International Journal of Neuropsychopharmacology

The muscarinic acetylcholine receptor 1 (mAChR1, M1) has been identified as a primary target for Alzheimers disease (AD) and better understanding of the receptor biology, especially in regard to biased signalling of the receptor, will allow for the development of improved drugs targeting cholinergic dysfunction in AD. The aim of this study was to determine the contribution of phosphorylation of M1 to the learning and memory (LM) effects of M1 agonism. The contribution of M1 phosphorylation dependent signalling in LM was assessed using the mAChR1 positive allosteric modulator, VU0486846, in a scopolamine (1.5 mg/kg) induced LM deficit model in mice expressing HA-tagged M1 (M1-WT), phosphorylation deficient HA-tagged M1 (M1-PD), or mice deficient in M1 (M1-KO). LM was assessed using a fear conditioning (FC) testing paradigm where context and cued memory retrieval was measured 24 hrs after training and a higher level of freezing indicated intact memory. Results demonstrated that scopolamine induced a significant LM deficit in both context and cued retrieval in M1-WT mice which was partially rescued by VU0486846 confirming a contribution of M1 signalling in LM. The scopolamine induced deficit in contextual retrieval in M1-KO mice was not rescued by VU0486846, which is an M1 selective ligand, while scopolamine did not induce a deficit in cued retrieval in M1-KO mice. In M1-PD mice, scopolamine induced a LM deficit in contextual retrieval, however this was also not rescued by VU0486846 treatment. Similarly to M1-KO animals, M1-PD mice did not display a scopolamine induced deficit in cued retrieval. When freezing responses were compared across strains, M1-PD mice displayed a deficit compared to M1-WT and M1-KO mice in contextual retrieval, while both M1-PD and M1-KO mice displayed a deficit compared to M1-WT mice in cued retrieval. These results demonstrate that although M1 agonism can restore a LM deficit in both contextual and cued testing paradigms, only the cued retrieval response is dependent on the M1. Additionally, biased Gq M1 signalling is not sufficient to restore contextual memory and requires phosphorylation of the receptor. Furthermore, biased M1 signalling results in LM deficits not seen with KO of the receptor. Overall, these results reiterate the importance of considering the bias of ligands when developing M1 agonists for dementia in the future.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental condition characterized by persistent deficits in working memory (WM) and executive control. Dysregulation of the Cyclin-dependent kinase 5 (Cdk5)/p35 signaling pathway has been implicated in ADHD pathophysiology due to its impact on neuronal connectivity and dopamine regulation. Using p35 knockout (p35KO) mice--a validated model exhibiting ADHD-like phenotypes--we investigated sex-specific WM performance, task-related neuronal activation patterns, and responses to acute treatment with methylphenidate (MPH) or fluoxetine (FLX), administered alone or in combination. Under basal conditions, p35KO mice of both sexes exhibited significant WM impairment in the Y-maze test compared with wild type (WT) counterparts, whereas recognition memory remained intact. Analysis of neuronal activation (c-Fos-IR) 90 min after testing revealed region-, sex-, and genotype-dependent alterations. Overall, p35KO animals of both sexes showed reduced c-Fos-IR expression in prefrontal cortical regions, while exhibiting increased c-Fos-IR in hippocampal regions. Acute MPH or FLX treatment improved WM in p35KO males, but this benefit was not observed following combined treatment (MPH+FLX). In contrast, p35KO females showed no WM improvement with any treatment. Notably, WT females exhibited a pronounced decline in WM after exposure to MPH, FLX, or their combination, indicating sex-specific pharmacological sensitivity in healthy animals. These findings support an important role of Cdk5/p35 signaling in the functional engagement of prefrontal and hippocampal networks and demonstrate that pharmacological responses in this ADHD model are strongly influenced by sex and neurobiological background, highlighting the importance of incorporating sex as a biological variable in preclinical and translational ADHD research. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/696253v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@12b4330org.highwire.dtl.DTLVardef@14826c3org.highwire.dtl.DTLVardef@1e8f3d8org.highwire.dtl.DTLVardef@e108a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

