International Journal of Neuropsychopharmacology

Treatment-resistant depression and anxiety remain major challenges in psychiatry, particularly in female patients, who are disproportionately affected yet remain underrepresented in preclinical ketamine research. The present study investigated short- and long-term anxiolytic effects of acute subanesthetic ketamine administration in female Wistar-Kyoto (WKY) rats, a validated genetic model of treatment-resistant affective dysfunction. Subjects received a single intraperitoneal injection of saline vehicle or racemic ketamine (5, 10, or 15 mg/kg), followed by acoustic startle response (ASR) testing 24 hours and 7 days later. Oxidative stress was assessed using 8-oxo-2'-deoxyguanosine (8-oxo-dG) immunofluorescence in the basolateral amygdala (BLA), prefrontal cortex (PFC), and hippocampus, alongside analysis of parvalbumin-positive (PV+) interneurons. Ketamine treatment produced dose- and time-dependent behavioral effects with 10 mg/kg eliciting the strongest delayed anxiolytic-like response at 7 days, while 15 mg/kg showed more immediate behavioral effects at 24 hours. While ketamine did not alter PV+ cell count, it significantly increased oxidative stress markers globally in the BLA and prelimbic region of the PFC and specifically in the PV+ interneurons in the BLA. The findings suggest that ketamine's therapeutic effects in female WKY rats may involve region-specific modulation of stress circuitry and oxidative signaling rather than gross interneuron loss. Overall, the study provides evidence for sex-dependent and temporally dynamic effects of ketamine in a translational model of treatment-resistant anxiety and depression.

Evidence suggests that insomnia disorder is associated with pathophysiological alterations that may contribute to long-term physical, mental and inflammatory-related health risks. Cognitive behavioral therapy for insomnia (CBTi) is the first-line treatment for insomnia disorder, yet its effects on physiological outcomes remain unclear. This randomized-controlled trial examined the effects of CBTi on cardiovascular and immunological biomarkers. Sixty-two participants with insomnia disorder were randomized to group-CBTi (N = 33, 75.8% female, Mage = 48.8 + 17.1 years) or Waitlist (WL) control (N = 29, 75.9% female, Mage = 52.2 + 15.6 years). Cardiovascular parameters included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and nocturnal heart rate variability (HRV). Inflammatory markers from blood samples included C-reactive protein (CRP), tumor necrosis factor-alpha (TNF- ), interleukin-6 (IL-6) and brain-derived neurotrophic factor (BDNF). All outcomes were assessed at baseline (T1), post-treatment assessment (T2, following completion of CBTi or WL period), and 6-months for the WL group (T3, after CBTi for the WL participants). No significant Group-by-time effects were observed for SBP, DBP, HR, HRV and any inflammatory markers (ps > .05) from T1 to T2. When pooling treatment effects following CBTi exposure across both groups (T1 to T2 in CBTi group and T1 to T3 in WL group), no significant biomarker changes were observed. Overall, results indicate that CBTi did not produce detectable changes in cardiovascular or inflammatory markers among healthy individuals with insomnia disorder. These findings suggest physiological responses to CBTi are complex and may reflect dynamic and context-dependent processes (https://www.isrctn.com/ISRCTN13983243).

This study examined whether connectivity-guided accelerated intermittent theta-burst stimulation (iTBS) improves depressive symptoms beyond routine multimodal inpatient care in hospitalized patients with treatment-resistant depression (TRD). In this randomized, double-blind, sham-controlled trial, patients with unipolar TRD received active or sham iTBS. Stimulation targeted an individualized left dorsolateral prefrontal cortex site showing most functional anticorrelation with the subgenual anterior cingulate cortex on resting-state functional MRI. Treatment was delivered as 3 daily sessions over 10 weekdays (30 sessions; 54,000 pulses) as an inpatient augmentation strategy. Primary and secondary outcomes were changes in Montgomery-Asberg Depression Rating Scale (MADRS) and Beck Depression Inventory-II (BDI-II) scores during the 2-week stimulation phase. Exploratory endpoints included response and remission rates. Of the 57 randomized patients, 51 completed treatment (active, n=27; sham, n=24). The cohort exhibited moderate-to-severe treatment resistance (mean Maudsley Staging Method score, 10.9) and high psychiatric comorbidity. Active iTBS was associated with significantly steeper MADRS improvement than sham (-3.54 points/week; 95% CI, -5.53 to -1.55; PFDR=.02), corresponding to model-estimated reductions of 12.06 versus 4.98 points with a large effect size (d=-0.89). BDI-II trajectories similarly favored active treatment, though with a smaller effect (group-by-time estimate, -0.23 points/day; 95% CI, -0.41 to -0.05; PFDR=.04; d=-0.22). MADRS response rates were higher with active iTBS (42.3% vs 13.0%), while remission rates were numerically but not significantly higher (26.9% vs 12.5%). No serious adverse events occurred. In conclusion, connectivity-guided iTBS produced significant add-on antidepressant effects during acute inpatient treatment of TRD. Larger multicenter trials are needed to establish durability and optimize implementation.

