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Background: Understanding the neurobiological effects of stress is critical for addressing the etiology of major depressive disorder (MDD). Using a dimensional approach involving individuals with differing degree of MDD risk, we investigated 1) the effects of acute stress on cortico-cortical and subcortical-cortical functional connectivity (FC) and 2) how such effects are related to gene expression and receptor maps., Methods: Across 115 participants (37 control, 39 remitted MDD, 39 current MDD), we evaluated the effects of stress on FC during the Montreal Imaging Stress Task. Using partial least squares regression, we investigated genes whose expression in the Allen Human Brain Atlas was associated with anatomical patterns of stress-related FC change. Finally, we correlated stress-related FC change maps with opioid and GABA A (gamma-aminobutyric acid A) receptor distribution maps derived from positron emission tomography., Results: Results revealed robust effects of stress on global cortical connectivity, with increased global FC in frontoparietal and attentional networks and decreased global FC in the medial default mode network. Moreover, robust increases emerged in FC of the caudate, putamen, and amygdala with regions from the ventral attention/salience network, frontoparietal network, and motor networks. Such regions showed preferential expression of genes involved in cell-to-cell signaling (OPRM1, OPRK1, SST, GABRA3, GABRA5), similar to previous genetic MDD studies., Conclusions: Acute stress altered global cortical connectivity and increased striatal connectivity with cortical regions that express genes that have previously been associated with imaging abnormalities in MDD and are rich in μ and κ opioid receptors. These findings point to overlapping circuitry underlying stress response, reward, and MDD., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Deficits in cognitive control are implicated in numerous neuropsychiatric disorders. However, relevant pharmacological treatments are limited, likely due to weak translational validity of applicable preclinical models used. Neural indices derived from electroencephalography (EEG) may prove useful in comparing and translating the effects of cognition-enhancing drugs between species. In the current study, we aimed to extend our previous cross-species results by examining if methylphenidate (MPH) modulates behavioral and neural indices of cognitive control in independent cohorts of humans and rats., Methods: We measured continuous EEG data from healthy adults (n=25; 14 female) and Long Evans rats (n=22; 8 female) and compared both stimulus- and response-locked event-related potentials (ERPs) and spectral power measures across species, and their MPH-related moderation following treatment with vehicle (placebo) or one of two doses of MPH., Results: Across both species, linear mixed effects modeling confirmed the expected Flanker interference effect on behavior (e.g., accuracy) and response-related ERPs. Unexpectedly, in contrast to past work, we did not observe any task-related effects on the spectral power of rodents. Moreover, MPH generally did not modulate cognitive control of either species, although some species-specific patterns offer insight for future research., Conclusions: Collectively, these findings in independent human and rodent subjects replicate some of our previously reported behavioral and neurophysiological patterns partly consistent with the notion that similar neural mechanisms may regulate cognitive control in both species. Nonetheless, these results showcase an approach to accelerate translation using a coordinated between-species platform to evaluate pro-cognitive treatments., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Perceived control is strongly related to mental health and well-being. Specifically, lack of perceived control has been associated with learned helplessness and stress-related disorders, such as depression and anxiety. However, it is unknown whether brain activation to control and its protective effect against stress can predict changes in quality of life. To address this gap, we examined the neural underpinning of controllability in healthy females (N=40) performing the Value of Control task in an fMRI scanner. Quality of life and perceived stress were assessed at baseline and 6-month follow-up. Increased brain activation for control was found within the putamen, insula, thalamus, mid-cingulate, dorsolateral prefrontal cortex, motor cortex, and cerebellum. In contrast, increased brain activation for lack of control was found within the posterior cingulate and prefrontal cortices. In an exploratory analysis, an elastic-net algorithm was used to identify brain predictors of quality of life 6 months later. The right putamen's activation to control was selected as the best prospective predictor of improvement in life enjoyment and satisfaction and this association was mediated by changes in perceived stress. Our findings suggest that neural responsiveness to control may have utility as a potential marker of quality of life and resilience to adversity., (© The Author(s) 2024. Published by Oxford University Press.)

Objective: This study aimed to examine the potential of experiencing aesthetic chills to enhance reward learning in individuals with elevated depressive symptoms, specifically anhedonia, by investigating the effect of chills on participants' ability to modulate behavior as a function of rewards., Methods: A total of 103 participants with elevated depressive symptoms took part in the experiment. Among them, 59 participants had depressive symptoms (BDI ≥ 20), with 26 classified as "High Anhedonic" (HA) and 33 as "Low Anhedonic" (LA). Additionally, 39 participants without elevated depressive symptoms (BDI < 20 and SHAPs <32) were included as the control group. We utilized ChillsDB, an open-source database of validated audiovisual stimuli known to elicit chills in the US population., Results: Anhedonic participants who experienced chills demonstrated a significant increase in response bias (p = .004) towards rewards compared to those who did not experience chills. Highlighting specificity, no significant difference in reward bias was observed among LA participants., Conclusions: These findings suggest that the experience of chills has the potential to impact reward learning in anhedonic individuals, aligning with the known neurobiology of this phenomenon. These results highlight the potential of aesthetic chills as a novel approach to elicit and enhance positive affect in depressed populations., Competing Interests: Declaration of competing interest Dr. Schoeller is the co-founder of BeSound SAS and Nested Minds LTD, holds ownership shares and has received compensation from both companies. Over the past 3 years, Dr. Pizzagalli has received consulting fees from Boehringer Ingelheim, Compass Pathways, Engrail Therapeutics, Neumora Therapeutics (formerly BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Otsuka, Sunovion, Sage Therapeutics, Sama Therapeutics, and Takeda; he has received honoraria from the American Psychological Association, Psychonomic Society and Springer (for editorial work) and from Alkermes; he has received research funding from the Brain and Behavior Research Foundation, BIRD Foundation, the Dana Foundation, DARPA, Millennium Pharmaceuticals, NIMH, and Wellcome Leap MCPsych; he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, and Neuroscience Software; he has a financial interest in Neumora Therapeutics, which has licensed the copyright to the probabilistic reward task through Harvard University. Dr. Pizzagalli's interests were reviewed and are managed by McLean Hospital and Partners HealthCare in accordance with their conflict of interest policies. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. All other authors have no conflicts of interest or relevant disclosures., (Copyright © 2024. Published by Elsevier B.V.)

Background: Trauma is a risk factor for developing maladaptive alcohol use. Preclinical research has shown that stress alters the processing of midbrain and striatal reward and incentive signals. However, little research has been conducted on alterations in reward-related neurocircuitry post-trauma in humans. Neuroimaging markers may be particularly useful as they can provide insight into the mechanisms that may make an individual vulnerable to developing trauma-related psychopathologies. This study aimed to identify reward-related neural correlates associated with changes in alcohol use after trauma exposure., Methods: Participants were recruited from U.S. emergency departments for the AURORA study (N=286, 178 female). Trauma-related change in alcohol use at 8 weeks post-trauma relative to pre-trauma was quantified as a change in 30-day total drinking per the PhenX Toolkit Alcohol 30-Day Quantity and Frequency Measure. Reward-related neurocircuitry activation and functional connectivity (FC) were assessed 2 weeks post-trauma using fMRI during a monetary reward task using region of interest and whole-brain voxelwise analyses., Results: Greater increase in alcohol use from pre-trauma to 8 weeks post-trauma was predicted by (1) greater ventral tegmental area (VTA) and (2) greater cerebellum activation during Gain>Loss trials measured 2 weeks post-trauma and (3) greater seed-based FC between the VTA and lateral occipital cortex and precuneus., Conclusions: Altered VTA activation and FC early post-trauma may be associated with reward-seeking and processing, contributing to greater alcohol use post-trauma. These data provide novel evidence of neural correlates that underlie increased alcohol use early post-trauma that may be targeted via early interventions to prevent the development of maladaptive alcohol use., (Copyright © 2024. Published by Elsevier Inc.)

