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Objective: Heightened reactivity to stress is associated with poor treatment outcome in people with substance use disorders (SUDs). Behavioral strategies can reduce stress reactivity; however, these strategies are understudied in people with SUDs. The objective of this study was to test the effect of two behavioral strategies (cognitive reappraisal and affect labeling) on stress reactivity in people with SUDs., Method: Treatment-seeking adults with SUDs ( N = 119) were randomized to receive brief training in cognitive reappraisal, affect labeling, or a psychoeducational control, followed by a standardized stress induction. Markers of stress reactivity were collected before and following stress induction and included self-reported negative affect and substance craving, as well as salivary cortisol, and skin conductance response., Results: Analyses of covariance did not indicate a significant effect of treatment condition on negative affect, cortisol, or skin conductance response. Participants in the affect labeling condition had greater increase in craving than those in the cognitive reappraisal condition; neither condition differed from control., Conclusions: Results indicated that, although participants were able to implement behavioral skills following a brief training, training condition did not modify stress reactivity, on average, relative to control. Future directions include consideration of individual differences in response to training and determination of whether higher "dosing" of skills via multiple sessions or extended practice is needed to influence stress reactivity in people with SUDs. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

In patients with out-of-hospital cardiac arrest (OHCA) who attain return of spontaneous circulation (ROSC), rearrest while in the prehospital setting represents a significant barrier to survival. To date, there are limited data to guide prehospital emergency medical services (EMS) management immediately following successful resuscitation resulting in ROSC and prior to handoff in the emergency department. Post-ROSC care encompasses a multifaceted approach including hemodynamic optimization, airway management, oxygenation, and ventilation. We sought to develop an evidenced-based, goal-directed bundle of care targeting specified vital parameters in the immediate post-ROSC period, with the goal of decreasing the incidence of rearrest and improving survival outcomes. Here, we describe the rationale and development of this goal-directed bundle of care, which will be adopted by several EMS agencies within California. We convened a group of EMS experts, including EMS Medical Directors, quality improvement officers, data managers, educators, EMS clinicians, emergency medicine clinicians, and resuscitation researchers to develop a goal-directed bundle of care to be applied in the field during the period immediately following ROSC. This care bundle includes guidance for prehospital personnel on recognition of impending rearrest, hemodynamic optimization, ventilatory strategies, airway management, and diagnosis of underlying causes prior to the initiation of transport., Competing Interests: James J. Menegazzi was supported in part by a grant from the National Heart, Lung, and Blood Institute, National Institutes of Health (NHLBI 1RO1HL117979‐01) and David G Dillon was supported in this work by NHLBI grant K38HL165363. They have three patents issued and has been loaned equipment for use in his lab. These are described in more detail in his conflicts of interest form. The other authors declare no conflicts of interest., (© 2024 The Author(s). Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Importance: The incidence of opioid-associated out-of-hospital cardiac arrest (OA-OHCA) has grown from less than 1% of OHCA in 2000 to between 7% and 14% of OHCA in recent years; American Heart Association (AHA) protocols suggest that emergency medical service (EMS) clinicians consider naloxone in OA-OHCA. However, it is unknown whether naloxone improves survival in these patients or in patients with undifferentiated OHCA., Objective: To evaluate the association of naloxone with clinical outcomes in patients with undifferentiated OHCA., Design, Setting, and Participants: Retrospective cohort study of EMS-treated patients aged 18 or older who received EMS treatment for nontraumatic OHCA in 3 Northern California counties between 2015 and 2023. Data were analyzed using propensity score-based models from February to April 2024., Exposure: EMS administration of naloxone., Main Outcomes and Measures: The primary outcome was survival to hospital discharge; the secondary outcome was sustained return of spontaneous circulation (ROSC). Covariates included patient and cardiac arrest characteristics (eg, age, sex, nonshockable rhythm, any comorbidity, unwitnessed arrest, and EMS agency) and EMS clinician determination of OHCA cause as presumed drug-related., Results: Among 8195 patients (median [IQR] age, 65 [51-78] years; 5540 male [67.6%]; 1304 Asian, Native Hawaiian, or Pacific Islander [15.9%]; 1119 Black [13.7%]; 2538 White [31.0%]) with OHCA treated by 5 EMS agencies from 2015 to 2023, 715 (8.7%) were believed by treating clinicians to have drug-related OHCA. Naloxone was administered to 1165 patients (14.2%) and was associated with increased ROSC using both nearest neighbor propensity matching (absolute risk difference [ARD], 15.2%; 95% CI, 9.9%-20.6%) and inverse propensity-weighted regression adjustment (ARD, 11.8%; 95% CI, 7.3%-16.4%). Naloxone was also associated with increased survival to hospital discharge using both nearest neighbor propensity matching (ARD, 6.2%; 95% CI, 2.3%-10.0%) and inverse propensity-weighted regression adjustment (ARD, 3.9%; 95% CI, 1.1%-6.7%). The number needed to treat with naloxone was 9 for ROSC and 26 for survival to hospital discharge. In a regression model that assessed effect modification between naloxone and presumed drug-related OHCA, naloxone was associated with improved survival to hospital discharge in both the presumed drug-related OHCA (odds ratio [OR], 2.48; 95% CI, 1.34-4.58) and non-drug-related OHCA groups (OR, 1.35; 95% CI, 1.04-1.77)., Conclusions and Relevance: In this retrospective cohort study, naloxone administration as part of EMS management of OHCA was associated with increased rates of ROSC and increased survival to hospital discharge when evaluated using propensity score-based models. Given the lack of clinical practice data on the efficacy of naloxone in OA-OHCA and OHCA in general, these findings support further evaluation of naloxone as part of cardiac arrest care.

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: In 2015, California passed AB 71 to create a state-wide Use of Force Incident Reporting Database (URSUS) to tabulate law enforcement-reported encounters that resulted in serious bodily injury, death or discharge of a firearm. We use these data to analyse encounters that resulted in fatal and non-fatal civilian injuries in California between 2016 and 2021., Methods: We performed a retrospective review of URSUS from January 2016 to December 2021. The main outcomes were the number of law enforcement encounters that involved civilian serious bodily injury or death and encounter-level characteristics., Results: URSUS recorded 3677 incidents between 2016 and 2021 resulting in 942 civilian fatalities and 2735 instances of serious civilian injuries. Injury rates were highest for civilians who identified as Hispanic (1.80 injuries per 100 000 population) or black (5.17 injuries per 100 000 population). Injuries involving a firearm were usually fatal (58.9% fatality rate; 1471 injuries), while non-firearm incidents were more likely to result in serious injuries (4.2% fatality rate; 2929 injuries). We did not find statistically significant trends in rates of civilian injuries per 100 000 population., Conclusion: Rates of law enforcement-related injuries were highest for Hispanic and black civilians in California between 2016 and 2021 and firearm-related injuries were overwhelmingly fatal. The URSUS database represents an important effort by law enforcement agencies to collect information on injuries and fatalities resulting from law enforcement encounters. Given similar databases exist in fewer than half of states, additional legislative efforts are needed to improve systematic national data collection on these encounters., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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: Despite frequent treatment of alcohol withdrawal syndrome (AWS) in the emergency department (ED), evidence for phenobarbital (PB) as an ED alternative therapy is mixed. We conducted a systematic review and meta-analysis comparing safety and efficacy of PB to benzodiazepines (BZDs) for treatment of AWS in the ED., Methods: We searched articles and references published in English in PubMed, Web of Science, and Embase from inception through May 2022. We included randomized trials and cohort studies comparing treatment with PB to BZD controls and excluded studies focused on non-AWS conditions. Review was conducted by two blinded investigators and a third author; eight of 59 (13.6%) abstracts met inclusion criteria for review and meta-analysis using a random-effects model. Treatment superiority was evaluated through utilization, pharmacologic, and clinical outcomes. Primary outcomes for meta-analysis were the proportion of patients (1) admitted to the intensive care unit (ICU), (2) admitted to the hospital, (3) readmitted to the ED after discharge, and (4) who experienced adverse events., Results: Eight studies (two randomized controlled trials, six retrospective cohorts) comprised data from 1507 patients in 2012 treatment encounters for AWS. All studies were included in meta-analysis for adverse events, seven for hospital admission, five for ICU admission, and three for readmission to the ED after discharge. Overall methodological quality was low-moderate, risk of bias moderate-high, and statistical heterogeneity moderate. Pooled relative risk of ICU admission for those treated with PB versus BZD was 0.92 (95% confidence interval [CI] 0.54-1.55). Risk for admission to the hospital was 0.98 (95% CI 0.89-1.07) and for any adverse event was 1.1 (95% CI 0.78-1.57); heterogeneity prevented meta-analysis for ED readmission., Conclusions: The current literature base does not show that treatment with PB significantly reduces ICU admissions, hospital admissions, ED readmissions, or adverse events in ED patients with AWS compared with BZDs alone., (© 2024 The Authors. Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)