BackgroundSerotonergic psychedelics are advancing as psychiatric treatments, yet acute responses vary between individuals and the contribution of sex, a fundamental biological variable, remains largely unexamined. MethodsWe pooled two double-blind, placebo-controlled studies in healthy volunteers (N = 72; 31 male, 41 female) comparing psilocybin 15 mg, 2C-B 20 mg, and LSD 50 {micro}g. Linear mixed models tested sex differences in acute subjective effects (visual analogue scales), retrospective altered-states ratings (5D- and 11-ASC), empathy (Multifaceted Empathy Test), and peak plasma blood concentrations (Cmax, AUC), with treatment, sex, their interaction, as fixed factors, and age as a covariate. ResultsFemale participants reported numerically higher subjective ratings than male participants on most measures. After adjustment for age, sex differences remained significant for feeling under the drugs influence, reduced vigilance, and impaired control and cognition, with medium-to-large effects. These effects were largely consistent across the three drugs. No sex differences emerged on any empathy measure or in peak drug concentrations. ConclusionsFemale participants may experience more intense acute subjective effects and greater perceived impairment under psychedelics, independent of age and not explained by drug exposure. These preliminary findings, implicating pharmacodynamic rather than pharmacokinetic mechanisms, have implications for dosing, informed consent, and safety monitoring, and underscore the need to treat sex as a biological variable in adequately powered psychedelic trials.

Stroboscopic light stimulation (SLS) is a candidate non-pharmacological intervention that induces transient visual and affective experiences, with potential application in depression. Before efficacy testing, clinical development requires safety, tolerability and feasibility data. We report a staged, single-site programme in adults reporting depressive symptoms. Work Package (WP) 1 tested 11 SLS parameter sets for safety and tolerability. An interim bridge study assessed whether a low-phenomenology SLS control reduced subjective visual effects while preserving session context. WP2 randomised 84 participants to four weekly supervised 31-minute sessions of the intervention or a low-phenomenology control. In WP1, 31 participants were analysed; no severe adverse reactions occurred, mean discomfort was low (0.49/10), and the highest session-level upper 80% confidence limit was 1.13/10, well below the prespecified threshold. The interim study supported experiential separation between intervention and control. In WP2, endpoint data were available for 70/84 participants (83.3%): 39/42 in the intervention arm and 31/42 in the control arm. Overall retention met the criterion, but lower control-arm retention remains a design issue; protocol adherence was high, discomfort remained low, and no serious SLS-attributable adverse events occurred. Exploratory depressive-symptom changes suggested a possible BDI-II signal, but do not establish efficacy. Supervised SLS met key safety, tolerability, and feasibility criteria, and a lower visual-phenomenology active control can be carried forward, while masking and comparator credibility remain to be established. The next step is a diagnostically defined, CTU-governed Phase 2a feasibility trial that pre-registers a locked protocol and tests masking, credibility, retention and endpoint precision.

