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.

T1-/T2-weighted ratio reveals no alterations to gray matter myelination in temporal lobe epilepsy.

Short-range functional connectivity in the limbic network is increased in patients with temporal lobe epilepsy (TLE), and recent studies have shown that cortical myelin content correlates with fMRI connectivity. We thus hypothesized that myelin may increase progressively in the epileptic network. We compared T1w/T2w gray matter myelin maps between TLE patients and age-matched controls and assessed relationships between myelin and aging. While both TLE patients and healthy controls exhibited increased T1w/T2w intensity with age, we found no evidence for significant group-level aberrations in overall myelin content or myelin changes through time in TLE.

Quality control procedures and metrics for resting-state functional MRI.

The monitoring and assessment of data quality is an essential step in the acquisition and analysis of functional MRI (fMRI) data. Ideally data quality monitoring is performed while the data are being acquired and the subject is still in the MRI scanner so that any errors can be caught early and addressed. It is also important to perform data quality assessments at multiple points in the processing pipeline. This is particularly true when analyzing datasets with large numbers of subjects, coming from multiple investigators and/or institutions. These quality control procedures should monitor not only the quality of the original and processed data, but also the accuracy and consistency of acquisition parameters. Between-site differences in acquisition parameters can guide the choice of certain processing steps (e.g., resampling from oblique orientations, spatial smoothing). Various quality control metrics can determine what subjects to exclude from the group analyses, and can also guide additional processing steps that may be necessary. This paper describes a combination of qualitative and quantitative assessments to determine the quality of fMRI data. Processing is performed using the AFNI data analysis package. Qualitative assessments include visual inspection of the structural T1-weighted and fMRI echo-planar images, functional connectivity maps, functional connectivity strength, and temporal signal-to-noise maps concatenated from all subjects into a movie format. Quantitative metrics include the acquisition parameters, statistics about the level of subject motion, temporal signal-to-noise ratio, smoothness of the data, and the average functional connectivity strength. These measures are evaluated at different steps in the processing pipeline to catch gross abnormalities in the data, and to determine deviations in acquisition parameters, the alignment to template space, the level of head motion, and other sources of noise. We also evaluate the effect of different quantitative QC cutoffs, specifically the motion censoring threshold, and the impact of bandpass filtering. These qualitative and quantitative metrics can then provide information about what subjects to exclude and what subjects to examine more closely in the analysis of large datasets.

Vagus nerve stimulation in the non-human primate: implantation methodology, characterization of nerve anatomy, target engagement and experimental applications.

BACKGROUND: Vagus nerve stimulation (VNS) is a FDA approved therapy regularly used to treat a variety of neurological disorders that impact the central nervous system (CNS) including epilepsy and stroke. Putatively, the therapeutic efficacy of VNS results from its action on neuromodulatory centers via projections of the vagus nerve to the solitary tract nucleus. Currently, there is not an established large animal model that facilitates detailed mechanistic studies exploring how VNS impacts the function of the CNS, especially during complex behaviors requiring motor action and decision making. METHODS: We describe the anatomical organization, surgical methodology to implant VNS electrodes on the left gagus nerve and characterization of target engagement/neural interface properties in a non-human primate (NHP) model of VNS that permits chronic stimulation over long periods of time. Furthermore, we describe the results of pilot experiments in a small number of NHPs to demonstrate how this preparation might be used in an animal model capable of performing complex motor and decision making tasks. RESULTS: VNS electrode impedance remained constant over months suggesting a stable interface. VNS elicited robust activation of the vagus nerve which resulted in decreases of respiration rate and/or partial pressure of carbon dioxide in expired air, but not changes in heart rate in both awake and anesthetized NHPs. CONCLUSIONS: We anticipate that this preparation will be very useful to study the mechanisms underlying the effects of VNS for the treatment of conditions such as epilepsy and depression, for which VNS is extensively used, as well as for the study of the neurobiological basis underlying higher order functions such as learning and memory.

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.

Reduction of Motion Artifacts in Functional Connectivity Resulting from Infrequent Large Motion.