Introduction: Estimates of the prevalence of drug-related out of hospital cardiac arrest (OHCA) vary, ranging from 1.8% to 10.0% of medical OHCA. However, studies conducted prior to the recent wave of fentanyl deaths likely underestimate the current prevalence of drug-related OHCA. We evaluated recent trends in drug-related OHCA, hypothesizing that the proportion of presumed drug-related OHCA treated by emergency medical services (EMS) has increased since 2015., Methods: We conducted a retrospective analysis of OHCA patients treated by EMS providers in San Francisco, California between 2015 and 2023. Participants included OHCA cases in which resuscitation was attempted by EMS. The study exposure was the year of arrest. Our primary outcome was the occurrence of drug-related OHCA, defined as the EMS impression of OHCA caused by a presumed or known overdose of medication(s) or drug(s)., Results: From 2015 to 2023, 5044 OHCA resuscitations attended by EMS (average 561 per year) met inclusion criteria. The median age was 65 (IQR 50-79); 3508 (69.6%) were male. The EMS impression of arrest etiology was drug-related in 446/5044 (8.8%) of OHCA. The prevalence of presumed drug-related OHCA increased significantly each year from 1% in 2015 to 17.6% in 2023 (p-value for trend = 0.0001). After adjustment, presumed drug-related OHCA increased by 30% each year from 2015-2023., Conclusion: Drug-related OHCA is an increasingly common etiology of OHCA. In 2023, one in six OHCA was presumed to be drug related. Among participants less than 60 years old, one in three OHCA was presumed to be drug related., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Importance: Recent studies have demonstrated that people of color are more likely to be restrained in emergency department (ED) settings compared with other patients, but many of these studies are based at a single site or health care system, limiting their generalizability., Objective: To synthesize existing literature on risk of physical restraint use in adult EDs, specifically in reference to patients of different racial and ethnic backgrounds., Data Sources: A systematic search of PubMed, Embase, Web of Science, and CINAHL was performed from database inception to February 8, 2022., Study Selection: Included peer-reviewed studies met 3 criteria: (1) published in English, (2) original human participants research performed in an adult ED, and (3) reported an outcome of physical restraint use by patient race or ethnicity. Studies were excluded if they were conducted outside of the US, or if full text was unavailable., Data Extraction and Synthesis: Four independent reviewers (V.E., M.M., D.D., and A.H.) abstracted data from selected articles following Meta-Analysis of Observational Studies in Epidemiology guidelines. A modified Newcastle-Ottawa scale was used to assess quality. A meta-analysis of restraint outcomes among minoritized racial and ethnic groups was performed using a random-effects model in 2022., Main Outcome(s) and Measure(s): Risk of physical restraint use in adult ED patients by racial and ethnic background., Results: The search yielded 1597 articles, of which 10 met inclusion criteria (0.63%). These studies represented 2 557 983 patient encounters and 24 030 events of physical restraint (0.94%). In the meta-analysis, Black patients were more likely to be restrained compared with White patients (RR, 1.31; 95% CI, 1.19-1.43) and to all non-Black patients (RR, 1.27; 95% CI, 1.23-1.31). With respect to ethnicity, Hispanic patients were less likely to be restrained compared with non-Hispanic patients (RR, 0.85; 95% CI, 0.81-0.89)., Conclusions and Relevance: Physical restraint was uncommon, occurring in less than 1% of encounters, but adult Black patients experienced a significantly higher risk of physical restraint in ED settings compared with other racial groups. Hispanic patients were less likely to be restrained compared with non-Hispanic patients, though this observation may have occurred if Black patients, with a higher risk of restraint, were included in the non-Hispanic group. Further work, including qualitative studies, to explore and address mechanisms of racism at the interpersonal, institutional, and structural levels are needed.

Background: The efficacy of empiric calcium for patients with undifferentiated cardiac arrest has come under increased scrutiny, including a randomized controlled trial that was stopped early due to a trend towards harm with calcium administration. However, small sample sizes and non-significant findings have hindered precise effect estimates. In this analysis we evaluate the association of calcium administration with survival in a large retrospective cohort of patients with cardiac arrest treated in the emergency department (ED)., Methods: We conducted a retrospective review of medical records from two academic hospitals (one quaternary care center, one county trauma center) in San Francisco between 2011 and 2019. Inclusion criteria were patients aged greater than or equal to 18 years old who received treatment for cardiac arrest during their ED course. Our primary exposure was the administration of calcium while in the ED and the main outcome was survival to hospital admission. The association between calcium and survival to admission was estimated using a multivariable log-binomial regression, and also with two propensity score models., Results: We examined 781 patients with cardiac arrest treated in San Francisco EDs between 2011 and 2019 and found that calcium administration was associated with decreased survival to hospital admission (RR 0.74; 95% CI 0.66-0.82). These findings remained significant after adjustment for patient age, sex, whether the cardiac arrest was witnessed, and including an interaction term for shockable cardiac rhythms (RR 0.60; 95% CI 0.50-0.72) and non-shockable cardiac rhythms (RR 0.87; 95% CI 0.76-0.99). Risk ratios for the association between calcium and survival to hospital admission were also similar between two propensity score-based models: nearest neighbor propensity matching model (RR 0.79; 95% CI 0.68-0.89) and inverse propensity weighted regression adjustment model (RR 0.75; 95% CI 0.67-0.84)., Conclusions: Calcium administration as part of ED-directed treatment for cardiac arrest was associated with lower survival to hospital admission. Given the lack of statistically significant outcomes from smaller, more methodologically robust evaluations on this topic, we believe these findings have an important role to serve in confirming previous results and allowing for more precise effect estimates. Our data adds to the growing body evidence against the empiric use of calcium in cardiac arrest., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Variability in decision-making capacity and reward responsiveness may underlie differences in the ability to abstain from smoking. Computational modeling of choice behavior, as with the Hierarchical Drift Diffusion Model (HDDM), can help dissociate reward responsiveness from underlying components of decision-making. Here we used the HDDM to identify which decision-making or reward-related parameters, extracted from data acquired in a reward processing task, contributed to the ability of people who smoke that are not seeking treatment to abstain from cigarettes during a laboratory task., Methods: 80 adults who smoke cigarettes completed the Probabilistic Reward Task (PRT) - a signal detection task with a differential reinforcement schedule - following smoking as usual, and the Relapse Analogue Task (RAT) - a task in which participants could earn money for delaying smoking up to 50min - after a period of overnight abstinence. Two cohorts were defined by the RAT; those who waited either 0-min (n=36) or the full 50-min (n=44) before smoking., Results: PRT signal detection metrics indicated all subjects learned the task contingencies, with no differences in response bias or discriminability between the two groups. However, HDDM analyses indicated faster drift rates in 50-min vs. 0-min waiters., Conclusions: Relative to those who did not abstain, computational modeling indicated that people who abstained from smoking for 50min showed faster evidence accumulation during reward-based decision-making. These results highlight the importance of decision-making mechanisms to smoking abstinence, and suggest that focusing on the evidence accumulation process may yield new targets for treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Background: The orbitofrontal cortex (OFC) is essential for decision making, and functional disruptions within the OFC are evident in schizophrenia. Postnatal phencyclidine (PCP) administration in rats is a neurodevelopmental manipulation that induces schizophrenia-relevant cognitive impairments. We aimed to determine whether manipulating OFC glutamate cell activity could ameliorate postnatal PCP-induced deficits in decision making., Methods: Male and female Wistar rats ( n  = 110) were administered saline or PCP on postnatal days 7, 9, and 11. In adulthood, we expressed YFP (yellow fluorescent protein) (control), ChR2 (channelrhodopsin-2) (activation), or eNpHR 3.0 (enhanced halorhodopsin) (inhibition) in glutamate neurons within the ventromedial OFC (vmOFC). Rats were tested on the probabilistic reversal learning task once daily for 20 days while we manipulated the activity of vmOFC glutamate cells. Behavioral performance was analyzed using a Q-learning computational model of reinforcement learning., Results: Compared with saline-treated rats expressing YFP, PCP-treated rats expressing YFP completed fewer reversals, made fewer win-stay responses, and had lower learning rates. We induced similar performance impairments in saline-treated rats by activating vmOFC glutamate cells (ChR2). Strikingly, PCP-induced performance deficits were ameliorated when the activity of vmOFC glutamate cells was inhibited (halorhodopsin)., Conclusions: Postnatal PCP-induced deficits in decision making are associated with hyperactivity of vmOFC glutamate cells. Thus, normalizing vmOFC activity may represent a potential therapeutic target for decision-making deficits in patients with schizophrenia., (© 2023 The Authors.)