The search for neural markers of depression remains challenging. Despite progress, neuroimaging results have generally not yielded actionable findings that could transform how we understand and treat this disorder. However, in a recent study, Lynch and colleagues identified enlargement of the frontrostriatal salience network as a reproducible, trait-like marker of depression., Competing Interests: Declaration of interests Over the past 3 years, D.A.P. has received consulting fees from Boehringer Ingelheim, Compass Pathways, Engrail Therapeutics, Neumora Therapeutics (formerly BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Sage Therapeutics, Sama Therapeutics, Otsuka, and Takeda; he has received honoraria from the American Psychological Association, Psychonomic Society and Springer (for editorial work) as well as from Alkermes; he has received research funding from the BIRD Foundation, Brain and Behavior Research Foundation, Dana Foundation, Millennium Pharmaceuticals, NIMH, and Wellcome Leap; and he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, and Neuroscience Software. No funding or any involvement from these entities was used to support the current work, and all views expressed are solely those of the author., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: The neural underpinnings underlying individual differences in nicotine-enhanced reward sensitivity (NERS) and smoking progression are poorly understood. Thus, we investigated whether brain resting-state functional connectivity (rsFC.) during smoking abstinence predicts NERS 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 NERS and smoking progression., Aims and Methods: Young light smokers (N = 64, age 18-24, M = 1.89 cigarettes/day) participated in the study. These individuals smoked between 5 and 35 cigarettes per week and lifetime use never exceeded 35 cigarettes per week. Their rsFC was assessed using functional magnetic resonance imaging after 14 hours of nicotine deprivation. Subjects also completed a probabilistic reward task after smoking a placebo on 1 day and a regular cigarette on another day., Results: The probabilistic-reward-task assessed greater NERS 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 NERS., 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., Clinical Trial Registration: NCT02129387 (preregistered hypothesis: www.clinicaltrials.gov)., Implications: Weaker rsFC within the salience network predicted greater NERS 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

As a neurobiological process, addiction involves pathological patterns of engagement with substances and a range of behaviors with a chronic and relapsing course. Neuroimaging technologies assess brain activity, structure, physiology, and metabolism at scales ranging from neurotransmitter receptors to large-scale brain networks, providing unique windows into the core neural processes implicated in substance use disorders. Identified aberrations in the neural substrates of reward and salience processing, response inhibition, interoception, and executive functions with neuroimaging can inform the development of pharmacological, neuromodulatory, and psychotherapeutic interventions to modulate the disordered neurobiology. Based on our systematic search, 409 protocols registered on ClinicalTrials.gov include the use of one or more neuroimaging paradigms as an outcome measure in addiction, with the majority (N=268) employing functional magnetic resonance imaging (fMRI), followed by positron emission tomography (PET) (N=71), electroencephalography (EEG) (N=50), structural magnetic resonance imaging (MRI) (N=35) and magnetic resonance spectroscopy (MRS) (N=35). Furthermore, in a PubMed systematic review, we identified 61 meta-analyses including 30 fMRI, 22 structural MRI, 8 EEG, 7 PET, and 3 MRS meta-analyses suggesting potential biomarkers in addictions. These studies can facilitate the development of a range of biomarkers that may prove useful in the arsenal of addiction treatments in the coming years. There is evidence that these markers of large-scale brain structure and activity may indicate vulnerability or separate disease subtypes, predict response to treatment, or provide objective measures of treatment response or recovery. Neuroimaging biomarkers can also suggest novel targets for interventions. Closed or open loop interventions can integrate these biomarkers with neuromodulation in real-time or offline to personalize stimulation parameters and deliver the precise intervention. This review provides an overview of neuroimaging modalities in addiction, potential neuroimaging biomarkers, and their physiologic and clinical relevance. Future directions and challenges in bringing these putative biomarkers from the bench to the bedside are also discussed., Competing Interests: O.C. has received grant funding from Eli Lilly, Inc, and Nestle, Inc. He has provided paid consulting to Novo Nordisk. Dr. Paulus is an advisor to Spring Care, Inc., a behavioral health startup, he has received royalties for an article about methamphetamine in UpToDate. M.P.P. has a consulting agreement with and receives compensation from F. Hoffmann-La Roche Ltd. P.O. is an employee and shareholder of Sage Therapeutics. Other authors report no conflicts of interest. Disclaimer: The views and opinions expressed in this manuscript are those of the authors only and do not necessarily represent the views, official policy or position of the U.S. Department of Health and Human Services or any of its affiliated institutions or agencies.

This article describes primary data and resources available from the Boston Adolescent Neuroimaging of Depression and Anxiety (BANDA) study, a novel arm of the Human Connectome Project (HCP). Data were collected from 215 adolescents (14-17 years old), 152 of whom had current diagnoses of anxiety and/or depressive disorders at study intake. Data include cross-sectional structural (T1- and T2-weighted), functional (resting state and three tasks), and diffusion-weighted magnetic resonance images. Both unprocessed and HCP minimally-preprocessed imaging data are available within the data release packages. Adolescent and parent clinical interview data, as well as cognitive and neuropsychological data are also included within these packages. Release packages additionally provide data collected from self-report measures assessing key features of adolescent psychopathology, including: anxious and depressive symptom dimensions, behavioral inhibition/activation, exposure to stressful life events, and risk behaviors. Finally, the release packages include 6- and 12-month longitudinal data acquired from clinical measures. Data are publicly accessible through the National Institute of Mental Health Data Archive (ID: #2505)., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Background: Loneliness and social isolation have detrimental consequences for mental health and act as vulnerability factors for the development of depressive symptoms, such as anhedonia. The mitigation strategies used to contain COVID-19, such as social distancing and lockdowns, allowed us to investigate putative associations between daily objective and perceived social isolation and anhedonic-like behavior., Methods: Reward-related functioning was objectively assessed using the Probabilistic Reward Task. A total of 114 unselected healthy individuals (71% female) underwent both a laboratory and an ecological momentary assessment. Computational modeling was applied to performance on the Probabilistic Reward Task to disentangle reward sensitivity and learning rate., Results: Findings revealed that objective, but not subjective, daily social interactions were associated with motivational behavior. Specifically, higher social isolation (less time spent with others) was associated with higher responsivity to rewarding stimuli and a reduced influence of a given reward on successive behavioral choices., Conclusions: Overall, the current results broaden our knowledge of the potential pathways that link (COVID-19-related) social isolation to altered motivational functioning., (© 2024 The Authors.)