Social isolation is commonly used to model social stress and is a known risk factor for depression, with impacts on hippocampal function and postnatal neurogenesis. However, most studies focus on social isolation in juvenile mice isolation during adolescence, leaving the effects of prolonged adult isolation less understood. Post-transcriptional regulation of gene expression by microRNAs (miRNAs) plays a role in hippocampal function, and altered miRNA, as well as gene expression, has been reported in the hippocampus of mice exposed to social isolation. A single-nucleotide polymorphism in miR-30e in humans is associated with increased expression of the mature miRNA, impaired cognition, electroencephalogram waveform latency, depression, and schizophrenia. We investigated whether adult isolation in mice alters gene regulation via microRNAs, particularly miR-30e-5p, and affects hippocampal function. In adult BALB/c male mice, 10 weeks of isolation increased miR-30e-5p expression in the ventral hippocampus, reduced its target gene Neurod1, and impaired hippocampal-dependent cognition (object pattern separation), without clear anxiety- or depression-like behaviours. Isolated mice also showed a blunted response to acute stress. These findings suggest that adult social isolation affects hippocampal function through post-transcriptional gene regulation, highlighting a role for miR-30e-5p in neurogenesis and cognition in response to psychological stress.

Post-traumatic stress disorder (PTSD) is associated with high rates of comorbid personality disorders, which may contribute to PTSD severity. Among veterans with PTSD, obsessive compulsive personality disorder (OCPD) is common, with reported prevalence estimates ranging from 7-44%. Despite this, the relationship between OCPD traits and PTSD severity remains poorly understood. This retrospective, cross-sectional study examined associations between PTSD severity and OCPD traits in a naturalistic sample of 99 Veterans evaluated by a single clinician in a PTSD/Trauma Recovery Services clinic. PTSD symptoms were measured with the PTSD Checklist for DSM-V (PCL-5), and OCPD traits were measured with the Pathological Obsessive-Compulsive Personality Scale (POPS). Relationships between these two constructs were examined using Pearson correlations. Overall PTSD severity was significantly and positively correlated with total OCPD traits (r = 0.46, p < 0.001). Among OCPD domains, maladaptive perfectionism showed the strongest association with PTSD severity (r = 0.44, p <.001), followed by emotional overcontrol and reluctance to delegate (both r = .38, p < .01), rigidity (r = .35, p < .01), and difficulty with change (r = .28, p < .05). These findings suggest OCPD traits impact PTSD symptom burden in veterans, warranting further research and clinical attention.

Abstract Objectives To evaluate and compare the neuro-behavioural safety profiles of piroxicam and nitroglycerine by investigating their differential effects on cognitive function, spatial and recognition memory, and hippocampal neurochemistry in a di-oestrous female Wistar rat model. Methods Female Wistar rats at di-oestrous were randomly assigned to receive distilled water, piroxicam, or nitroglycerine orally for four consecutive days. Following treatment, spatial and recognition memory were evaluated using standard behavioural paradigms. Hippocampal tissues were analysed for acetylcholinesterase and glutamate activity, oxidative stress markers, and neuroinflammatory indices. Results Piroxicam improved recognition memory and was associated with increased glutamatergic activity and a compensatory rise in superoxide dismutase. However, it also elicited elevated nitric oxide signaling, lipid peroxidation, and localized neuroinflammatory markers in the hippocampus. In contrast, nitroglycerine impaired non-spatial memory during di-oestrous. Although both treatments preserved working memory, they produced distinct effects on object recognition, memory discrimination, oxidative stress parameters, and neuroinflammatory mediators. Conclusions Piroxicam and nitroglycerine exert differential effects on cognition and hippocampal neurochemistry during di-oestrous. Piroxicam improved recognition memory and produced distinct hippocampal neurochemical alterations, whereas nitroglycerine impaired recognition memory. These findings highlight the influence of menstrual pain therapeutics on cognitive function and hippocampal physiology under hormonally sensitive conditions. Keywords: cognitive function; cognitive impairment; cyclooxygenase inhibitors; neuroinflammation; neurochemistry