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.)

The ability to appropriately update the value of a given action is a critical component of flexible decision making. Several psychiatric disorders, including schizophrenia, are associated with impairments in flexible decision making that can be evaluated using the probabilistic reversal learning (PRL) task. The PRL task has been reverse-translated for use in rodents. Disrupting glutamate neurotransmission during early postnatal neurodevelopment in rodents has induced behavioral, cognitive, and neuropathophysiological abnormalities relevant to schizophrenia. Here, we tested the hypothesis that using the NMDA receptor antagonist phencyclidine (PCP) to disrupt postnatal glutamatergic transmission in rats would lead to impaired decision making in the PRL. Consistent with this hypothesis, compared to controls the postnatal PCP-treated rats completed fewer reversals and exhibited disruptions in reward and punishment sensitivity (i.e., win-stay and lose-shift responding, respectively). Moreover, computational analysis of behavior revealed that postnatal PCP-treatment resulted in a pronounced impairment in the learning rate throughout PRL testing. Finally, a deep neural network (DNN) trained on the rodent behavior could accurately predict the treatment group of subjects. These data demonstrate that disrupting early postnatal glutamatergic neurotransmission impairs flexible decision making and provides evidence that DNNs can be trained on behavioral datasets to accurately predict the treatment group of new subjects, highlighting the potential for DNNs to aid in the diagnosis of schizophrenia., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

The balance between exploration and exploitation is essential for decision-making. The present study investigated the role of ventromedial orbitofrontal cortex (vmOFC) glutamate neurons in mediating value-based decision-making by first using optogenetics to manipulate vmOFC glutamate activity in rats during a probabilistic reversal learning (PRL) task. Rats that received vmOFC activation during informative feedback completed fewer reversals and exhibited reduced reward sensitivity relative to rats. Analysis with a Q-learning computational model revealed that increased vmOFC activity did not affect the learning rate but instead promoted maladaptive exploration. By contrast, vmOFC inhibition increased the number of completed reversals and increased exploitative behavior. In a separate group of animals, calcium activity of vmOFC glutamate neurons was recorded using fiber photometry. Complementing our results above, we found that suppression of vmOFC activity during the latter part of rewarded trials was associated with improved PRL performance, greater win-stay responding and selecting the correct choice on the next trial. These data demonstrate that excessive vmOFC activity during reward feedback disrupted value-based decision-making by increasing the maladaptive exploration of lower-valued options. Our findings support the premise that pharmacological interventions that normalize aberrant vmOFC glutamate activity during reward feedback processing may attenuate deficits in value-based decision-making., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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

Healthy adults show better memory for low-arousal positive versus negative stimuli, but depression compromises this positive memory advantage. Existing studies are limited by small samples or analyses that provide limited insight into underlying mechanisms. Our study addresses these concerns by using a multistaged analysis, including diffusion modeling, to identify precise psychological processes underlying the positive memory advantage and its disruption by depression in a large sample. A total of 1,358 participants completed the BDI-II (Beck et al., 1996) and an emotional memory task. At encoding, participants judged whether positive and negative words were positive or self-descriptive. After a free recall test, participants viewed an equal mix of studied and unstudied words and judged whether each was "old" or "new"; if judged "old," they indicated whether the study source was a valence or self-reference judgment. We replicate the positive memory advantage and its decrease in depression in recall, recognition, and source accuracy. The hierarchical drift diffusion model (HDDM; Wiecki et al., 2013) revealed that higher BDI-II scores are associated with more efficient evidence accumulation for negative words in the recognition and source memory tasks. By contrast, evidence accumulation for positive words is unaffected by BDI-II during the recognition task but becomes less efficient with increased BDI-II during the source memory task. In conclusion, in a well-controlled design with a large sample, we find that depression reduces the positive memory advantage. HDDM analyses suggest that this reflects differential effects of depression on the speed of evidence accumulation during the retrieval of positive versus negative memories. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: A hyperactive default mode network (DMN) has been observed in people with major depressive disorder (MDD), and weak DMN suppression has been linked to depressive symptoms. However, whether dysregulation of the DMN contributes to blunted positive emotional experience in people with MDD is unclear., Methods: We recorded 128-channel electroencephalograms (EEGs) from 24 participants with MDD and 31 healthy controls in a resting state (RS) and an emotion-induction state (ES), in which participants engaged with emotionally positive pictures. We combined Granger causality analysis and data-driven decomposition to extract latent brain networks shared among states and groups, and we further evaluated their interactions across individuals., Results: We extracted 2 subnetworks. Subnetwork 1 represented a delta (δ)-band (1~4 Hz) frontal network that was activated more in the ES than the RS (i.e., task-positive). Subnetwork 2 represented an alpha (α)-band (8~13 Hz) parietal network that was suppressed more in the ES than the RS (i.e., task-negative). These subnetworks were anticorrelated in both the healthy control and MDD groups, but with different sensitivities: for participants with MDD to achieve the same level of task-positive (subnetwork 1) activation as healthy controls, more suppression of task-negative (subnetwork 2) activation was necessary. Furthermore, the anticorrelation strength in participants with MDD correlated with the severity of 2 core MDD symptoms: anhedonia and rumination., Limitations: The sample size was small., Conclusion: Our findings revealed altered coordination between 2 functional networks in MDD and suggest that weak suppression of the task-negative α-band parietal network contributes to blunted positive emotional responses in adults with depression. The subnetworks identified here could be used for diagnosis or targeted for treatment in the future., Competing Interests: Competing interests: None declared., (© 2022 CMA Impact Inc. or its licensors.)

Although depression is associated with poor memory for positive material, the underlying mechanisms remain unclear. We used the Hierarchical Drift Diffusion Model (HDDM) to determine whether slow evidence accumulation at retrieval contributes to depressed individuals' difficulty remembering positive events. Participants completed the Beck Depression Inventory-II and were stratified into High BDI (HBDI; BDI-II > 20, n = 49) and Low BDI (LBDI; BDI-II < 6, n = 46) groups. Next, participants completed an oddball task in which neutral, negative, and positive pictures served as rare targets. One day later, recognition memory was tested by presenting the encoded ("old") pictures along with closely matched ("new") lures. Recognition accuracy was analyzed with a generalized linear model, and choice and response time data were analyzed with the HDDM. Recognition accuracy for old positive pictures was lower in HBDI versus LBDI participants, and the HDDM highlighted slow evidence accumulation during positive memory retrieval in the HBDI group. Impaired memory for positive material in depressed adults was related to slow evidence accumulation at retrieval. Because oddballs should elicit prediction errors that normally strengthen memory formation, these retrieval findings may reflect weak positive prediction errors, at encoding, in depressed adults., (© 2022. The Psychonomic Society, Inc.)