Importance: Research on resilience after trauma has often focused on individual-level factors (eg, ability to cope with adversity) and overlooked influential neighborhood-level factors that may help mitigate the development of posttraumatic stress disorder (PTSD)., Objective: To investigate whether an interaction between residential greenspace and self-reported individual resources was associated with a resilient PTSD trajectory (ie, low/no symptoms) and to test if the association between greenspace and PTSD trajectory was mediated by neural reactivity to reward., Design, Setting, and Participants: As part of a longitudinal cohort study, trauma survivors were recruited from emergency departments across the US. Two weeks after trauma, a subset of participants underwent functional magnetic resonance imaging during a monetary reward task. Study data were analyzed from January to November 2023., Exposures: Residential greenspace within a 100-m buffer of each participant's home address was derived from satellite imagery and quantified using the Normalized Difference Vegetation Index and perceived individual resources measured by the Connor-Davidson Resilience Scale (CD-RISC)., Main Outcome and Measures: PTSD symptom severity measured at 2 weeks, 8 weeks, 3 months, and 6 months after trauma. Neural responses to monetary reward in reward-related regions (ie, amygdala, nucleus accumbens, orbitofrontal cortex) was a secondary outcome. Covariates included both geocoded (eg, area deprivation index) and self-reported characteristics (eg, childhood maltreatment, income)., Results: In 2597 trauma survivors (mean [SD] age, 36.5 [13.4] years; 1637 female [63%]; 1304 non-Hispanic Black [50.2%], 289 Hispanic [11.1%], 901 non-Hispanic White [34.7%], 93 non-Hispanic other race [3.6%], and 10 missing/unreported [0.4%]), 6 PTSD trajectories (resilient, nonremitting high, nonremitting moderate, slow recovery, rapid recovery, delayed) were identified through latent-class mixed-effect modeling. Multinominal logistic regressions revealed that for individuals with higher CD-RISC scores, greenspace was associated with a greater likelihood of assignment in a resilient trajectory compared with nonremitting high (Wald z test = -3.92; P < .001), nonremitting moderate (Wald z test = -2.24; P = .03), or slow recovery (Wald z test = -2.27; P = .02) classes. Greenspace was also associated with greater neural reactivity to reward in the amygdala (n = 288; t277 = 2.83; adjusted P value = 0.02); however, reward reactivity did not differ by PTSD trajectory., Conclusions and Relevance: In this cohort study, greenspace and self-reported individual resources were significantly associated with PTSD trajectories. These findings suggest that factors at multiple ecological levels may contribute to the likelihood of resiliency to PTSD after trauma.

Poor inhibitory control contributes to deficits in emotion regulation, which are often targeted by treatments for major depressive disorder (MDD), including cognitive behavioral therapy (CBT). Brain regions that contribute to inhibitory control and emotion regulation overlap; thus, inhibitory control might relate to response to CBT. In this study, we examined whether baseline inhibitory control and resting state functional connectivity (rsFC) within overlapping emotion regulation-inhibitory control regions predicted treatment response to internet-based CBT (iCBT). Participants with MDD were randomly assigned to iCBT (N = 30) or a monitored attention control (MAC) condition (N = 30). Elastic net regression was used to predict post-treatment Patient Health Questionnaire-9 (PHQ-9) scores from baseline variables, including demographic variables, PHQ-9 scores, Flanker effects (interference, sequential dependency, post-error slowing), and rsFC between the dorsal anterior cingulate cortex, bilateral anterior insula (AI), and right temporoparietal junction (TPJ). Essential prognostic predictor variables retained in the elastic net regression included treatment group, gender, Flanker interference response time (RT), right AI-TPJ rsFC, and left AI-right AI rsFC. Prescriptive predictor variables retained included interactions between treatment group and baseline PHQ-9 scores, age, gender, Flanker RT, sequential dependency effects on accuracy, post-error accuracy, right AI-TPJ rsFC, and left AI-right AI rsFC. Inhibitory control and rsFC within inhibitory control-emotion regulation regions predicted reduced symptom severity following iCBT, and these effects were stronger in the iCBT group than in the MAC group. These findings contribute to a growing literature indicating that stronger inhibitory control at baseline predicts better outcomes to psychotherapy, including iCBT., (© 2024. The Author(s).)

Background: Exposure to adversity, including unpredictable environments, during early life is associated with neuropsychiatric illness in adulthood. One common factor in this sequela is anhedonia, the loss of responsivity to previously reinforcing stimuli. To accelerate the development of new treatment strategies for anhedonic disorders induced by early-life adversity, animal models have been developed to capture critical features of early-life stress and the behavioral deficits that such stressors induce. We have previously shown that rats exposed to the limited bedding and nesting protocol exhibited blunted reward responsivity in the probabilistic reward task, a touchscreen-based task reverse translated from human studies., Methods: To test the quantitative limits of this translational platform, we examined the ability of Bayesian computational modeling and probability analyses identical to those optimized in previous human studies to quantify the putative mechanisms that underlie these deficits with precision. Specifically, 2 parameters that have been shown to independently contribute to probabilistic reward task outcomes in patient populations, reward sensitivity and learning rate, were extracted, as were trial-by-trial probability analyses of choices as a function of the preceding trial., Results: Significant deficits in reward sensitivity, but not learning rate, contributed to the anhedonic phenotypes in rats exposed to early-life adversity., Conclusions: The current findings confirm and extend the translational value of these rodent models by verifying the effectiveness of computational modeling in distinguishing independent features of reward sensitivity and learning rate that complement the probabilistic reward task's signal detection end points. Together, these metrics serve to objectively quantify reinforcement learning deficits associated with anhedonic phenotypes., (© 2024 The Authors.)