The use of neuromodulation techniques for the treatment of alcohol use disorder is receiving increasing attention, especially non-invasive approaches, such as repetitive transcranial magnetic stimulation or transcranial direct current stimulation, while the hypothetical use of electroconvulsive therapy remains unexplored. Given our experience inducing electroconvulsive seizures (ECS) for therapeutic purposes in psychopathology rodent models, we evaluated the role of ECS on reducing the increased voluntary ethanol consumption caused by adolescent ethanol exposure in our validated preclinical model. Rats were treated in adolescence with a binge paradigm of ethanol (2 g/kg, i.p.; 3 rounds of 2 days at 48-h intervals; post-natal day, PND 29-30, PND 33-34 and PND 37-38) or saline. Following persistent withdrawal until adulthood, rats were allowed to: voluntarily drink ethanol (20%) by a two-bottle choice test, for 3 days (PND 80-82); treated with ECS (95 mA for 0.6 s, 100 Hz, pulse width 0.6 ms; ear-clip electrodes) or SHAM for 5 days (PND 86-90); re-exposed to voluntarily ethanol exposure (PND 94-96). Brains were collected on PND 97 to evaluate hippocampal markers of ethanol toxicity and/or treatment response (e.g., NeuroD, NF-L, BDNF and NF-L/BDNF ratio). Our results reproduced the increased voluntary ethanol consumption in adult rats induced by adolescent ethanol exposure and demonstrated that ECS could improve this abuse-prone response. Moreover, we suggested a possible role for BDNF in the beneficial effects induced by ECS, especially reducing the neurotoxic ratio NF-L/BDNF. Overall, we provide preclinical evidence for the potential use of ECS as an efficacious treatment for alcohol use disorder.

BackgroundThe Michigan Freshman Study on Stress and Resilience aims to identify factors that predict the emergence of depression and/or anxiety symptoms in college freshmen. We previously showed that a combination of psychiatric instruments (Affect Score) strongly predicts who will develop such symptoms during the freshman year. Here, we ask: a) Can we replicate the predictive power of the Affect Score in an independent cohort? and b) Can the neuroendocrine profile during the Trier Social Stress Test (TSST) serve as an additional predictor? MethodsA new cohort of subjects (N= 357) was used for Affect Score replication. The TSST study involved 337 subjects (Females 184, Males 153). Self-report questionnaires at the start of the year were used to derive the Affect Score. GAD-7 and PHQ-9 were used to monitor anxiety and depression, respectively. TSST measures involved plasma ACTH and Cortisol and heart rate monitoring. ResultsThe Affect Score proved to be a highly replicable predictor of future depression and anxiety. In the TSST, subjects not currently depressed but who developed depression at another timepoint during the year showed a higher and delayed peak of the CORT response. Female subjects not currently anxious but who developed anxiety at another timepoint had an elevated CORT response throughout the TSST. This hyperresponsiveness was not correlated with Affect Score and was an independent predictor of anxiety. Present addressMichigan Neuroscience Institute, University of Michigan, A. Alfred Taubman Biomedical Science Research Building, Rm 2009, Ann Arbor, MI, 48109-9901, USA Author ContributionsHK performed research, analyzed data, wrote the paper; CAT designed research, performed research, wrote the paper; VM-W designed research, performed research; LG, FL, AO, KA and LW performed research; CS coded and analyzed data; JFL designed research; SJW Jr designed research; HA designed research, wrote the paper. FundingThis work was supported by the Office of Naval Research (ONR) Grant N00014-09-1-0598, N00014-12-1-0366 and N00014-19-1-2149, the Pritzker Neuropsychiatric Disorders Research Consortium Fund, LLC and the Hope for Depression Research Foundation. This project was also supported by Grant Number P30DK020572 (MDRC) from the National Institute of Diabetes and Digestive and Kidney Diseases. Competing interestsThe authors declare no competing interests. ConclusionsThe Affect Score is a powerful predictor of depression and anxiety in college freshmen. The combination of Affect Score and TSST is strongly predictive of anxiety in females.

