Translational In Vivo Assays in Behavioral Biology.

The failure of preclinical research to advance successful candidate medications in psychiatry has created a paradigmatic crisis in psychiatry. The Research Domain Criteria (RDoC) initiative was designed to remedy this situation with a neuroscience-based approach that employs multimodal and cross-species in vivo methodology to increase the probability of translational findings and, consequently, drug discovery. The present review underscores the feasibility of this methodological approach by briefly reviewing, first, the use of multidimensional and cross-species methodologies in traditional behavioral pharmacology and, subsequently, the utility of this approach in contemporary neuroimaging and electrophysiology research-with a focus on the value of functionally homologous studies in nonhuman and human subjects. The final section provides a brief review of the RDoC, with a focus on the potential strengths and weaknesses of its domain-based underpinnings. Optimistically, this mechanistic and multidimensional approach in neuropsychiatric research will lead to novel therapeutics for the management of neuropsychiatric disorders.

Preclinical animal models and assays of neuropsychiatric disorders: Old problems and New Vistas - introduction to the special issue.

Preclinical research is an essential aspect of biomedical science that aids in clarifying the pathophysiology of underlying illness and devising new treatments. This special issues brings together original research and review papers that pertain to the development of novel models and behavioral assays of symptoms of neuropsychiatric disorders, which may help to refine preclinical studies and to improve their translatability to the human condition.

The neurobiology of aesthetic chills: How bodily sensations shape emotional experiences.

The phenomenon of aesthetic chills-shivers and goosebumps associated with either rewarding or threatening stimuli-offers a unique window into the brain basis of conscious reward because of their universal nature and simultaneous subjective and physical counterparts. Elucidating the neural mechanisms underlying aesthetic chills can reveal fundamental insights about emotion, consciousness, and the embodied mind. What is the precise timing and mechanism of bodily feedback in emotional experience? How are conscious feelings and motivations generated from interoceptive predictions? What is the role of uncertainty and precision signaling in shaping emotions? How does the brain distinguish and balance processing of rewards versus threats? We review neuroimaging evidence and highlight key questions for understanding how bodily sensations shape conscious feelings. This research stands to advance models of brain-body interactions shaping affect and may lead to novel nonpharmacological interventions for disorders of motivation and pleasure.

A core component of psychological therapy causes adaptive changes in computational learning mechanisms.

BACKGROUND: Cognitive distancing is an emotion regulation strategy commonly used in psychological treatment of various mental health disorders, but its therapeutic mechanisms are unknown. METHODS: 935 participants completed an online reinforcement learning task involving choices between pairs of symbols with differing reward contingencies. Half (49.1%) of the sample was randomised to a cognitive self-distancing intervention and were trained to regulate or 'take a step back' from their emotional response to feedback throughout. Established computational (Q-learning) models were then fit to individuals' choices to derive reinforcement learning parameters capturing clarity of choice values (inverse temperature) and their sensitivity to positive and negative feedback (learning rates). RESULTS: Cognitive distancing improved task performance, including when participants were later tested on novel combinations of symbols without feedback. Group differences in computational model-derived parameters revealed that cognitive distancing resulted in clearer representations of option values (estimated 0.17 higher inverse temperatures). Simultaneously, distancing caused increased sensitivity to negative feedback (estimated 19% higher loss learning rates). Exploratory analyses suggested this resulted from an evolving shift in strategy by distanced participants: initially, choices were more determined by expected value differences between symbols, but as the task progressed, they became more sensitive to negative feedback, with evidence for a difference strongest by the end of training. CONCLUSIONS: Adaptive effects on the computations that underlie learning from reward and loss may explain the therapeutic benefits of cognitive distancing. Over time and with practice, cognitive distancing may improve symptoms of mental health disorders by promoting more effective engagement with negative information.

Associations of alcohol and cannabis use with change in posttraumatic stress disorder and depression symptoms over time in recently trauma-exposed individuals.

BACKGROUND: Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians. METHODS: In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance. RESULTS: Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12. CONCLUSIONS: Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.

Distinct profiles of anhedonia and reward processing and their prospective associations with quality of life among individuals with mood disorders.