Background: Deeper phenotyping may improve our understanding of depression. Because depression is heterogeneous, extracting cognitive signatures associated with severity of depressive symptoms, anhedonia, and affective states is a promising approach., Methods: Sequential sampling models decomposed behavior from an adaptive approach-avoidance conflict task into computational parameters quantifying latent cognitive signatures. Fifty unselected participants completed clinical scales and the approach-avoidance conflict task by either approaching or avoiding trials offering monetary rewards and electric shocks., Results: Decision dynamics were best captured by a sequential sampling model with linear collapsing boundaries varying by net offer values, and with drift rates varying by trial-specific reward and aversion, reflecting net evidence accumulation toward approach or avoidance. Unlike conventional behavioral measures, these computational parameters revealed distinct associations with self-reported symptoms. Specifically, passive avoidance tendencies, indexed by starting point biases, were associated with greater severity of depressive symptoms (R = 0.34, p = .019) and anhedonia (R = 0.49, p = .001). Depressive symptoms were also associated with slower encoding and response execution, indexed by nondecision time (R = 0.37, p = .011). Higher reward sensitivity for offers with negative net values, indexed by drift rates, was linked to more sadness (R = 0.29, p = .042) and lower positive affect (R = -0.33, p = .022). Conversely, higher aversion sensitivity was associated with more tension (R = 0.33, p = .025). Finally, less cautious response patterns, indexed by boundary separation, were linked to more negative affect (R = -0.40, p = .005)., Conclusions: We demonstrated the utility of multidimensional computational phenotyping, which could be applied to clinical samples to improve characterization and treatment selection., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Preclinical work suggests that excess glucocorticoids and reduced cortical γ-aminobutyric acid (GABA) may affect sex-dependent differences in brain regions implicated in stress regulation and depressive phenotypes. The authors sought to address a critical gap in knowledge, namely, how stress circuitry is functionally affected by glucocorticoids and GABA in current or remitted major depressive disorder (MDD)., Methods: Multimodal imaging data were collected from 130 young adults (ages 18-25), of whom 44 had current MDD, 42 had remitted MDD, and 44 were healthy comparison subjects. GABA+ (γ-aminobutyric acid and macromolecules) was assessed using magnetic resonance spectroscopy, and task-related functional MRI data were collected under acute stress and analyzed using data-driven network modeling., Results: Across modalities, trait-related abnormalities emerged. Relative to healthy comparison subjects, both clinical groups were characterized by lower rostral anterior cingulate cortex (rACC) GABA+ and frontoparietal network amplitude but higher amplitude in salience and stress-related networks. For the remitted MDD group, differences from the healthy comparison group emerged in the context of elevated cortisol levels, whereas the MDD group had lower cortisol levels than the healthy comparison group. In the comparison group, frontoparietal and stress-related network connectivity was positively associated with cortisol level (highlighting putative top-down regulation of stress), but the opposite relationship emerged in the MDD and remitted MDD groups. Finally, rACC GABA+ was associated with stress-induced changes in connectivity between overlapping default mode and salience networks., Conclusions: Lifetime MDD was characterized by reduced rACC GABA+ as well as dysregulated cortisol-related interactions between top-down control (frontoparietal) and threat (task-related) networks. These findings warrant further investigation of the role of GABA in the vulnerability to and treatment of MDD., Competing Interests: Dr. Misra has served on the advisory boards of AbbVie and Ipsen, served as a consultant for AbbVie and Sanofi, and served as a Key Opinion Leader for Lumos Pharmaceuticals; she has received study drug donations from Tonix Pharmaceuticals; and she is a contributor to UpToDate. Dr. Goldstein has served on the scientific advisory board of and has an equity interest in Cala Health. Dr. Pizzagalli has served as a consultant for Boehringer Ingelheim, Compass Pathways, Engrail Therapeutics, Neumora Therapeutics (formerly BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Otsuka, Sage Therapeutics, Sama Therapeutics, Sunovion Pharmaceuticals, and Takeda Pharmaceuticals; he has received honoraria from the American Psychological Association, the Psychonomic Society, and Springer (for editorial work) and from Alkermes; he has received research funding from the Bird Foundation, the Brain and Behavior Research Foundation, the Dana Foundation, Millennium Pharmaceuticals, and Wellcome Leap; and he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, and Neuroscience Software. The other authors report no financial relationships with commercial interests.

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 (β = .22, CI 95  = 0.01-0.42, p = .041), independent (β = .34, CI 95  = 0.12-0.56, p = .003), and interpersonal (β = .23, CI 95  = 0.004-0.45, p = .047) stress severity. By contrast, the MDD group reported significantly more severe chronic (β = .62, CI 95  = 0.45-0.79, p < .001) and dependent (β = .41, CI 95  = 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, CI 95  = 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., (© 2023 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Approximately 40% of dementia cases could be prevented or delayed by modifiable risk factors related to lifestyle and environment. These risk factors, such as depression and vascular disease, do not affect all individuals in the same way, likely due to inter-individual differences in genetics. However, the precise nature of how genetic risk profiles interact with modifiable risk factors to affect brain health is poorly understood. Here we combine multiple data resources, including genotyping and postmortem gene expression, to map the genetic landscape of brain structure and identify 367 loci associated with cortical thickness and 13 loci associated with white matter hyperintensities (P < 5×10 -8 ), with several loci also showing a significant association with cognitive function. We show that among 220 unique genetic loci associated with cortical thickness in our genome-wide association studies (GWAS), 95 also showed evidence of interaction with depression or cardiovascular conditions. Polygenic risk scores based on our GWAS of inferior frontal thickness also interacted with hypertension in predicting executive function in the Canadian Longitudinal Study on Aging. These findings advance our understanding of the genetic underpinning of brain structure and show that genetic risk for brain and cognitive health is in part moderated by treatable mid-life factors., (© 2024. The Author(s).)