BackgroundWhile commonly accepted depressive subtypes reflect phenotypic differences, there has been minimal progress in identifying discrete pathophysiological pathways, biomarkers or differential therapeutic approaches which effectively guide clinical management. AimsTo test the biological validity and clinical utility of a circadian subtype of depression on the basis of clinical course, differential medication response (self-reported) and genetic risk profile. MethodsCross-sectional data were drawn from the nationwide, genetically-informative Australian Genetics of Depression Study. Participants were classified as having a "circadian" versus "non-circadian" subtype of depression on the basis of meeting criteria for at least three binary circadian features: social jetlag, seasonality, delayed sleep midpoint, evening chronotype, sleep inertia, and hypersomnia. Clinical course characteristics were compared. Associations with response to commonly prescribed antidepressants and polygenic risk scores (PGS) for mental disorders and sleep, circadian, metabolic and inflammatory traits, were investigated using logistic regression models. Results2,604 participants (23%; 80% females; mean age=37.87{+/-}13.62) had a circadian subtype. These cases reported an earlier age of onset (p<0.001), more severe clinical features including hypo/manic-like and psychotic-like experiences, suicidality, psychological distress and somatic complaints (ps<0.001), weight gain during depressive episodes (p<0.001), poorer response to SSRIs (OR=0.88 [0.82, 0.94]) and SNRIs (OR=0.89 [0.83, 0.97]) and more side-effects, compared to those with a non-circadian subtype. Having a circadian subtype was associated with higher PGS for attention-deficit/hyperactivity disorder (OR=1.11 [1.06, 1.17]), major depression (OR=1.11 [1.06, 1.16]), bipolar disorder (OR=1.09 [1.04, 1.14]), body mass index (OR=1.09 [1.05, 1.14]), triglycerides (OR=1.10 [1.06, 1.16]), interleukin-6 (OR=1.08 [1.03, 1.13]), higher insulin resistance (OR=1.08 [1.04, 1.13]), later sleep midpoint (OR=1.15 [1.10, 1.21]), insomnia (OR=1.08 [1.03, 1.13]), and later chronotype (OR=0.68 [0.65, 0.71]). ConclusionThese findings support the face validity and potential clinical utility of circadian subtype of depression as a clinical profile. Pending independent replication, investigation of its biology and predictive utility are warranted.

BackgroundMajor depressive disorder (MDD) involves immune-metabolic dysregulation, psychosocial adversity, and multidomain cognitive disturbances, yet single cognitive indices often show small and inconsistent effects. We derived a multivariate Cambridge Neuropsychological Test Automated Battery (CANTAB)-based cognitive phenotype ("cognitype") and tested whether it adds explanatory value beyond adverse childhood experiences (ACEs) and an acute-phase protein (APP) index in acute-phase MDD. MethodsEighty-seven acute-phase MDD patients and 40 healthy controls completed CANTAB testing; key outcomes from DMS, RVP, OTS, and ERT were summarized as a cognitype score (PC1). ACEs were assessed, and peripheral inflammatory markers were combined into an APP index. Logistic and multiple regression models tested discrimination between MDD and controls and prediction of multidimensional phenome features (affective, physio-somatic, vegetative, recurrence-related, personality, and suicidality domains). ResultsIndividual CANTAB outcomes showed limited between-group differences after FDR correction, but multivariable models integrating cognitive measures with ACEs and APP robustly discriminated MDD from controls (AUC up to 0.907). The cognitype independently predicted multiple phenome domains when modeled alongside ACEs and APP, and their combined effects explained [~]40-55% of variance across symptom dimensions. ConclusionA data-driven cognitype derived from core CANTAB tasks captures clinically meaningful cognitive variation in acute-phase MDD and contributes significant predictive value beyond psychosocial adversity and inflammatory activation. Integrating cognition, ACEs, and inflammation improves characterization of symptom heterogeneity and supports precision approaches targeting neurocognitive-immune-environmental mechanisms.

New treatments for depression are needed that combine robust efficacy with improved scalability. Although psilocybin has demonstrated antidepressant effects in Phase 3 clinical trials, some of its psychedelic effects limit tolerability, necessitating administration in highly supervised clinical settings, and thus motivating development of serotonergic therapeutics that preserve antidepressant efficacy while reducing the acute psychedelic experience. We combined psilocybin with a phosphodiesterase-9 inhibitor (PDE9i), which raises cyclic GMP levels, and observed substantial reduction in the mouse head twitch response (HTR) -- a proxy for 5-HT2A receptor-mediated psychedelic-like behavior in rodents -- suggesting attenuation of acute psychedelic effects. Significantly, rescue of chronic stress-induced depressive-like behavior by psilocybin was maintained with the coadministration of PDE9i. Proteomic analysis of medial prefrontal cortex (mPFC) synaptosomes showed that the combination of PDE9i and psilocybin enhanced synaptogenesis pathways relative to psilocybin alone, while reducing pathways involved in G protein-coupled receptor (GPCR) signaling. Together, these results suggest that the combination of PDE9i and psilocybin may be a promising direction for psychedelic treatment, and point towards molecular pathways that dissociate acute psychedelic and antidepressant responses.

