Emotional responses to sensory experience are central to the human condition in health and disease. We hypothesized that principles governing the emergence of emotion from sensation might be discoverable through their conservation across the mammalian lineage. We therefore designed a cross-species neural activity screen, applicable to humans and mice, combining precise affective behavioral measurements, clinical medication administration, and brain-wide intracranial electrophysiology. This screen revealed conserved biphasic dynamics in which emotionally salient sensory signals are swiftly broadcast throughout the brain and followed by a characteristic persistent activity pattern. Medication-based interventions that selectively blocked persistent dynamics while preserving fast broadcast selectively inhibited emotional responses in humans and mice. Mammalian emotion appears to emerge as a specifically distributed neural context, driven by persistent dynamics and shaped by a global intrinsic timescale.

Importance Large language model (LLM)-assisted early warning system may help overcome existing barriers to timely depression diagnosis in patients with cardiovascular disease (CVD). This novel application of LLMs to screen patient messages could be applied to other chronic diseases, facilitating automated symptom-driven diagnoses and interventions. Objective To prospectively simulate the impact (change in time to diagnosis) of population mental health screening using LLMs by screening patient portal messages, and measure LLMs accuracy to identify individuals at high risk for depression diagnosis in patients with CVD. Design Prospective cohort study Setting Electronic health records from an academic hospital (Stanford Health Care) Participants Individuals with CVD diagnosed 2014-2024, subsequently diagnosed with depression Intervention/Exposure LLMs (Llama 3.1 8B, July 2024 version, Meta LLC, and MedGemma 4B, July 2025 version, Google DeepMind, LLC) to identify individuals with depression Main outcome Accuracy of LLMs in sensitivity for completeness to capture positive cases and positive predictive value (PPV) for correctness to capture positive cases, and changes in time to depression diagnosis Results We identified 115,156 patients with CVD, and 23.1% (N = 26,578/115,156) of those had co-morbid depression. We included individuals (n=2,314) who sent at least one message between CVD and depression diagnoses. Participants were mostly 65 years and older (n = 1,718/2,314, 74.2%), or of non-Hispanic ethnicity (N = 2,078/2,314, 89.9%), or of the White race (N = 1,506/2,314, 66.1%), but sex was balanced (females, N = 1,197/2,314, 51.7%). PPV was 51.2% [95% CI: 47.5-54.5%] Llama 3.1 8B, and sensitivity was 83.6% [81.1-85.9] Llama 3.1 8B and 71.0% [67.0-75.3] MedGemma 4B. On average, the LLM (Llama 3.1 8B) detected depression 660 days earlier than the first charted diagnosis over a 1,746-day assessment period, a typical timeline from CVD to depression diagnoses in our cohort. Conclusion/Relevance LLMs identified individuals with depression significantly earlier than official diagnosis among patients with CVD, relying solely on longitudinal patient messages without additional medical information, with high sensitivity and Patient Health Questionnaire-9 comparable PPV. This novel approach is applicable to various diagnoses. ### Competing Interest Statement In the last 3 years, C.Rodriguez has served as a consultant for Biohaven Pharmaceuticals, Osmind, and Biogen; and receives research grant support from Biohaven Pharmaceuticals, a stipend from American Psychiatric Association Publishing for her role as Deputy Editor at The American Journal of Psychiatry, and book royalties from American Psychiatric Association Publishing. F. Rodriguez reports consulting fees from Novartis, NovoNordisk, Esperion Therapeutics, Movano Health, Kento Health, Inclusive Health, Edwards, Arrowhead Pharmaceuticals, HeartFlow, iRhythm, Amgen, and Cleerly Health outside the submitted work. ### Funding Statement Kim is supported by the NIH (K01MH137386). Linos is supported by the NIH (grants R01AR082109 and K24AR075060). F. Rodriguez was funded by grants from the NIH National Heart, Lung, and Blood Institute (R01HL168188; R01HL167974; R01HL169345). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Stanford University Institutional Review Board approved this study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data (patient messages) used in this study is not publicly sharable.

