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Abstract Background Studies of individuals who do not meet criteria for major depressive disorder (MDD) but with subclinical levels of depressive symptoms may aid in the identification of neurofunctional abnormalities that possibly precede and predict the development of MDD. The purpose of this study was to evaluate relations between subclinical levels of depressive symptoms and neural activation patterns during tasks previously shown to differentiate individuals with and without MDD. Methods Functional magnetic resonance imaging (fMRI) was used to assess neural activations during active emotion regulation, a resting state scan, and reward processing. Participants were twelve females with a range of depressive symptoms who did not meet criteria for MDD. Results Increased depressive symptom severity predicted (1) decreased left midfrontal gyrus activation during reappraisal of sad stimuli; (2) increased right midfrontal gyrus activation during distraction from sad stimuli; (3) increased functional connectivity between a precuneus seed region and left orbitofrontal cortex during a resting state scan; and (4) increased paracingulate activation during non-win outcomes during a reward-processing task. Conclusions These pilot data shed light on relations between subclinical levels of depressive symptoms in the absence of a formal MDD diagnosis and neural activation patterns. Future studies will be needed to test the utility of these activation patterns for predicting MDD onset in at-risk samples.

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.)

Objective: Homework is a key theoretical component of cognitive-behavioral therapies, however, the effects of homework on clinical outcomes have largely been evaluated between-persons rather than within-persons., Methods: The effects of homework completion on treatment response were examined in a randomized trial comparing Behavioral Activation Treatment for Anhedonia (BATA, n = 38), a novel psychotherapy, to Mindfulness-Based Cognitive Therapy (MBCT, n=35). The primary endpoint was consummatory reward sensitivity, measured weekly by the Snaith Hamilton Pleasure Scale (SHAPS), up to 15 weeks. Multilevel models evaluated change in SHAPS scores over time and the effects of clinician-reported and participant-reported homework., Results: BATA and MBCT resulted in significant, equivalent reductions in SHAPS scores. Unexpectedly, participants who completed greater mean total amounts of homework did not improve at a faster rate (i.e., no between-person effect). However, sessions with greater than average participant-reported homework completion were associated with greater than average reductions in SHAPS scores (i.e., a within-person effect). For clinician-reported homework, this effect was only evident within the BATA condition., Conclusion: This study shows psychotherapy homework completion relates to symptomatic improvement in cognitive-behavioral treatments for anhedonia when session-to-session changes are examined within-person. On the contrary, we found no evidence that total homework completion predicted greater improvements between-person. When possible, psychotherapy researchers should evaluate their constructs of interest across multiple sessions (not just pre/post) to allow more direct tests of hypotheses predicted by theoretical models of individual change processes., Competing Interests: Declaration of competing interest The work described in this manuscript has not been published previously, is not under consideration for publication elsewhere, and the publication of this manuscript is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out. If accepted, this work will not be published elsewhere in the same form, in English or in any other language, including electronically, without the written consent of the copyright–holder. We have no conflicts of interest, financial or otherwise, that would preclude a fair review or publication of this manuscript. Some data reported in this manuscript have been previously published and were collected as part of a larger data collection. Findings from the data collection have been reported in a separate manuscript focused on resting-state functional connectivity data from fMRI obtained within the same participants (Cernasov et al., 2021)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Chronic stress alters reward sensitivity and contributes to the emergence of anhedonia. In clinical samples, the perception of stress is a strong predictor of anhedonia. While there is substantial evidence demonstrating psychotherapy reduces perceived stress, little is known regarding the effects of treatment-related decreases in perceived stress on anhedonia., Methods: The current study investigated reciprocal relations between perceived stress and anhedonia using a cross-lagged panel model approach in a 15-week clinical trial examining the effects of Behavioral Activation Treatment for Anhedonia (BATA), a novel psychotherapy to treat anhedonia, compared to a Mindfulness-Based Cognitive Therapy (MBCT) comparison intervention (ClinicalTrials.gov Identifiers NCT02874534 and NCT04036136)., Results: Treatment completers (n = 72) experienced significant reductions in anhedonia (M = -8.94, SD = 5.66) on the Snaith-Hamilton Pleasure Scale (t(71) = 13.39, p < .0001), and significant reductions in perceived stress (M = -3.71, SD = 3.88) on the Perceived Stress Scale (t(71) = 8.11, p < .0001) following treatment. Across all treatment-seeking participants (n = 87), a longitudinal autoregressive cross-lagged model revealed significant paths showing that higher levels of perceived stress at treatment Week 1 predicted reductions in anhedonia at treatment Week 4; lower levels of perceived stress at Week 8 predicted reductions in anhedonia at Week 12. Anhedonia did not significantly predict perceived stress at any stage of treatment., Conclusions: This study showed specific timing and directional effects of perceived stress on anhedonia during psychotherapy treatment. Individuals with relatively high perceived stress at the start of treatment were more likely to report relatively lower anhedonia a few weeks into treatment. At mid-treatment, individuals with low perceived stress were more likely to report lower anhedonia towards the end of treatment. These results demonstrate that early treatment components reduce perceived stress, thus allowing for downstream changes in hedonic functioning during mid-late treatment. The findings presented here suggest it will be critically important for future clinical trials evaluating novel interventions for anhedonia to measure stress levels repeatedly, as an important mechanism of change., Trial Name: Development of a Novel Transdiagnostic Intervention for Anhedonia - R61 Phase. TRIAL URL: https://clinicaltrials.gov/ct2/show/NCT02874534., Trial Registration Number: NCT02874534., Competing Interests: Conflict of interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Anhedonia is the loss of pleasure or motivation to engage in previously enjoyable activities, and is a transdiagnostic symptom associated with significant clinical impairment. Anhedonia is implicated in several different psychiatric disorders, presenting a promising opportunity for transdiagnostic treatment. Thus, developing targeted treatments for anhedonia is of critical importance for population mental health. An important first step in doing so is establishing a thorough understanding of the neural correlates of anhedonia. The Triple Network Model of Psychopathology provides a frame for how brain activity may go awry in anhedonia, specifically in the context of Salience Network (SN) function (i.e., saliency-mapping). We present a narrative review examining saliency-mapping as it relates to anhedonia severity in depressed and transdiagnostic adult samples. Results revealed increased anhedonia to be associated with hyperactivity of the SN at rest and in the context of negative stimuli, as well as a global lack of SN engagement in the context of positive stimuli. Potential treatments for anhedonia are placed within this model, and future directions for research are discussed., (Copyright © 2021. Published by Elsevier B.V.)