Numerous studies have shown that adults with depression have distinct oculomotor alterations during saccade tasks, but whether similar alterations occur in adolescents is largely unknown. The purpose of this study was to test if eye-tracking during a structured saccade task could distinguish a group of adolescents with depression from healthy controls. We hypothesized that, due to overlapping circuitry between depression pathology and the oculomotor system, adolescents with depression would show alterations in fixation, saccade, and pupil behaviour. 51 adolescents with depression and 66 age-matched healthy controls completed the Interleaved Pro- and Anti-Saccade Task (IPAST) and several self-reported questionnaires for psychiatric symptoms. Oculomotor outcomes included fixation acquisition, fixation breaks, correct rate, saccadic reaction time, rate of correct express-latency pro-saccades, rate of express- and regular-latency anti-saccade errors, baseline pupil size, as well as pupil constriction and dilation sizes following task instruction. In comparison to healthy controls, adolescents with depression displayed impairments acquiring fixation (p<.001), made more fixation breaks in pro- (p=.023) and anti-saccade trials (p=.005), more anti-saccade errors (p=.013), more express-latency saccades overall (ps=.016), had a smaller pupil constriction in pro-saccade trials (p=.047) and had a smaller pupil dilation in pro- (p=.011) and anti-saccade trials (p=.041). No differences were found for saccadic reaction time, rate of correct pro-saccades, rate of regular-latency anti-saccade errors, pupil constriction size during anti-saccade trials, or baseline pupil size. Patients had psychiatric comorbidities and were using psychotropic medication. While this reflected clinical reality, these factors may have influenced oculomotor behaviour. Adolescents with depression had altered fixation, saccade, and pupil behaviour during IPAST. Given that many cases of adolescent depression remain undetected, accessible and objective screening approaches are highly needed. This oculomotor phenotype may be used in the development of such a screening tool to detect those at risk.

BackgroundAntidepressants exert their therapeutic effects through ameliorating negative emotional biases that underpin depression. However, therapeutic gains may depend upon restructuring how emotional information is processed. This can be achieved through Cognitive Bias Modification (CBM), a technique for positively shifting recognition of emotional facial expressions. Here, we examined how CBM modifies emotional processing circuits in individuals with depression who were taking Selective Serotonin Reuptake Inhibitors (SSRIs). MethodsA double-blind Randomised Controlled Trial was conducted in 84 participants with depression who had recently started SSRI medication. Participants received five sessions of active or sham CBM over one week before fMRI scanning where they viewed emotional faces (happy, fearful, sad). ResultsAcross all emotional expressions, greater Blood Oxygen Level Dependent (BOLD) signal was observed in the inferior occipital gyrus for the active compared to sham CBM. Emotional-specific effects were observed in the medial Prefrontal Cortex (mPFC), with reduced BOLD signal in the active (compared to sham) group for viewing happy vs. fearful faces. Changes in BOLD signal were also associated with individual differences in response to CBM. Enhanced functional connectivity between mPFC and right Dorsolateral Prefrontal Cortex (rDLPFC) predicted improvement in depressive symptoms four weeks later. ConclusionsThese results indicate that CBM modifies the neural circuits involved in emotion processing in people with depression currently taking antidepressants. Converting these changes in emotional perception to improved depressive symptoms was related to changing mPFC-rDLPFC connectivity. Future trials are needed to test CBMs clinical utility as a simple, affordable and accessible adjunct therapy for depression.

Attention-deficit/hyperactivity disorder (ADHD) is a developmental psychiatric disorder associated with a complex interplay of genetic and environmental risk factors. We have shown embryonic dorsal forebrain loss in mice of fibroblast growth factor receptor 2 (Fgfr2), which has a critical role in normal brain development, results in ADHD-relevant phenotypes: increased locomotion and sociability, and impaired working memory postnatally. How such genetic vulnerabilities interact with environmental exposures to translationally model human ADHD risk remains unclear. Here, we pair the embryonic hGFAP-cre Fgfr2 conditional knockout (Fgfr2 cKO) mouse model with prenatal repetitive restraint stress, modeling an environmental factor associated with ADHD risk, to assess adult offspring behaviors and dopamine transporter (DAT) levels. Offspring of prenatally stressed, Fgfr2 cKO mice show increased locomotion (80% compared to non-stressed, Fgfr2 cKO animals). Prenatal stress led to a trend increase in impulsivity and trend decrease in working memory but did not affect sociability. There were no interactions with Fgfr2 cKO observed in these behaviors. Neurobiologically, prenatal stress led to a trend decrease in medial frontal cortex DAT, but these changes did not correlate with behavior. Taken together, our findings implicate prenatal stress as a potential contributor to gene-environment interactions for ADHD risk, supporting its use in translational animal models of childhood psychiatric disorders.