Rapidly acting therapeutics like 3,4-methylenedioxymethamphetamine (MDMA) are promising treatments for disorders such as posttraumatic stress disorder (PTSD). However, understanding who benefits most and the underlying neural mechanisms remains a critical gap. Stratifying individuals by neural circuit profiles could help differentiate neural, behavioral, and affective responses to MDMA, enabling personalized treatment strategies. To investigate whether baseline stratification of individuals based on negative affect circuit profiles, particularly in response to nonconscious threat stimuli, can differentiate acute responses to MDMA. This randomized clinical trial, implementing a double-blinded, within-participant, placebo- and baseline-controlled design, was conducted at Stanford University School of Medicine between November 2, 2021, and November 9, 2022, for wave 1 data collection. Participants had used MDMA on at least 2 prior occasions, but not in the past 6 months, and had subthreshold PTSD symptoms and early life trauma but no current psychiatric disorders. Data were analyzed from March 1, 2023, to January 1, 2024. Participants completed 4 visits: 1 baseline session followed by 1 placebo session and 2 MDMA sessions in a randomized order, totaling 64 visits. Baseline functional magnetic resonance imaging (fMRI) assessed the negative affect circuit using a nonconscious threat processing task (NTN). Primary outcomes included activity and connectivity of amygdala and subgenual anterior cingulate cortex (sgACC) defining the negative affect circuit. Secondary outcomes were behavioral measures of implicit threat bias, likability of threat expressions, and affective assessments. Sixteen participants (10 [63%] female; mean [SD] age, 40.8 [7.6] years) were stratified into subgroups with high and low levels of NTN activity in the amygdala (NTNA+ [n = 8] and NTNA− [n = 8], respectively), based on a median split of baseline nonconscious threat-evoked fMRI responses. Following administration of the 120 mg of MDMA vs placebo, the NTNA+ subgroup showed significant reductions in amygdala (contrast estimate [CE], −1.43; 95% CI, −2.60 to −0.27; Cohen d, −1.22; P = .02) and sgACC activity (CE, −1.48; 95% CI, −2.42 to −0.54; Cohen d, −1.56; P = .004), increased sgACC-amygdala connectivity (CE, 0.65; 95% CI, 0.02-1.28; Cohen d, 1.02; P = .04), and increased likability of threat expressions (CE, 14.38; 95% CI, 1.46-27.29; Cohen d, 0.86; P = .03) compared with the NTNA− subgroup. In this randomized clinical trial of MDMA’s acute profiles, 120 mg of MDMA acutely normalized negative affect circuit reactivity in participants stratified by heightened amygdala reactivity at baseline, demonstrating the potential of neuroimaging to identify prospective biomarkers and guide personalized MDMA-based therapies. ClinicalTrials.gov Identifier: NCT04060108

BACKGROUND:Hoarding disorder (HD) is characterized by difficulty discarding possessions and clutter that impairs daily functioning. Previous research has demonstrated a high correlation between hoarding behaviors and suicidal thoughts and behaviors; however, there is limited research on suicidal thoughts and behaviors in individuals meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for HD. Our aim in this study was to report our findings about suicidal thoughts and behaviors in a HD sample. METHODS:We used existing data from participants meeting DSM-5 criteria for HD (n = 99). Data about suicidal thoughts and behaviors was collected using a structured instrument, the Columbia-Suicide Severity Rating Scale (C-SSRS). RESULTS:Among the 99 participants, 49.5 % and 26.3 % had passive and active suicidal ideation (SI), respectively. Of those with active ideation, 11 participants endorsed thinking about overdose during their most severe SI. 13 participants reported attempting suicide at least once in their lifetime. CONCLUSIONS:To our knowledge, this is the first study examining suicidal thoughts and behaviors in HD using the structured assessment C-SSRS. In this HD data set, participants reported suicidal thoughts and behaviors at higher rates than the general U.S. POPULATION:Our study highlights the importance of screening for suicidal thoughts and behaviors in individuals with HD.

