Ovarian Hormone Fluctuation, Neurosteroids, and HPA Axis Dysregulation in Perimenopausal Depression: A Novel Heuristic Model

In this conceptual review, we propose a novel mechanistic candidate in the etiology of depression with onset in the menopause transition (a.k.a. perimenopausal depression) involving alterations in stress-responsive pathways, induced by ovarian hormone fluctuation

An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology

BACKGROUND: In humans, serotonin has typically been investigated as a neurotransmitter. However, serotonin also functions as a hormone across animal phyla, including those lacking an organized central nervous system. This hormonal action allows serotonin to have physiological consequences in systems outside the central nervous system. Fluctuations in estrogen levels over the lifespan and during ovarian cycles cause predictable changes in serotonin systems in female mammals. DISCUSSION: We hypothesize that some of the physiological effects attributed to estrogen may be a consequence of estrogen-related changes in serotonin efficacy and receptor distribution. Here, we integrate data from endocrinology, molecular biology, neuroscience, and epidemiology to propose that serotonin may mediate the effects of estrogen. In the central nervous system, estrogen influences pain transmission, headache, dizziness, nausea, and depression, all of which are known to be a consequence of serotonergic signaling. Outside of the central nervous system, estrogen produces changes in bone density, vascular function, and immune cell self-recognition and activation that are consistent with serotonin's effects. For breast cancer risk, our hypothesis predicts heretofore unexplained observations of the opposing effects of obesity pre- and post-menopause and the increase following treatment with hormone replacement therapy using medroxyprogesterone. SUMMARY: Serotonergic mediation of estrogen has important clinical implications and warrants further evaluation

In Search of Neural Endophenotypes of Postpartum Psychopathology and Disrupted Maternal Caregiving

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108651/1/jne12183.pd

The influence of motherhood on neural systems for reward processing in low income, minority, young women

OBJECTIVE: Given the association between maternal caregiving behavior and heightened neural reward activity in experimental animal studies, the present study examined whether motherhood in humans positively modulates reward-processing neural circuits, even among mothers exposed to various life stressors and depression. METHODS: Subjects were 77 first-time mothers and 126 nulliparous young women from the Pittsburgh Girls Study, a longitudinal study beginning in childhood. Subjects underwent a monetary reward task during functional magnetic resonance imaging in addition to assessment of current depressive symptoms. Life stress was measured by averaging data collected between ages 8–15 years. Using a region-of-interest approach, we conducted hierarchical regression to examine the relationship of psychosocial factors (life stress and current depression) and motherhood with extracted ventral striatal (VST) response to reward anticipation. Whole-brain regression analyses were performed post-hoc to explore non-striatal regions associated with reward anticipation in mothers vs nulliparous women. RESULTS: Anticipation of monetary reward was associated with increased neural activity in expected regions including caudate, orbitofrontal, occipital, superior and middle frontal cortices. There was no main effect of motherhood nor motherhood-by-psychosocial factor interaction effect on VST response during reward anticipation. Depressive symptoms were associated with increased VST activity across the entire sample. In exploratory whole brain analysis, motherhood was associated with increased somatosensory cortex activity to reward (FWE cluster forming threshold p<0.001). CONCLUSIONS: These findings indicate that motherhood is not associated with reward anticipation-related VST activity nor does motherhood modulate the impact of depression or life stress on VST activity. Future studies are needed to evaluate whether earlier postpartum assessment of reward function, inclusion of mothers with more severe depressive symptoms, and use of reward tasks specific for social reward might reveal an impact of motherhood on reward system activity

Disrupted posterior cingulate-amygdala connectivity in postpartum depressed women as measured with resting BOLD fMRI

Disengagement of emotion regulation circuits was previously shown in depressed mothers and was hypothesized to underlie the impaired maternal–infant sensitivity described in postpartum depression (PPD). We hypothesized similarly reduced resting-state functional connectivity in default mode network (DMN) regions involved in social cognition in PPD. Resting-state functional MRI, clinical and mother–infant attachment data were obtained from 14 unmedicated postpartum women with major depression and 23 healthy postpartum women. Posterior cingulate cortex (PCC) time series were extracted, filtered between 0.007 and 0.08 Hz and used as regressors in a whole brain general linear model analysis. PCC–right amygdala connectivity was significantly disrupted in depressed compared to healthy mothers for low-frequency neural activity, showing a negative (inverse) coupling in the depressed group but not in the controls. PCC–right amygdala connectivity was positively correlated with PCC–parahippocampus connectivity. Resting connectivity patterns of positive co-activations in postpartum women mirrored the canonical DMN. These findings of reduced PCC–amygdala coupling raise the possibility that PPD might involve the disruption of outward, preventative aspects of self-relevant thought and theory of mind/empathy processes. Further integrated studies of neural connectivity and these cognitive/behavioral dimensions are warranted

Abnormally reduced dorsomedial prefrontal cortical activity and effective connectivity with amygdala in response to negative emotional faces in postpartum depression

