European Neuropsychopharmacology

Nicotine intake by cigarettes is linked to the maintenance and development of anxiety disorders and impairs adaptive discrimination of threat and safety in humans. Yet, it is unclear if nicotine exerts a causal pharmacological effect on the affective and neural mechanisms that underlie aversive learning. We conducted a pre-registered, pseudo-randomly and double-blinded pharmacological fMRI study to investigate the effect of acute nicotine on Fear Acquisition and Extinction in non-smokers (n=88). Our results show that nicotine administration led to decreased discrimination between threat and safety in subjective fear. Nicotine furthermore decreased differential (threat vs. safety) activation in the hippocampus, which was functionally coupled with Nucleus Accumbens and amygdala, compared to placebo controls. Additionally, nicotine led to overactivation of the ventral tegmental area. This study provides mechanistic evidence that single doses of nicotine impair neural substrates of adaptive aversive learning in line with the risk for the development of pathological anxiety.

Anxiety and maladaptive fear remain difficult to treat, and despite initial promising findings, evidence regarding the anxiolytic and translational potential of oxytocin (OT) remains inconsistent. In a preregistered, randomized, double-blind, placebo-controlled, parallel-group pharmaco-fMRI study in 67 healthy men, we tested whether intranasal OT reduces post-exposure subjective fear during prolonged naturalistic viewing a horror movie comprising independently defined low-, medium-, and high-fear segments. OT reduced subjective fear following naturalistic threat exposure after accounting for pre-exposure baseline ratings. Neuroimaging analyses revealed that OT attenuated recruitment of the dorsolateral prefrontal cortex particularly during higher fear, and enhanced coupling of this region with the bilateral amygdala. At the large-scale network level, OT increased communication between frontoparietal/default-mode control networks and subcortical/limbic networks during high fear indicating more integrative fear regulation. A whole-brain fear neuromarker (CAFE) further confirmed intensity-dependent OT effects. Together, these findings indicate that OT modulates post-exposure fear experience and fear-related neural dynamics in ecologically valid contexts.

Psychedelic drugs are emerging as potentially efficacious tools for treating psychiatric conditions and probing the neural basis of consciousness. Although drug administration context is widely believed to shape psychedelic effects, it remains unclear whether it can independently generate placebo and nocebo effects resembling psychedelic experiences and side effects. In a pre-registered experiment, 78 non-clinical participants inhaled inert medical air under placebo and control conditions while completing a time perception task and a resting-state period. In the placebo condition, the gas was presented as nitrous oxide, whereas in the control, it was correctly identified. Placebo administration increased altered states of consciousness, ego dissolution, dissociation, and side effects, but did not significantly impact time perception. Predictive modelling indicated that placebo-induced psychedelic effects were predicted by trait responsiveness to verbal suggestion and absorption. These findings demonstrate that context alone can induce psychedelic effects, with implications for its causal role in psychedelic action.

BackgroundClinical efficacy of chronic intranasal administration of oxytocin is increasingly explored in autism spectrum disorder (ASD), but to date, little is known regarding its biological effects and in particular how chronic administration regimes impact endogenous oxytocinergic function. MethodsTo fill this gap, this double-blind, randomized, placebo-controlled study explored chronic oxytocin administration effects on endogenous salivary oxytocin levels and oxytocin receptor gene (OXTR) epigenetics (DNA methylation) in 8-to-12-year-old children with ASD (n = 79, 16 females). Biological sampling was performed at baseline (pre-treatment), immediately (24 hours) after the four-week oxytocin administration period (12 IU, twice daily) and at a follow-up session, four weeks after the last nasal spray administration. ResultsCompared to placebo, children receiving the oxytocin nasal spray displayed significantly higher salivary oxytocin levels 24 hours after the last oxytocin nasal spray administration, but no longer at the four-week follow up session. Regarding epigenetics, oxytocin-induced reductions in OXTR methylation were observed, reflecting a facilitation of oxytocin receptor expression in the oxytocin, compared to the placebo group. Notably, heightened oxytocin levels post-treatment were significantly associated with reduced OXTR DNA methylation and improved feelings of secure attachment. ConclusionFour weeks of chronic oxytocin administration stimulated the endogenous oxytocinergic system in children with ASD, as evidenced by increased salivary oxytocin levels and reduced OXTR DNA methylation (indicating increased receptor expression).