Background: The neural mechanisms associated with anhedonia treatment response are poorly understood. Additionally, no study has investigated changes in resting-state functional connectivity (rsFC) accompanying psychosocial treatment for anhedonia., Methods: We evaluated a novel psychotherapy, Behavioral Activation Therapy for Anhedonia (BATA, n = 38) relative to Mindfulness-Based Cognitive Therapy (MBCT, n = 35) in a medication-free, transdiagnostic, anhedonic sample in a parallel randomized controlled trial. Participants completed up to 15 sessions of therapy and up to four 7T MRI scans before, during, and after treatment (n = 185 scans). Growth curve models estimated change over time in anhedonia and in rsFC using average region-of-interest (ROI)-to-ROI connectivity within the default mode network (DMN), frontoparietal network (FPN), salience network, and reward network. Changes in rsFC from pre- to post-treatment were further evaluated using whole-network seed-to-voxel and ROI-to-ROI edgewise analyses., Results: Growth curve models showed significant reductions in anhedonia symptoms and in average rsFC within the DMN and FPN over time, across BATA and MBCT. There were no differences in anhedonia reductions between treatments. Within-person, changes in average rsFC were unrelated to changes in anhedonia. Between-person, higher than average FPN rsFC was related to less anhedonia across timepoints. Seed-to-voxel and edgewise rsFC analyses corroborated reductions within the DMN and between the DMN and FPN over time, across the sample., Conclusions: Reductions in rsFC within the DMN, FPN, and between these networks co-occurred with anhedonia improvement across two psychosocial treatments for anhedonia. Future anhedonia clinical trials with a waitlist control group should disambiguate treatment versus time-related effects on rsFC., (Copyright © 2021. Published by Elsevier B.V.)