Objective: Postpartum major depression is a significant public health problem that strikes 15% of new mothers and confers adverse consequences for mothers, children, and families. The neural mechanisms involved in postpartum depression remain unknown, but brain processing of affective stimuli appears to be involved in other affective disorders. The authors examined activity in response to negative emotional faces in the dorsomedial pre-frontal cortex and amygdala, key emotion regulatory neural regions of importance to both mothering and depression. Method: Postpartum healthy mothers (N=16) and unmedicated depressed mothers (N=14) underwent functional magnetic resonance imaging blood-oxygen-level-dependent acquisition during a block-designed face versus shape matching task. A two-way analysis of variance was performed examining main effects of condition and group and group-by-condition interaction on activity in bilateral dorsomedial prefrontal cortical and amygdala regions of interest. Results: Depressed mothers relative to healthy mothers had significantly reduced left dorsomedial prefrontal cortical face-related activity. In depressed mothers, there was also a significant negative correlation between left amygdala activity and postpartum depression severity and a significant positive correlation between right amygdala activity and absence of infant-related hostility. There was reliable top-down connectivity from the left dorsomedial prefrontal cortex to the left amygdala in healthy, but not depressed, mothers. Conclusions: Significantly diminished dorsomedial prefrontal cortex activity and dorsomedial prefrontal cortical-amygdala effective connectivity in response to negative emotional faces may represent an important neural mechanism, or effect, of postpartum depression. Reduced amygdala activity in response to negative emotional faces is associated with greater postpartum depression severity and more impaired maternal attachment processes in postpartum depressed mothers

The influence of motherhood on neural systems for reward processing in low income, minority, young women

ObjectiveGiven the association between maternal caregiving behavior and heightened neural reward activity in experimental animal studies, the present study examined whether motherhood in humans positively modulates reward-processing neural circuits, even among mothers exposed to various life stressors and depression.MethodsSubjects were 77 first-time mothers and 126 nulliparous young women from the Pittsburgh Girls Study, a longitudinal study beginning in childhood. Subjects underwent a monetary reward task during functional magnetic resonance imaging in addition to assessment of current depressive symptoms. Life stress was measured by averaging data collected between ages 8-15 years. Using a region-of-interest approach, we conducted hierarchical regression to examine the relationship of psychosocial factors (life stress and current depression) and motherhood with extracted ventral striatal (VST) response to reward anticipation. Whole-brain regression analyses were performed post-hoc to explore non-striatal regions associated with reward anticipation in mothers vs nulliparous women.ResultsAnticipation of monetary reward was associated with increased neural activity in expected regions including caudate, orbitofrontal, occipital, superior and middle frontal cortices. There was no main effect of motherhood nor motherhood-by-psychosocial factor interaction effect on VST response during reward anticipation. Depressive symptoms were associated with increased VST activity across the entire sample. In exploratory whole brain analysis, motherhood was associated with increased somatosensory cortex activity to reward (FWE cluster forming threshold p&lt;0.001).ConclusionsThese findings indicate that motherhood is not associated with reward anticipation-related VST activity nor does motherhood modulate the impact of depression or life stress on VST activity. Future studies are needed to evaluate whether earlier postpartum assessment of reward function, inclusion of mothers with more severe depressive symptoms, and use of reward tasks specific for social reward might reveal an impact of motherhood on reward system activity

Ovarian Hormone Fluctuation, Neurosteroids, and HPA Axis Dysregulation in Perimenopausal Depression: A Novel Heuristic Model

OBJECTIVE: In this conceptual review, we propose a novel mechanistic candidate in the etiology of depression with onset in the menopause transition (a.k.a. perimenopausal depression) involving alterations in stress-responsive pathways, induced by ovarian hormone fluctuation. METHODS: The relevant literature in perimenopausal depression was reviewed, including its prevalence, predictors, and treatment with estrogen therapy. Subsequently, the growing evidence from animal models and clinical research in other reproductive mood disorders was synthesized to describe a heuristic model of perimenopausal depression development. RESULTS: The rate of major depressive disorder and of clinically meaningful elevations in depressive symptoms increases two- to threefold during the menopause transition. While the mechanisms by which ovarian hormone fluctuation might impact mood are poorly understood, growing evidence from basic and clinical research suggests that fluctuations in ovarian hormones and their derived neurosteroids result in altered GABAergic regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Our heuristic model suggests that for some women, failure of the GABA(A) receptor to regulate overall GABAergic tone in the face of shifting levels of these neurosteroids may induce HPA axis dysfunction, thereby increasing sensitivity to stress, and generating a period of greater vulnerability to depression. CONCLUSIONS: The proposed model provides a basis for understanding the mechanisms by which the changing hormonal environment of the menopause transition may interact with the psychosocial environment of mid-life to contribute to perimenopausal depression risk. Future research investigating this model may inform the development of novel pharmacological treatments for perimenopausal depression and related disorders such as postpartum depression and premenstrual dysphoric disorder