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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: 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: 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.)

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.)

Increase in stress-related disorders in women begins post-puberty and persists throughout the lifespan. To characterize sex differences in stress response in early adulthood, we used functional magnetic resonance imaging while participants underwent a stress task in conjunction with serum cortisol levels and questionnaires assessing anxiety and mood. Forty-two healthy subjects aged 18-25 years participated (21M, 21F). Interaction of stress and sex in brain activation and connectivity were examined. Results demonstrated significant sex differences in brain activity with women exhibiting increased activation in regions that inhibit arousal compared to men during the stress paradigm. Women had increased connectivity among stress circuitry regions and default mode network, whereas men had increased connectivity between stress and cognitive control regions. In a subset of subjects (13F, 17M), we obtained gamma-aminobutyric acid (GABA) magnetic resonance spectroscopy in rostral anterior cingulate cortex (rostral ACC) and dorsolateral prefrotal cortex (dlPFC) and conducted exploratory analyses to relate GABA measurements with sex differences in brain activation and connectivity. Prefrontal GABA levels were negatively associated with inferior temporal gyrus activation in men and women and with ventromedial prefrontal cortex activation in men. Despite sex differences in neural response, we found similar subjective ratings of anxiety and mood, cortisol levels, and GABA levels between sexes, suggesting sex differences in brain activity result in similar behavioral responses among the sexes. These results help establish sex differences in healthy brain activity from which we can better understand sex differences underlying stress-associated illnesses., Competing Interests: Declaration of Competing Interest Dr. Goldstein is on the scientific advisory board and has an equity interest in Cala Health, a neuromodulation device company, but there is no conflict of interest with this study. The relationship is managed by the Mass General Brigham Office of Industry Interactions. 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 Alkermes; he has received research funding from the Brain and Behavior Research Foundation, the Dana Foundation, Millennium Pharmaceuticals, and National Institute of Mental Health (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. Dr. Misra has served on the advisory board of Ipsen and Abbvie and served as a consultant for Abbvie and Sanofi, but no conflicts of interest with this work. 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 financial disclosures., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The interplay between cortical and limbic regions in stress circuitry calls for a neural systems approach to investigations of acute stress responses in major depressive disorder (MDD). Advances in multimodal imaging allow inferences between regional neurotransmitter function and activation in circuits linked to MDD, which could inform treatment development. The current study investigated the role of the inhibitory neurotransmitter GABA in stress circuitry in females with current and remitted MDD. Multimodal imaging data were analyzed from 49 young female adults across three groups (current MDD, remitted MDD (rMDD), and healthy controls). GABA was assessed at baseline using magnetic resonance spectroscopy, and functional MRI data were collected before, during, and after an acute stressor and analyzed using a network modeling approach. The MDD group showed an overall lower cortisol response than the rMDD group and lower rostral anterior cingulate cortex (ACC) GABA than healthy controls. Across groups, stress decreased activation in the frontoparietal network (FPN) but increased activation in the default mode network (DMN) and a network encompassing the ventromedial prefrontal cortex-striatum-anterior cingulate cortex (vmPFC-Str-ACC). Relative to controls, the MDD and rMDD groups were characterized by decreased FPN and salience network (SN) activation overall. Rostral ACC GABA was positively associated with connectivity between an overlapping limbic network (Temporal-Insula-Amygdala) and two other circuits (FPN and DMN). Collectively, these findings indicate that reduced GABA in females with MDD was associated with connectivity differences within and across key networks implicated in depression. GABAergic treatments for MDD might alleviate stress circuitry abnormalities in females., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Background: Symptoms of borderline personality disorder (BPD) and post-traumatic stress disorder (PTSD) commonly co-occur. Recent evidence supports the concomitant treatment of BPD and PTSD., Methods: This study uses a longitudinal cross-lagged panel model to examine BPD and PTSD symptom response in a sample of 110 women undergoing residential treatment for BPD. The naturalistic treatment primarily followed a dialectical-behavior therapy protocol, with individualized integration of other major evidence-based treatments (EBTs) for BPD, including mentalization-based treatment, good psychiatric management, and transference-focused psychotherapy., Results: A residentially-based integration of treatment approaches resulted in significant reductions in BPD ( d =  0.71) and PTSD ( d =  0.75) symptoms. Moreover, changes in BPD symptoms prospectively predicted changes in PTSD symptoms (constrained path b  = 1.73), but the reverse was not true (constrained path b  = 0.05)., Conclusions: A naturalistic integration of EBTs for BPD may benefit both BPD and PTSD symptoms even in the absence of PTSD-oriented intervention. Additionally, the attenuation of BPD symptoms may have positive impact on PTSD symptoms., Competing Interests: Competing interestsThe authors have no competing interests to declare., (© The Author(s). 2019.)