Cannabis use has been linked to deficient reward processing; however, little is known about its relation to the specific construct of reward learning, in which behavior is modified through associating novel stimuli with a positive outcome. The probabilistic reward task was used to objectively evaluate reward learning in 38 individuals who use recreational cannabis and 34 control comparison participants from the community. Reward learning was evidenced by the development of a response bias, which indicates the propensity to modulate behavior as a function of prior reinforcement. Both cannabis and control groups demonstrated reward learning, with no group differences in response bias development. Among cannabis participants, trending significant relationships between greater chronicity, r (36) = -.30, p = .077, self-reported potency, r (19) = -.33, p = .052, and poorer reward learning were found. Nonsignificant relationships were found between reward learning and frequency, age of initiation, weekly quantity or Cannabis Use Disorder Identification Test-Revised (CUDIT-R) scores (all p > .05). The ability to form noncannabis reward associations is promising for the success of therapeutic interventions for problematic cannabis use; however, indications of severity of use in relation to poorer reward learning suggests a need for a better pharmacological and pharmacokinetic understanding of cannabis. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Neuroimaging studies of major depression have typically been conducted using group-level approaches. However, given interindividual differences in brain systems, there is a need for individualized approaches to brain systems mapping and putative links toward diagnosis, symptoms, and behavior., Methods: We used an iterative parcellation approach to map individualized brain systems in 328 participants from a multisite, placebo-controlled clinical trial. We hypothesized that participants with depression would show abnormalities in salience, control, default, and affective systems, which would be associated with higher levels of self-reported anhedonia, anxious arousal, and worse cognitive performance. Within hypothesized brain systems, we compared patch sizes (number of vertices) between depressed and healthy control groups. Within depressed groups, abnormal patches were correlated with hypothesized clinical and behavioral measures., Results: Significant group differences emerged in hypothesized patches of 1) the lateral salience system (parietal operculum; t 326  = -3.11, p = .002) and 2) the control system (left medial posterior prefrontal cortex region; z = -3.63, p < .001), with significantly smaller patches in these regions in participants with depression than in healthy control participants. Results suggest that participants with depression with significantly smaller patch sizes in the lateral salience system and control system regions experience greater anxious arousal and cognitive deficits., Conclusions: The findings imply that neural features mapped at the individual level may relate meaningfully to diagnosis, symptoms, and behavior. There is strong clinical relevance in taking an individualized brain systems approach to mapping neural functional connectivity because these associated region patch sizes may help advance our understanding of neural features linked to psychopathology and foster future patient-specific clinical decision making., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Neurocognitive factors including aberrant reward learning, blunted GABA (gamma-aminobutyric acid), and potentiated stress sensitivity have been linked to anhedonia, a hallmark depressive symptom, possibly in a sex-dependent manner. However, previous research has not investigated the putative associations among these factors or the extent to which they represent trait- or state-based vulnerabilities for depression., Methods: Young adults with current major depressive disorder (MDD) (n = 44), remitted MDD (n = 42), and healthy control participants (HCs) (n = 44), stratified by sex assigned at birth, underwent magnetic resonance spectroscopy to assess macromolecular contaminated GABA (GABA+) and then a reward learning task before and after acute stress. We assessed changes in reward learning after stress and associations with GABA+., Results: Results revealed blunted baseline reward learning in participants with remitted MDD versus participants with current MDD and HCs but, surprisingly, no differences between participants with current MDD and HCs. Reward learning was reduced following acute stress regardless of depressive history. GABA+ in the rostral anterior cingulate cortex, but not the dorsolateral prefrontal cortex, was associated with reduced baseline reward learning only in female participants. GABA+ did not predict stress-related changes in reward learning., Conclusions: To our knowledge, this is the first study to investigate associations among GABA, reward learning, and stress reactivity in current versus past depression. Hypothesized depression-related differences in reward learning did not emerge, precluding claims about state versus trait vulnerabilities. However, our finding that blunted GABA was associated with greater reward learning in female participants provides novel insights into sex-selective associations between the frontal GABAergic inhibitory system and reward processing., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Clinical assessments often fail to discriminate between unipolar and bipolar depression and identify individuals who will develop future (hypo)manic episodes. To address this challenge, we developed a brain-based graph-theoretical predictive model (GPM) to prospectively map symptoms of anhedonia, impulsivity, and (hypo)mania. Individuals seeking treatment for mood disorders (n = 80) underwent an fMRI scan, including (i) resting-state and (ii) a reinforcement-learning (RL) task. Symptoms were assessed at baseline as well as at 3- and 6-month follow-ups. A whole-brain functional connectome was computed for each fMRI task, and the GPM was applied for symptom prediction using cross-validation. Prediction performance was evaluated by comparing the GPM to a corresponding null model. In addition, the GPM was compared to the connectome-based predictive modeling (CPM). Cross-sectionally, the GPM predicted anhedonia from the global efficiency (a graph theory metric that quantifies information transfer across the connectome) during the RL task, and impulsivity from the centrality (a metric that captures the importance of a region) of the left anterior cingulate cortex during resting-state. At 6-month follow-up, the GPM predicted (hypo)manic symptoms from the local efficiency of the left nucleus accumbens during the RL task and anhedonia from the centrality of the left caudate during resting-state. Notably, the GPM outperformed the CPM, and GPM derived from individuals with unipolar disorders predicted anhedonia and impulsivity symptoms for individuals with bipolar disorders. Importantly, the generalizability of cross-sectional models was demonstrated in an external validation sample. Taken together, across DSM mood diagnoses, efficiency and centrality of the reward circuit predicted symptoms of anhedonia, impulsivity, and (hypo)mania, cross-sectionally and prospectively. The GPM is an innovative modeling approach that may ultimately inform clinical prediction at the individual level., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Introduction: Behavioral and pharmacological smoking cessation treatments are hypothesized to increase patients' reward learning to reduce craving. Identifying changes in reward learning processes that support effective tobacco-dependence interventions among smokers who experience depression may guide patients toward efficient treatment strategies. The objective was to investigate the extent to which adult daily cigarette smokers with current or past major depressive disorder (MDD) learned to seek reward during 12 weeks of treatment combining behavioral activation and varenicline. We hypothesized that a decline in reward learning would be attenuated (least to most) in the following order: (1) behavioral activation integrated with ST (BASC) + varenicline, (2) BASC + placebo, (3) standard behavioral cessation treatment (ST) + varenicline, (4) ST + placebo., Methods: We ran a phase IV, placebo-controlled, randomized clinical trial with 300 participants receiving 12 weeks of one of four conditions across two urban medical centers. Depressive symptoms were measured using the Beck Depression Inventory-II (BDI). Reward learning was ascertained at weeks 1, 7, and 14 using the Probabilistic Reward Task (PRT), a laboratory task that uses an asymmetric reinforcement schedule to assess (a) learning to seek reward (response bias), (b) differentiate between stimuli, and (c) time to react to cues., Results: There was a significant interaction of BDI group × PRT response bias. Response bias declined from weeks 7 to 14 among participants with high baseline depression symptoms. The other two BDI groups showed no change in response bias., Conclusions: Controlling for baseline depression, participants showed a decrease in response bias from weeks 1 to 14, and from weeks 7 to 14. Treatment condition and abstinence status were unassociated with change in reward learning., Implications: Smokers who report greater depression severity show a decline in reward learning despite their participation in smoking cessation treatments, suggesting that depressed populations pose unique challenges with standard smoking cessation approaches., Trial Registration: ClinicalTrials.gov Identifier: NCT02378714., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The Probabilistic Reward Task (PRT) is a signal detection task that assesses reward learning. In laboratory versions of the task, individuals with current or past major depressive disorder (MDD) were characterized by reduced response bias towards a more frequently rewarded stimuli, compared to controls. Our main goal was to develop and validate a novel online version of the PRT, and, in exploratory analyses, evaluate whether lifetime history of depression was associated with blunted reward learning., Methods: 429 participants recruited via CloudResearch completed questionnaires assessing psychiatric history and an online PRT featuring visually appealing stimuli. 108 participants reported either current or past diagnosis of MDD (lifetime MDD group), and were compared to 321 without lifetime MDD., Results: Participants showed overall increase in response bias, validating the online PRT. Females with lifetime MDD (N = 43), compared to females without prior history of MDD (N = 173), exhibited blunted response bias towards the more frequently rewarded stimulus (i.e., reduced reward learning)., Limitations: Participants did not undergo a structured clinical interview, thus we cannot confirm whether they met full diagnostic criteria for depression., Conclusions: The online PRT yielded similar psychometric properties as laboratory versions of the task. In exploratory analyses, females with lifetime MDD showed a lower propensity to modulate behavior as a function of rewards, which might contribute to heightened vulnerability for developing MDD in females. Future studies should consider social, cultural, and neurobiological factors contributing to sex differences in reward responsiveness and how factors may relate to disease prognosis and treatment outcomes., Competing Interests: Declaration of competing interest Over the past 3 years, Dr. Pizzagalli has received consulting fees from Boehringer Ingelheim, Compass Pathways, Engrail Therapeutics, Neumora Therapeutics (formerly BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Otsuka Pharmaceutical, Sage Therapeutics, Sama Therapeutics, Sunovion Pharmaceuticals, and Takeda; he has received honoraria from the American Psychological Association, Psychonomic Society and Springer (for editorial work) and from Alkermes; he has received research funding from the Brain and Behavior Research Foundation, the Dana Foundation, Millennium Pharmaceuticals, Wellcome Leap MCPsych, and NIMH; he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, and Neuroscience Software; he has a financial interest in Neumora Therapeutics, which has licensed the copyright to the probabilistic reward task through Harvard University. Dr. Pizzagalli's interests were reviewed and are managed by McLean Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. All other authors have no conflicts of interest or relevant disclosures., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sex-specific neurobiological changes have been implicated in Major Depressive Disorder (MDD). Dysfunctions of the default mode network (DMN), salience network (SN) and frontoparietal network (FPN) are critical neural characteristics of MDD, however, the potential moderating role of sex on resting-state network dynamics in MDD has not been sufficiently evaluated. Thus, resting-state functional magnetic resonance imaging (fMRI) data were collected from 138 unmedicated patients with first-episode MDD (55 males) and 243 healthy controls (HCs; 106 males). Recurring functional network co-activation patterns (CAPs) were extracted, and time spent in each CAP (the total amount of volumes associated to a CAP), persistence (the average number of consecutive volumes linked to a CAP), and transitions across CAPs involving the SN, DMN and FPN were quantified. Relative to HCs, MDD patients exhibited greater persistence in a CAP involving activation of the DMN and deactivation of the FPN (DMN + FPN-). In addition, relative to the sex-matched HCs, the male MDD group spent more time in two CAPs involving the SN and DMN (i.e., DMN + SN- and DMN-SN + ) and transitioned more frequently from the DMN + FPN- CAP to the DMN + SN- CAP relative to the male HC group. Conversely, the female MDD group showed less persistence in the DMN + SN- CAP relative to the female HC group. Our findings highlight that the imbalance between SN and DMN could be a neurobiological marker supporting sex differences in MDD. Moreover, the dominance of the DMN accompanied by the deactivation of the FPN could be a sex-independent neurobiological correlate related to depression., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

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., (© 2024. The Psychonomic Society, Inc.)