RationaleAppetitive Pavlovian cues can drive maladaptive reward seeking via stimulus-reward memories. Disrupting memory reconsolidation offers a potential strategy to reduce their influence, but evidence for {beta}-adrenergic blockade with propranolol is inconsistent across behavioural paradigms, particularly relative to NMDA receptor antagonism. ObjectivesWe tested whether propranolol disrupts reconsolidation of appetitive sucrose memories in a discriminative goal-tracking paradigm, and compared its effects with those of the most commonly used NMDA receptor antagonist, MK-801. MethodsAdult Lister hooded rats underwent discriminative Pavlovian conditioning. Thirty minutes before a brief memory reminder (non-reinforced or reinforced), rats received systemic drug treatment or saline control. In study 1, MK-801 (0.1 mg/kg) was administered to male rats. In study 2, propranolol (10 mg/kg) was administered to equal numbers of male and female rats. Goal-tracking was tested drug-free at 1 and 8 days. ResultsIn study 1, MK-801 impaired subsequent discriminated responding at test. These effects were observed not only when reminder was non-reinforced as in previous successful demonstrations, but also with reinforced reminder. In study 2, Propranolol also impaired subsequent goal-tracking, regardless of reminder type, and the effects were consistent across sexes. ConclusionsPropranolol can disrupt reconsolidation of appetitive goal-tracking memories to a similar extent as MK-801 under conditions that promote memory destabilisation. These findings demonstrate that {beta}-adrenergic blockade can impair appetitive memory reconsolidation in a goal-tracking paradigm, challenging prior null findings and revitalising the potential for propranolol-based interventions in maladaptive reward-seeking behaviours.

BackgroundCognitive restructuring, the process of identifying and challenging negative thoughts, is a key technique for treating depressive and anxiety disorders. Although neuroimaging studies have characterised the brain systems supporting cognitive restructuring in healthy individuals, it remains unclear how these systems are altered in depression and anxiety, or whether each disorder is associated with distinct neural dysfunction. MethodsSeventy-three clinical participants with depressive or anxiety disorders and 70 healthy controls completed a cognitive restructuring paradigm during 7 Tesla functional magnetic resonance imaging (fMRI). The task required participants to either repeat a series of negative statements or challenge them using Socratic questioning. Group-level fMRI analyses examined the effects of depressive and anxiety symptom severity on brain activation, while dynamic causal modelling characterized the directional neural influences between implicated regions. ResultsDuring challenging compared to repeating statements, greater depressive symptoms were associated with reduced dorsolateral prefrontal cortex (dlPFC) activation. Conversely, greater anxiety symptoms were associated with greater dlPFC activation. Effective connectivity results revealed that depressive symptoms were associated with greater inhibition from the ventrolateral prefrontal cortex (vlPFC) to the ventromedial prefrontal cortex, whereas anxiety symptoms were associated with greater excitation from the dlPFC to amygdala and greater inhibition from the vlPFC to amygdala. ConclusionsWhile clinical participants modified negative beliefs as effectively as healthy controls, depressive and anxiety symptoms were associated with dissociable neural signatures during restructuring. This suggests that cognitive behavioral therapy may engage partially distinct mechanisms depending on symptom profile, a possibility that warrants longitudinal investigation of treatment response.

Background: Serotonin has been implicated in cognitive flexibility and pathological perseverative thinking (PT), including rumination, worry, and obsessions. However, evidence remains fragmented across pharmacological manipulations, clinical populations, and outcome measures. This multilevel meta-analysis examined whether serotonergic interventions influence PT and cognitive flexibility. Methods: Preregistered and following PRISMA guidelines, we synthesized studies investigating three classes of serotonergic manipulations: acute tryptophan depletion (ATD), serotonin elevation via selective serotonin reuptake inhibitors (SSRIs), and classic serotonergic psychedelics. Three multilevel random-effects meta-analyses with cluster-robust variance estimation were conducted: (A) effects of ATD on cognitive flexibility (N = 266; 10 effect sizes), (B) effects of serotonin elevation on cognitive flexibility (N = 654; 15 effect sizes), and (C) effects of serotonin elevation on pathological perseverative thinking (N = 1,100; 20 effect sizes). Across analyses, the total sample comprised 2,030 participants and 45 effect sizes. Results: ATD did not significantly impair cognitive flexibility (g = 0.15, 95% CI [-0.07, 0.38], p = .23), and no moderation by task type, sex, or age was observed. Serotonin elevation similarly did not improve cognitive flexibility (g = -0.07, 95% CI [-0.36, 0.22], p = .63), with no significant performance differences emerging between SSRIs, classical psychedelics, or tryptophan enrichment. In contrast, serotonin elevation was associated with a significant medium-to-large reduction in perseverative thinking (g = -0.58, 95% CI [-0.76, -0.41], p < .001). Notably, while both pharmacological classes effectively reduced cognitive rigidity, SSRIs demonstrated a marginally smaller magnitude of symptom reduction compared to acute psilocybin interventions (p = .081). Furthermore, samples with a higher proportion of female participants showed larger reductions in perseverative thinking ({beta} = -1.86, p = .014), while worries exhibited marginally smaller reductions relative to obsessions ({beta} = 0.42, p = .055). Publication bias tests were non-significant across analyses. Conclusions: Serotonergic interventions robustly reduce perseverative thinking but do not consistently alter performance on laboratory measures of cognitive flexibility. These findings suggest that serotonin may influence cognitive-emotional rigidity and the subjective experience of repetitive thought more strongly than objective executive task performance. The dissociation between task-based and phenomenological outcomes aligns with contemporary models of serotonergic plasticity and highlights perseverative thinking as a potentially transdiagnostic therapeutic target of serotonergic interventions.