BackgroundSelective serotonin reuptake inhibitors (SSRIs) are limited by inadequate response in a significant minority of patients, slow onset, minimal cognitive benefit, and side effects. Preclinical studies suggest selective serotonin 4 receptor (5-HT4R) agonists may produce faster antidepressant effects via distinct mechanisms, however there has been no experimental research in clinical populations to date. AimsTo test whether the novel 5-HT4R partial agonist PF-04995274 produces early behavioural and neural changes in emotional cognition similar to SSRIs in patients with unmedicated major depressive disorder (MDD). MethodIn a double-blind, placebo-controlled trial, 90 participants with MDD were randomised to 7 days of PF-04995274 (15 mg), citalopram (20 mg), or placebo. Emotional processing was assessed using a behavioural facial expression recognition task and fMRI of implicit emotional face processing (days 6-9). Observer- and self-reported symptoms of depression were also measured at baseline and study end. ResultsAs anticipated, citalopram reduced accuracy and reaction time for negative faces, with corresponding fMRI changes (reduced left amygdala activation to emotional faces and valence-specific shifts in cortical regions). In contrast, PF-04995274 produced no change in behavioural negative bias or amygdala activity but increased medial-frontal cortex activation across valences. While this was not a clinical trial, both active treatments reduced observer-rated depression severity relative to placebo; PF-04995274 also reduced self-reported depression, state anxiety, and negative affect. No major adverse events occurred. ConclusionsPF-04995274 was not associated with the typical antidepressant profile of negative bias reductions seen with citalopram but was associated with distinct medial-frontal activation during an emotional faces task and displayed preliminary evidence of early clinical improvement, suggesting a potential alternative mechanism for antidepressant effects. Findings support further clinical trials of 5-HT4R agonists and investigation of pro-cognitive and mood effects. Clinicaltrials.gov registration numberNCT03516604. Data set informationAnalysis scripts and selected data will be available on publication.

In the past decade, intranasal administration of the neuropeptide oxytocin is increasingly explored as a new treatment for reducing the core symptoms of autism spectrum disorder (ASD). The efficacy of continual oxytocin treatment in school-aged children with ASD is, however, not well established. Using a double-blind, randomized, placebo-controlled, parallel design, the current trial explored the effects of four weeks of intranasal oxytocin treatment (12 IU, twice daily) on social functioning in pre-pubertal school-aged children (aged 8-12 years, 61 boys, 16 girls). The double-blind phase was followed by a four-week single-blind extension phase during which all participants received intranasal oxytocin. In the double-blind phase, no treatment-specific effects were identified in the primary outcome assessing social functioning (parent-rated Social Responsiveness Scale), as well as on secondary outcomes assessing repetitive behaviors, anxiety, and attachment. Exploratory moderator analyses revealed that children who received the oxytocin treatment in combination with concomitant psychosocial treatment displayed a greater benefit than those who received psychosocial treatment or oxytocin alone. A modulating effect of parents beliefs about allocated treatment was also identified, indicating that parents who believed their child assigned to the active treatment reported greater benefit than those who believed their child received placebo, particularly in the actual oxytocin group. Finally, participants who were allocated to receive the placebo treatment during the double-blind phase of the trial and later crossed-over to receive the active treatment during the single-blind extension phase, displayed a significant within-group improvement in social responsiveness, over and above the placebo-induced improvements noted in the first phase. While no overall treatment-specific improvements were identified, our results provide important indications that clinical efficacy can be augmented when oxytocin administration is paired with targeted psychosocial interventions that similarly stimulate socio-communicative behaviors. Future trials are urged to further elucidate the potential of embedding oxytocin treatment within a socially stimulating context.