Introduction: Subject head motion is an ongoing challenge in functional magnetic resonance imaging, particularly in the estimation of functional connectivity. Infants (1-month old) scanned during nonsedated sleep often have occasional but large movements of several millimeters separated by periods with relatively little movement. This results in residual signal changes even after image realignment and can distort estimates of functional connectivity. A new motion correction technique, JumpCor, is introduced to reduce the effects of this motion and compared to other existing techniques. Methods: Different approaches for reducing residual motion artifacts after image realignment were compared both in actual and simulated data: JumpCor, regressing out the estimated subject motion, and regressing out the average white matter, cerebrospinal fluid (CSF), and global signals and their temporal derivatives. Results: Motion-related signal changes resulting from infrequent large motion were significantly reduced both by regressing out the estimated motion parameters and by JumpCor. Furthermore, JumpCor significantly reduced artifacts and improved the quality of functional connectivity estimates when combined with typical preprocessing approaches. Discussion: Motion-related signal changes resulting from occasional large motion can be effectively corrected using JumpCor and to a certain extent also by regressing out the estimated motion. This technique should reduce the data loss in studies where participants exhibit this type of motion, such as sleeping infants.

Cortisol effects on brain functional connectivity during emotion processing in women with depression.

BACKGROUND: Depression is associated with altered functional connectivity and altered cortisol sensitivity, but the effects of cortisol on functional connectivity in depression are unknown. Previous research shows that brief cortisol augmentation (CORT) has beneficial neurocognitive effects in depression. METHODS: We investigated the effects of CORT (20mg oral cortisol) on functional connectivity during emotion processing in women with depression. Participants included 75 women with no depression or a depressive disorder. In a double-blind, crossover study, we used functional magnetic resonance imaging to measure effects of CORT vs. placebo on task-based functional connectivity during presentation of emotionally-laden images. We performed psychophysiological interaction (PPI) to test interactions among depression severity, cortisol administration, and task-dependent functional connectivity using the hippocampus and amygdala as seeds. RESULTS: During the presentation of negative images, CORT (vs. placebo) increased functional connectivity between the hippocampus and putamen in association with depression severity. During the presentation of positive pictures CORT increased functional connectivity between the hippocampus and middle frontal gyrus as well as superior temporal gyrus in association with depression. LIMITATIONS: Because cortisol was pharmacologically manipulated, results cannot be extrapolated to endogenous increases in cortisol levels. The sample did not permit investigation of differences due to race, ethnicity, or sex. Co-morbidities such as anxiety or PTSD were not accounted for. CONCLUSIONS: The results suggest that CORT has normalizing effects on task-dependent functional connectivity in women with depression during emotion processing. Increasing cortisol availability or signaling may have therapeutic benefits within affective disorders.

A Pilot Adaptive Neurofeedback Investigation of the Neural Mechanisms of Implicit Emotion Regulation Among Women With PTSD.

Posttraumatic stress disorder (PTSD) is widely associated with deficits in implicit emotion regulation. Recently, adaptive fMRI neurofeedback (A-NF) has been developed as a methodology that offers a unique probe of brain networks that mediate implicit emotion regulation and their impairment in PTSD. We designed an A-NF paradigm in which difficulty of an emotional conflict task (i.e., embedding trauma distractors onto a neutral target stimulus) was controlled by a whole-brain classifier trained to differentiate attention to the trauma distractor vs. target. We exploited this methodology to test whether PTSD was associated with: (1) an altered brain state that differentiates attention towards vs. away from trauma cues; and (2) an altered ability to use concurrent feedback about brain states during an implicit emotion regulation task. Adult women with a current diagnosis of PTSD (n = 10) and healthy control (n = 9) women participated in this task during 3T fMRI. During two initial non-feedback runs used to train a whole-brain classifier, we observed: (1) poorer attention performance in PTSD; and (2) a linear relationship between brain state discrimination and attention performance, which was significantly attenuated among the PTSD group when the task contained trauma cues. During the A-NF phase, the PTSD group demonstrated poorer ability to regulate brain states as per attention instructions, and this poorer ability was related to PTSD symptom severity. Further, PTSD was associated with the heightened encoding of feedback in the insula and hippocampus. These results suggest a novel understanding of whole-brain states and their regulation that underlie emotion regulation deficits in PTSD.