Cognitive impairment is a debilitating feature of mood disorders (MD) linked to decreased neuroplasticity. Moderate hypoxia upregulates neuroplasticity and may improve cognition when combined with cognitive training. In this outcome assessor-blinded randomized controlled trial, we investigate the effects of three weeks of repeated hypoxia (12% O2) with concurrent cognitive training (H-CT) for 3.5 hours, 5-6 days per week compared with treatment as usual (TAU). Cognitively impaired individuals with remitted MD were randomized to H-CT or TAU and assessed at baseline, treatment completion, and one-month follow-up. The primary outcome was a broad cognitive composite measure. Additional cognitive, functioning, blood-based, and neuroimaging (SV2A as a presynaptic marker with [11C]UCB-J positron emission tomography (PET) and neural activity during working memory functional magnetic resonance imaging (fMRI)) outcomes were assessed. Sixty-four participants were randomized to H-CT (n=34) or TAU (n=30), and 26 H-CT and 29 TAU completed the intervention and assessments. There was no effect of H-CT on the primary outcome (ps[&ge;]0.24) but H-CT induced improvements in the secondary executive function outcome (treatment effect=0.76, 95% CI=[0.23;1.28], adj. p=0.02) that prevailed at follow-up (treatment effect=1.07, 95% CI=[0.36;1.77], adj. p=0.02). Executive function improvement was accompanied by H-CT-related lower presynaptic [11C]UCB-J binding in the nucleus accumbens (p=0.03). H-CT also produced sustained improvements in everyday functioning (adj. ps[&le;]0.049). No effects were observed on dorsolateral prefrontal cortex activity or real-life cognitive skills (ps[&ge;]0.54). Two serious but treatment-unrelated adverse events occurred. In conclusion, H-CT produces robust effects on executive functions, but not broader cognition, in MD, and H-CT may thus be particularly promising for targeting executive dysfunction in this population.

Background Negative symptoms in schizophrenia spectrum disorders (SSD) remain insufficiently treated and require novel therapeutic approaches. Oxytocin may improve negative symptoms, although its effects appear highly context-dependent according to the social salience hypothesis. We conducted a randomized, triple-blind, placebo-controlled pilot study combining intranasal oxytocin with mindfulness-based group therapy (MBGT), hypothesizing that the positive social context of MBGT would enhance oxytocin-related effects. Methods 47 participants with SSD (34% female) were randomized to receive either 24 IU oxytocin (MBGT+OXT; n = 26) or placebo (MBGT+PLA; n = 21) before four MBGT sessions. Primary outcome was negative symptoms assessed with the Positive and Negative Syndrome Scale negative subscale (PANSS-N) at post-intervention and 4-week follow-up. Secondary outcomes included the Brief Negative Symptom Scale (BNSS), Self-Evaluation of Negative Symptoms Scale (SNS), and additional clinical measures. Linear mixed models estimated within- and between-group effects. Results Overall dropout rate was 14.89%, with one dropout potentially treatment-related. Blinding was successful. Participants completed 95.63% of sessions. Only the MBGT+OXT group showed significant improvements in PANSS-N from baseline to post-intervention (d = -0.74) and follow-up (d = -0.77), with a small between-group effect at follow-up (d = 0.39). BNSS total improved significantly only in the MBGT+OXT group from baseline to post-intervention (d = -0.88) and follow-up (d = -0.91), with between-group effects favoring MBGT+OXT at follow-up (d = -0.38). No serious adverse events occurred. Conclusions These findings suggest, oxytocin combined with MBGT may improve negative symptoms in SSD and support further large-scale trials. Clinical Trials Registration: https://clinicaltrials.gov/study/NCT06136390, Registration number: NCT06136390