Leading professional health bodies have called for the wider adoption of Patient Reported Outcome Measures, such as quality of life, in research and clinical practice as a means for understanding why the global burden of depression continues to climb despite increased rates of treatment use. Here, we examined whether anhedonia-an often recalcitrant and impairing symptom of depression-along with its neural correlates, was associated with longitudinal changes in patient-reported quality of life among individuals seeking treatment for mood disorders. We recruited 112 participants, including n = 80 individuals with mood disorders (58 unipolar, 22 bipolar) and n = 32 healthy controls (63.4% female). We assessed anhedonia severity along with two electroencephalographic markers of neural reward responsiveness (scalp-level 'Reward Positivity' amplitude and source-localized reward-related activation in the dorsal anterior cingulate cortex), and assessed quality of life at baseline, 3- and 6-month follow-up. Anhedonia emerged as a robust correlate of quality of life cross-sectionally and longitudinally among individuals with mood disorders. Furthermore, increased neural reward responsiveness at baseline was associated with greater improvements in quality of life over time, and this improvement was mediated by longitudinal improvements in anhedonia severity. Finally, differences in quality of life observed between individuals with unipolar and bipolar mood disorders were mediated by differences in anhedonia severity. Our findings indicate that anhedonia and its reward-related neural correlates are linked to variability in quality of life over time in individuals with mood disorders. Treatments capable of improving anhedonia and normalizing brain reward function may be necessary for improving broader health outcomes for individuals seeking treatment for depression.ClinicalTrials.gov identifier: NCT01976975.

Structural inequities contribute to racial/ethnic differences in neurophysiological tone, but not threat reactivity, after trauma exposure.

Considerable racial/ethnic disparities persist in exposure to life stressors and socioeconomic resources that can directly affect threat neurocircuitry, particularly the amygdala, that partially mediates susceptibility to adverse posttraumatic outcomes. Limited work to date, however, has investigated potential racial/ethnic variability in amygdala reactivity or connectivity that may in turn be related to outcomes such as post-traumatic stress disorder (PTSD). Participants from the AURORA study (n = 283), a multisite longitudinal study of trauma outcomes, completed functional magnetic resonance imaging and psychophysiology within approximately two-weeks of trauma exposure. Seed-based amygdala connectivity and amygdala reactivity during passive viewing of fearful and neutral faces were assessed during fMRI. Physiological activity was assessed during Pavlovian threat conditioning. Participants also reported the severity of posttraumatic symptoms 3 and 6 months after trauma. Black individuals showed lower baseline skin conductance levels and startle compared to White individuals, but no differences were observed in physiological reactions to threat. Further, Hispanic and Black participants showed greater amygdala connectivity to regions including the dorsolateral prefrontal cortex (PFC), dorsal anterior cingulate cortex, insula, and cerebellum compared to White participants. No differences were observed in amygdala reactivity to threat. Amygdala connectivity was associated with 3-month PTSD symptoms, but the associations differed by racial/ethnic group and were partly driven by group differences in structural inequities. The present findings suggest variability in tonic neurophysiological arousal in the early aftermath of trauma between racial/ethnic groups, driven by structural inequality, impacts neural processes that mediate susceptibility to later PTSD symptoms.

Internal capsule microstructure mediates the relationship between childhood maltreatment and PTSD following adulthood trauma exposure.