Mindfulness video game improves connectivity of the fronto-parietal attentional network in adolescents: A multi-modal imaging study.

Mindfulness training has been shown to improve attention and change the underlying brain substrates in adults. Most mindfulness training programs involve a myriad of techniques, and it is difficult to attribute changes to any particular aspect of the program. Here, we created a video game, Tenacity, which models a specific mindfulness technique - focused attention on one's breathing - and assessed its potential to train an attentional network in adolescents. A combined analysis of resting state functional connectivity (rs-FC) and diffusion tensor imaging (DTI) yielded convergent results - change in communication within the left fronto-parietal network after two weeks of playing Tenacity compared to a control game. Rs-FC analysis showed greater connectivity between left dorsolateral prefrontal cortex (dlPFC) and left inferior parietal cortex (IPC) in the Tenacity group. Importantly, changes in left dlPFC - IPC rs-FC and changes in structural connectivity of the white matter tract that connects these regions -left superior longitudinal fasiculus (SLF) - were associated with changes in performance on an attention task. Finally, changes in left dlPFC - IPC rs-FC correlated with the change in left SLF structural connectivity as measured by fractional anisotropy (FA) in the Tenacity group only.

Changes in Endogenous Dopamine Induced by Methylphenidate Predict Functional Connectivity in Nonhuman Primates.

Dopamine (DA) levels in the striatum are increased by many therapeutic drugs, such as methylphenidate (MPH), which also alters behavioral and cognitive functions thought to be controlled by the PFC dose-dependently. We linked DA changes and functional connectivity (FC) using simultaneous [18F]fallypride PET and resting-state fMRI in awake male rhesus monkeys after oral administration of various doses of MPH. We found a negative correlation between [18F]fallypride nondisplaceable binding potential (BPND) and MPH dose in the head of the caudate (hCd), demonstrating increased extracellular DA resulting from MPH administration. The decreased BPND was negatively correlated with FC between the hCd and the PFC. Subsequent voxelwise analyses revealed negative correlations with FC between the hCd and the dorsolateral PFC, hippocampus, and precuneus. These results, showing that MPH-induced changes in DA levels in the hCd predict resting-state FC, shed light on a mechanism by which changes in striatal DA could influence function in the PFC.SIGNIFICANCE STATEMENT Dopamine transmission is thought to play an essential role in shaping large scale-neural networks that underlie cognitive functions. It is the target of therapeutic drugs, such as methylphenidate (Ritalin), which blocks the dopamine transporter, thereby increasing extracellular dopamine levels. Methylphenidate is used extensively to treat attention deficit hyperactivity disorder, even though its effects on cognitive functions and their underlying neural mechanisms are not well understood. To date, little is known about the link between changes in dopamine levels and changes in functional brain organization. Using simultaneous PET/MR imaging, we show that methylphenidate-induced changes in endogenous dopamine levels in the head of the caudate predict changes in resting-state functional connectivity between this structure and the prefrontal cortex, precuneus, and hippocampus.

Association of Prenatal Maternal Depression and Anxiety Symptoms With Infant White Matter Microstructure.

