, parietal and cingulate sub-regions in which CBF and CVR were calculated. The depressed group exhibited an anterior-posterior gradient in CBF, with lower CBF throughout the frontal lobe but higher CBF in the parietal lobe, temporal lobe, thalamus and hippocampus. A similar anterior to posterior gradient was observed in the cingulate cortex, with anterior regions exhibiting lower CBF and posterior regions exhibiting higher CBF. We did not observe any group differences in CVR measures. We did not observe significant relationships between CBF and CVR with vascular risk or WMH volumes, aside from an isolated finding associating higher WMH volumes with lower CBF in the rostral anterior cingulate cortex. Decreased anterior CBF in depressed elders might reflect decreased metabolic activity in these regions, while increased posterior CBF may represent either compensatory processes or different activity of posterior intrinsic functional networks. Future work should examine how these findings are related to compensatory changes with aging.

Cognitive performance in antidepressant-free recurrent major depressive disorder

Cognitive complaints are common in depression, and cognition may be an important treatment target as cognitive problems often remain during remission and may contribute to recurrence risk. Previous studies of cognitive performance in depression have mainly examined late‐life depression, with a focus on older adults, or assessed performance in specific cognitive tasks rather than cognitive domains.

Transdermal Nicotine for the Treatment of Mood and Cognitive Symptoms in Nonsmokers With Late-Life Depression

OBJECTIVE Late-life depression (LLD) is characterized by poor antidepressant response and cognitive dysfunction. This study examined whether transdermal nicotine benefits mood symptoms and cognitive performance in LLD. METHODS In a 12-week open-label outpatient study conducted between November 2016 and August 2017, transdermal nicotine was given to 15 nonsmoking older adults (≥ 60 years of age). Eligible participants met DSM-IV-TR criteria for major depressive disorder with ≥ 15 on the Montgomery-Asberg Depression Rating scale (MADRS) and endorsed subjective cognitive impairment. Transdermal nicotine patches were applied daily and titrated in a rigid dose escalation strategy to a maximum dose of 21.0 mg/d, allowing dose reductions for tolerability. The primary mood outcome was MADRS change measured every 3 weeks, with response defined as ≥ 50% improvement from baseline and remission as MADRS score ≤ 8. The primary cognitive outcome was the Conners Continuous Performance Test (CPT), a test of attention. RESULTS Robust rates of response (86.7%; 13/15 subjects) and remission (53.3%; 8/15 subjects) were observed. There was a significant decrease in MADRS scores over the study (β = -1.51, P < .001), with improvement seen as early as 3 weeks (Bonferroni-adjusted P value = .004). We also observed improvement in apathy and rumination. We did not observe improvement on the CPT but did observe improvement in subjective cognitive performance and signals of potential drug effects on secondary cognitive measures of working memory, episodic memory, and self-referential emotional processing. Overall, transdermal nicotine was well tolerated, although 6 participants could not reach the maximum targeted dose. CONCLUSIONS Nicotine may be a promising therapy for depressed mood and cognitive performance in LLD. A definitive placebo-controlled trial and establishment of longer-term safety are necessary before clinical usage. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02816138​.