Stress and reward: A multimodal assessment of childhood sexual abuse.

Background: Childhood adversity has been found to impact stress and brain reward systems but it is unclear whether interactions between these systems might explain resilient vs. non-resilient trajectories following childhood sexual abuse (CSA). To address this gap, we adopted a multimodal approach in which cortisol reactivity to an acute stressor was assessed in conjunction with behavioral and neural measures of reward responsiveness in females with major depressive disorder (MDD) or no psychiatric disorders (i.e., resilient) who experienced CSA compared to females with and without MDD who did not experience abuse. Methods: Latent Class Mixed Modelling (LCMM) identified classes of adults (n = 62; MAge = 26.48, SD = 5.68) characterized by distinct cortisol trajectories in response to a combined social evaluative cold pressor task. Classes were examined for their history of CSA and resilience as well as behavioral and neural measures of reward responsiveness using 128-channel electroencephalography (event-related potentials and source localization analysis). Results: LCMM analysis identified two distinct classes of individuals with increased (Responders) or blunted (Non-Responders) cortisol reactivity to an acute stressor. Unlike Responders, Non-Responders did not modulate reward responses throughout the stress manipulation. No differences emerged between Responders and Non-Responders in terms of CSA or resilience. However, exploratory results showed that blunted cortisol response and non-modulation of reward responses emerged for those who experienced CSA at a younger age. Conclusions: Co-occurring blunted stress and reward reactivity emerged irrespective of adults' experience of CSA or resilience. However, preliminary findings showed that CSA ending during peripubertal development was associated with blunted cortisol and reward responsiveness. Future research needs to replicate findings in larger samples and could investigate if increasing reward responsiveness during critical times of neurodevelopment could normalize stress reactivity to future stressors and thus promote resilience.

Resting state brain dynamics: Associations with childhood sexual abuse and major depressive disorder.

Early life stress (ELS) and major depressive disorder (MDD) share neural network abnormalities. However, it is unclear how ELS and MDD may separately and/or jointly relate to brain networks, and whether neural differences exist between depressed individuals with vs without ELS. Moreover, prior work evaluated static versus dynamic network properties, a critical gap considering brain networks show changes in coordinated activity over time. Seventy-one unmedicated females with and without childhood sexual abuse (CSA) histories and/or MDD completed a resting state scan and a stress task in which cortisol and affective ratings were collected. Recurring functional network co-activation patterns (CAPs) were examined and time in CAP (number of times each CAP is expressed) and transition frequencies (transitioning between different CAPs) were computed. The effects of MDD and CSA on CAP metrics were examined and CAP metrics were correlated with depression and stress-related variables. Results showed that MDD, but not CSA, related to CAP metrics. Specifically, individuals with MDD (N = 35) relative to HCs (N = 36), spent more time in a posterior default mode (DMN)-frontoparietal network (FPN) CAP and transitioned more frequently between posterior DMN-FPN and prototypical DMN CAPs. Across groups, more time spent in a posterior DMN-FPN CAP and greater DMN-FPN and prototypical DMN CAP transition frequencies were linked to higher rumination. Imbalances between the DMN and the FPN appear central to MDD and might contribute to MDD-related cognitive dysfunction, including rumination. Unexpectedly, CSA did not modulate such dysfunctions, a finding that needs to be replicated by future studies with larger sample sizes.

Machine Learning Identifies Large-Scale Reward-Related Activity Modulated by Dopaminergic Enhancement in Major Depression.

BACKGROUND: Theoretical models have emphasized systems-level abnormalities in major depressive disorder (MDD). For unbiased yet rigorous evaluations of pathophysiological mechanisms underlying MDD, it is critically important to develop data-driven approaches that harness whole-brain data to classify MDD and evaluate possible normalizing effects of targeted interventions. Here, using an experimental therapeutics approach coupled with machine learning, we investigated the effect of a pharmacological challenge aiming to enhance dopaminergic signaling on whole-brain response to reward-related stimuli in MDD. METHODS: Using a double-blind, placebo-controlled design, we analyzed functional magnetic resonance imaging data from 31 unmedicated MDD participants receiving a single dose of 50 mg amisulpride (MDDAmisulpride), 26 MDD participants receiving placebo (MDDPlacebo), and 28 healthy control subjects receiving placebo (HCPlacebo) recruited through two independent studies. An importance-guided machine learning technique for model selection was used on whole-brain functional magnetic resonance imaging data probing reward anticipation and consumption to identify features linked to MDD (MDDPlacebo vs. HCPlacebo) and dopaminergic enhancement (MDDAmisulpride vs. MDDPlacebo). RESULTS: Highly predictive classification models emerged that distinguished MDDPlacebo from HCPlacebo (area under the curve = 0.87) and MDDPlacebo from MDDAmisulpride (area under the curve = 0.89). Although reward-related striatal activation and connectivity were among the most predictive features, the best truncated models based on whole-brain features were significantly better relative to models trained using striatal features only. CONCLUSIONS: Results indicate that in MDD, enhanced dopaminergic signaling restores abnormal activation and connectivity in a widespread network of regions. These findings provide new insights into the pathophysiology of MDD and pharmacological mechanism of antidepressants at the system level in addressing reward processing deficits among depressed individuals.

Frontoinsular Network Markers of Current and Future Adolescent Mood Health.