Childhood trauma is a known risk factor for trauma and stress-related disorders in adulthood. However, limited research has investigated the impact of childhood trauma on brain structure linked to later posttraumatic dysfunction. We investigated the effect of childhood trauma on white matter microstructure after recent trauma and its relationship with future posttraumatic dysfunction among trauma-exposed adult participants (n = 202) recruited from emergency departments as part of the AURORA Study. Participants completed self-report scales assessing prior childhood maltreatment within 2-weeks in addition to assessments of PTSD, depression, anxiety, and dissociation symptoms within 6-months of their traumatic event. Fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI) collected at 2-weeks and 6-months was used to index white matter microstructure. Childhood maltreatment load predicted 6-month PTSD symptoms (b = 1.75, SE = 0.78, 95% CI = [0.20, 3.29]) and inversely varied with FA in the bilateral internal capsule (IC) at 2-weeks (p = 0.0294, FDR corrected) and 6-months (p = 0.0238, FDR corrected). We observed a significant indirect effect of childhood maltreatment load on 6-month PTSD symptoms through 2-week IC microstructure (b = 0.37, Boot SE = 0.18, 95% CI = [0.05, 0.76]) that fully mediated the effect of childhood maltreatment load on PCL-5 scores (b = 1.37, SE = 0.79, 95% CI = [-0.18, 2.93]). IC microstructure did not mediate relationships between childhood maltreatment and depressive, anxiety, or dissociative symptomatology. Our findings suggest a unique role for IC microstructure as a stable neural pathway between childhood trauma and future PTSD symptoms following recent trauma. Notably, our work did not support roles of white matter tracts previously found to vary with PTSD symptoms and childhood trauma exposure, including the cingulum bundle, uncinate fasciculus, and corpus callosum. Given the IC contains sensory fibers linked to perception and motor control, childhood maltreatment might impact the neural circuits that relay and process threat-related inputs and responses to trauma.

Stress exposure in at-risk, depressed, and suicidal adolescents.

BACKGROUND: Stress exposure contributes to the onset, maintenance, and recurrence of major depressive disorder (MDD) in adolescents. However, the precise stress facets (e.g. chronicity, domain) most strongly linked to outcomes at different stages along the depression severity continuum remain unclear. Across two studies, chronic and episodic stressors were comprehensively assessed among: (a) healthy youth with (High-Risk [HR]) and without (Low-Risk [LR]) a maternal history of MDD and (b) adolescents with current MDD and suicide ideation and healthy controls (HC). METHOD: Study 1 included LR (n = 65) and HR (n = 22) 12- to 14-year-olds (49 females; 56.32%) with no lifetime history of mental disorders. Study 2 enrolled 87 mid-to-late adolescents (64 females; 73.56%), including 57 MDD youth from a short-term intensive treatment service and 30 HCs from the community. All depressed youth reported recent suicide ideation; some had no lifetime history suicide attempts (SI; n = 31) and others reported at least one past year attempt (SA; n = 26). The Life Events and Difficulties Schedule was used to capture stressor severity in both studies. RESULTS: We used multiple linear regression models that adjusted for demographic and clinical covariates. Being in the HR versus LR group was associated with more severe chronic (ß = .22, CI95 = 0.01-0.42, p = .041), independent (ß = .34, CI95 = 0.12-0.56, p = .003), and interpersonal (ß = .23, CI95 = 0.004-0.45, p = .047) stress severity. By contrast, the MDD group reported significantly more severe chronic (ß = .62, CI95 = 0.45-0.79, p < .001) and dependent (ß = .41, CI95 = 0.21-0.61, p < .001) stress than the HC group, but not independent (p = .083) stress. Stress severity did not differ between recent attempters versus youth who reported suicide ideation alone (SA vs. SI contrast). However, the SA group reported a higher rate of targeted rejection events (RR = 3.53, CI95 = 1.17-10.70, p = .026). CONCLUSIONS: Our findings clarify the stressor features that may most strongly contribute to adolescent depression and its clinical correlates at two important points along depression's clinical course.

Smoking Progression and Nicotine-Enhanced Reward Sensitivity Predicted by Resting-State Functional Connectivity in Salience and Executive Control Networks.