Animal models of depression show that acute stress negatively impacts functioning in neural regions sensitive to reward and punishment, often manifesting as anhedonic behaviors. However, few human studies have probed stress-induced neural activation changes in relation to anhedonia, which is critical for clarifying risk for affective disorders. Participants (N = 85, 12-14 years-old, 53 female), oversampled for risk of depression, were administered clinical assessments and completed an fMRI guessing task during a baseline (no-stress) period to probe neural response to receipt of rewards and losses. After the initial task run of the fMRI guessing task, participants received an acute stressor and then, were re-administered the guessing task. Including baseline, participants provided up to 10 self-report assessments of life stress and symptoms over a 2 year period. Linear mixed-effects models estimated whether change in neural activation (post- vs. pre-acute stressor) moderated the longitudinal associations between life stress and symptoms. Primary analyses indicated that adolescents with stress-related reductions in right ventral striatum response to rewards exhibited stronger longitudinal associations between life stress and anhedonia severity (β = -0.06, 95%CI[-0.11, -0.02], p = 0.008, p FDR  = 0.048). Secondary analyses showed that longitudinal positive associations between life stress and depression severity were moderated by stress-related increases in dorsal striatum response to rewards (left caudate β = 0.11, 95%CI[0.07,0.17], p < 0.001, p FDR  = 0.002; right caudate β = 0.07, 95%CI[0.02,0.12], p = 0.002, p FDR  = 0.003; left putamen β = 0.09, 95%CI[0.04, 0.14], p < 0.001, p FDR  = 0.002; right putamen β = 0.08, 95%CI[0.03, 0.12], p < 0.001, p FDR  = 0.002). Additionally, longitudinal positive associations among life stress and anxiety severity were moderated by stress-related reductions in dorsal anterior cingulate cortex (β = -0.07, 95%CI[-0.12,.02], p = 0.008, p FDR  = 0.012) and right anterior insula (β = -0.07, 95%CI[-0.12,-0.02], p = 0.002, p FDR  = 0.006) response to loss. All results held when adjusting for comorbid symptoms. Results show convergence with animal models, highlighting mechanisms that may facilitate stress-induced anhedonia as well as a separable pathway for the emergence of depressive and anxiety symptoms., (© 2024. The Author(s).)

Background: Anhedonia is a transdiagnostic symptom of severe mental illness (SMI) and emerges during adolescence. Possible subphenotypes and neural mechanisms of anhedonia in adolescents at risk for SMI are understudied., Methods: Adolescents at familial risk for SMI (N = 81) completed anhedonia (e.g., consummatory, anticipatory, social), demographic, and clinical measures and one year prior, a subsample (N = 46) completed fMRI scanning during a monetary reward task. Profiles were identified using k-means clustering of anhedonia type and differences in demographics, suicidal ideation, impulsivity, and emotional processes were examined. Moderation analyses were conducted to investigate whether levels of brain activation of reward regions moderated the relationships between anhedonia type and behaviors., Results: Two-clusters emerged: a high anhedonia profile (high-anhedonia), characterized by high levels of all types of anhedonia, (N = 32) and a low anhedonia profile (low-anhedonia), characterized by low levels of anhedonia types (N = 49). Adolescents in the high-anhedonia profile reported more suicidal ideation and negative affect, and less positive affect and desire for emotional closeness than low-anhedonia profile. Furthermore, more suicidal ideation, less positive affect, and less desire for emotional closeness differentiated the familial high-risk, high-anhedonia profile adolescents from the familial high-risk, low-anhedonia profile adolescents. Across anhedonia profiles, moderation analyses revealed that adolescents with high dmPFC neural activation in response to reward had positive relationships between social, anticipatory, and consummatory anhedonia and suicidal ideation., Limitations: Small subsample with fMRI data., Conclusion: Profiles of anhedonia emerge transdiagnostically and vary on clinical features. Anhedonia severity and activation in frontostriatal reward areas have value for clinically important outcomes such as suicidal ideation., Competing Interests: Declaration of competing interest Over the past 3 years, Dr. Pizzagalli has received consulting fees from Albright Stonebridge Group, Boehringer Ingelheim, Compass Pathways, Engrail Therapeutics, Karla Therapeutics, Neumora Therapeutics (formerly BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Otsuka, Sage Therapeutics, Sunovion, and Takeda; he has received honoraria from the Psychonomic Society and American Psychological Association (for editorial work) and from Alkermes; he has received research funding from the Brain and Behavior Research Foundation, Dana Foundation, Wellcome Leap, Millennium Pharmaceuticals, and NIMH; he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, and Neuroscience Software. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.

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.

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.

Background: Anhedonia may contribute to individual differences in delay discounting (DD). In prior work, we found that higher anhedonia was associated with shallower DD in healthy control (HC) participants but steeper DD in individuals with posttraumatic stress disorder (PTSD). In this study, we aimed to directly compare the relationship between anhedonia and DD across groups and to identify functional brain correlates of this interaction., Methods: Participants (HC group: n = 23, DSM-5 PTSD group: n = 23) completed a questionnaire assessing anhedonia (Snaith-Hamilton Pleasure Scale [SHAPS]), task-based functional magnetic resonance imaging of decision making including DD, and resting-state functional magnetic resonance imaging. Task-based activity and resting-state functional connectivity were evaluated in reward-related regions that have also been implicated in PTSD (nucleus accumbens [NAcc], right anterior insula)., Results: Higher SHAPS scores were associated with steeper DD in PTSD, but there was no relationship between DD and SHAPS in the HC group. There was a significant group-by-SHAPS interaction for NAcc activity, t 31  = 2.92, p = .007: Greater NAcc activity when immediate rewards were chosen was associated with higher SHAPS in the PTSD group but lower SHAPS in the HC group. In resting-state functional connectivity, there was a group-by-SHAPS interaction between the NAcc seed and right parietal and frontal pole clusters., Conclusions: These results extend prior findings that anhedonia is associated with steeper DD in PTSD and demonstrate that this behavioral finding occurs in the context of NAcc hyperactivity to immediate rewards and hyperconnectivity in anhedonic individuals with PTSD., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: The ICD-11 and DSM-5 are the leading systems for the classification of mental disorders, and their relevance for clinical work and research, as well as their impact for policy making and legal questions, has increased considerably. In recent years, other frameworks have been proposed to supplement or even replace the ICD and the DSM, raising many questions regarding clinical utility, scientific relevance, and, at the core, how best to conceptualize mental disorders., Method: As examples of the new approaches that have emerged, here we introduce the Hierarchical Taxonomy of Psychopathology (HiTOP), the Research Domain Criteria (RDoC), systems and network approaches, process-based approaches, as well as a new approach to the classification of personality disorders., Results and Discussion: We highlight main distinctions between these classification frameworks, largely related to different priorities and goals, and discuss areas of overlap and potential compatibility. Synergies among these systems may provide promising new avenues for research and clinical practice., Competing Interests: Winfried Rief is Editor-in-Chief for Clinical Psychology in Europe but played no editorial role in this particular article or intervened in any form in the peer review process.