This study presents qualitative data on the retirement experiences of retired professional ice hockey players and the relationship of these experiences to self-reported depressive symptoms and measures of athletic identity. Data were obtained from an online survey sent to retired professional hockey players within the Professional Hockey Players’ Association (PHPA) database. A total of 213 retired players completed the qualitative section of the survey and were included in the study. Former players expressed an array of responses to questions about the best and most difficult parts of their athletic retirement experiences, and what they believe would help future generations of retiring hockey players. Within these responses, there were two distinct patterns of identity-based challenges among depressed former players. One subset of depressed former players, captured by our proposed term athletic identity flight, scored lower in athletic identity, and emphasized positive aspects of retirement related to “building a new identity.” A second subset of depressed former players, who we described with the term athletic identity gripping, noted an identity crisis upon retiring and retained a strong athletic identity post-career. Non-depressed former players in our sample were more likely to emphasize the importance of career support to help future retiring hockey players, whereas depressed former players emphasized the importance of mental health support. Our findings may inform future preventative interventions to assist retiring hockey players in their end-of-athletic-career transition and suggest the value of tailoring interventions based on the strength of athletic identity and the presence of depressive symptoms.Lay summary: Retired professional ice hockey players with self-reported depression symptoms experienced two distinct identity challenges when transitioning out of sport. Some appeared to actively distance themselves from their former athletic identity (athletic identity flight). Others experienced an identity crisis and appeared to maintain their athletic identity over time (athletic identity gripping).Implications for practice: Based on both quantitative and qualitative data analysis, results suggest that athletic identity is a factor to consider when tailoring interventions for professional hockey players transitioning to athletic retirement. Interventions may vary based on relationship with athletic identity during the transition; some will experience an “identity crisis” and attempt to hold onto their athletic identity, which may be a risk factor for long-term depressive symptoms. Others may actively distance themselves from their athletic identity during the transition, possibly due to emotional pain associated with the athlete role.Depending on the presence of depressive symptoms, retiring players may have different intervention needs to assist with athletic retirement. Non-depressed players may benefit from practical support, such as planning their next career. Depressed players may benefit more from mental health outreach. Aligned with duty of care principles, results indicate a need for screening retiring athletes to identify those at risk for depression.

Objective: The Buried in Treasures (BIT) workshop is a promising treatment for hoarding disorder (HD), though many participants struggle with home uncluttering. This randomized waitlist-controlled trial investigated the efficacy of a version of BIT, augmented with in-home uncluttering practice (BIT+). Method: Adults (N = 41) with hoarding disorder were recruited from the community and randomly assigned to BIT+ or waitlist. BIT+ consisted of 16 sessions of the BIT workshop and 10 uncluttering home visits over 18 weeks. Outcome measures included the Saving Inventory-Revised (self-report) and the Clutter Image Rating Scale (self and independent evaluator rated). Between group repeated measures analyses using general linear modeling examined the effect of BIT+ vs waitlist control on hoarding symptoms after 18 weeks. Within group analyses examined pre-post effects for all BIT+ participants combined after 18 weeks. Results: After 18 weeks, BIT+ participants benefited significantly more than waitlist controls on hoarding severity with large effect size (Cohen's d = 1.5, p < .001). BIT+ was also associated with improvement reductions in hoarding symptoms, clutter, and functional impairment. Conclusions: The BIT+ intervention offers promise as a treatment option for hoarding. Adding in-home uncluttering practice may incrementally improve discarding practices. Future controlled trials are warranted.

3,4-Methylenedioxymethamphetamine (MDMA), a serotonin releaser, reduces interpersonal defensiveness but is also thought to open a “critical period” in the brain in which alterations in consciousness may enhance a therapeutic process. However, the relationship between MDMA-induced effects on brain connectomes and these altered states has not been directly examined.

Background: Traumatic life events are common among individuals with hoarding disorder (HD), though rates of posttraumatic stress disorder are no higher than in other groups. HD symptoms typically begin to appear in mid -childhood, and early life stress (ELS) is a known associated feature of negative mental health outcomes. The specifics of this relationship are still unclear. Methods: We obtained Early Life Stress Questionnaire (ELSQ) responses from 35 participants with HD, 22 par-ticipants with obsessive-compulsive disorder (OCD), and 23 non-clinical control participants. We combined these quantitative data with qualitative interviews exploring what role ELS experiences play in HD. Results: Per the ELSQ, individuals with HD reported significantly more ELS events than the non-clinical control participants. In qualitative interviews, HD participants described the ELS events that were most impactful in shaping their relationship to material possessions; these events tended to be long in duration and elicited feelings of scarcity of emotional support. Participants described relying on possessions in place of relationships and viewed possessions as potential sources of connection to peers. Conclusions: Our qualitative and quantitative results build on the cognitive behavioral model of HD, emphasizing early experiences of prolonged stress or scarcity of emotional support as a key contributing vulnerability factor. Specific differences are consistent with earlier research that people with HD experience absence of early warmth. They further suggest that screening for ELS experiences is important when working with individuals with HD, and that HD treatments may benefit from increased focus on social and emotional connection building.