Importance: Maternal depression and anxiety can have deleterious and lifelong consequences on child development. However, many aspects of the association of early brain development with maternal symptoms remain unclear. Understanding the timing of potential neurobiological alterations holds inherent value for the development and evaluation of future therapies and interventions. Objective: To examine the association between exposure to prenatal maternal depression and anxiety symptoms and offspring white matter microstructure at 1 month of age. Design, Setting, and Participants: This cohort study of 101 mother-infant dyads used a composite of depression and anxiety symptoms measured in mothers during the third trimester of pregnancy and measures of white matter microstructure characterized in the mothers' 1-month offspring using diffusion tensor imaging and neurite orientation dispersion and density imaging performed from October 1, 2014, to November 30, 2016. Magnetic resonance imaging was performed at an academic research facility during natural, nonsedated sleep. Main Outcomes and Measures: Brain mapping algorithms and statistical models were used to evaluate the association between maternal depression and anxiety and 1-month infant white matter microstructure as measured by diffusion tensor imaging and neurite orientation dispersion and density imaging findings. Results: In the 101 mother-infant dyads (mean [SD] age of mothers, 33.22 [3.99] years; mean age of infants at magnetic resonance imaging, 33.07 days [range, 18-50 days]; 92 white mothers [91.1%]; 53 male infants [52.5%]), lower 1-month white matter microstructure (decreased neurite density and increased mean, radial, and axial diffusivity) was associated in right frontal white matter microstructure with higher prenatal maternal symptoms of depression and anxiety. Significant sex × symptom interactions with measures of white matter microstructure were also observed, suggesting that white matter development may be differentially sensitive to maternal depression and anxiety symptoms in males and females during the prenatal period. Conclusions and Relevance: These data highlight the importance of the prenatal period to early brain development and suggest that the underlying white matter microstructure is associated with the continuum of prenatal maternal depression and anxiety symptoms.

Functional Connectivity within the Primate Extended Amygdala Is Heritable and Associated with Early-Life Anxious Temperament.

Children with an extremely inhibited, anxious temperament (AT) are at increased risk for anxiety disorders and depression. Using a rhesus monkey model of early-life AT, we previously demonstrated that metabolism in the central extended amygdala (EAc), including the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST), is associated with trait-like variation in AT. Here, we use fMRI to examine relationships between Ce-BST functional connectivity and AT in a large multigenerational family pedigree of rhesus monkeys (n = 170 females and 208 males). Results demonstrate that Ce-BST functional connectivity is heritable, accounts for a significant but modest portion of the variance in AT, and is coheritable with AT. Interestingly, Ce-BST functional connectivity and AT-related BST metabolism were not correlated and accounted for non-overlapping variance in AT. Exploratory analyses suggest that Ce-BST functional connectivity is associated with metabolism in the hypothalamus and periaqueductal gray. Together, these results suggest the importance of coordinated function within the EAc for determining individual differences in AT and metabolism in brain regions associated with its behavioral and neuroendocrine components.SIGNIFICANCE STATEMENT Anxiety disorders directly impact the lives of nearly one in five people, accounting for substantial worldwide suffering and disability. Here, we use a nonhuman primate model of anxious temperament (AT) to understand the neurobiology underlying the early-life risk to develop anxiety disorders. Leveraging the same kinds of neuroimaging measures routinely used in human studies, we demonstrate that coordinated activation between the central nucleus of the amygdala and the bed nucleus of the stria terminalis is correlated with, and coinherited with, early-life AT. Understanding how these central extended amygdala regions work together to produce extreme anxiety provides a neural target for early-life interventions with the promise of preventing lifelong disability in at-risk children.

Association of acute depressive symptoms and functional connectivity of emotional processing regions following sport-related concussion.

Acute mood disturbance following sport-related concussion is common and is known to adversely affect post-concussion symptoms and recovery. The physiological underpinnings of depressive symptoms following concussion, however, are relatively understudied. We hypothesized that functional connectivity of the emotional processing network would be altered in concussed athletes and associated with the severity of depressive symptoms following concussion. Forty-three concussed collegiate athletes were assessed at approximately one day (N = 34), one week (N = 34), and one month post-concussion (N = 30). Fifty-one healthy contact-sport athletes served as controls and completed a single visit. The Hamilton Rating Scale for Depression (HAM-D) was used to measure depressive symptoms. Resting state fMRI data was collected on a 3 T scanner (TR = 2 s) and functional connectivity was calculated in a meta-analytically derived network of regions associated with emotional processing. Concussed athletes had elevated depressive symptoms across the first month post-concussion relative to control athletes, but showed partial recovery by one month relative to more acute visits (ps < 0.05). Concussed athletes had significantly different connectivity in regions associated with emotional processing at one month post-concussion relative to one day post-concussion (p = 0.002) and relative to controls (p = 0.003), with higher connectivity between default mode and attention regions being common across analyses. Additionally, depressive symptoms in concussed athletes at one day (p = 0.003) and one week post-concussion (p = 7 × 10-8) were inversely correlated with connectivity between attention (e.g., right anterior insula) and default mode regions (e.g., medial prefrontal cortex). Finally, the relationships with HAM-D scores were not driven by a general increase in somatic complaints captured by the HAM-D, but were strongly associated with mood-specific HAM-D items. These results suggest that connectivity of emotional processing regions is associated with acute mood disturbance following sport-related concussion. Increased connectivity between attention and default mode regions may reflect compensatory mechanisms.