Tobacco use disorder is a chronic condition characterized by compulsive nicotine use, withdrawal, and relapse following abstinence. Impulsivity contributes to persistent nicotine use and poor cessation outcomes. This study examined whether nicotinic acetylcholine receptor (nAChR) modulators alter impulsive action in a nicotine self-administration Go/No-Go task in male and female rats. Rats acquired intravenous nicotine self-administration and were then trained in a Go/No-Go procedure in which active lever presses were reinforced during Go periods but not during No-Go periods. We then assessed the effects of varenicline (0.1-3 mg/kg), nicotine (0.1-0.6 mg/kg), and the nAChR antagonist mecamylamine (0.5-2 mg/kg) in the Go/No-Go procedure. Varenicline and nicotine pretreatment reduced active responding during both Go and No-Go periods, whereas mecamylamine selectively reduced responding during No-Go periods. Mecamylamine decreased the percentage of active responses during No-Go trials, indicating reduced bias toward the nicotine-associated lever. In contrast, nicotine and varenicline did not alter response allocation, suggesting that their effects reflected nonspecific reductions in responding rather than changes in impulsive action. No sex differences were observed. Substituting saline for nicotine during self-administration did not alter active responding during Go periods, but rats in the saline group had fewer active responses during No-Go periods than rats in the nicotine group. These results show that chronic nicotine self-administration increases impulsive action and that nAChR antagonism, but not agonism or partial agonism, reduces nicotine-related impulsive action. This work supports the utility of the Go/No-Go self-administration task for investigating nAChR-dependent mechanisms underlying nicotine-induced impulsivity.

Sex differences in responses to chronic stress are implicated in the higher prevalence of major depression and PTSD in females. Evidence of sex differences in endocannabinoid (eCB) physiology suggests that eCB signaling contributes to sexual disparities in fear conditioning and extinction. In adolescent male Sprague-Dawley rats, exposure to chronic-mild-unpredictable stress (CMS) resulted in enhanced trace-fear conditioning that was reversed by CB1 activation (Reich et al, 2013). In the present study, we assessed the effects of CMS and CB1 activation on hippocampal-dependent trace and contextual fear conditioning in adolescent female Sprague-Dawley rats. CMS exposure enhanced trace freezing behavior during memory recall compared to non-stress controls. This effect was not observed in contextually conditioned females. The CB1 receptor agonist, ACEA (0.1 mg/kg), administered prior to trace memory recall, but not prior to acquisition, significantly decreased freezing in both stress and non-stress females. ACEA significantly reduced baseline freezing behavior during trace memory recall in both stress and non-stress rats, however ACEA either 1) did not affect or 2) impaired short and long-term extinction in stress and non-stress females. In contextually conditioned females, ACEA decreased freezing during memory recall, although the effect was more robust in stress rats. ACEA impaired long-term contextual extinction in stress females while facilitating this in non-stress controls. However, ACEA had no effect or impaired short-term contextual extinction in both stress and non-stress groups. The results demonstrate that CMS enhances hippocampal-dependent episodic fear memories but has limited effects on contextual fear conditioning in female rats. These findings have implications in the use of medical cannabinoid treatment of disorders such as PTSD, as well as recreational cannabis use in adolescent/young adult females.

ObjectiveTobacco and cannabis are the most used substances among individuals at clinical high risk for psychosis (CHR-P), but it remains controversial whether substance use drives symptom exacerbation and psychosis transition, or vice versa. We investigated longitudinal dose-response relationships of tobacco and cannabis use with clinical presentation in a CHR-P population. MethodsData was obtained from the North American Prodrome Longitudinal Study (NAPLS2) CHR-P cohort (n=764). Participants were assessed every 6 months over two years. Substance use frequency, psychiatric symptoms (psychosis, depression, anxiety, and social anxiety), global social and role functioning, and neurocognitive performance were measured. Linear mixed effect models were used to model the relationship between substance use and clinical measurements across visits, and that between baseline use and trajectory of symptoms, functioning, and cognition. ResultsPsychiatric symptoms, functioning, and cognitive performance improved, while tobacco and cannabis use frequency did not change over two years for CHR-P individuals in NAPLS2. Heavier tobacco and cannabis use at current visit predicted worse anxiety at next visit (tobacco: {beta}=0.178, p=0.033; cannabis: {beta}=0.162, p=0.018). Better social functioning predicted heavier tobacco ({beta}=0.178, p<0.001) and cannabis: ({beta}=0.162, p<0.001) use at next visit. We observed a significant baseline cannabis-by-time interaction, where heavier baseline cannabis use predicted slower improvement of negative symptoms ({beta}=0.159, p=0.0017, FDRp=0.0067) and deterioration of role function ({beta}=-0.046, p=0.018). ConclusionsIn CHR-R, current tobacco and cannabis use predicted worse anxiety at future visits. Baseline cannabis use frequency predicts worse clinical trajectory, especially for negative symptoms.

