Effects of cortisol administration on heart rate variability and functional connectivity across women with different depression histories.

Abnormalities within the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system have been implicated in depression. Studies have reported glucocorticoid insensitivity and reduced heart rate variability (HRV) in depressive disorders. However, little is known about the effects of cortisol on HRV and resting-state functional connectivity (rsFC) of the central autonomic network (CAN) in depression. We collected resting-state fMRI and cardiac data for women with different depression histories (n = 61) after administration of cortisol and placebo using a double-blind crossover design. We computed rsFC for R-amygdala and L-amygdala seeds and assessed the change in HRV after cortisol (cortisol-placebo). Analyses examined the effects of acute cortisol administration on HRV and rsFC of the R-amygdala and L-amygdala. There was a significant interaction between HRV and treatment for rsFC between the amygdala and CAN regions. We found lower rsFC between the L-amygdala and putamen for those with a greater decrease in HRV after cortisol. There was also reduced rsFC between the R-amygdala and dorsomedial prefrontal cortex, putamen, middle cingulate cortex, insula, and cerebellum in those with lower HRV after cortisol. These results remained significant after adjusting for depression symptoms, age, and race. Our findings suggest that the effect of cortisol on CAN connectivity is related to its effects on HRV. Overall, these results could inform transdiagnostic interventions targeting HRV and the stress response systems across clinical and non-clinical populations.

Effects of Cortisol Administration on Resting-State Functional Connectivity in Women with Depression.

Previous resting-state functional connectivity (rsFC) research has identified several brain networks impacted by depression and cortisol, including default mode (DMN), frontoparietal (FPN), and salience networks (SN). In the present study, we examined the effects of cortisol administration on rsFC of these networks in individuals varying in depression history and severity. We collected resting-state fMRI scans and self-reported depression symptom severity for 74 women with and without a history of depression after cortisol and placebo administration using a double-blind, crossover design. We conducted seed-based rsFC analyses for DMN, FPN, and SN seeds to examine rsFC changes after cortisol vs. placebo administration in relation to depression history group and severity. Results revealed a main effect of depression group, with lower left amygdala (SN)-middle temporal gyrus connectivity in women with a history of depression. Cortisol administration increased insula (SN)-inferior frontal gyrus and superior temporal gyrus connectivity. We also found that greater depression severity was associated with increased PCC (DMN)-cerebellum connectivity after cortisol. These results did not survive Bonferroni correction for seed ROIs and should be interpreted with caution. Our findings indicate that acute cortisol elevation may normalize aberrant connectivity of DMN and SN regions, which could help inform clinical treatments for depression.

Neural signal variability relates to maladaptive rumination in depression.

Rumination is a common feature of depression and predicts the onset and maintenance of depressive episodes. Maladaptive and adaptive subtypes of rumination contribute to distinct outcomes, with brooding worsening negative mood and reflection related to fewer depression symptoms in healthy populations. Neuroimaging studies have implicated several cortical midline and lateral prefrontal brain regions in rumination. Recent research indicates that blood oxygen level-dependent (BOLD) signal variability may be a novel predictor of cognitive flexibility. However, no prior studies have investigated whether brooding and reflection are associated with distinct patterns of BOLD signal variability in depression. We collected resting-state fMRI data for 79 women with different depression histories: no history, past history, and current depression. We examined differences in BOLD signal variability (BOLDSD) related to rumination subtypes for the following regions of interest previously implicated in rumination: amygdala, medial prefrontal, anterior cingulate, posterior cingulate, and dorsolateral prefrontal cortices (dlPFC). Rumination subtype was associated with BOLDSD in the dlPFC, with greater levels of brooding associated with lower BOLDSD in the dlPFC, even after controlling for depression severity. Depression history was related to BOLDSD in the dlPFC, with reduced BOLDSD in those with current depression versus no history of depression. These findings provide a novel demonstration of the neural circuitry associated with maladaptive rumination in depression and implicate decreased prefrontal neural signal variability in the pathophysiology of depression.

Resting-state neural signal variability in women with depressive disorders.