Anhedonia remains a major clinical issue for which there is few effective interventions. Untreated or poorly controlled anhedonia has been linked to worse disease course and increased suicidal behavior across disorders. Taking a proof-of-mechanism approach under the auspices of the National Institute of Mental Health FAST-FAIL initiative, we were the first to show that, in a transdiagnostic sample screened for elevated self-reported anhedonia, 8 weeks of treatment with a kappa-opioid receptor (KOR) antagonist resulted in significantly higher reward-related activation in one of the core hubs of the brain reward system (the ventral striatum), better reward learning in the Probabilistic Reward Task (PRT), and lower anhedonic symptoms, relative to 8 weeks of placebo. Here, we performed secondary analyses of the PRT data to investigate the putative effects of KOR antagonism on anhedonic behavior with more precision by using trial-level model-based Bayesian computational modeling and probability analyses. We found that, relative to placebo, KOR antagonism resulted in significantly higher learning rate (i.e., ability to learn from reward feedback) and a more sustained preference toward the more frequently rewarded stimulus, but unaltered reward sensitivity (i.e., the hedonic response to reward feedback). Collectively, these findings provide novel evidence that in a transdiagnostic sample characterized by elevated anhedonia, KOR antagonism improved the ability to modulate behavior as a function of prior rewards. Together with confirmation of target engagement in the primary report (Krystal et al., Nat Med, 2020), the current findings suggest that further transdiagnostic investigation of KOR antagonism for anhedonia is warranted.

The National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P < 0.01; effect size = 0.58 (95% confidence interval, 0.13-0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the 'fast-fail' approach.

Mindfulness-based interventions have been shown to be effective in alleviating depressive symptoms. While much work has examined the effects of mindfulness training on subjective symptoms and experiences, and less is known regarding whether mindfulness training may alter relatively uncontrollable cognitive processes associated with depressed mood, particularly implicit dysfunctional attitudes. The present study examined the effects of a brief mindful acceptance induction on implicit dysfunctional attitudes and degree of concordance between implicit and explicit dysfunctional attitudes in the context of sad mood. A total of 79 adult participants with elevated depressive symptoms underwent an autobiographical mood induction procedure before being randomly assigned to mindful acceptance or thought wandering inductions. Results showed that the effect of mindful acceptance on implicit dysfunctional attitude was significantly moderated by trait mindfulness. Participants high on trait mindfulness demonstrated significant improvements in implicit dysfunctional attitudes following the mindful acceptance induction. Those low on trait mindfulness demonstrated significantly worse implicit dysfunctional attitudes following the induction. Significantly greater levels of concordance between implicit and explicit dysfunctional attitudes were observed in the mindful acceptance condition versus the thought wandering condition. The findings highlight changes in implicit dysfunctional attitudes and improvements in self-concordance as two potential mechanisms underlying the effects of mindfulness-based interventions., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Major depressive disorder (MDD) is characterized by abnormal resting-state functional connectivity (RSFC), especially in medial prefrontal cortical (MPFC) regions of the default network. However, prior research in MDD has not examined dynamic changes in functional connectivity as networks form, interact, and dissolve over time. We compared unmedicated individuals with MDD (n=100) to control participants (n=109) on dynamic RSFC (operationalized as SD in RSFC over a series of sliding windows) of an MPFC seed region during a resting-state functional magnetic resonance imaging scan. Among participants with MDD, we also investigated the relationship between symptom severity and RSFC. Secondary analyses probed the association between dynamic RSFC and rumination. Results showed that individuals with MDD were characterized by decreased dynamic (less variable) RSFC between MPFC and regions of parahippocampal gyrus within the default network, a pattern related to sustained positive connectivity between these regions across sliding windows. In contrast, the MDD group exhibited increased dynamic (more variable) RSFC between MPFC and regions of insula, and higher severity of depression was related to increased dynamic RSFC between MPFC and dorsolateral prefrontal cortex. These patterns of highly variable RSFC were related to greater frequency of strong positive and negative correlations in activity across sliding windows. Secondary analyses indicated that increased dynamic RSFC between MPFC and insula was related to higher levels of recent rumination. These findings provide initial evidence that depression, and ruminative thinking in depression, are related to abnormal patterns of fluctuating communication among brain systems involved in regulating attention and self-referential thinking.