BackgroundCognitive-behavioral therapy (CBT) is a widely used treatment for mental disorders, yet the biological mechanisms underlying its effects, and the factors contributing to response, remain poorly understood. DNA methylation, an epigenetic mechanism shaped by both genetic and environmental factors, may offer insights into individual differences in psychotherapy outcomes. MethodsSaliva samples were collected before treatment, after treatment, and three months post-treatment from individuals with OCD undergoing the Bergen 4-Day Treatment (n = 889). DNA methylation was measured using the Illumina EPIC v02 array, followed by epigenome-wide DNA methylation analyses of CBT response. ResultsWe identified ten differentially methylated regions (DMRs) associated with treatment response at baseline, 23 DMRs showing consistent associations with response across multiple time points, and three DMRs displaying longitudinal methylation changes associated with response. These loci were annotated to genes with roles in neuroplasticity, stress response, immune function, mitochondrial processes, and gene regulation. Baseline and stable methylation signals were largely influenced by genetic variation, whereas all longitudinal associations appeared to be confounded by psychoactive medication use and psychiatric comorbidities. In addition, changes in monocyte and CD4+T cell proportions were associated with treatment response. ConclusionsWe identified DNA methylation markers associated with CBT response in OCD at baseline. Stable methylation patterns associated with treatment response are likely driven by genetic factors. Longitudinal methylation analyses should be interpreted cautiously, as medication and comorbidities can exert substantial effects - even when they remain unchanged over time. Baseline methylation profiles may ultimately help predict treatment outcomes, thereby advancing precision psychiatry.

Deficits in inhibitory control are common across a wide range of psychiatric disorders and are closely linked to symptom severity, including emotional dysregulation, anxiety, substance misuse, and self-harm, making them an appealing target for intervention. Cognitive training offers a low-cost, scalable, and non-invasive strategy to strengthen inhibitory control; however, most existing paradigms target only a single facet of inhibition and rarely account for environmental influences, such as affective context. To address these gaps, we developed a computerized inhibitory control training paradigm to simultaneously engage three components of inhibition: preemptive, proactive, and reactive, while embedding trials within positive and negative affective contexts to assess the impact of emotional stimuli. Across two online experiments, participants completed the GAMBIT task in one session (Experiment 1, N = 300) or repeated over three sessions (Experiment 2, N = 65). The task included No-Go trials to train preemptive inhibition, stop-signal trials for reactive inhibition, and stop-signal anticipation trials to train proactive inhibition. Affective images of differing valence were presented as background stimuli to evaluate their impact on inhibitory performance. In Experiment 1, participants showed higher accuracy on No-Go versus reference Go trials ({beta}=1.45, SE=0.09, p<.001), confirming successful manipulation of preemptive inhibition. Reaction times were slower during anticipation trials across two different conditions ({beta}=0.16, SE=0.04, p<.001; {beta} = 0.07, SE = 0.04, p = 0.047), consistent with proactive slowing when anticipating a potential stop signal. Additionally, positive affective images ({beta} = 0.10, SE= 0.009, p < 0.001) further slowed RTs, indicating emotional interference with proactive control. In Experiment 2, the pattern of higher No-Go accuracy was replicated ({beta} = 0.91, SE = 0.11, p < .001) and accuracy generally improved over sessions ({beta} = 0.38, SE = 0.06, p < .001). In anticipation trials, RTs become shorter across sessions (session 2: {beta} = -0.25, SE = 0.06, p < .001; session 3: {beta} = -0.45, SE = 0.06, p < .001), reflecting practice-related gains, and SSRTs decreased over time (F(2,56) = 6.26, p = .004), consistent with enhanced reactive inhibition. Proactive inhibition was modulated by affective images, with both negative ({beta} = 0.04, SE = 0.02, p = .039) and positive ({beta} = 0.16, SE = 0.02, p < .001) affective images associated with slower RTs. Participants also reported reductions in self-assessed temper control by the last session (W = 25.5, p = .007, q = .037, d = -0.51) and usability ratings were high (all means [&ge;] 3.87/5). Together, these findings show that this paradigm recruits multiple forms of inhibitory control and yields training-related improvements in both performance and affective outcomes. This provides preliminary validation of a scalable, fully online inhibitory control training tool targeting multiple dissociable inhibitory processes within affective contexts. The approach holds promise as an accessible transdiagnostic intervention to support symptom improvement across psychiatric disorders, with future work needed to evaluate clinical efficacy in patient populations.