Aberrant activity and connectivity in default mode (DMN), frontoparietal (FPN), and salience (SN) network regions is well-documented in depression. Recent neuroimaging research suggests that altered variability in the blood oxygen level-dependent (BOLD) signal may disrupt normal network integration and be an important novel predictor of psychopathology. However, no studies have yet determined the relationship between resting-state BOLD signal variability and depressive disorders nor applied BOLD signal variability features to the classification of depression history using machine learning (ML). We collected resting-state fMRI data for 79 women with different depression histories: no history, past history, and current depressive disorder. We tested voxelwise differences in BOLD signal variability related to depression group and severity. We also investigated whether BOLD signal variability of DMN, FPN, and SN regions could predict depression history group using a supervised random forest ML model. Results indicated that individuals with any history of depression had significantly decreased BOLD signal variability in the left and right cerebellum and right parietal cortex (pFWE <0.05). Furthermore, greater depression severity was also associated with reduced BOLD signal variability in the cerebellum. A random forest model classified participant depression history with 74% accuracy, with the ventral anterior cingulate cortex of the DMN as the most important variable in the model. These findings provide novel support for resting-state BOLD signal variability as a marker of neural dysfunction in depression and implicate decreased neural signal variability in the pathophysiology of depression.

Alterations in Systemic and Cognitive Glucocorticoid Sensitivity in Depression.

BACKGROUND: Decades of research point to cortisol insensitivity as a biomarker of depression. Despite a vast literature on cortisol's effects on memory, the role of cortisol insensitivity in core psychological features of depression, such as emotional memory biases, is unknown. METHODS: Sixty-five premenopausal women with varying levels of depression completed this study involving an at-home low-dose dexamethasone suppression test and four experimental sessions (i.e., two visits for memory encoding of emotionally arousing pictures, each of which was followed 48 hours later by a recall test). Participants received 20 mg of oral cortisol (CORT) or placebo prior to encoding. We tested whether systemic cortisol insensitivity measured with the dexamethasone suppression test predicted cognitive sensitivity to CORT, which was operationalized as the change in negatively biased memory formation for pictures encoded following CORT versus placebo administration. RESULTS: Cortisol insensitivity was associated with more severe depression and flatter diurnal cortisol levels. Cortisol insensitivity predicted negative memory bias for pictures encoded during the placebo session and reduction in negative memory bias for pictures encoded during the CORT (compared with placebo) session, even after accounting for psychiatric symptomatology. CONCLUSIONS: Our findings replicate research showing that cortisol insensitivity predicts depression severity and flatter diurnal cortisol levels. The results further suggest that systemic cortisol insensitivity is related to negative memory bias and its alleviation by cortisol administration. These novel cognitive findings tie together knowledge regarding endocrine and psychological dysfunction in depression and suggest that boosting cortisol signal may cognitively benefit individuals with cortisol insensitivity.

Childhood Emotional Abuse Moderates Associations Among Corticomotor White Matter Structure and Stress Neuromodulators in Women With and Without Depression.

Adverse caregiving during development can produce long-lasting changes to neural, endocrine, and behavioral responses to stress, and is strongly related to elevated risk of adult psychopathology. While prior experience of adversity is associated with altered sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis activity, the underlying neural pathways are not completely understood. In a double-blind crossover study, we used diffusion tensor imaging (DTI) to examine whether variation in white matter structure predicts differences in HPA-SNS interactions as a function of early adversity. Participants included 74 women who exhibited a wide range of depression severity and/or childhood emotional abuse (EA). Participants attended two experimental sessions during which they were administered 20 mg cortisol (CORT) or placebo and after 90 min, viewed emotionally laden pictures while undergoing MRI scanning. Immediately after emotional picture-viewing, we collected salivary alpha-amylase (sAA) to index SNS activation. We tested whether EA moderated the relation between fractional anisotropy (FA), a measure of white matter fiber structure, and sAA. In the placebo condition, for participants with minimal history of EA, higher FA in corticomotor projections was negatively correlated with sAA, whereas in participants with severe EA, the correlation was trending in the opposite direction. Following CORT administration, FA and sAA were not related, suggesting that SNS tone during acute cortisol elevation may depend on neural pathways other than corticomotor projections. The results suggest that at baseline-though not during cortisol elevation-increased FA in these tracts is associated with lower levels of SNS activity in women with minimal EA, but not in women with severe EA. These findings provide evidence that corticomotor projections may be a key component of altered neural circuitry in adults with history of maltreatment, and may be related to alterations in stress neuromodulators in psychopathology.