BACKGROUND: Adolescence is a developmental period in which depression and related mood syndromes often emerge, but few objective markers exist to guide diagnosis or predict symptoms. One potential mood marker is the functioning of frontoinsular networks, which undergo substantial development in adolescence and have been implicated in adult depression. To test this hypothesis, we used task-based neuroimaging to evaluate whether frontoinsular network dysfunction was linked to current and prospective mood health in adolescents. METHODS: Adolescents (n = 40, 13-19 years of age) reporting varying levels of depressive symptom severity performed an emotional working memory task with neuroimaging. Next, teens completed a 2-week follow-up consisting of a daily diary report of negative affect and final report of depressive symptoms (n = 28 adherent). Analyses tested associations between task-related functional connectivity in frontoinsular networks and baseline or prospective measures of mood health over 2-week follow-up. RESULTS: Frontoinsular task response was associated with higher current depression severity (p = .049, ηp2 = .12), increases in future depression severity (p = .018, ηp2 = .23), and more intense and labile negative affect in daily life (ps = .015 to .040, ηp2 = .22 to .30). In particular, hypoconnectivity between insula and lateral prefrontal regions of the frontoparietal network was related to both baseline and prospective mood health, and hyperconnectivity between insula and midline or temporal regions of the default network was related to prospective mood health. CONCLUSIONS: These findings indicate that frontoinsular imbalances are related to both current depression and changes in mood health in the near future and suggest that frontoinsular markers may hold promise as translational tools for risk prediction.

Abnormal frontoinsular-default network dynamics in adolescent depression and rumination: a preliminary resting-state co-activation pattern analysis.

Clinical depression commonly emerges in adolescence, which is also a time of developing cognitive ability and related large-scale functional brain networks implicated in depression. In depressed adults, abnormalities in the dynamic functioning of frontoinsular networks, in particular, have been observed and linked to negative rumination. Thus, network dynamics may provide new insight into teen pathophysiology. Here, adolescents (n = 45, ages 13-19) with varying severity of depressive symptoms completed a resting-state functional MRI scan. Functional networks were evaluated using co-activation pattern analysis to identify whole-brain states of spatial co-activation that recurred across participants and time. Measures included: dwell time (proportion of scan spent in that network state), persistence (volume-to-volume maintenance of a network state), and transitions (frequency of moving from state A to state B). Analyses tested associations between depression or trait rumination and dynamics of network states involving frontoinsular and default network systems. Results indicated that adolescents showing increased dwell time in, and persistence of, a frontoinsular-default network state involving insula, dorsolateral and medial prefrontal cortex, and posterior regions of default network, reported more severe symptoms of depression. Further, adolescents who transitioned more frequently between the frontoinsular-default state and a prototypical default network state reported higher depression. Increased dominance and transition frequency of frontoinsular-default network states were also associated with higher rumination, and rumination mediated the associations between network dynamics and depression. Findings support a model in which abnormal frontoinsular dynamics confer vulnerability to maladaptive introspection, which in turn contributes to symptoms of adolescent depression.

Attention Bias in Rumination and Depression: Cognitive Mechanisms and Brain Networks.

Depressed individuals exhibit biased attention to negative emotional information. However, much remains unknown about (1) the neurocognitive mechanisms of attention bias (e.g., qualities of negative information that evoke attention bias, or functional brain network dynamics that may reflect a propensity for biased attention) and (2) distinctions in the types of attention bias related to different dimensions of depression (e.g., ruminative depression). Here, in 50 women, clinical depression was associated with facilitated processing of negative information only when such information was self-descriptive and task-relevant. However, among depressed individuals, trait rumination was associated with biases towards negative self-descriptive information regardless of task goals, especially when negative self-descriptive material was paired with self-referential images that should be ignored. Attention biases in ruminative depression were mediated by dynamic variability in frontoinsular resting-state functional connectivity. These findings highlight potential cognitive and functional network mechanisms of attention bias specifically related to the ruminative dimension of depression.

5-Fluorouracil "Chemowraps" in the Treatment of Multiple Actinic Keratoses: A Norwich Experience.

INTRODUCTION: Topical 5-fluorouracil (5-FU) has been used to treat actinic keratosis for decades. It has been an important and effective treatment which the patient can self-administer, but is limited by the surface area of skin to be treated (according to the manufacturer's guidelines) of 500 cm(2). Other topical treatments can be painful, or require hospital/health care professional input. The use of 5-FU under occlusion (chemowraps) for large areas of sun-damaged skin on the arms or legs has been described and is a potentially useful treatment option. We describe our experiences with this technique in the Norfolk and Norwich University Hospital Dermatology Department (Norwich, UK). METHODS: Five patients were recruited into this pilot study. Topical 5-FU was applied to sun-damaged limbs under occlusion, and reviewed weekly for response, and local or systemic side effects. Treatment duration was 12-14 weeks. Clinical photography was undertaken prior to, during, and after treatment to document response. RESULTS: We show that there was substantial clinical improvement in the treated skin in our patients. Experienced dermatologists reviewed all the patients, and documented the changes photographically, and by counting lesions. All patients were satisfied with their treatment regimen, and also with the end result; although two did not complete the treatment regimen due to complications not directly attributable to the treatment. CONCLUSION: Topical 5-FU under occlusion (chemowraps) may be a valid treatment option for large areas of sun-damaged skin with field cancerization changes, due to low systemic and local toxicity, and acceptability to patients.