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.

Bayesian convolutional neural network based MRI brain extraction on nonhuman primates.

Brain extraction or skull stripping of magnetic resonance images (MRI) is an essential step in neuroimaging studies, the accuracy of which can severely affect subsequent image processing procedures. Current automatic brain extraction methods demonstrate good results on human brains, but are often far from satisfactory on nonhuman primates, which are a necessary part of neuroscience research. To overcome the challenges of brain extraction in nonhuman primates, we propose a fully-automated brain extraction pipeline combining deep Bayesian convolutional neural network (CNN) and fully connected three-dimensional (3D) conditional random field (CRF). The deep Bayesian CNN, Bayesian SegNet, is used as the core segmentation engine. As a probabilistic network, it is not only able to perform accurate high-resolution pixel-wise brain segmentation, but also capable of measuring the model uncertainty by Monte Carlo sampling with dropout in the testing stage. Then, fully connected 3D CRF is used to refine the probability result from Bayesian SegNet in the whole 3D context of the brain volume. The proposed method was evaluated with a manually brain-extracted dataset comprising T1w images of 100 nonhuman primates. Our method outperforms six popular publicly available brain extraction packages and three well-established deep learning based methods with a mean Dice coefficient of 0.985 and a mean average symmetric surface distance of 0.220 mm. A better performance against all the compared methods was verified by statistical tests (all p-values < 10-4, two-sided, Bonferroni corrected). The maximum uncertainty of the model on nonhuman primate brain extraction has a mean value of 0.116 across all the 100 subjects. The behavior of the uncertainty was also studied, which shows the uncertainty increases as the training set size decreases, the number of inconsistent labels in the training set increases, or the inconsistency between the training set and the testing set increases.

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 correlates of video game empathy training in adolescents: a randomized trial.

The ability to understand emotional experiences of others, empathy, is a valuable skill for effective social interactions. Various types of training increase empathy in adolescents, but their impact on brain circuits underlying empathy has not been examined. Video games provide a unique medium familiar and engaging to adolescents and can be used to deliver training at scale. We developed an empathy training video game, Crystals of Kaydor (Crystals), and investigated whether playing Crystals increases empathic accuracy (EA) and related brain activation in adolescents (N = 74; 27 female; mean age(sd) = 12.8(0.7) years; age range 11-14 years). Participants completed a resting state functional MRI (rs-fMRI) scan and an EA task during an fMRI scan before and after 2 weeks of daily gameplay with either the empathy training game, Crystals (N = 34), or the commercial video game Bastion (N = 40), an active control condition. There were no group differences in EA improvement following gameplay, however, engagement with training aspects of Crystals was associated with a higher increase in EA-related activation in right temporoparietal junction following gameplay. Moreover, rs-fMRI connectivity in empathy-related brain circuits (posterior cingulate-medial prefrontal cortex; MPFC) was stronger after Crystals gameplay compared to Bastion. The more individuals' EA increased following Crystals versus Bastion, the stronger their rs-fMRI connectivity in brain circuits relevant for emotion regulation (amygdala-MPFC). These findings suggest that a video game designed to increase empathic accuracy produces behaviorally-relevant, functional neural changes in fewer than 6 h of gameplay in adolescents.