Neural Signaling of Cortisol, Childhood Emotional Abuse, and Depression-Related Memory Bias.

BACKGROUND: Cortisol has potent effects on learning and neuroplasticity, but little is known about its effects on negative memory biases in depression. Animal models show that aversive caregiving alters effects of glucocorticoids (primarily corticosterone in rodents and cortisol in primates) on learning and neuroplasticity into adulthood. METHODS: We investigated whether history of childhood emotional abuse (EA) moderated effects of cortisol administration (CORT) versus placebo on emotional memory formation in depression. Participants included 75 unmedicated women with varying levels of depression severity and/or EA history. In a double-blind crossover investigation, we used functional magnetic resonance imaging to measure effects of CORT (vs. placebo) on neural function during emotional memory formation. RESULTS: CORT eliminated the well-known relationship between depression severity and negative memory bias, a finding explained by EA severity. For women with a history of severe EA, CORT reduced depression-related negative memory bias and normalized recall for pleasant stimuli. EA severity also moderated CORT effects on neural function: in women with history of severe EA, CORT increased activation in the supplementary motor area during viewing of unpleasant relative to pleasant pictures. Additionally, supplementary motor area activation predicted reduced negative bias for pictures encoded during CORT. CONCLUSIONS: These results suggest that increasing cortisol signaling may be neurocognitively beneficial in depressed women with a history of maltreatment. The findings corroborate prior research suggesting that presence or absence of adverse caregiving is etiologically important in depression. These findings suggest potential neurocognitive mechanisms of therapeutics targeting cortisol signaling, which show promise in treating affective disorders.

Neural and behavioral correlates of negative self-focused thought associated with depression.

A central feature of major depression (MDD) is heightened negative self-focused thought (negative-SFT). Neuroscientific research has identified abnormalities in a network of brain regions in MDD, including brain areas associated with SFT such as medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). To our knowledge no studies have investigated the behavioral and neural correlates of negative-SFT using a sentence completion task in a sample of individuals with varying depression histories and severities. We test the following hypotheses: (1) negative-SFT will be associated with depression; and (2) depression and negative-SFT will be related to resting-state functional connectivity (rsFC) for brain regions implicated in SFT. Seventy-nine women with varying depression histories and severities completed a sentence completion task and underwent resting-state functional magnetic resonance imaging (rs-fMRI). Standard seed-based voxelwise rsFC was conducted for self-network regions of interest: dorsomedial PFC (dmPFC) and pregenual ACC (pgACC). We performed linear regression analyses to examine the relationships among depression, negative-SFT, and rsFC for the dmPFC and pgACC. Greater negative-SFT was associated with depression history and severity. Greater negative-SFT predicted increased rsFC between dmPFC and pgACC seeds and dorsolateral prefrontal (dlPFC) and parietal regions; depression group was also associated with increased pgACC-dlPFC connectivity. These findings are consistent with previous literature reporting elevated negative-SFT thought in MDD. Our rs-fMRI results provide novel support linking negative-SFT with increased rsFC between self-network and frontoparietal network regions across different levels of depression. Broadly, these findings highlight a dimension of social-affective functioning that may underlie MDD and other psychiatric conditions.

Reduced resting-state thalamostriatal functional connectivity is associated with excessive daytime sleepiness in persons with and without depressive disorders.

BACKGROUND: Excessive daytime sleepiness (EDS) is a common and significant problem encountered in affective illness, however, the biological underpinnings of EDS in persons with psychiatric disorders are not clear. This study evaluated the associations between thalamic connectivity with cortical and subcortical brain regions with EDS in persons with and without depressive disorders (DD). METHODS: Resting-state functional connectivity magnetic resonance imaging scans from 67 unmedicated young to middle-aged women with current DD (n = 30), remitted DD (n = 13), and healthy controls (n = 24) were utilized to examine the associations between thalamic connectivity with cortical/subcortical structures and EDS. RESULTS: After correction for multiple comparisons and adjustment for age, habitual sleep duration, and depressive symptomatology, reduced resting-state connectivity between the bilateral thalamus and left rostral striatum (caudate/putamen) was significantly associated with EDS. LIMITATIONS: Causal inferences between thalamostriatal connectivity and EDS could not be determined. CONCLUSIONS: These results further implicate the role of the striatum and thalamus as central components of the experience of EDS. Further research is indicated to clarify the specific role these structures play in EDS in psychiatric disorders.

