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.

Directional learning, but no spatial mapping by rats performing a navigational task in an inverted orientation.

Previous studies have identified neurons throughout the rat limbic system that fire as a function of the animal's head direction (HD). This HD signal is particularly robust when rats locomote in the horizontal and vertical planes, but is severely attenuated when locomoting upside-down (Calton & Taube, 2005). Given the hypothesis that the HD signal represents an animal's sense of directional heading, we evaluated whether rats could accurately navigate in an inverted (upside-down) orientation. The task required the animals to find an escape hole while locomoting inverted on a circular platform suspended from the ceiling. In Experiment 1, Long-Evans rats were trained to navigate to the escape hole by locomoting from either one or four start points. Interestingly, no animals from the 4-start point group reached criterion, even after 29 days of training. Animals in the 1-start point group reached criterion after about six training sessions. In Experiment 2, probe tests revealed that animals navigating from either 1- or 2-start points utilized distal visual landmarks for accurate orientation. However, subsequent probe tests revealed that their performance was markedly attenuated when navigating to the escape hole from a novel start point. This absence of flexibility while navigating upside-down was confirmed in Experiment 3 where we show that the rats do not learn to reach a place, but instead learn separate trajectories to the target hole(s). Based on these results we argue that inverted navigation primarily involves a simple directional strategy based on visual landmarks.