Option generation is a critical process in decision making, but previous studies have largely focused on choices between options given by a researcher. Consequently, how we self-generate options for behaviour remain poorly understood. Here, we investigated option generation in major depressive disorder and how dopamine might modulate this process, as well as the effects of modafinil (a putative cognitive enhancer) on option generation in healthy individuals. We first compared differences in self-generated options between healthy non-depressed adults [n = 44, age = 26.3 years (SD 5.9)] and patients with major depressive disorder [n = 54, age = 24.8 years (SD 7.4)]. In the second study, a subset of depressed individuals [n = 22, age = 25.6 years (SD 7.8)] underwent PET scans with 11C-raclopride to examine the relationships between dopamine D2/D3 receptor availability and individual differences in option generation. Finally, a randomized, double-blind, placebo-controlled, three-way crossover study of modafinil (100 mg and 200 mg), was conducted in an independent sample of healthy people [n = 19, age = 23.2 years (SD 4.8)] to compare option generation under different doses of this drug. The first study revealed that patients with major depressive disorder produced significantly fewer options [t(96) = 2.68, P = 0.009, Cohen's d = 0.54], albeit with greater uniqueness [t(96) = -2.54, P = 0.01, Cohen's d = 0.52], on the option generation task compared to healthy controls. In the second study, we found that 11C-raclopride binding potential in the putamen was negatively correlated with fluency (r = -0.69, P = 0.001) but positively associated with uniqueness (r = 0.59, P = 0.007). Hence, depressed individuals with higher densities of unoccupied putamen D2/D3 receptors in the putamen generated fewer but more unique options, whereas patients with lower D2/D3 receptor availability were likely to produce a larger number of similar options. Finally, healthy participants were less unique [F(2,36) = 3.32, P = 0.048, partial η2 = 0.16] and diverse [F(2,36) = 4.31, P = 0.021, partial η2 = 0.19] after taking 200 mg versus 100 mg and 0 mg of modafinil, while fluency increased linearly with dosage at a trend level [F(1,18) = 4.11, P = 0.058, partial η2 = 0.19]. Our results show, for the first time, that option generation is affected in clinical depression and that dopaminergic activity in the putamen of patients with major depressive disorder may play a key role in the self-generation of options. Modafinil was also found to influence option generation in healthy people by reducing the creativity of options produced., (© The Author(s) (2022). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The brain circuitry of depression and anxiety/fear is well-established, involving regions such as the limbic system and prefrontal cortex. We expand prior literature by examining the extent to which four discrete factors of anxiety (immediate state anxiety, physiological/panic, neuroticism/worry, and agitation/restlessness) among depressed outpatients are associated with differential responses during reactivity to and regulation of emotional conflict., Methods: A total of 172 subjects diagnosed with major depressive disorder underwent functional magnetic resonance imaging while performing an Emotional Stroop Task. Two main contrasts were examined using whole brain voxel wise analyses: emotional reactivity and emotion regulation. We also evaluated the association of these contrasts with the four aforementioned anxiety factors., Results: During emotional reactivity, participants with higher immediate state anxiety showed potentiated activation in the rolandic operculum and insula, while individuals with higher levels of physiological/panic demonstrated decreased activation in the posterior cingulate. No significant results emerged for any of the four factors on emotion regulation. When re-analyzing these statistically-significant brain regions through analyses of a subsample with (n = 92) and without (n = 80) a current anxiety disorder, no significant associations occurred among those without an anxiety disorder. Among those with an anxiety disorder, results were similar to the full sample, except the posterior cingulate was associated with the neuroticism/worry factor., Conclusions: Divergent patterns of task-related brain activation across four discrete anxiety factors could be used to inform treatment decisions and target specific aspects of anxiety that involve intrinsic processing to attenuate overactive responses to emotional stimuli., (Copyright © 2022. Published by Elsevier Ltd.)

Choices and response times in two-alternative decision-making tasks can be modeled by assuming that individuals steadily accrue evidence in favor of each alternative until a response boundary for one of them is crossed, at which point that alternative is chosen. Prior studies have reported that evidence accumulation during decision-making tasks takes longer in adults with psychopathology than in healthy controls, indicating that slow evidence accumulation may be transdiagnostic. However, few studies have examined perceptual decision making in anxiety disorders, where hypervigilance might enhance performance. Therefore, this study used the Hierarchical Drift Diffusion model to investigate evidence accumulation in adults with social anxiety disorder (SAD) and healthy controls as they performed a probabilistic reward task (PRT), in which social rewards were delivered for correct perceptual judgments. Adults with SAD completed the PRT before and after gaze-contingent music reward therapy (GCMRT), which trains attention allocation and has shown efficacy for SAD. Healthy controls also completed the PRT twice. Results revealed excellent performance in adults with SAD, especially after GCMRT: relative to controls, they showed faster evidence accumulation, better discriminability, and earned more rewards. These data highlight a positive effect of attention training on performance in anxious adults and show how a behavioral trait that is typically problematic-hypervigilance in SAD-can nevertheless confer advantages in certain contexts. The data also indicate that, in contrast to other forms of psychopathology, SAD is not characterized by slow evidence accumulation, at least in the context of the social PRT. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background: Emotional eating has emerged as a contributing factor to overeating, potentially leading to obesity or disordered eating behaviors. However, the underlying biological mechanisms related to emotional eating remain unclear. The present study examined emotional, hormonal, and neural alterations elicited by an acute laboratory stressor in individuals with and without emotional eating., Methods: Emotional (n = 13) and non-emotional eaters (n = 15) completed two main study visits, one week apart: one visit included a Stress version and the other a No-stress version of the Maastricht Acute Stress Task (MAST). Immediately pre- and post-MAST, blood was drawn for serum cortisol and participants rated their anxiety level. After the MAST, participants completed a Food Incentive Delay (FID) task during functional magnetic resonance imaging (fMRI), followed by an ad libitum snack period., Results: Emotional eaters exhibited elevated anxiety (p = 0.037) and cortisol (p = 0.001) in response to the Stress MAST. There were no changes in anxiety or cortisol among non-emotional eaters in response to the Stress MAST or in either group in response to the No-stress MAST. In response to the Stress MAST, emotional eaters exhibited reduced activation during anticipation of food reward in mesolimbic reward regions (caudate: p = 0.014, nucleus accumbens: p = 0.022, putamen: p = 0.013), compared to non-emotional eaters. Groups did not differ in snack consumption., Conclusions: These data indicate disrupted neuroendocrine and neural responsivity to psychosocial stress amongst otherwise-healthy emotional eaters, who demonstrated hyperactive HPA-axis response coupled with hypoactivation in reward circuitry. Differential responsivity to stress may represent a risk factor in the development of maladaptive eating behaviors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Although chest x-ray (CXR) is often used as a screening tool for thoracic injury in adult blunt trauma assessment, its screening performance is unclear. Using chest CT as the referent standard, we sought to determine the screening performance of CXR for injury., Methods: We analyzed data from the NEXUS Chest CT study, in which we prospectively enrolled blunt trauma patients older than 14 years who received chest imaging as part of their evaluation at nine level I trauma centers. For this analysis, we included patients who had both CXR and chest CT. We used CT as the referent standard and categorized injuries as clinically major or minor according to an a priori expert panel classification., Results: Of 11,477 patients enrolled, 4501 had both CXR and chest CT; 1496 (33.2%) were found to have injury, of which 256 (17%) were classified as major injury. CXR missed injuries in 818 patients (54.7%), of which 63 (7.7%) were classified as major injuries. For injuries of major clinical significance, CXR had a sensitivity of 75.4% (95% confidence interval [CI] 69.6-80.4%), specificity of 86.2% (95% CI 85.1-87.2%), negative predictive value of 98.3 (95%CI 97.9-98.6%), and positive predictive value of 24.7 (95%CI 22.9-26.7%). For any injury CXR had a sensitivity of 45.3% (95% CI 42.8-47.9%), specificity of 96.6% (95% CI 95.9-97.2%), negative predictive value of 78% (95% CI 77.2-78.8%), and positive predictive value of 86.9% (95% CI 84.5-89.0%). The most common missed major injuries were pneumothorax (30/185; 16.2%), spinal fractures (19/39; 48.7%), and hemothorax (8/70; 11.4%). The most common missed minor injuries were rib fractures (381/836; 45.6%), pulmonary contusion (203/462; 43.9%), and sternal fractures (153/229; 66.8%)., Conclusions: When used alone, without other trauma screening criteria, CXR has poor screening performance for blunt thoracic injury., Competing Interests: Declaration of Competing Interest No conflicts were declared for any of the authors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Threat-related attention bias has been implicated in the etiology and maintenance of social anxiety disorder (SAD), with attentional research increasingly using eye-tracking methodology to overcome the poor psychometric properties of response-time-based tasks and measures. Yet, extant eye-tracking research in social anxiety has mostly failed to report on psychometrics and attempts to replicate past results are rare. Therefore, we attempted to replicate a previously published eye-tracking study of gaze patterns in socially anxious and nonanxious participants as they viewed social threatening and neutral faces, while also exploring the psychometric properties of the attentional measures used., Methods: Gaze was monitored as participants freely viewed 60 different matrices comprised of eight socially-threatening and eight neutral faces, presented for 6000 ms each. Gaze patterns directed at threat and neutral areas of interest (AOIs) were compared by group. Internal consistency and test-retest reliability were also evaluated., Results: Relative to healthy controls, socially anxious patients dwelled significantly longer on threat faces, replicating prior findings with the same task. Internal consistency of total dwell time on threat and neutral AOIs was high, and two-week test-retest reliability was acceptable., Limitations: Test-retest reliability was only examined for the control group, which had a small sample size., Conclusion: Increased dwell time on socially threatening stimuli is a reliable, stable, and generalizable measure of attentional bias in adults with social anxiety., (Copyright © 2021. Published by Elsevier B.V.)