BackgroundIntermittent theta burst stimulation (iTBS) and H-coil repetitive transcranial magnetic stimulation (rTMS) are FDA-cleared treatments for major depression; yet their comparative effectiveness in treatment-resistant depression (TRD) has not been evaluated in randomized trials. This pilot randomized trial was designed to obtain preliminary comparative estimates and to explore whether baseline cognitive functioning relates to early remission. MethodsTwenty-eight adults with TRD were randomized to six weeks of iTBS delivered to the dorsolateral prefrontal cortex (DLPFC) using a figure-8 coil (n=15) or H-coil rTMS delivered to the dorsomedial prefrontal cortex (DMPFC) using a H7-coil (n=13). The primary outcome was change in 17-item Hamilton Depression Rating Scale (HRSD-17) score from baseline to week 6, analyzed with ANCOVA. Additional outcomes included response, remission, and symptom trajectories through week 18. Exploratory analyses examined the association between baseline cognitive functioning, such as executive functions and memory, and remission. ResultsTwenty-five participants completed all 30 sessions. Adjusted week-6 HRSD-17 scores did not differ between groups (mean difference -0.40, 95% CI -5.23 to 4.43; p=.865). Response rates were 40.0% for iTBS and 50.0% for H-coil (p>.60), and remission rates were identical across groups (20.0%). Remitters showed higher baseline executive functioning than non-remitters in exploratory analyses, although these associations were not confirmed in adjusted models. ConclusionIn this pilot trial, iTBS and H7-coil rTMS showed symptom improvement, with no clear between-group pattern. Exploratory findings suggest a potential signal involving executive functioning that warrants further investigation. These results inform the feasibility and design of larger comparative trials. Trial registrationClinicalTrials.gov (NCT05902312)

Major depressive disorder (MDD) involves dysregulated neuroimmune, metabolic, and oxidative stress (NIMETOX) pathways. Recently, it was shown that NIMETOX pathways should be evaluated in MDD patients stratified for metabolic syndrome (MetS). The current study aims to characterize the metabolic hormone and adipokine profiles of Chinese MDD patients stratified for MetS and to delineate their associations with overall severity of depression (OSOD), suicidal ideation (SI), recurrence of illness (ROI), and physiosomatic symptoms. We enrolled 125 MDD inpatients and 40 healthy controls and measured fasting serum insulin, glucose, glucagon, Glucose-dependent Insulinotropic Polypeptide (GIP), Glucagon-Like Peptide-1 (GLP-1), leptin, secretin, Plasminogen Activator Inhibitor-1 (PAI-1), resistin, ghrelin, and adiponectin, as well as the acute-phase inflammatory (API) response using albumin, transferrin (Tf), and monomeric CRP (mCRP). The results revealed a distinct metabolic hormone and adipokine signature in MDD with significantly lower insulin, glucagon, and PAI-1 levels, alongside an elevated API index (after adjusting for age, MetS, and body mass index). A composite GAP index (ghrelin, adiponectin, PAI-1) correlated negatively with OSOD, SI, ROI, physiosomatic symptoms, and adverse childhood experiences (ACEs). Integrative modeling combining the GAP index, API index, and ACEs achieved an area under the receiver operating characteristic (ROC) curve of 0.864 with an accuracy of 80% for discriminating MDD from controls. In conclusion, the findings delineated that many inpatients with severe MDD suffer from suppressed anabolic hormones and lower adipokine levels coupled with a mild, chronic inflammatory response. The deviations in this "hormonal-immune-metabolic" axis are components of the NIMETOX pathways in MDD and are not associated with MetS.