Background. Despite growing evidence that lifestyle interventions reduce depressive symptoms, the psychological mechanisms underlying these effects remain poorly understood. This study examined whether mindfulness and rumination mediate the antidepressant effects of heated yoga (HY), a multicomponent intervention combining physical activity, attentional training, and thermoregulatory stress. Methods. This prespecified secondary mediation analysis builds on a randomized controlled trial in which 80 adults with moderate-to-severe depression (IDS-CR > 23) were randomized to 8 weeks of twice-weekly HY or waitlist control. Subsamples with complete mediator data contributed to rumination (n = 56) and mindfulness (n = 60) models. Causal mediation analyses with 10,000 bootstrap resamples estimated indirect effects on Week 8 depression severity via Week 4 mediator changes. Sensitivity analyses assessed unmeasured confounding required to nullify observed effects. ClinicalTrials.gov: NCT02607514. Results. As previously reported, HY produced significantly greater IDS-CR reductions at Week 8 versus controls (p < .001). HY was associated with decreased rumination (p < .01) and increased mindfulness (p < .001) at Week 4. Increased mindfulness was statistically consistent with mediating depressive symptom reductions (ACME: -2.71, 95% CI [-5.42, -0.99]), whereas decreased rumination was not (ACME: -2.41, 95% CI [-6.28, 0.43]). Results were resilient to sensitivity analyses. Conclusion. In this RCT of a behavioral lifestyle intervention, mindfulness but not rumination emerged as a statistically significant mediator of depressive symptom reductions, identifying mindfulness as a key candidate mechanism through which multicomponent lifestyle interventions may exert antidepressant effects and suggesting a target for optimizing behavioral treatments for depression.

Background: Emotion dysregulation is a core feature of bipolar disorder (BD), yet its behavioral expression during depressive episodes, and potential differences between its types, BD-I and BD-II, remain unclear. This study used automated facial-expression analysis during naturalistic affective film viewing to examine subtype-specific and context-dependent emotional responding in bipolar depression. Methods: The sample included 135 participants: 69 healthy controls and 66 patients with BD (BD-I, 23; BD-II, 43). Participants viewed nine emotionally evocative film clips spanning negative, positive, neutral, and socially threatening contexts, while their facial expressions were continuously recorded and quantified using computer vision-based facial-expression analysis. Results: Patients with BD-I showed a distinct, context-dependent facial-expression profile, characterized by greater negative responses across multiple contexts than other groups. Specifically, they showed increased sadness during sad, reward, and amusing clips, and elevated anger during sad and neutral clips. In socially threatening contexts, BD-I participants showed a multivalent pattern of elevated anger, fear, and joy, suggesting poorly coordinated or context-incongruent affective expression. In contrast, BD-II participants did not differ significantly from healthy controls on any emotion, despite depressive symptom severity comparable to BD-I participants. Conclusions: These findings suggest that facial-expression patterns in bipolar depression differ across subtypes. BD-I may be characterized by heightened negative reactivity and altered context-appropriate modulation of emotional expression, whereas BD-II may not show comparable alterations in overt facial output. Automated facial-expression analysis during naturalistic stimulation may provide a useful behavioral marker for characterizing subtype-specific affective disturbance in bipolar depression and related psychopathology.