Objectives: More than 2 million people in the United States had an opioid use disorder in 2017. Treatment for opioid use disorder-particularly medication combined with psychosocial support-is effective for reducing opioid use and decreasing overdose risk. However, approximately 50% of people who receive treatment will relapse or drop out. Stress reactivity, defined as the subjective and physiological response to stress, is heightened in people with opioid use disorder and higher stress reactivity is associated with poorer outcomes. Preliminary studies suggest that stress reactivity may be a key mechanistic target for improving outcomes. This article describes the design of an ongoing study examining behavioral strategies for reducing stress reactivity in adults with opioid use disorder. Our objective is to test the efficacy of two behavioral strategies for reducing stress reactivity and enhancing behavioral persistence in the context of stress (distress tolerance)., Method: We will recruit 120 adults with opioid use disorder and randomly assign them to brief training in (a) cognitive reappraisal, (b) affect labeling, or (c) a psychoeducational control. Participants will receive the training intervention followed by a laboratory stressor during which they will be instructed to apply the trained skill., Results: Subjective and physiological responses to stress will be measured as indices of stress reactivity and the stressor task will include a behavioral persistence component as a measure of distress tolerance., Conclusions: The ultimate goal of this study is to inform the development of behavioral interventions that can be used as an adjunct to medication-based treatment for opioid use disorder. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Background: Cognitive deficits in depressed adults may reflect impaired decision-making. To investigate this possibility, we analyzed data from unmedicated adults with Major Depressive Disorder (MDD) and healthy controls as they performed a probabilistic reward task. The Hierarchical Drift Diffusion Model (HDDM) was used to quantify decision-making mechanisms recruited by the task, to determine if any such mechanism was disrupted by depression., Methods: Data came from two samples (Study 1: 258 MDD, 36 controls; Study 2: 23 MDD, 25 controls). On each trial, participants indicated which of two similar stimuli was presented; correct identifications were rewarded. Quantile-probability plots and the HDDM quantified the impact of MDD on response times (RT), speed of evidence accumulation (drift rate), and the width of decision thresholds, among other parameters., Results: RTs were more positively skewed in depressed v. healthy adults, and the HDDM revealed that drift rates were reduced-and decision thresholds were wider-in the MDD groups. This pattern suggests that depressed adults accumulated the evidence needed to make decisions more slowly than controls did., Conclusions: Depressed adults responded slower than controls in both studies, and poorer performance led the MDD group to receive fewer rewards than controls in Study 1. These results did not reflect a sensorimotor deficit but were instead due to sluggish evidence accumulation. Thus, slowed decision-making-not slowed perception or response execution-caused the performance deficit in MDD. If these results generalize to other tasks, they may help explain the broad cognitive deficits seen in depression.

Dopamine is thought to provide reward prediction error signals to temporal lobe memory systems, but the role of these signals in episodic memory has not been fully characterized. Here we developed an incidental memory paradigm to (i) estimate the influence of reward prediction errors on the formation of episodic memories, (ii) dissociate this influence from surprise and uncertainty, (iii) characterize the role of temporal correspondence between prediction error and memoranda presentation and (iv) determine the extent to which this influence is dependent on memory consolidation. We found that people encoded incidental memoranda more strongly when they gambled for potential rewards. Moreover, the degree to which gambling strengthened encoding scaled with the reward prediction error experienced when memoranda were presented (and not before or after). This encoding enhancement was detectable within minutes and did not differ substantially after 24 h, indicating that it is not dependent on memory consolidation. These results suggest a computationally and temporally specific role for reward prediction error signalling in memory formation.