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., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

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., (© 2023. The Author(s).)

Background: Growing evidence indicates that anhedonia is a multifaceted construct. This study examined the possibility of identifying subgroups of people with anhedonia using multiple reward-related measures to provide greater understanding the Research Domain Criteria's Positive Valence Systems Domain and pathways for developing treatments., Methods: Latent profile analysis of baseline data from a study that examined the effects of a novel kappa opioid receptor (KOR) antagonist drug on measures and biomarkers associated with anhedonia was used to identify subgroups. Measures included ventral striatal activation during the Monetary Incentive Delay task, response bias in the Probabilistic Reward Task, reward valuation scores from the Effort-Expenditure for Rewards Task, and scores from reward-related self-report measures., Results: Two subgroups were identified, which differed on self-report measures of reward. Participants in the subgroup reporting more anhedonia also reported more depression and had greater illness severity and functional impairments. Graphs of change with treatment showed a trend for the less severe subgroup to demonstrate higher response to KOR antagonist treatment on the neuroimaging measure, probabilistic reward task, and ratings of functioning; the subgroup with greater severity showed a trend for higher treatment response on reward-related self-report measures., Limitations: The main limitations include the small sample size and exploratory nature of analyses., Conclusions: Evidence of possible dissociation between self-reported measures of anhedonia and other measures with respect to treatment response emerged. These results highlight the importance for future research to consider severity of self-reported reward-related deficits and how the relationship across measurement methods may vary with severity., Competing Interests: Declaration of competing interest Darrow: reports no financial relationship with commercial interests. Pizzagalli: Over the past 3 years, Dr. Pizzagalli has received consulting fees from Albright Stonebridge Group, Boehringer Ingelheim, Compass Pathways, Engrail Therapeutics, Neumora Therapeutics (formerly BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Otsuka, Sunovion, and Takeda; he has received honoraria from the Psychonomic Society and American Psychological Association (for editorial work) and from Alkermes; he has received research funding from the Brain and Behavior Research Foundation, Dana Foundation, Wellcome Leap, Millennium Pharmaceuticals, and NIMH; he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, and Neuroscience Software; he has a financial interest in Neumora Therapeutics, which has licensed the copyright to the human version of the probabilistic reward task through Harvard University. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. Smoski: reports no financial relationships with commercial interests. Mathew: Dr. Mathew has been a consultant for Allergan, Alkermes, Axsome Therapeutics, BioXcel Therapeutics, Clexio Biosciences, Eleusis, EMA Wellness, Engrail Therapeutics, Intra-Cellular Therapies, Greenwich Biosciences, Janssen, Levo Therapeutics, Neurocrine, Perception Neuroscience, Praxis Precision Medicines, Relmada Therapeutics, Sage Therapeutics, Signant Health and Seelos Therapeutics, and received research support from Biohaven, Janssen, Merck, NIH, NeuroRx, PCORI, Sage Therapeutics, VA, and VistaGen Therapeutics, drug from Biohaven for NIMH-funded study, and support from the Michael E. Debakey VA Medical Center (Houston, TX) for use of resources and facilities and The Menninger Clinic, Houston, Texas. Nurnberger: J.N. has received research funding from Janssen and Assurex. Lisanby: S.H.L. is a co-inventor on a patent for TMS Technology, unrelated to this manuscript. S.H.L. contributed to this article while at Duke University, before joining the National Institute of Mental Health. The views expressed are her own and do not necessarily represent the views of the National Institutes of Health, the Department of Health, or the US government. Iosifescu: In the past 5 years, Dr. Iosifescu has received consulting fees from Alkermes, Axsome, Allergan, Biogen, the Centers for Psychiatric Excellence, Global Medical Education, MyndAnalytics (CNS Response), Jazz, Lundbeck, Otsuka, Precision Neuroscience, Sage, Sunovion; and he has received research grant support (through his academic institutions) from Alkermes, AstraZeneca, Brainsway, LiteCure, NeoSync, Roche, and Shire. Murrough: In the past 5 years, Dr. Murrough has served as a consultant to Allergan, Boehreinger Ingelheim, Clexio Biosciences, Global Medical Education (GME), Otsuka, Sage Therapeutics, and Engrail Therapeutics. Dr. Murrough is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders and on a patent pending for the use of KCNQ channel openers to treat depression and related conditions. The Icahn School of Medicine (employer of Dr. Murrough) is named on a patent and has entered into a licensing agreement and will receive payments related to the use of ketamine or esketamine for the treatment of depression. The Icahn School of Medicine is also named on a patent related to the use of ketamine for the treatment of PTSD. Dr. Murrough is not named on these patents and will not receive any payments. Yang: reports no financial relationship with commercial interests. Weiner: reports no financial relationship with commercial interests. Sanacora: has consulted for Allergan, Alkermes, AstraZeneca, Avanier Pharmaceuticals, Axsome Therapeutics, Biogen, Biohaven Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Clexio Biosciences, Denovo Biopharma, EMA- Wellness, Engrail, Freedom, Gilgamesh, Hoffman La-Roche, Intra-Cellular Therapies, Janssen, Levo, Lundbeck, Merck, Naurex, Navitor Pharmaceuticals, Neurocrine Biosciences, Novartis, Noven Pharmaceuticals, Otsuka, Praxis Therapeutics, Perception Neuroscience, Praxis Therapeutics, Sage Pharmaceuticals, Seelos Pharmaceuticals, Taisho Pharmaceuticals, Teva, Valeant, Vistagen Therapeutics, and XW Labs. GS also received research funding from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Hoffman La-Roche, Merck, Naurex, Servier and Usona Institute. G.S. holds equity in BioHaven Pharmaceuticals and is a co-inventor on a US patent (#8,778,979) held by Yale University and a co-inventor on US Provisional Patent Application No. 047162-7177P1 (00754) filed on August 20, 2018, by Yale University Office of Cooperative Research. Yale University (Employer of Dr. Sanacora) has a financial relationship with Janssen Pharmaceuticals and may in the future receive financial benefits from this relationship. Keefe: During the period that work was conducted on this study, R.S.E.K. was the owner of VeraSci, a for-profit company that provides clinical trial support and other services for over 100 pharmaceutical companies and other institutions. Song: has received research support from the NIH and GE Healthcare. Goodman: W.G. has consulted for Biohaven Pharmaceuticals, received research funding from the NIH, the McNair Foundation, and Biohaven Pharmaceuticals, and received donated devices from Medtronic. Whitton: Dr. Whitton was partially supported by a grant from the National Health and Medical Research Council of Australia (GNT: 1110773). Potter: Is on a DSMB for Agene-Bio and Regenacy, has stock ownership in Merck, and has received consulting fees from Karuna, Eliem, Neurocrine, Emerald Lake Safety, Boston Pharmaceuticals, and Otsuka and receives research funding from the NIH as a co-PI on a small business grant to praxis Bioresearch. Krystal: Dr. Krystal has received research grants from Janssen Pharmaceuticals, Axsome Pharmaceutics, Reveal Biosensors, The Ray and Dagmar Dolby Family Fund, and the National Institutes of Health. He has received consulting fees from Adare, Axsome Therapeutics, Big Health, Eisai, Evecxia, Ferring Pharmaceuticals, Galderma, Harmony Biosciences, Idorsia, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Millenium Pharmaceuticals, Merck, Neurocrine Biosciences, Neurawell, Pernix, Otsuka Pharmaceuticals, Sage, Takeda, and Angelini. He owns options of Big Health., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Distinguishing between trait- and state-like neural alternations in major depressive disorder (MDD) may advance our understanding of this recurring disorder. We aimed to investigate dynamic functional connectivity alternations in unmedicated individuals with current or past MDD using co-activation pattern analyses., Methods: Resting-state functional magnetic resonance imaging data were acquired from individuals with first-episode current MDD (cMDD, n = 50), remitted MDD (rMDD, n = 44), and healthy controls (HCs, n = 64). Using a data-driven consensus clustering technique, four whole-brain states of spatial co-activation were identified and associated metrics (dominance, entries, transition frequency) were analyzed with respect to clinical characteristics., Results: Relative to rMDD and HC, cMDD showed increased dominance and entries of state 1 (primarily involving default mode network (DMN)), and decreased dominance of state 4 (mostly involving frontal-parietal network (FPN)). Among cMDD, state 1 entries correlated positively with trait rumination. Conversely, relative to cMDD and HC, individuals with rMDD were characterized by increased state 4 entries. Relative to HC, both MDD groups showed increased state 4-to-1 (FPN to DMN) transition frequency but reduction in state 3 (spanning visual attention, somatosensory, limbic networks), with the former metric specifically related to trait rumination., Limitations: Further confirmation with longitudinal studies are required., Conclusions: Regardless of symptoms, MDD was characterized by increased FPN-to-DMN transitions and reduced dominance of a hybrid network. State-related effect emerged in regions critically implicated in repetitive introspection and cognitive control. Asymptomatic individuals with past MDD were uniquely linked to increased FPN entries. Our findings identify trait-like brain network dynamics that might increase vulnerability to future MDD., Competing Interests: Declaration of competing interest Over the past 3 years, Dr. Pizzagalli has received consulting fees from Albright Stonebridge Group, Boehringer Ingelheim, Compass Pathways, Concert Pharmaceuticals, Engrail Therapeutics, Neumora Therapeutics (former BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Otsuka Pharmaceuticals, Sunovion Pharmaceuticals, and Takeda Pharmaceuticals; honoraria from the Psychonomic Society and American Psychological Association (for editorial work) and Alkermes, and research funding from Bird Foundation, Brain and Behavior Research Foundation, Dana Foundation, Millennium Pharmaceuticals, NIMH, and Wellcome Leap. In addition, he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics (former BlackThorn Therapeutics), and Neuroscience Software. In the past 3 years, Dr. Auerbach has been an unpaid consultant for Ksana Health, and he serves on the Research Grants Committee for the American Foundation for Suicide Prevention. Dr. Auerbach's research is funded through NIMH, Morgan Stanley Foundation, and the Tommy Fuss Fund. Dr. Belleau's research is funded by NIMH K23MH122668 and the Klingenstein Third Generation Foundation. All other authors confirm they have no disclosures to make in association with the work presented in this manuscript., (Copyright © 2023. Published by Elsevier B.V.)