Background: Childhood trauma exposure (TE) may heighten negative emotional responses, overwhelm cognitive control, and increase risk for anxiety disorders. Cognitive control is facilitated by glutamatergic (Glu) excitatory neurotransmission within the dorsal anterior cingulate cortex (dACC). Dynamic changes in dACC Glu levels were investigated using 1H functional magnetic resonance spectroscopy (1H fMRS) to assess the impact of negative emotional processing on neural mechanisms supporting cognitive control in TE-youth. Methods: Fifty adolescents were categorized into two TE-Groups: Higher (Mtrauma=6{+/-}1events) and Lower (Mtrauma=3{+/-}1events). 1H fMRS from the dACC was acquired during an inhibitory motor control task requiring tapping responses to stimuli under two Response Modes, NonSelective (100% response) and Selective (80% response, 20% inhibition), executed with two Stimuli Conditions, Squares (no emotion) and Faces (emotion). Glu modulation (relative to basal levels) was tested across TE-Group, Stimuli Condition, and their interaction. Within each Stimuli Condition, Glu modulation was tested across Response Modes by TE-Group. Results: We observed a 2-way interaction of TE-Group x Stimuli Condition ({chi}2=4.66, p=0.031). Post-hoc tests revealed significantly lower Glu modulation in Higher TE vs Lower TE (p=.023) during Faces but not Squares. This Glu modulation did not differ across Response Modes. Within the Higher TE-Group, Glu was significantly reduced during Faces compared to Squares (p<.001). Basal dACC Glu levels did not differ between groups. Conclusions: TE-Group differences in adolescent dACC Glu modulation were observed during cognitive control performed with emotional, but not non-emotional, stimuli, highlighting the value of 1H fMRS for detecting trauma-related differences in task-related excitatory neurochemical dynamics.

Rationale: Early life stress (ELS) is acknowledged to underlie cognitive and emotional abnormalities linked to stress-related mood disorders. ELS can lead to persistent biases in how uncertain feedback is processed to affect the flexibility of decision-making. Objectives: (1) To investigate the effects of ELS on the flexibility of rats trained on a serial probabilistic reversal learning (PRL) task involving spurious positive and negative feedback. (2) To elucidate the involvement of the stress hormone corticosterone and the noradrenergic and serotonergic systems in modulating how ELS affects PRL. Methods: Male and female rats were intermittently separated from maternal care on postnatal days five to nineteen, inclusively. As adults, the same rats were trained on a deterministic reversal learning task involving certain rewarded or non-rewarded outcomes followed by a PRL task where correct and incorrect responses were rewarded on 80% and 20% of trials, respectively. Dose-dependent effects of the beta-blocker, propranolol, selective serotonin reuptake inhibitor, citalopram and corticosterone were subsequently determined. Results: ELS resulted in an increased responsivity to feedback, specifically in males making more win-stay responses following a reward, that was associated with an increased punishment learning rate. In both control and MS rats, propranolol increased feedback sensitivity, but delayed updating following a rule switch. In contrast, neither citalopram nor corticosterone significantly affected reversal learning. Conclusions: ELS is sufficient to cause persistent changes in how feedback is processed by male rats on a reversal learning task. Activation of beta-adrenergic receptors may be necessary for updating learned associations during decision-making involving uncertain feedback.

Serotonin (5-HT) 2A receptors (5-HT2AR) modulate corticolimbic circuits regulating fear extinction. Although activation of these receptors has been shown to facilitate fear extinction, the behavioral consequences of 5-HT2AR antagonism during extinction is not well defined. Here, we examined the systemic effects of two 5-HT2A receptor antagonists, the mixed 5-HT2A/2C antagonist MDL 11,939 (Glemanserin) and the selective 5-HT2A antagonist MDL 100,907 (Volinanserin) on fear extinction in adult C57BL/6J mice. Prior to drug administration, mice assigned to future treatment groups acquired comparable conditioned freezing responses during delay fear conditioning. Twenty-four hours later, acute administration of MDL 11,939 (1.0 mg/kg) or MDL 100,907 (0.01 mg/kg) increased freezing to the first conditioned stimulus (CS) presentation on Extinction Day 1, indicating enhanced expression of conditioned fear. However, acquisition of fear extinction differed between the respective cohorts of mice treated with the two 5-HT2AR antagonists. Repeated administration of MDL 11,939 significantly impaired extinction, as evidenced by increased freezing across extinction trials and an increased number of trials required to reach extinction criterion. In contrast, MDL 100,907 has reported affinity for did not significantly alter extinction under either acute or repeated dosing conditions. Because MDL 11,939 has reported affinity for 5-HT2C receptors, we tested potential contributions of 5-HT2C receptor antagonism in a separate cohort of mice using two doses of the selective 5-HT2C antagonist, SB 242084. Neither dose affected conditioned fear expression, extinction learning, or trials required to reach extinction criterion. Together, these findings demonstrate ligand-specific and dose-dependent effects of 5-HT2AR antagonism on fear extinction and suggest that distinct intracellular receptor signaling pathways may differentially regulate extinction-related behavior.