Background: Major depressive disorder (MDD) is associated with poor recollection, but the neural mechanisms responsible for this deficit are unclear. Recollection is supported by interactions between the hippocampus and cortex that appear to be mediated by oscillatory activity in the theta band (4-7 Hz) and that are elicited during source memory retrieval. Therefore, we tested the hypothesis that evoked theta power during source memory retrieval would be reduced in MDD, as this would provide a physiological basis for deficient recollection in adults with depression., Methods: Morlet wavelets were applied to event-related potentials collected from 24 unmedicated adults with MDD and 24 healthy control adults during the retrieval of source and semantic memories. Whole-scalp analyses focused on group differences in evoked theta power., Results: There were no group differences in behavior. Nevertheless, from 400 to 799 ms, theta power was broadly reduced in adults with depression versus healthy adults. This reduction was observed during source and semantic retrieval. Parietal midline electrodes showed significantly reduced theta power during source-but not semantic-retrieval in adults with depression versus healthy adults in this interval. Furthermore, theta power over parietal midline sites from 400 to 799 ms was more strongly related to source memory accuracy in healthy adults versus adults with depression., Conclusions: Relative to healthy control adults, adults with depression showed reduced theta power during memory retrieval and a weaker relationship between parietal midline theta power and source memory accuracy. These findings indicate that abnormal theta signals may contribute to memory deficits in adults with MDD., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Baseline rostral anterior cingulate cortex (rACC) activity is a well-replicated nonspecific predictor of depression improvement. The rACC is a key hub of the default mode network, which prior studies indicate is hyperactive in major depressive disorder. Because default mode network downregulation is reliant on input from the salience network and frontoparietal network, an important question is whether rACC connectivity with these systems contributes to depression improvement., Methods: Our study evaluated this hypothesis in outpatients (N = 238; 151 female) enrolled in the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) 8-week randomized clinical trial of sertraline versus placebo for major depressive disorder. Depression severity was measured using the Hamilton Rating Scale for Depression, and electroencephalography was recorded at baseline and week 1. Exact low-resolution electromagnetic tomography was used to compute activity from the rACC, and key regions within the default mode network (posterior cingulate cortex), frontoparietal network (left dorsolateral prefrontal cortex), and salience network (right anterior insula [rAI]). Connectivity in the theta band (4.5-7 Hz) and beta band (12.5-21 Hz) was computed using lagged phase synchronization., Results: Stronger baseline theta-band rACC-rAI (salience network hub) connectivity predicted greater depression improvement across 8 weeks of treatment for both treatment arms (B = -0.57, 95% confidence interval = -1.07, -0.08, p = .03). Early increases in theta-band rACC-rAI connectivity predicted greater likelihood of achieving remission at week 8 (odds ratio = 2.90, p = .03)., Conclusions: Among patients undergoing treatment, theta-band rACC-rAI connectivity is a prognostic, albeit treatment-nonspecific, indicator of depression improvement, and early connectivity changes may predict clinically meaningful outcomes., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Major depressive disorder (MDD) is a highly heterogeneous condition in terms of symptom presentation and, likely, underlying pathophysiology. Accordingly, it is possible that only certain individuals with MDD are well-suited to antidepressants. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes of depression, such as neuroticism, anhedonia, and cognitive control deficits., Methods: Within an 8-week multisite trial of sertraline v. placebo for depressed adults (n = 216), we examined whether the combination of machine learning with a Personalized Advantage Index (PAI) can generate individualized treatment recommendations on the basis of endophenotype profiles coupled with clinical and demographic characteristics., Results: Five pre-treatment variables moderated treatment response. Higher depression severity and neuroticism, older age, less impairment in cognitive control, and being employed were each associated with better outcomes to sertraline than placebo. Across 1000 iterations of a 10-fold cross-validation, the PAI model predicted that 31% of the sample would exhibit a clinically meaningful advantage [post-treatment Hamilton Rating Scale for Depression (HRSD) difference ⩾3] with sertraline relative to placebo. Although there were no overall outcome differences between treatment groups (d = 0.15), those identified as optimally suited to sertraline at pre-treatment had better week 8 HRSD scores if randomized to sertraline (10.7) than placebo (14.7) (d = 0.58)., Conclusions: A subset of MDD patients optimally suited to sertraline can be identified on the basis of pre-treatment characteristics. This model must be tested prospectively before it can be used to inform treatment selection. However, findings demonstrate the potential to improve individual outcomes through algorithm-guided treatment recommendations.

Converging evidence indicates that groups of patients with nominally distinct psychiatric diagnoses are not separated by sharp or discontinuous neurobiological boundaries. In healthy populations, individual differences in behavior are reflected in variability across the collective set of functional brain connections (functional connectome). These data suggest that the spectra of transdiagnostic symptom profiles observed in psychiatric patients may map onto detectable patterns of network function. To examine the manner through which neurobiological variation might underlie clinical presentation, we obtained fMRI data from over 1,000 individuals, including 210 diagnosed with a primary psychotic disorder or affective psychosis (bipolar disorder with psychosis and schizophrenia or schizoaffective disorder), 192 presenting with a primary affective disorder without psychosis (unipolar depression, bipolar disorder without psychosis), and 608 demographically matched healthy comparison participants recruited through a large-scale study of brain imaging and genetics. Here, we examine variation in functional connectomes across psychiatric diagnoses, finding striking evidence for disease connectomic "fingerprints" that are commonly disrupted across distinct forms of pathology and appear to scale as a function of illness severity. The presence of affective and psychotic illnesses was associated with graded disruptions in frontoparietal network connectivity (encompassing aspects of dorsolateral prefrontal, dorsomedial prefrontal, lateral parietal, and posterior temporal cortices). Conversely, other properties of network connectivity, including default network integrity, were preferentially disrupted in patients with psychotic illness, but not patients without psychotic symptoms. This work allows us to establish key biological and clinical features of the functional connectomes of severe mental disease., Competing Interests: Conflict of interest statement: Over the past 3 years, D.A.P. has received consulting fees from Akili Interactive Labs, BlackThorn Therapeutics, Boehringer Ingelheim, Compass, Posit Science, and Takeda Pharmaceuticals and honoraria from Alkermes for activities unrelated to the current review. J.T.B. has received consulting fees from Pear Therapeutics and Niraxx Therapeutics. J.L.R. has received investigator-initiated funding from Pamlab. D.Ö. served on an Advisory Board for Neurocrine Inc. in December 2016, unrelated to the current work. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors., (Copyright © 2019 the Author(s). Published by PNAS.)

Background: Despite the fact that higher levels of anxiety and anhedonia in Major Depressive Disorder (MDD) are linked to poorer treatment outcomes, mechanisms contributing to these clinical presentations remain unclear. Neuroticism, impaired cognitive control, and blunted reward learning may be critical processes involved in MDD and may help to explain symptoms of anxiety and anhedonia., Methods: Using baseline data from patients with early-onset MDD (N = 296) in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) trial, we conducted a path analysis to model relationships between neuroticism, cognitive control, and reward learning to levels of anxiety and anhedonia., Results: Neuroticism was positively associated with both anhedonia (standardized coefficient = 0.26, p < .001) and anxiety (standardized coefficient = 0.40, p < .001). Cognitive control was negatively associated with anxiety (standardized coefficient = -0.18, p < .05). Reward learning was not significantly associated with either anxiety or anhedonia., Limitations: Extraneous variables not included in the model may have even more influence in explaining symptoms of anxiety and anhedonia. Restricted range in these variables may have attenuated some of the hypothesized relationships. Most important, because this was a cross-sectional analysis in a currently depressed sample, we cannot draw any causal conclusions without experimental and longitudinal data., Conclusions: These cross-sectional findings suggest that neuroticism may contribute to anxiety and anhedonia in patients with early onset and either chronic or recurrent MDD, while enhanced cognitive control may protect against anxiety., (Copyright © 2018. Published by Elsevier B.V.)

Human functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) studies, as well as animal studies, indicate that the amygdala and frontomedial brain regions are critically involved in conditioned fear and that frontomedial oscillations in the theta range (4-8 Hz) may support communication between these brain regions. However, few studies have used a multimodal approach to probe interactions among these key regions in humans. Here, our goal was to bridge the gap between prior human fMRI, EEG, and animal findings. Using simultaneous EEG-fMRI recordings 24 h after fear conditioning and extinction, conditioned stimuli presented (CS+E, CS-E) and not presented during extinction (CS+N, CS-N) were compared to identify effects specific to extinction versus fear recall. Differential (CS+ vs. CS-) electrodermal, frontomedial theta (EEG) and amygdala responses (fMRI) were reduced for extinguished versus nonextinguished stimuli. Importantly, effects on theta power covaried with effects on amygdala activation. Fear and extinction recall as indicated by theta explained 60% of the variance for the analogous effect in the right amygdala. Our findings show for the first time the interplay of amygdala and frontomedial theta activity during fear and extinction recall in humans and provide insight into neural circuits consistently linked with top-down amygdala modulation in rodents.