Serotonin reuptake inhibitor (SRI) medications are well established as first-line pharmacotherapeutic treatment for Obsessive-Compulsive Disorder (OCD). However, despite the excellent safety profile and demonstrated efficacy of these medications, a substantial proportion of individuals with OCD fail to attain sufficient benefit from SRIs. In this narrative review, we discuss clinical features of OCD that have been associated with poorer response to SRIs, and we present pharmacotherapeutic interventions that have been explored as augmenting or alternative treatments for treatment-resistant OCD. We additionally highlight non-SRI interventions for OCD that are currently under investigation. Pharmacotherapeutic interventions were identified via expert consensus. To assess the evidence base for individual pharmacotherapies, targeted searches for relevant English-language publications were performed on standard biomedical research databases, including MEDLINE. Information relevant to ongoing registered clinical trials in OCD was obtained by search of ClinicalTrials.gov. Pharmacotherapies are grouped for review in accordance with the general principles of Neuroscience-based Nomenclature (NbN). Clinical features of OCD that may suggest poorer response to SRI treatment include early age of onset, severity of illness, duration of untreated illness, and the presence of symmetry/ordering or hoarding-related symptoms. Based on evolving pathophysiologic models of OCD, diverse agents engaging serotonin, dopamine, norepinephrine, glutamate, and anti-inflammatory pathways have been explored as alternative or adjunctive therapies for treatment-resistant OCD and have at least preliminary evidence of efficacy. Medications with dopamine antagonist activity remain the most robustly evidence-based of augmenting interventions, yet dopamine antagonists benefit only a minority of those who try them and carry elevated risks of adverse effects. Interventions targeting glutamatergic and anti-inflammatory pathways are less well evidenced, but may offer more favorable benefit to risk profiles. Ongoing research should explore whether specific interventions may benefit individuals with particular features of treatment-resistant OCD.

Ketamine commonly and rapidly induces dissociative and other altered states of consciousness (ASCs) in humans. However, the neural mechanisms that contribute to these experiences remain unknown. We used functional neuroimaging to engage key regions of the brain’s affective circuits during acute ketamine-induced ASCs within a randomized, multi-modal, placebo-controlled design examining placebo, 0.05 mg/kg ketamine, and 0.5 mg/kg ketamine in nonclinical adult participants (NCT03475277). Licensed clinicians monitored infusions for safety. Linear mixed effects models, analysis of variance, t-tests, and mediation models were used for statistical analyses. Our design enabled us to test our pre-specified primary and secondary endpoints, which were met: effects of ketamine across dose conditions on (1) emotional task-evoked brain activity, and (2) sub-components of dissociation and other ASCs. With this design, we also could disentangle which ketamine-induced affective brain states are dependent upon specific aspects of ASCs. Differently valenced ketamine-induced ASCs mediated opposing effects on right anterior insula activity. Participants experiencing relatively higher depersonalization induced by 0.5 mg/kg of ketamine showed relief from negative brain states (reduced task-evoked right anterior insula activity, 0.39 SD). In contrast, participants experiencing dissociative amnesia showed an exacerbation of insula activity (0.32 SD). These results in nonclinical participants may shed light on the mechanisms by which specific dissociative states predict response to ketamine in depressed individuals.

3,4-Methylenedioxymethamphetamine (MDMA) has been shown to reduce interpersonal defensiveness, but the neural mechanisms by which it promotes enhanced trust and openness are not well understood.

We previously reported the rapid OCD symptom reduction of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, vs saline infusions in a proof-of-concept crossover trial (n=15) in unmedicated adults with OCD. Building on this initial finding, we evaluated the efficacy of ketamine in a larger group of unmedicated OCD patients with improved control conditions (active placebo control condition).