Serotonin is known to have state-dependent modulatory influences on exteroceptive sensory processes and the processing of pain, but much less is known about its role in ordinary interoceptive processes and their relationships to affective states. This experiment compared the impact of a selective serotonin reuptake inhibitor (SSRI) (20mg CITALOPRAM), acutely increasing extracellular serotonin, to that of a PLACEBO on the neural processing of ordinary interoceptive sensations and the relationship of these influences to anxious states. Twenty-one healthy young volunteers completed the visceral interoceptive attention (VIA) task with each treatment, focusing attention on heart, stomach, or visual sensation control while scanned with functional magnetic resonance imaging (fMRI). The relative neural interoceptive response (IR) to heart sensation [heart minus visual] and stomach sensation [stomach minus visual] were compared between treatment conditions, controlling for general effects on sensory processing. CITALOPRAM reduced interoceptive processing in viscerosensory (bilateral posterior insular cortex, stomach-IR) and integrative/affective components (bilateral amygdala, stomach-IR and heart-IR) of known interoceptive pathways. We then searched for state-dependent modulatory effects of CITALOPRAM that varied with current levels of anxiety. The anterior insular cortex response to heart sensation increased with anxiety, replicating prior findings. This relationship disappeared on CITALOPRAM. Preliminary post hoc exploration found that CITALOPRAMS effects on amygdalae response to stomach sensation predicted acute increases and decreases in anxiety. Overall, this evidence of general and state-dependent serotonergic influence advances our understanding of interoception, its regulation, and its relationship to anxious states.

BackgroundRacemic ketamine and its enantiomer, esketamine, have emerged as fast-acting antidepressant options for individuals with treatment-resistant depression (TRD). Yet, despite growing clinical use, little is known about how sex assigned at birth shapes symptom-specific responses to these interventions, a critical gap in the move toward personalized psychiatry. MethodsWe conducted a pooled analysis of five randomized, double-blind, placebo-controlled trials in which adults with TRD received intranasal esketamine or placebo twice weekly for four weeks, alongside a newly initiated oral antidepressant. We evaluated the effects of sex assigned at birth on overall depression severity, measured via total Montgomery-[A]sberg Depression Rating Scale (MADRS) scores, and across four symptom factors: sadness, negative thoughts, detachment, and neurovegetative symptoms. Rates of clinical response and remission were also analyzed by sex assigned at birth. FindingsOverall, esketamine treatment improved total MADRS scores in both sexes; however, significant sex-specific patterns emerged. Females showed greater improvement in total MADRS scores than males towards the end of the trials, in both the placebo and esketamine arms. Females also showed more pronounced reductions in the sadness and detachment factors at the end of the trials, as well as in the neurovegetative factor on day 15, regardless of the treatment group. On the other hand, males showed a significant reduction in sadness symptoms after esketamine on day 2 of the treatment. Females had higher odds of responding, regardless of treatment arm, during later time points. InterpretationThese findings reveal that sex assigned at birth influences overall antidepressant response and shapes the trajectory and symptom profile of improvement. Our findings emphasize the critical importance of incorporating sex assigned at birth as a key variable, essential for optimizing TRD treatment strategies and advancing individualized mental healthcare. FundingCanadian Institutes for Health Research.

Serotonin (5-HT) has long been implicated in adaptive emotion regulation as well as the development and treatment of emotional dysregulations in mental disorders. Accumulating evidence suggests that a genetic vulnerability may render some individuals at a greater risk for the detrimental effects of transient variations in 5-HT signaling. The present study aimed to investigate whether individual variations in the Tryptophan hydroxylase 2 (TPH2) genetics influence susceptibility for behavioral and neural threat reactivity dysregulations during transiently decreased 5-HT signaling. To this end, interactive effects between TPH2 (rs4570625) genotype and acute tryptophan depletion (ATD) on reactivity towards angry, neutral and happy faces were examined in a within-subject placebo-controlled pharmacological fMRI trial (n = 51). An a priori genotype stratification approach of extreme groups (GG vs. TT) allowed balanced sampling. While no main effects of ATD on neural reactivity to threat-related stimuli and mood state were observed in the entire sample, accounting for TPH2 genotype revealed an ATD-induced increase in subjective anxious arousal in the GG but not the TT carriers. The effects were mirrored on the neural level, such that ATD specifically reduced ventromedial prefrontal cortex (vmPFC) reactivity towards threat-related stimuli in the GG carriers. Furthermore, the ATD-induced increase in subjective anxiety positively associated with the extent of ATD-induced changes in vmPFC activity in response to threat-related stimuli in GG carriers. Together the present findings suggest for the first time that individual variations in TPH2 genetics render individuals susceptible to the anxiogenic and neural effects of a transient decrease in 5-HT signaling.