The current study aimed to characterize the multifaceted nature of anxiety in patients with major depression by evaluating distinct anxiety factors. We then related these derived anxiety factors to performance on a Flanker Task of cognitive control, in order to further validate these factors. Data were collected from 195 patients with nonpsychotic chronic or recurrent major depression or dysthymic disorder. At baseline, participants completed self-report measures of anxiety, depression, and other related symptoms (mania, suicidality) and clinicians administered a structured diagnostic interview and the Hamilton Rating Scale for Depression, including anxiety/somatization items. Four discrete factors (State Anxiety, Panic, Neuroticism/Worry, and Restlessness/Agitation) emerged, with high degrees of internal consistency. Discriminant and convergent validity analyses also yielded findings in the expected direction. Furthermore, the neuroticism/worry factor was associated with Flanker Task interference, such that individuals higher on neuroticism/worry responded more incorrectly (yet faster) to incongruent vs. congruent trials whereas individuals higher on the fear/panic factor responded more slowly, with no accuracy effect, to the Flanker Task stimuli. These results parse anxiety into four distinct factors that encompass physiological, psychological, and cognitive components of anxiety. While state anxiety, panic and neuroticism/worry are related to existing measures of anxiety, the Restlessness/Agitation factor appears to be a unique measure of general anxious arousal. Furthermore, two factors were independently validated through the Flanker Task. These results suggest that these anxiety domains have distinct behavioral profiles and could have differential responses to distinct treatments., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Importance: Major depressive disorder (MDD) remains challenging to treat. Although several clinical and demographic variables have been found to predict poor antidepressant response, these markers have not been robustly replicated to warrant implementation in clinical care. Increased pretreatment rostral anterior cingulate cortex (rACC) theta activity has been linked to better antidepressant outcomes. However, no prior study has evaluated whether this marker has incremental predictive validity over clinical and demographic measures., Objective: To determine whether increased pretreatment rACC theta activity would predict symptom improvement regardless of randomization arm., Design, Setting, and Participants: A multicenter randomized clinical trial enrolled outpatients without psychosis and with chronic or recurrent MDD between July 29, 2011, and December 15, 2015 (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care [EMBARC]). Patients were consecutively recruited from 4 university hospitals: 634 patients were screened, 296 were randomized to receive sertraline hydrochloride or placebo, 266 had electroencephalographic (EEG) recordings, and 248 had usable EEG data. Resting EEG data were recorded at baseline and 1 week after trial onset, and rACC theta activity was extracted using source localization. Intent-to-treat analysis was conducted. Data analysis was performed from October 7, 2016, to January 19, 2018., Interventions: An 8-week course of sertraline or placebo., Main Outcomes and Measures: The 17-item Hamilton Rating Scale for Depression score (assessed at baseline and weeks 1, 2, 3, 4, 6, and 8)., Results: The 248 participants (160 [64.5%] women, 88 [35.5%] men) with usable EEG data had a mean (SD) age of 36.75 (13.15) years. Higher rACC theta activity at both baseline (b = -1.05; 95% CI, -1.77 to -0.34; P = .004) and week 1 (b = -0.83; 95% CI, -1.60 to -0.06; P < .04) predicted greater depressive symptom improvement, even when controlling for clinical and demographic variables previously linked with treatment outcome. These effects were not moderated by treatment arm. The rACC theta marker, in combination with clinical and demographic variables, accounted for an estimated 39.6% of the variance in symptom change (with 8.5% of the variance uniquely attributable to the rACC theta marker)., Conclusions and Relevance: Increased pretreatment rACC theta activity represents a nonspecific prognostic marker of treatment outcome. This is the first study to date to demonstrate that rACC theta activity has incremental predictive validity., Trial Registration: clinicaltrials.gov Identifier: NCT01407094.

Anhedonia (hyposensitivity to rewards) and negative bias (hypersensitivity to punishments) are core features of major depressive disorder (MDD), which could stem from abnormal reinforcement learning. Emerging evidence highlights blunted reward learning and reward prediction error (RPE) signaling in the striatum in MDD, although inconsistencies exist. Preclinical studies have clarified that ventral tegmental area (VTA) neurons encode RPE and habenular neurons encode punishment prediction error (PPE), which are then transmitted to the striatum and cortex to guide goal-directed behavior. However, few studies have probed striatal activation, and functional connectivity between VTA-striatum and VTA-habenula during reward and punishment learning respectively, in unmedicated MDD. To fill this gap, we acquired fMRI data from 25 unmedicated MDD and 26 healthy individuals during a monetary instrumental learning task and utilized a computational modeling approach to characterize underlying neural correlates of RPE and PPE. Relative to controls, MDD individuals showed impaired reward learning, blunted RPE signal in the striatum and overall reduced VTA-striatal connectivity to feedback. Critically, striatal RPE signal was increasingly blunted with more major depressive episodes (MDEs). No group differences emerged in PPE signals in the habenula and VTA or in connectivity between these regions. However, PPE signals in the habenula correlated positively with number of MDEs. These results highlight impaired reward learning, disrupted RPE signaling in the striatum (particularly among individuals with more lifetime MDEs) as well as reduced VTA-striatal connectivity in MDD. Collectively, these findings highlight reward-related learning deficits in MDD and their underlying pathophysiology.

Background: Diffusion tensor imaging (DTI) studies report reduced fractional anisotropy (FA) in major depressive disorder (MDD). However, whether FA covaries with key depressive symptoms, such as anhedonia, is unclear., Methods: Magnetic resonance imaging data were acquired from 38 unmedicated adults with MDD and 52 healthy controls. DTI metrics were extracted from regions of interest that have consistently shown reduced FA in MDD. Analyses focused first on identifying group differences, and then determining whether reduced FA in depressed adults was related to individual differences in anhedonia and depressive severity. To establish specificity to depression, these analyses controlled for symptoms of anxiety., Results: Relative to controls, depressed adults showed reduced FA in the genu of the corpus callosum, the anterior limb of the internal capsule (ALIC), the cingulum bundle near the anterior cingulate cortex, and the uncinate fasciculus (UF). In the depressed group, anhedonia negatively correlated with FA in the genu, cingulum, and UF, but positively correlated with radial diffusivity (RD)-a metric previously linked to demyelination-in the genu and ALIC. Depressive severity positively correlated with RD in the ALIC. These relationships remained significant after accounting for anxiety., Conclusion: Anhedonia was positively correlated with reduced FA and increased RD in white matter pathways that connect regions critical for value coding, representing stimulus-reward associations, and guiding value-based action selection. Thus, a cardinal symptom of MDD-anhedonia-was lawfully related to abnormalities in reward network connectivity., (© 2018 Wiley Periodicals, Inc.)

Depressed individuals typically show poor memory for positive events, potentiated memory for negative events, and impaired recollection. These phenomena are clinically important but poorly understood. Compelling links between stress and depression suggest promising candidate mechanisms. Stress can suppress hippocampal neurogenesis, inhibit dopamine neurons, and sensitize the amygdala. We argue that these phenomena may impair pattern separation, disrupt the encoding of positive experiences, and bias retrieval toward negative events, respectively, thus recapitulating core aspects of memory disruption in depression. Encouragingly, optogenetic reactivation of cells engaged during the encoding of positive memories rapidly reduces depressive behavior in preclinical models. Thus, many memory deficits in depression appear to be downstream consequences of chronic stress, and addressing memory disruption can have therapeutic value., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We collected event-related potentials (ERPs) from 24 unmedicated adults with Major Depressive Disorder (MDD) and 24 controls during source memory retrieval. Words were encoded on the left or right during animacy and mobility judgments. Mobility judgments were slower than animacy judgments, suggesting deeper encoding. Participants then recalled the encoding judgment (Question cue) and position (Side cue) for each word. Depressed adults, but not controls, showed better accuracy for words from the mobility task presented under the Question vs. Side Cue. Furthermore, depressed adults showed larger left parietal ERPs to words from the mobility task presented under the Question vs. the Side Cue from 400 to 800 ms and 800-1400 ms. This ERP effect was negatively correlated with sleep quality. Thus, deep encoding followed by retrieval of the encoding judgment supported memory in MDD and augmented left parietal ERPs that have been linked to recollection and that appear sensitive to sleep disturbance., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Anti-retroviral therapy (ART) regimes for HIV are associated with raised levels of circulating triglycerides (TG) in western populations. However, there are limited data on the impact of ART on cardiometabolic risk in sub-Saharan African (SSA) populations., Methods: Pooled analyses of 14 studies comprising 21 023 individuals, on whom relevant cardiometabolic risk factors (including TG), HIV and ART status were assessed between 2003 and 2014, in SSA. The association between ART and raised TG (>2.3 mmol/L) was analysed using regression models., Findings: Among 10 615 individuals, ART was associated with a two-fold higher probability of raised TG (RR 2.05, 95% CI 1.51-2.77, I 2 =45.2%). The associations between ART and raised blood pressure, glucose, HbA1c, and other lipids were inconsistent across studies., Interpretation: Evidence from this study confirms the association of ART with raised TG in SSA populations. Given the possible causal effect of raised TG on cardiovascular disease (CVD), the evidence highlights the need for prospective studies to clarify the impact of long term ART on CVD outcomes in SSA., Competing Interests: Conflict of interest The authors declare no conflict of interest.