Circulating cortisol levels after exogenous cortisol administration are higher in women using hormonal contraceptives: data from two preliminary studies.

Exogenous cortisol administration has been used to test the influence of glucocorticoids on a variety of outcomes, including memory and affect. Careful control of factors known to influence cortisol and other endogenous hormone levels is central to the success of this research. While the use of hormonal birth control (HBC) is known to exert many physiological effects, including decreasing the salivary cortisol response to stress, it is unknown how HBC influences circulating cortisol levels after exogenous cortisol administration. To determine those effects, we examined the role of HBC on participants' cortisol levels after receiving synthetic cortisol (hydrocortisone) in two separate studies. In Study 1, 24 healthy women taking HBC and 26 healthy men were administered a 0.1 mg/kg body weight intravenous dose of hydrocortisone, and plasma cortisol levels were measured over 3 h. In Study 2, 61 participants (34 women; 16 were on HBC) received a 15 mg hydrocortisone pill, and salivary cortisol levels were measured over 6 h. Taken together, results from these studies suggest that HBC use is associated with a greater cortisol increase following cortisol administration. These data have important methodological implications: (1) when given a controlled dose of hydrocortisone, cortisol levels may increase more dramatically in women taking HBC versus women not on HBC or men; and (2) in studies manipulating cortisol levels, women on hormonal contraceptives should be investigated as a separate group.

Inter-individual differences in trait negative affect moderate cortisol's effects on memory formation: preliminary findings from two studies.

Acute emotional arousal moderates the effects of cortisol on memory. However, it is currently unknown how stable inter-individual differences (i.e., traits) moderate cortisol's effects on memory. In two studies using within-subjects designs - 31 healthy males in Study 1 and 42 healthy subjects (22 female) in Study 2 - we measured trait negative affect (NA) and presented emotional and neutral pictures. In Study 1, we manipulated endogenous cortisol levels using a speech stressor following encoding. In Study 2, using a randomized placebo-controlled design, we pharmacologically manipulated cortisol levels prior to encoding (0.1mg/kg hydrocortisone vs. saline infused over 30min). Free recall for pictures was subsequently assessed. Trait NA repeatedly moderated the relationship between cortisol and memory formation. Findings suggested the speculative conclusion that the direction of effects may vary by sex. In males, cortisol was related to memory facilitation in subjects with lower Trait NA. Conversely, females with higher Trait NA showed greater cortisol-related increases in memory. Trait NA may be a stable inter-individual difference predicting neurocognitive effects of cortisol during stressors.

The effect of cortisol on emotional responses depends on order of cortisol and placebo administration in a within-subject design.

Cortisol does not exhibit a straightforward relationship with mood states; administration of glucocorticoids to human subjects has produced mixed effects on mood and emotional processing. In this study, participants (N=46) received intravenous hydrocortisone (synthetic cortisol; 0.1mg/kg body weight) and placebo in randomized order over two sessions 48h apart. Following the infusion, participants rated neutral and unpleasant pictures. In Session 1, participants reported elevated negative affect (NA) following the picture-rating task, regardless of treatment. In Session 2, however, only participants who received cortisol (and thus who had received placebo in Session 1) reported elevated NA. Arousal ratings for unpleasant pictures followed a similar pattern. These findings suggest that the effects of cortisol on emotion vary based on situational factors, such as drug administration order or familiarity with the tasks and setting. Such factors can influence cortisol's effects on emotion in two ways: (A) cortisol may only potentiate NA and arousal ratings in the absence of other, overwhelming influences on affect, such as the novelty of the setting and tasks in Session 1; and (B) cortisol in Session 1 may facilitate learning processes (e.g., habituation to the stimuli and setting; extinction of aversive responses) such that emotional responses to the pictures are lessened in Session 2. This interpretation is compatible with a body of literature on the effects of glucocorticoids on learning and memory processes.