INTRODUCTION: The neural underpinnings underlying individual differences in nicotine-enhanced reward sensitivity and smoking progression are poorly understood. Thus, we investigated whether brain resting-state functional connectivity (rsFC) during smoking abstinence predicts nicotine-enhanced reward sensitivity and smoking progression in young light smokers. We hypothesized that high rsFC between brain areas with high densities of nicotinic receptors (insula, anterior cingulate cortex [ACC], hippocampus, thalamus) and areas involved in reward-seeking (nucleus accumbens [NAcc], prefrontal cortex [PFC]) would predict nicotine-enhanced reward sensitivity and smoking progression. METHODS: Young light smokers (N=64, age 18-24, M = 1.89 cigarettes/day) participated in the study. These individuals smoked between 5 to 35 cigarettes per week and lifetime use never exceeded 35 cigarettes per week. Their rsFC was assessed using functional magnetic resonance imaging after 14-hour nicotine-deprivation. Subjects also completed a probabilistic reward task after smoking a placebo on one day and a regular cigarette on another day. RESULTS: The probabilistic-reward-task assessed greater nicotine-enhanced reward sensitivity was associated with greater rsFC between the right anterior PFC and right NAcc, but with reduced rsFC between the ACC and left inferior prefrontal gyrus and the insula and ACC. Decreased rsFC within the salience network (ACC and insula) predicted increased smoking progression across 18 months and greater nicotine-enhanced reward sensitivity. CONCLUSIONS: These findings provide the first evidence that differences in rsFCs in young light smokers are associated with nicotine-enhanced reward sensitivity and smoking progression. IMPLICATIONS: Weaker rsFC within the salience network predicted greater nicotine-enhanced reward sensitivity and smoking progression. These findings suggest that salience network rsFC and drug-enhanced reward sensitivity may be useful tools and potential endophenotypes for reward sensitivity and drug-dependence research.

Hippocampal Threat Reactivity Interacts with Physiological Arousal to Predict PTSD Symptoms.

Hippocampal impairments are reliably associated with post-traumatic stress disorder (PTSD); however, little research has characterized how increased threat-sensitivity may interact with arousal responses to alter hippocampal reactivity, and further how these interactions relate to the sequelae of trauma-related symptoms. In a sample of individuals recently exposed to trauma (N=116, 76 Female), we found that PTSD symptoms at 2-weeks were associated with decreased hippocampal responses to threat as assessed with functional magnetic resonance imaging (fMRI). Further, the relationship between hippocampal threat sensitivity and PTSD symptomology only emerged in individuals who showed transient, high threat-related arousal, as assayed by an independently collected measure of Fear Potentiated Startle. Collectively, our finding suggests that development of PTSD is associated with threat-related decreases in hippocampal function, due to increases in fear-potentiated arousal.Significance StatementAlterations in hippocampal function linked to threat-related arousal are reliably associated with post-traumatic stress disorder (PTSD); however, how these alterations relate to the sequelae of trauma-related symptoms is unknown. Prior models based on non-trauma samples suggest that arousal may impact hippocampal neurophysiology leading to maladaptive behavior. Here we show that decreased hippocampal threat sensitivity interacts with fear-potentiated startle to predict PTSD symptoms. Specifically, individuals with high fear-potentiated startle and low, transient hippocampal threat sensitivity showed the greatest PTSD symptomology. These findings bridge literatures of threat-related arousal and hippocampal function to better understand PTSD risk.

Limited impacts of biogenetic messaging on neural correlates of cognitive control and beliefs about depression.

During the past 60 years, perceptions about the origins of mental illness have shifted toward a biomedical model, depicting depression as a biological disorder caused by genetic abnormalities and/or chemical imbalances. Despite benevolent intentions to reduce stigma, biogenetic messages promote prognostic pessimism, reduce feelings of agency, and alter treatment preferences, motivations, and expectations. However, no research has examined how these messages influence neural markers of ruminative activity or decision-making, a gap this study sought to fill. In this pre-registered, clinical trial (NCT03998748), 49 participants with current or past depressive experiences completed a sham saliva test and were randomly assigned to receive feedback that they either have (gene-present; n = 24) or do not have (gene-absent; n = 25) a genetic predisposition to depression. Before and after receiving the feedback, resting-state activity and neural correlates of cognitive control (error-related negativity [ERN] and error positivity [Pe]) were measured using high-density electroencephalogram (EEG). Participants also completed self-report measures of beliefs about the malleability and prognosis of depression and treatment motivation. Contrary to hypotheses, biogenetic feedback did not alter perceptions or beliefs about depression, nor did it alter EEG markers of self-directed rumination nor neurophysiological correlates of cognitive control. Explanations of these null findings are discussed in the context of prior studies.

Cognitive effort-based decision-making in major depressive disorder.