Background: One in three clinical trial patients with major depressive disorder report symptomatic improvement with placebo. Strategies to mitigate the effect of placebo responses have focused on modifying study design with variable success. Identifying and excluding or controlling for individuals with a high likelihood of responding to placebo may improve clinical trial efficiency and avoid unnecessary medication trials., Methods: Participants included those assigned to the placebo arm (n = 141) of the Establishing Moderators and Biosignatures for Antidepressant Response in Clinical Care (EMBARC) trial. The elastic net was used to evaluate 283 baseline clinical, behavioral, imaging, and electrophysiological variables to identify the most robust yet parsimonious features that predicted depression severity at the end of the double-blind 8-week trial. Variables retained in at least 50% of the 100 imputed data sets were used in a Bayesian multiple linear regression model to simultaneously predict the probabilities of response and remission., Results: Lower baseline depression severity, younger age, absence of melancholic features or history of physical abuse, less anxious arousal, less anhedonia, less neuroticism, and higher average theta current density in the rostral anterior cingulate predicted a higher likelihood of improvement with placebo. The Bayesian model predicted remission and response with an actionable degree of accuracy (both AUC > 0.73). An interactive calculator was developed predicting the likelihood of placebo response at the individual level., Conclusion: Easy-to-measure clinical, behavioral, and electrophysiological assessments can be used to identify placebo responders with a high degree of accuracy. Development of this calculator based on these findings can be used to identify potential placebo responders., (© 2018 S. Karger AG, Basel.)

Objective: Major depressive disorder is characterized by reduced reward-related striatal activation and dysfunctional reward learning, putatively reflecting decreased dopaminergic signaling. The goal of this study was to test whether a pharmacological challenge designed to facilitate dopaminergic transmission can enhance striatal responses to reward and improve reward learning in depressed individuals., Method: In a double-blind placebo-controlled design, 46 unmedicated depressed participants and 43 healthy control participants were randomly assigned to receive either placebo or a single low dose (50 mg) of the D 2 /D 3 receptor antagonist amisulpride, which is believed to increase dopamine signaling through presynaptic autoreceptor blockade. To investigate the effects of increased dopaminergic transmission on reward-related striatal function and behavior, a monetary incentive delay task (in conjunction with functional MRI) and a probabilistic reward learning task were administered at absorption peaks of amisulpride., Results: Depressed participants selected previously rewarded stimuli less frequently than did control participants, indicating reduced reward learning, but this effect was not modulated by amisulpride. Relative to depressed participants receiving placebo (and control participants receiving amisulpride), depressed participants receiving amisulpride exhibited increased striatal activation and potentiated corticostriatal functional connectivity between the nucleus accumbens and the midcingulate cortex in response to monetary rewards. Stronger corticostriatal connectivity in response to rewards predicted better reward learning among depressed individuals receiving amisulpride as well as among control participants receiving placebo., Conclusions: Acute enhancement of dopaminergic transmission potentiated reward-related striatal activation and corticostriatal functional connectivity in depressed individuals but had no behavioral effects. Taken together, the results suggest that targeted pharmacological treatments may normalize neural correlates of reward processing in depression; despite such acute effects on neural function, behavioral modification may require more chronic exposure. This is consistent with previous reports that antidepressant effects of amisulpride in depression emerged after sustained administration.

Deficits in cognitive control are a hallmark characteristic of depression, however less is known about the degree to which they persist beyond symptom remission and might contribute to symptom recurrence in remitted individuals (rMDD). Evidence indicates that stress interferes with cognitive control, highlighting a potential mechanism by which stress precipitates depression relapse. Therefore, this study examined whether stress exposure elicits deficits in error monitoring - a component of cognitive control thought to be particularly implicated in the ability to adaptively respond to negative feedback - in individuals with rMDD. Unmedicated individuals with rMDD (n=30) and healthy controls (n=34) performed an Eriksen Flanker task before and 45min after an acute stressor while 128-channel event-related potentials (ERPs) were recorded. Flanker interference effects and post-error adjustments were examined, and ERP analyses focused on the error-related negativity (ERN) and error positivity (Pe). Standardized low resolution electromagnetic tomography (sLORETA) was used to examine stress-induced changes in current source density. Individuals with rMDD showed blunted cortisol reactivity to the stressor, coupled with heightened self-reported stress reactivity. Although no significant effects of group or stress were observed in scalp-level ERPs, source-level analyses indicated that among the rMDD group only, stress caused a reduction in activation in frontocingulate regions critically implicated in error monitoring. The magnitude of stress-induced decreases in frontocingulate activation correlated with heightened self-reported stress reactivity, and also predicted heightened levels of stress and depression 18 months later in the entire sample. These findings suggest that individuals with rMDD show a stress-induced disruption in frontocingulate function that is linked to heightened stress reactivity, and this disruption prospectively predicts heightened levels of future stress and depressive symptomatology., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Growing evidence suggests that loudness dependency of auditory evoked potentials (LDAEP) and resting EEG alpha and theta may be biological markers for predicting response to antidepressants. In spite of this promise, little is known about the joint reliability of these markers, and thus their clinical applicability. New standardized procedures were developed to improve the compatibility of data acquired with different EEG platforms, and used to examine test-retest reliability for the three electrophysiological measures selected for a multisite project-Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC). Thirty-nine healthy controls across four clinical research sites were tested in two sessions separated by about 1 week. Resting EEG (eyes-open and eyes-closed conditions) was recorded and LDAEP measured using binaural tones (1000 Hz, 40 ms) at five intensities (60-100 dB SPL). Principal components analysis of current source density waveforms reduced volume conduction and provided reference-free measures of resting EEG alpha and N1 dipole activity to tones from auditory cortex. Low-resolution electromagnetic tomography (LORETA) extracted resting theta current density measures corresponding to rostral anterior cingulate (rACC), which has been implicated in treatment response. There were no significant differences in posterior alpha, N1 dipole, or rACC theta across sessions. Test-retest reliability was .84 for alpha, .87 for N1 dipole, and .70 for theta rACC current density. The demonstration of good-to-excellent reliability for these measures provides a template for future EEG/ERP studies from multiple testing sites, and an important step for evaluating them as biomarkers for predicting treatment response., Competing Interests: All other authors have no biomedical financial interests or potential conflicts of interest., (© 2016 Society for Psychophysiological Research.)

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.

Major depressive disorder (MDD) is clinically, and likely pathophysiologically, heterogeneous. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes. Guided by the NIMH Research Domain Criteria initiative, we used source localization of scalp-recorded EEG resting data to examine the neural correlates of three emerging endophenotypes of depression: neuroticism, blunted reward learning, and cognitive control deficits. Data were drawn from the ongoing multi-site EMBARC study. We estimated intracranial current density for standard EEG frequency bands in 82 unmedicated adults with MDD, using Low-Resolution Brain Electromagnetic Tomography. Region-of-interest and whole-brain analyses tested associations between resting state EEG current density and endophenotypes of interest. Neuroticism was associated with increased resting gamma (36.5-44 Hz) current density in the ventral (subgenual) anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC). In contrast, reduced cognitive control correlated with decreased gamma activity in the left dorsolateral prefrontal cortex (dlPFC), decreased theta (6.5-8 Hz) and alpha2 (10.5-12 Hz) activity in the dorsal ACC, and increased alpha2 activity in the right dlPFC. Finally, blunted reward learning correlated with lower OFC and left dlPFC gamma activity. Computational modeling of trial-by-trial reinforcement learning further indicated that lower OFC gamma activity was linked to reduced reward sensitivity. Three putative endophenotypes of depression were found to have partially dissociable resting intracranial EEG correlates, reflecting different underlying neural dysfunctions. Overall, these findings highlight the need to parse the heterogeneity of MDD by focusing on promising endophenotypes linked to specific pathophysiological abnormalities.