BackgroundCognitive impairment is a common and persistent feature of depression, yet remains poorly understood and inadequately treated. Preclinical and human studies suggest that stimulating 5-HT4 receptors (5-HT4R) enhances neuroplasticity and rapidly improves learning and memory. This study is the first to examine the cognitive effects of 5-HT4R agonism in adults with a history of recurrent depression. We hypothesised that short term 5-HT4R agonist administration would produce a broad profile of pro-cognitive effects. Methods50 participants not currently depressed but with at least two previous episodes of depression (remitted depression) were randomised in a double-blind design to receive either prucalopride (2mg daily titrated from 1mg over 2 days) or placebo for 7-10 days. Participants completed self-report questionnaires and a cognitive task battery assessing declarative memory, working memory, emotional processing, and executive function before and after medication. ResultsCompared to placebo, prucalopride significantly improved word recall on an auditory verbal learning task, and was associated with faster response times on a complex working memory task without loss of accuracy. It also improved the accurate recognition of rapidly presented facial expressions. Prucalopride had minimal effects on emotionally-valenced cognitive tasks, consistent with previous findings. Cognitive improvements were independent of baseline mood symptoms or self-reported cognitive difficulties. ConclusionsShort-term 5-HT4R agonism improved performance on multiple objective cognitive measures in individuals with a history of depression. These findings replicate our previous results in healthy volunteers using prucalopride and support a role for 5-HT4Rs as a promising target for cognitive enhancement in mood disorders.

3,4-methylenedioxymethamphetamine (MDMA) has emerged as a potential treatment for post-traumatic stress disorder (PTSD), generating considerable enthusiasm in the field. However, rapidly changing evidence in a fast-moving field can be challenging to integrate. Here, we present a living systematic review and open-data meta-analytic resource on MDMA treatment for PTSD. In this initial release, six randomized controlled trials comprising 286 participants are included in the database. Our primary model uses inverse-variance random-effects meta-analysis of standardized mean differences on primary outcomes of PTSD. Compared to control conditions, MDMA showed a greater reduction in PTSD symptoms (Hedges' g = -0.71). Meta-regression on both the number of dosing sessions and cumulative dose showed that a higher number of dosing sessions and a higher cumulative dose was related to larger effects of MDMA. Treatment with MDMA as compared to placebo also resulted in higher response (risk ratio (RR) = 1.35) and remission (RR = 2.25) rates. Most studies included in the database had a low risk of bias according to Cochrane guidelines, though these fail to capture pertinent challenges in the field such as expectancy, functional unblinding, potential issues with study conduct, and safety. The current findings were assigned an overall low certainty rating using the GRADE approach. Together, this systematic review and meta-analysis suggests that MDMA-assisted therapy results in short-term decreases in PTSD symptoms across studies to date, though more trials are needed. This living systematic review, meta-analysis, database, and online dashboard (sypres.io) will continue to be updated as evidence emerges, providing a valuable, open, and transparent resource for researchers in a rapidly evolving field.