Accumulating evidence suggests alterations in neurocognitive, affective, interoceptive and autonomic processing in functional neurological disorder (FND), yet interventions targeting these processes remain underexplored. This study investigated the possible immediate and longer-term effects of a somatic yoga intervention on cognitive control, emotion regulation, state dissociation and affect, autonomic arousal, and interoceptive processing in FND. Twenty-three adults with FND completed six weeks of somatic yoga (N=12) or six weeks of a music-based relaxation control (N=11). At baseline, post-single session, and post-six weeks, participants completed laboratory measures of sustained attention, response inhibition, interoception, emotion regulation, and state dissociation and affect. Electrocardiography and galvanic skin conductance were recorded throughout. Linear mixed effects models assessed potential change on day one, immediately pre/post a single session, and from day 1 to the end of the six-week programme. After one session, stop signal reaction time, negative affect, and heartrate decreased in both groups ({Delta}=.69-.75). After one session and at six weeks, improved sustained attention, elevated positive affect, and reduced dissociation were seen in both groups, with a larger magnitude of change in yoga ({Delta}=.50-1.10). The yoga group exhibited fewer direction errors on the response inhibition task and shorter response times on the sustained attention task, with the opposite seen in the music group ({Delta}=.50-1.17). Both in the short- and longer-term, somatic yoga might lead to adaptive changes in attention and executive functioning, arousal, state affect and dissociation.

Importance Childhood sexual abuse (CSA) is linked to adverse psychiatric outcomes in adulthood, but evidence on its association with cardiovascular disease and mortality from large, diagnostically ascertained cohorts remains limited. Objective To assess the 10-year risk of all-cause mortality, suicide or self-harm, drug overdose or poisoning, and cardiovascular disease among patients with a diagnosed history of CSA compared with a matched unexposed cohort. Methods In this retrospective cohort study, we used deidentified electronic health record data from 68 health care organizations in the TriNetX US Collaborative Network. Patients diagnosed with confirmed or suspected childhood sexual abuse (CSA) before age 18 between January 1, 2003, and December 31, 2015, who had a subsequent adult encounter, were propensity score matched 1:1 with unexposed patients on age, sex, race and ethnicity, and baseline psychiatric and medical comorbidities (n = 9,083 per cohort). Outcomes--all-cause mortality, suicide or self-harm, drug overdose or poisoning, and cardiovascular disease--were assessed over 10 years from the index adult encounter using risk and time-to-event analyses to estimate risks, risk ratios, and hazard ratios. Results Among 18,166 matched patients (mean [SD] age, 19.0 [2.0] years; 14,813 [81.6%] female), CSA was associated with significantly elevated risk of suicide or self-harm (5.1% vs 2.8%; risk ratio [RR], 1.84; 95% CI, 1.57-2.16), drug overdose or poisoning (5.5% vs 3.7%; RR, 1.47; 95% CI, 1.28-1.69), and cardiovascular disease (12.3% vs 9.3%; RR, 1.31; 95% CI, 1.20-1.44), with concordant hazard ratios (all P < .001). All-cause mortality was numerically higher but not statistically significant (0.5% vs 0.4%; RR, 1.16; 95% CI, 0.75-1.79; P = .51). Conclusions and Relevance A diagnostically confirmed history of CSA was associated with substantially elevated 10-year risk of self-harm, overdose, and cardiovascular disease, independent of baseline demographic and psychiatric comorbidity. These findings support integrated psychiatric and cardiovascular screening for adult survivors of CSA and trauma-informed care extending beyond mental health services alone.