BACKGROUND: The association between major depressive disorder and motivation to invest cognitive effort for rewards is unclear. One reason might be that prior tasks of cognitive effort-based decision-making are limited by potential confounds such as physical effort and temporal delay discounting. METHODS: To address these interpretive challenges, we developed a new task - the Cognitive Effort Motivation Task - to assess one's willingness to exert cognitive effort for rewards. Cognitive effort was manipulated by varying the number of items (1, 2, 3, 4, 5) kept in spatial working memory. Twenty-six depressed patients and 44 healthy controls went through an extensive learning session where they experienced each possible effort level 10 times. They were then asked to make a series of choices between performing a fixed low-effort-low-reward or variable higher-effort-higher-reward option during the task. RESULTS: Both groups found the task more cognitively (but not physically) effortful when effort level increased, but they still achieved ⩾80% accuracy on each effort level during training and >95% overall accuracy during the actual task. Computational modelling revealed that a parabolic model best accounted for subjects' data, indicating that higher-effort levels had a greater impact on devaluing rewards than lower levels. These procedures also revealed that MDD patients discounted rewards more steeply by effort and were less willing to exert cognitive effort for rewards compared to healthy participants. CONCLUSIONS: These findings provide empirical evidence to show, without confounds of other variables, that depressed patients have impaired cognitive effort motivation compared to the general population.

Resting state connectivity predictors of symptom change during gaze-contingent music reward therapy of social anxiety disorder.

BACKGROUND: Social anxiety disorder (SAD) is common, first-line treatments are often only partially effective, and reliable predictors of treatment response are lacking. Here, we assessed resting state functional connectivity (rsFC) at pre-treatment and during early treatment as a potential predictor of response to a novel attention bias modification procedure, gaze-contingent music reward therapy (GC-MRT). METHODS: Thirty-two adults with SAD were treated with GC-MRT. rsFC was assessed with multi-voxel pattern analysis of fMRI at pre-treatment and after 2-3 weeks. For comparison, 20 healthy control (HC) participants without treatment were assessed twice for rsFC over the same time period. All SAD participants underwent clinical evaluation at pre-treatment, early-treatment (week 2-3), and post-treatment. RESULTS: SAD and depressive symptoms improved significantly from pre-treatment to post-treatment. After 2-3 weeks of treatment, decreased connectivity between the executive control network (ECN) and salience network (SN), and increased connectivity within the ECN predicted improvement in SAD and depressive symptoms at week 8. Increased connectivity between the ECN and default mode network (DMN) predicted greater improvement in SAD but not depressive symptoms at week 8. Connectivity within the DMN decreased significantly after 2-3 weeks of treatment in the SAD group, while no changes were found in HC over the same time interval. CONCLUSION: We identified early changes in rsFC during a course of GC-MRT for SAD that predicted symptom change. Connectivity changes within the ECN, ECN-DMN, and ECN-SN may be related to mechanisms underlying the clinical effects of GC-MRT and warrant further study in controlled trials.

Reduced anhedonia following internet-based cognitive-behavioral therapy for depression is mediated by enhanced reward circuit activation.

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent psychiatric condition, yet many patients do not receive adequate treatment. Novel and highly scalable interventions such as internet-based cognitive-behavioral-therapy (iCBT) may help to address this treatment gap. Anhedonia, a hallmark symptom of MDD that refers to diminished interest and ability to experience pleasure, has been associated with reduced reactivity in a neural reward circuit that includes medial prefrontal and striatal brain regions. Whether iCBT can reduce anhedonia severity in MDD patients, and whether these therapeutic effects are accompanied by enhanced reward circuit reactivity has yet to be examined. METHODS: Fifty-two MDD patients were randomly assigned to either 10-week iCBT (n = 26) or monitored attention control (MAC, n = 26) programs. All patients completed pre- and post-treatment assessments of anhedonia (Snaith-Hamilton Pleasure Scale; SHAPS) and reward circuit reactivity [monetary incentive delay (MID) task during functional magnetic resonance imaging (fMRI)]. Healthy control participants (n = 42) also underwent two fMRI scans while completing the MID task 10 weeks apart. RESULTS: Both iCBT and MAC groups exhibited a reduction in anhedonia severity post-treatment. Nevertheless, only the iCBT group exhibited enhanced nucleus accumbens (Nacc) and subgenual anterior cingulate cortex (sgACC) activation and functional connectivity from pre- to post-treatment in response to reward feedback. Enhanced Nacc and sgACC activations were associated with reduced anhedonia severity following iCBT treatment, with enhanced Nacc activation also mediating the reduction in anhedonia severity post-treatment. CONCLUSIONS: These findings suggest that increased reward circuit reactivity may contribute to a reduction in anhedonia severity following iCBT treatment for depression.