Objective: A general psychopathology (p) factor captures shared variation across mental disorders. Structural neural alterations have been associated with the p factor concurrently, but less is known about whether these alterations relate to within-person change in the p factor over time, especially during preadolescence, a period of neurodevelopmental changes., Method: This study examined whether baseline brain structure was prospectively related to the trajectory of the p factor and specific forms of psychopathology over 2 years in 9,220 preadolescents (aged 9-10 at baseline) from the Adolescent Brain Cognitive Development Study (ABCD). Longitudinal multilevel models were conducted to determine whether baseline brain structure (volume, surface area, thickness) was associated with between-person differences and within-person change in the p factor (from a higher-order confirmatory factor model) and internalizing, externalizing, neurodevelopmental, somatization, and detachment factor scores (from a correlated factors model) over 3 study waves., Results: Smaller global volume and surface area, but not thickness, were associated with higher between-person levels of the p factor scores, which persisted over time. None of the brain structure measures were related to within-person change in the p factor scores. Lower baseline cortical thickness was associated with steeper decreases in internalizing psychopathology, which was driven by lower thickness within sensorimotor and temporal regions., Conclusion: These novel results identify specific brain structure features that might contribute to transdiagnostic psychopathology development in preadolescence. Children with smaller total brain volume and surface area may be vulnerable to persistent general psychopathology during preadolescence. Cortical thinning reflective of pruning and myelination in sensorimotor and temporal brain regions specifically may protect against increases in internalizing, but not general psychopathology, during preadolescence., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

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.

Pleasure is a fundamental driver of human behaviour, yet its neural basis remains largely unknown. Rodent studies highlight opioidergic neural circuits connecting the nucleus accumbens, ventral pallidum, insula and orbitofrontal cortex as critical for the initiation and regulation of pleasure, and human neuroimaging studies exhibit some translational parity. However, whether activation in these regions conveys a generalizable representation of pleasure regulated by opioidergic mechanisms remains unclear. Here we use pattern recognition techniques to develop a human functional magnetic resonance imaging signature of mesocorticolimbic activity unique to states of pleasure. In independent validation tests, this signature is sensitive to pleasant tastes and affect evoked by humour. The signature is spatially co-extensive with mu-opioid receptor gene expression, and its response is attenuated by the opioid antagonist naloxone. These findings provide evidence for a basis of pleasure in humans that is distributed across brain systems., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Anhedonia is hypothesized to be associated with blunted mesocorticolimbic dopamine (DA) functioning in samples with major depressive disorder. The purpose of this study was to examine linkages between striatal DA, reward circuitry functioning, anhedonia, and, in an exploratory fashion, self-reported stress, in a transdiagnostic anhedonic sample., Methods: Participants with (n = 25) and without (n = 12) clinically impairing anhedonia completed a reward-processing task during simultaneous positron emission tomography and magnetic resonance (PET-MR) imaging with [ 11 C]raclopride, a DA D2/D3 receptor antagonist that selectively binds to striatal DA receptors., Results: Relative to controls, the anhedonia group exhibited decreased task-related DA release in the left putamen, caudate, and nucleus accumbens and right putamen and pallidum. There were no group differences in task-related brain activation (fMRI) during reward processing after correcting for multiple comparisons. General functional connectivity (GFC) findings revealed blunted fMRI connectivity between PET-derived striatal seeds and target regions in the anhedonia group. Associations were identified between anhedonia severity and the magnitude of task-related DA release to rewards in the left putamen, but not mesocorticolimbic GFC., Conclusions: Results provide evidence for reduced striatal DA functioning during reward processing and blunted mesocorticolimbic network functional connectivity in a transdiagnostic sample with clinically significant anhedonia., Competing Interests: Declaration of Competing Interest Over the past 3 years, Dr. Pizzagalli has received consulting fees from Albright Stonebridge Group, Boehringer Ingelheim, Compass Pathways, Engrail Therapeutics, Neumora Therapeutics (formerly BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Otsuka, Sunovion, and Takeda; he has received honoraria from the Psychonomic Society (for editorial work) and from Alkermes; he has received research funding from the Brain and Behavior Research Foundation, the Dana Foundation, Millennium Pharmaceuticals, and NIMH; he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, and Neuroscience Software. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. The other authors have no conflicts of interest or relevant disclosures., (Copyright © 2023 Elsevier B.V. All rights reserved.)