Patients characterized by stress-related disorders such as depression display elevated circulating concentrations of pro-inflammatory cytokines and a hyperactive HPA axis. Psychedelics are demonstrating promising results in treatment of such disorders, however the mechanisms of their therapeutic effects are still unknown. To date the evidence of acute and persisting effects of psychedelics on immune functioning, HPA axis activity in response to stress, and associated psychological outcomes is preliminary. To address this, we conducted a placebo-controlled, parallel group design comprising of 60 healthy participants who received either placebo (n=30) or 0.17 mg/kg psilocybin (n=30). Blood samples were taken to assess acute changes in immune status, and 7 days after drug administration. Seven days post-administration, participants in each treatment group were further subdivided: 15 underwent a stress induction protocol, and 15 underwent a control protocol. Ultra-high field magnetic resonance spectroscopy was used to assess whether acute changes in glutamate or glial activity were associated with changes in immune functioning. Finally, questionnaires assessed persisting self-report changes in mood and social behavior. Psilocybin immediately reduced concentrations of the pro-inflammatory cytokine tumor necrosis factor- (TNF-), while other inflammatory markers (interleukin (IL)-1, IL-1{beta}, IL-6, and C-reactive protein (CRP)) remained unchanged. Seven days later, TNF- concentrations returned to baseline, while IL-6 and CRP concentrations were persistently reduced in the psilocybin group. Changes in the immune profile were related to acute neurometabolic activity as acute reductions in TNF- were linked to lower concentrations of glutamate in the hippocampus. Additionally, the more of a reduction in IL-6 and CRP seven days after psilocybin, the more persisting positive mood and social effects participants reported. Regarding the stress response, after a psychosocial stressor, psilocybin blunted the cortisol response compared to placebo. Such acute and persisting changes may contribute to the psychological and therapeutic effects of psilocybin demonstrated in ongoing patient trials.

Co-occurrence of substance use disorders (SUD) and aggressive behaviour in the same individual has been frequently described. As dopamine (DA) and serotonin (5-HT) are key neurotransmitters for both phenotypes, we explored the genetic contribution of these pathways to SUD, aggressive behaviour and related behavioural traits. Here, we tested the association of 275 dopaminergic genes and 176 serotonergic genes with these phenotypes by performing gene-based, gene-set and transcriptome-wide association studies (TWAS) in 11 genome-wide association studies (GWAS) datasets on SUD (alcohol, cocaine, cannabis, opioids and a multivariate analysis of three drugs of abuse), aggressive behaviour (disruptive behaviour and antisocial behaviour) and related behaviours (irritability, neuroticism, risk taking and anxiety). At the gene-wide level, 68 DA and 27 5-HT genes were found to be associated with at least one GWAS on SUD or related behaviour. Among them, six genes had a pleiotropic effect, being associated with at least three phenotypes: ADH1C, ARNTL, CHRNA3, HPRT1, HTR1B and DRD2, the latter with five. Additionally, we found nominal associations between the DA gene sets and antisocial behaviour, opioid use disorder, SUD, irritability and neuroticism, and between the 5-HT-core gene set and neuroticism. Gene expression correlates in brain were also found for 19 genes, highlighting the association for CHRNA3 and CELSR3 with OUD, SUD and irritability and CELSR3 also with neuroticism. Our study shows a pleiotropic contribution of dopaminergic and serotonergic genes to addiction, aggression and related behaviours, highlighting a special role for DA genes, which could explain, in part, the co-occurrence of these phenotypes.

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder with changes in motivation to work for rewards being a core symptom. Transcutaneous vagus nerve stimulation (tVNS) has emerged as a promising therapy but its effects on the core features of MDD, such as changes in motivation, remained relatively unexplored. In this randomised, single-blind, cross-over, controlled trial, we used a grip strength effort task to investigate how tVNS impacted choices to exert different levels of physical effort for varying monetary rewards in MDD patients (n=53) and a non-depressed control group (n=45). Compared to sham stimulation, tVNS enhanced the efficiency with which participants with severe depressive symptoms allocated physical effort for rewards (reward-effort efficiency). These effects were not seen in participants with less severe symptoms. Specifically, we found that the effect of tVNS on reward-effort efficiency was driven by reduced unnecessary effort, i.e., a reduction in choices to exert additional effort when this was not required to gain a larger reward. These findings suggest a potential motivational mechanism by which tVNS exerts its therapeutic effects in MDD. Determining whether the effects of tVNS are linked to broader changes in executive functioning, such as improvements in cognitive flexibility in MDD, should be a key aim for future work.