Predicting states of elevated negative affect in adolescents from smartphone sensors: a novel personalized machine learning approach.

BACKGROUND: Adolescence is characterized by profound change, including increases in negative emotions. Approximately 84% of American adolescents own a smartphone, which can continuously and unobtrusively track variables potentially predictive of heightened negative emotions (e.g. activity levels, location, pattern of phone usage). The extent to which built-in smartphone sensors can reliably predict states of elevated negative affect in adolescents is an open question. METHODS: Adolescent participants (n = 22; ages 13-18) with low to high levels of depressive symptoms were followed for 15 weeks using a combination of ecological momentary assessments (EMAs) and continuously collected passive smartphone sensor data. EMAs probed negative emotional states (i.e. anger, sadness and anxiety) 2-3 times per day every other week throughout the study (total: 1145 EMA measurements). Smartphone accelerometer, location and device state data were collected to derive 14 discrete estimates of behavior, including activity level, percentage of time spent at home, sleep onset and duration, and phone usage. RESULTS: A personalized ensemble machine learning model derived from smartphone sensor data outperformed other statistical approaches (e.g. linear mixed model) and predicted states of elevated anger and anxiety with acceptable discrimination ability (area under the curve (AUC) = 74% and 71%, respectively), but demonstrated more modest discrimination ability for predicting states of high sadness (AUC = 66%). CONCLUSIONS: To the extent that smartphone data could provide reasonably accurate real-time predictions of states of high negative affect in teens, brief 'just-in-time' interventions could be immediately deployed via smartphone notifications or mental health apps to alleviate these states.

Multi-modal assessment of reward functioning in adolescent anhedonia.

BACKGROUND: Anhedonia is a core symptom of depression that predicts worse treatment outcomes. Dysfunction in neural reward circuits is thought to contribute to anhedonia. However, whether laboratory-based assessments of anhedonia and reward-related neural function translate to adolescents' subjective affective experiences in real-world contexts remains unclear. METHODS: We recruited a sample of adolescents (n = 82; ages 12-18; mean = 15.83) who varied in anhedonia and measured the relationships among clinician-rated and self-reported anhedonia, behaviorally assessed reward learning ability, neural response to monetary reward and loss (as assessed with functional magnetic resonance imaging), and repeated ecological momentary assessment (EMA) of positive affect (PA) and negative affect (NA) in daily life. RESULTS: Anhedonia was associated with lower mean PA and higher mean NA across the 5-day EMA period. Anhedonia was not related to impaired behavioral reward learning, but low PA was associated with reduced nucleus accumbens response during reward anticipation and reduced medial prefrontal cortex (mPFC) response during reward outcome. Greater mean NA was associated with increased mPFC response to loss outcome. CONCLUSIONS: Traditional laboratory-based measures of anhedonia were associated with lower subjective PA and higher subjective NA in youths' daily lives. Lower subjective PA and higher subjective NA were associated with decreased reward-related striatal functioning. Higher NA was also related to increased mPFC activity to loss. Collectively, these findings demonstrate that laboratory-based measures of anhedonia translate to real-world contexts and that subjective ratings of PA and NA may be associated with neural response to reward and loss.

Alterations in resting-state functional activity and connectivity for major depressive disorder appetite and weight disturbance phenotypes.