Hoarding disorder (HD) is characterized by distress and difficulty letting go of possessions, leading to clutter that congests living spaces and interferes with daily activities. HD is common, with an estimated overall pooled prevalence of 2.5% of the general population. Because it is a relatively newly defined disorder, there are questions and controversies regarding its diagnosis and treatment that warrant exploration. In this manuscript, we clarify diagnostic boundaries between HD and related neuropsychiatric conditions, and consider how both shared and unique features of HD may inform strategies for treatment. We additionally discuss specific manifestations of hoarding behavior (e.g., animal hoarding); review motivations, beliefs, and characteristics that may contribute to hoarding behaviors; examine available evidence regarding the efficacy of different treatment modalities; highlight the challenges of engaging individuals who do not want care; and suggest a potential explanatory model for insight impairment in HD.

Abnormalities in valence processing - the processing of aversive or appetitive stimuli - may be an underrecognized component of obsessive-compulsive disorder (OCD). Preclinical rodent models have been critical in furthering pathophysiological understanding of OCD, yet there is a dearth of investigations examining whether rodent models of compulsive behavior show alterations in valence systems congruent with those seen in individuals with OCD. In this study, we sought to assess valence processing in a preclinical rodent model of compulsive behavior, the SAPAP3 knockout (KO) mouse model, and compare our preclinical findings to similar behavioral phenomena in OCD patients. In SAPAP3 KO mice, we used auditory fear conditioning and extinction to examine alterations in negative valence processing and reward-based operant conditioning to examine alterations in positive valence processing. We find that SAPAP3 KO mice show evidence of heightened negative valence processing through enhanced fear learning and impaired fear extinction. SAPAP3 KO mice also show deficits in reward acquisition and goal-directed behavior, suggesting impaired positive valence processing. In OCD patients, we used validated behavioral tests to assess explicit and implicit processing of fear-related facial expressions (negative valence) and socially-rewarding happy expressions (positive valence). We find similar trends towards enhanced negative and impaired positive valence processing in OCD patients. Overall, our results reveal valence processing abnormalities in a preclinical rodent model of compulsive behavior similar to those seen in OCD patients, with implications for valence processing alterations as novel therapeutic targets across a translational research spectrum.

Obsessive-compulsive disorder has been associated with alterations in both cognitive and affective processing. In secondary analysis of data from an active placebo-controlled, randomized trial of intravenous ketamine for treatment of OCD, we explored behavioral measures of cognitive control and valence processing as potential moderators or mediators of treatment.

The neural mechanisms underlying the effect of subanesthetic ketamine, a rapidly acting antidepressant, on modulation of cognitive control remain controversial. We addressed this issue in a mechanistic study assessing real-time ketamine effects with acute post-infusion imaging.

Insight impairment contributes significantly to morbidity in psychiatric disorders. The neurologic concept of anosognosia, reflecting deficits in metacognitive awareness of illness, is increasingly understood as relevant to psychopathology, but has been little explored in psychiatric disorders other than schizophrenia. We explored anosognosia as an aspect of insight impairment in n = 71 individuals with DSM-5 hoarding disorder. We used a standardized clutter severity measure to assess whether individuals with hoarding disorder underreport home clutter levels relative to independent examiners. We then explored whether underreporting, as a proxy for anosognosia, is predicted by clinical or neurocognitive behavioral measures. We found that individuals with hoarding disorder underreport their clutter, and that underreporting is predicted by objective severity of clutter. In an n = 53 subset of participants, we found that underreporting is predicted by altered performance on tests of cognitive control and inhibition, specifically Go/No-Go and Stroop tests. The relation of underreporting to objective clutter, the cardinal symptom of hoarding disorder, suggests that anosognosia may reflect core pathophysiology of the disorder. The neurocognitive predictors of clutter underreporting suggest that anosognosia in hoarding disorder shares a neural basis with metacognitive awareness deficits in other neuropsychiatric disorders and that executive anosognosia may be a transdiagnostic manifestation of psychopathology.

It remains unclear whether subanesthetic racemic ketamine-induced cortisol elevations in healthy subjects are related to ketamine's acute affective and/or dissociative effects.