Clozapine is an important antipsychotic drug. However, its use is often accompanied by metabolic adverse effects and, in rare instances, agranulocytosis. The molecular mechanisms underlying these adverse events are unclear. To gain more insights into the response to clozapine at the molecular level, we exposed lymphoblastoid cell lines (LCLs) to increasing concentrations of clozapine and measured genome-wide gene expression and DNA methylation profiles. We observed robust and significant changes in gene expression levels due to clozapine (n = 463 genes at FDR < 0.05) affecting cholesterol and cell cycle pathways. At the level of DNA methylation, we find significant changes upstream of the LDL receptor, in addition to global enrichments of regulatory, immune and developmental pathways. By integrating these data with human tissue gene expression levels obtained from the Genotype-Tissue Expression project (GTEx), we identified specific tissues, including liver and several tissues involved in immune, endocrine and metabolic functions, that clozapine treatment may disproportionately affect. Notably, differentially expressed genes were not enriched for genome-wide disease risk of schizophrenia or for known psychotropic drug targets. However, we did observe a nominally significant association of genetic signals related to total cholesterol and low-density lipoprotein levels. Together, these results shed light on the biological mechanisms through which clozapine functions. The observed associations with cholesterol pathways, its genetic architecture and specific tissue effects may be indicative of the metabolic adverse effects observed in clozapine users. LCLs may thus serve as a useful tool to study these molecular mechanisms further.

Although non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has demonstrated a therapeutic-relevant potential by enhancing mood recovery and fear extinction, its influence on neural dynamics during naturalistic, sustained fear processing remains unclear. In this study, we employed a randomized, sham-controlled, parallel-group design involving 63 participants (taVNS: n = 33; sham: n = 30) who provided continuous subjective fear ratings (1170 timepoints) while watching a 10-minute fear-inducing video, with simultaneous fNIRS recordings. We employed: (1) a convolutional neural network (CNN) to decode fear ratings from frontal activations, (2) validation of stimulus-evoked activity comparing fNIRS with fMRI signal, (3) dynamic conditional correlation analysis to assess taVNS-induced connectivity changes, and (4) moderation analysis to examine anxiety state effects. Behaviorally, taVNS significantly attenuated fear responses during four threat phases by content analysis: T1 (ghost appearance), T2 (escape sequence), T3 (sudden threat emergence) and T4 (suicide scene). Neurally, taVNS suppressed medial prefrontal cortex (mPFC) activation during escape (T2) and disrupted the typical fear coupling between fear experience and brain activity. Furthermore, taVNS enhanced intra-mPFC functional connectivity, suggesting a potential neural basis for modulating subjective threat appraisal. Additionally, state anxiety significantly moderated brain-behavior relationships. These findings demonstrate that taVNS attenuates fear responses through modulation of mPFC engagement and strengthening frontal network integration. Our results highlight taVNS as a promising neuromodulatory intervention for fear-related disorders (e.g., anxiety disorder), particularly as an early adjunct to exposure-based therapies, warranting further clinical validation.

BackgroundMismatch negativity (MMN) is a component of the auditory event-related potential (ERP) that is elicited during a passive oddball paradigm where task-irrelevant infrequent deviants are presented in a stream of more frequent standard stimuli. MMN is believed to index a pre-attentive stage of auditory information processing closely linked to N-methyl-D-aspartate receptors (NMDAR). Ketamine is thought to act primarily as an NMDAR antagonist, has been used in clinical trials to model the symptoms of schizophrenia and is increasingly used in the clinic to treat depression. Various studies have reported that ketamine reduces MMN amplitude which, in turn, might reflect reduced function of NMDAR-mediated neurotransmission. Nonetheless, there is growing evidence showing MMN amplitude either having high variability or, paradoxically, moving in the opposite direction after ketamine in different individuals. MethodsIn here, we analyzed results from three independent ERP studies to test the hypothesis of a cross-over interaction ("disordinal" drug effect) between the duration-deviant MMN at baseline (without ketamine) and the direction and magnitude of the ketamine effect. To rule out regression to the mean (RTM), a statistical phenomenon that may also partially explain this cross-over interaction, we separately estimated RTM using a drug-free test-retest study. ResultsOur results are the first to statistically demonstrate the existence of a disordinal drug response to ketamine, where the direction and magnitude of ketamine-induced changes in MMN amplitude can be predicted by baseline MMN amplitude. ConclusionsThese new insights may contribute to novel precision medicine approaches to treatment of CNS disorders.