BACKGROUND: Major depressive disorder (MDD) is often accompanied by changes in appetite and weight. Prior task-based functional magnetic resonance imaging (fMRI) findings suggest these MDD phenotypes are associated with altered reward and interoceptive processing. METHODS: Using resting-state fMRI data, we compared the fractional amplitude of low-frequency fluctuations (fALFF) and seed-based connectivity (SBC) among hyperphagic (n = 77), hypophagic (n = 66), and euphagic (n = 42) MDD groups and a healthy comparison group (n = 38). We examined fALFF and SBC in a mask restricted to reward [nucleus accumbens (NAcc), putamen, caudate, ventral pallidum, and orbitofrontal cortex (OFC)] and interoceptive (anterior insula and hypothalamus) regions and also performed exploratory whole-brain analyses. SBC analyses included as seeds the NAcc and also regions demonstrating group differences in fALFF (i.e. right lateral OFC and right anterior insula). All analyses used threshold-free cluster enhancement. RESULTS: Mask-restricted analyses revealed stronger fALFF in the right lateral OFC, and weaker fALFF in the right anterior insula, for hyperphagic MDD v. healthy comparison. We also found weaker SBC between the right lateral OFC and left anterior insula for hyperphagic MDD v. healthy comparison. Whole-brain analyses revealed weaker fALFF in the right anterior insula, and stronger SBC between the right lateral OFC and left precentral gyrus, for hyperphagic MDD v. healthy comparison. Findings were no longer significant after controlling for body mass index, which was higher for hyperphagic MDD. CONCLUSIONS: Our results suggest hyperphagic MDD may be associated with altered activity in and connectivity between interoceptive and reward regions.

Neural sensitivity to peer feedback and depression symptoms in adolescents: a 2-year multiwave longitudinal study.

BACKGROUND: Depression risk increases during adolescent development, and individual differences in neural sensitivity to peer feedback (rejection vs. acceptance) may be a key diathesis in understanding stress-related depression risk. METHODS: At baseline, adolescents (12-14 years old; N = 124) completed clinical interviews and self-report symptom measures, and the Chatroom Task while MRI data were acquired. The majority of participants provided usable MRI data (N = 90; 76% female), which included adolescents with no maternal depression history (low risk n = 64) and those with a maternal depression history (high risk n = 26). Whole-brain regression models probed group differences in neural sensitivity following peer feedback, and whole-brain linear mixed-effects models examined neural sensitivity to peer feedback by peer stress interactions relating to depression symptoms at up to nine longitudinal assessments over 2 years. RESULTS: Whole-brain cluster-corrected results indicated brain activation moderating the strong positive association between peer interpersonal stress and depression over time. This included activation in the anterior insula, cingulate, amygdala, and striatum during anticipation and receipt of feedback (i.e., rejection vs. acceptance). Moderation effects were stronger when examining peer interpersonal (vs. non-interpersonal) stress and in relation to depression (vs. social anxiety) symptoms. CONCLUSIONS: Neural responses to peer feedback in key social and incentive processing brain regions may reflect core dispositional risk factors that interact with peer interpersonal stressors to predict adolescent depression symptom severity over time.

Derivation and Validation of a Brief Emergency Department-Based Prediction Tool for Posttraumatic Stress After Motor Vehicle Collision.

STUDY OBJECTIVE: To derive and initially validate a brief bedside clinical decision support tool that identifies emergency department (ED) patients at high risk of substantial, persistent posttraumatic stress symptoms after a motor vehicle collision. METHODS: Derivation (n=1,282, 19 ED sites) and validation (n=282, 11 separate ED sites) data were obtained from adults prospectively enrolled in the Advancing Understanding of RecOvery afteR traumA study who were discharged from the ED after motor vehicle collision-related trauma. The primary outcome was substantial posttraumatic stress symptoms at 3 months (Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders-5 ≥38). Logistic regression derivation models were evaluated for discriminative ability using the area under the curve and the accuracy of predicted risk probabilities (Brier score). Candidate posttraumatic stress predictors assessed in these models (n=265) spanned a range of sociodemographic, baseline health, peritraumatic, and mechanistic domains. The final model selection was based on performance and ease of administration. RESULTS: Significant 3-month posttraumatic stress symptoms were common in the derivation (27%) and validation (26%) cohort. The area under the curve and Brier score of the final 8-question tool were 0.82 and 0.14 in the derivation cohort and 0.76 and 0.17 in the validation cohort. CONCLUSION: This simple 8-question tool demonstrates promise to risk-stratify individuals with substantial posttraumatic stress symptoms who are discharged to home after a motor vehicle collision. Both external validation of this instrument, and work to further develop more accurate tools, are needed. Such tools might benefit public health by enabling the conduct of preventive intervention trials and assisting the growing number of EDs that provide services to trauma survivors aimed at promoting psychological recovery.