Adult ADHD is increasingly recognized across the lifespan, yet the psychometric equivalence of the Adult ADHD Self-Report Scale (ASRS) remains unverified for older populations. This study examined age-related Differential Item Functioning (DIF) in 600 adults (n = 100 per decade, ages 20-80) who completed the 18-item ASRS. Using a bi-factor Graded Response Model, we extracted latent ADHD trait scores ({omega}H = .895) and assessed DIF via ordinal logistic regression with adaptive age modeling. Five of 18 items exhibited significant uniform DIF. At equivalent latent severity, older adults were less likely to endorse hyperactivity symptoms in Part A (fidgeting, feeling "driven by a motor") but more likely to endorse specific symptoms in Part B (careless mistakes, misplacing items, interrupting). From ages 20 to 80, expected Part A scores decreased by 1.36 points (~0.27 per decade), while Part B scores increased by 1.15 points (~0.23 per decade). These findings indicate a phenotypic redistribution of ADHD symptoms as individuals age. Because the 6-item Part A screener serves as the primary clinical gatekeeper, its concentration of negative DIF suggests standard screening practice may systematically underestimate ADHD severity in older adults. We recommend using the full 18-item ASRS when screening older populations and suggest that developing age-adjusted norms would improve diagnostic accuracy.

Background and HypothesisSchizophrenia is a disease characterized by various symptoms and has severe lifelong impacts on patients and their families. Despite various hypotheses and associated studies, the key mechanism in schizophrenia is not fully elucidated. In the present study, we focused on adropin, a peptide regulating energy metabolism, antioxidation, and neuroprotection. Study DesignIn both the group of healthy volunteers (HV) and the group of patients with some schizophrenia spectrum and other psychotic disorders (SZ), we evaluated adropin along with other variables such as anthropological factors, psychological well-being indicators, and laboratory test results. Study ResultsThe adropin levels in SZ were not significantly different from those in HV. Correlation analysis indicated five significant correlations beyond various natural correlations arising from fundamental proportional relationships and multifaceted psychological well-being indicators: (1) adropin versus right handgrip strength in the SZ group ({tau} = -0.82, P = 0.066); (2) adropin versus selenium in the total group ({tau} = 0.44, P = 0.053); (3) ferritin versus perceived stress in the total group ({tau} = -0.44, P = 0.053); (4) right versus left handgrip strength in the total group ({tau} = 0.70, P = 0.001) and in the SZ group ({tau} = 0.82, P = 0.075); and (5) selenium versus state anxiety in the total group ({tau} = 0.44, P = 0.053) and the SZ group ({tau} = 0.84, P = 0.066). ConclusionsThe present study provides a foundation for future studies and sheds light on the role of adropin in schizophrenia.

Dopamine (DA) has been implicated in exploration-exploitation behaviour, i.e., exploring novel, potentially better options vs. exploiting known, previously rewarding options. Impairments in this trade-off occur in psychiatric disorders involving DAergic dysfunction, including addiction and schizophrenia. Pharmacological studies revealed a contribution of DA to exploration, but inconsistent findings suggest that interindividual variability in baseline DA may modulate effects. To address this, we investigated the effects of the DA precursor L-DOPA on exploration-exploitation during reinforcement learning in a sample of N = 75 healthy participants (n = 32 women), following a randomised, double-blind, placebo-controlled, pre-registered design (https://osf.io/p2r7u). We assessed whether putative baseline DA markers, including spontaneous eye blink rate, working memory (WM) capacity, and impulsivity, modulated drug effects and probed visual fixation patterns and pupil dilation as markers of exploration. L-DOPA had no overall effect on computational model parameters of random exploration, directed exploration or choice perseveration. WM capacity moderated drug effects on random exploration, with stronger effects at higher WM capacity. Remaining DA proxies showed no credible effects. Pooling the data from male participants with that from an earlier male-only study (Chakroun et al., 2020; total N = 74), L-DOPA increased uncertainty-dependent value weighting and perseveration strength, while decreasing habit updating, indicating a stronger tendency to repeat previous choices and slower decay of their influence over time. No credible drug effects were observed in female participants. Pupil dilation was tonically increased under L-DOPA and scaled with exploration behaviour and prediction error, confirming that pupillometry can index exploration-exploitation dynamics. Visual exploration patterns reflected uncertainty-driven sampling, but were unaffected by L-DOPA. Taken together, results suggest that DAergic modulation of exploration and perseveration behaviour may be contingent on cognitive capacity and sex, rather than exerting uniform effects across individuals.