The renin-angiotensin system (RAS), traditionally known for cardiovascular regulation, has increasingly been recognized as a modulator of cognitive and affective functions. However, whether the RAS regulates attentional control and whether such effects are sex-dependent remain unexplored. The present preregistered, randomized, double-blind, placebo-controlled pharmacological eye-tracking study (N = 79) examined the effects of transient angiotensin II type 1 receptor (AT1R) blockade via losartan (50 mg) on emotional attention control using a validated anti-saccade task with social (emotional faces) and non-social stimuli. Treatment effects on state anxiety and oculomotor responses were characterized using traditional performance metrics and a novel trial-history informed dynamic control (TIDC) framework for adaptive control. Losartan reduced state anxiety irrespective of sex and induced sexually dimorphic reconfiguration of attentional processing. In females, AT1R blockade enhanced performance by reducing endpoint error without altering latency. Conversely, in males, losartan increased endpoint error and prolonged latency of the first correct saccade. Trial-history analyses further revealed that losartan reduced error probabilities following error and repeat trials in both sexes. Yet, following correct trials, females receiving losartan maintained lower error probabilities, while males receiving losartan exhibited higher errors, potentially reflecting a failure to flexibly disengage from the effortful controlled mode. Findings indicate that the RAS modulates anxiety and attentional control, the latter in a sexdependent manner. AT1R blockade can reconfigure attentional processing and adaptive control, suggesting sex-specific therapeutic potential in disorders characterized by excessive anxiety and attentional dysregulation.

BackgroundChronic pain is one of the most common reasons for medicinal cannabis use, yet the neural mechanisms underlying cannabis-related modulation of pain remain poorly understood. Both pain and cannabis use independently alter functional connectivity within the brains default mode network (DMN) that modulate interoception and self-referential aspects of pain processing. The goal of this study was to examine the interaction between pain and cannabis use on DMN connectivity. MethodsWe measured DMN resting state fMRI functional connectivity (rsFC), past year pain frequency, and cannabis use measures (i.e., grams per day, days a week, years of regular use) from 119 adults who use cannabis near-daily (68 men; Mage= 22.66, SE= .31). Generalized linear models were used to test the main effects and interactions of pain frequency and cannabis use variables. ResultsResults indicated significant interactions between pain and cannabis use where more frequent pain was (1) negatively associated with weekly use or years of use in l-IPL-PCC and r-IPL-PCC rsFC, (2) whereas it was positively associated with daily grams of cannabis in l-IPL-r-IPL rsFC and r-IPL-PCC rsFC (BH-FDR-corrected p< .05). ConclusionsFirst, these findings demonstrate that pain frequency is a key context shaping the neurobiological correlates of exposure to cannabis. Second, divergent interaction effects suggest that, in the context of more frequent pain, cannabis use may relate to rsFC through distinct neural processes that depend on cumulative vs. proximal effects.

Anhedonia and motivational impairment are central features of major depressive disorder, yet the neural processes linking reward information to sustained goal-directed behaviour remain insufficiently understood. Using functional magnetic resonance imaging, we examined representations of reward levels during sustained effort expenditure (a construct in the RDoc framework) as a distinct component of reward processing in depressive patients under escitalopram treatment. Twenty-eight unmedicated patients with a current depressive episode and forty-three healthy control participants underwent fMRI scanning at two time points three weeks apart; patients started escitalopram immediately after the first measurement. Across participants, sustained effort expenditure engaged midbrain reward circuitry (ventral tegmental area, VTA), even in the absence of immediate reinforcement. A targeted analysis also revealed changes in activity of the dorsal raphe nucleus (DRN) in patients. Increases in VTA activity were associated with improvements in clinician-rated depressive symptoms, whereas self-reported anhedonia remained unchanged. By isolating neural mechanisms supporting sustained goal-directed behaviour, the study identifies novel and clinically relevant imaging phenotypes of reward processing and a potential pathway of escitalopram treatment in depression.