Autism spectrum disorder (ASD) is characterized by high rates of comorbid internalizing and externalizing disorders. One mechanistic account of these comorbidities is that ASD is characterized by impaired emotion regulation (ER) that results in deficits modulating emotional responses. We assessed neural activation during cognitive reappraisal of faces in high functioning adults with ASD. Groups did not differ in looking time, pupilometry, or subjective ratings of faces during reappraisal. However, instructions to increase positive and negative emotional responses resulted in less increase in nucleus accumbens and amygdala activations (respectively) in the ASD group, and both regulation instructions resulted in less change in dorsolateral prefrontal cortex activation in the ASD group. Results suggest a potential mechanistic account of impaired ER in ASD.

A dysfunction in the interaction between executive function and mood regulation has been proposed as the pathophysiology of depression. However, few studies have investigated the alteration in brain systems related to executive control over emotional distraction in depression. To address this issue, 19 patients with major depressive disorder (MDD) and 20 healthy controls were scanned using functional magnetic resonance imaging. Participants performed an emotional oddball task in which infrequently presented circle targets required detection while sad and neutral pictures were irrelevant novel distractors. Hemodynamic responses were compared for targets, sad distractors, and for targets that followed sad or neutral distractors (Target-after-Sad and Target-after-Neutral). Patients with MDD revealed attenuated activation overall to targets in executive brain regions. Behaviorally, MDD patients were slower in response to Target-after-Sad than Target-after-Neutra stimuli. Patients also revealed a reversed activation pattern from controls in response to this contrast in the left anterior cingulate, insula, right inferior frontal gyrus (IFG), and bilateral middle frontal gyrus. Those patients who engaged the right IFG more during Target-after-Neutral stimuli responded faster to targets, confirming a role of this region in coping with emotional distraction. The results provide direct evidence of an alteration in the neural systems that interplay cognition with mood in MDD.

Drawing from an affect-induction model of laughter (Bachorowski & Owren, 2001; Owren & Bachorowski, 2002), we propose that "antiphonal" laughter--that is, laughter that occurs during or immediately after a social partner's laugh--is a behavioural manifestation of a conditioned positive emotional response to another individual's laugh acoustics. To test hypotheses concerning the occurrence of antiphonal laughter, participants (n = 148) were tested as part of either same- or mixed-sex friend or stranger dyads, and were audiorecorded while they played brief games intended to facilitate laugh production. An index of antiphonal laughter for each dyad was derived using Yule's Q. Significantly more antiphonal laughter was produced in friend than in stranger dyads, and females in mixed-sex dyads produced more antiphonal laughter than did their male partners. Antiphonal laughter may therefore reflect a mutually positive stance between social partners, and function to reinforce shared positive affective experiences.

Remarkably little is known about the acoustic features of laughter. Here, acoustic outcomes are reported for 1024 naturally produced laugh bouts recorded from 97 young adults as they watched funny video clips. Analyses focused on temporal features, production modes, source- and filter-related effects, and indexical cues to laugher sex and individual identity. Although a number of researchers have previously emphasized stereotypy in laughter, its acoustics were found now to be variable and complex. Among the variety of findings reported, evident diversity in production modes, remarkable variability in fundamental frequency characteristics, and consistent lack of articulation effects in supralaryngeal filtering are of particular interest. In addition, formant-related filtering effects were found to be disproportionately important as acoustic correlates of laugher sex and individual identity. These outcomes are examined in light of existing data concerning laugh acoustics, as well as a number of hypotheses and conjectures previously advanced about this species-typical vocal signal.