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.

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.

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.

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.

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.

Esketamine is a fast-acting antidepressant drug which induces acute psychoactive effects. The most frequent is a dissociative state which seems unrelated to therapeutic efficacy. Other esketamine-induced effects, including psychedelic-like mystical experiences, have been poorly studied in terms of phenomenology and frequency, and may carry specific therapeutic relevance. In this study, we characterised esketamine-induced mystical experiences in relation with clinical outcomes. We conducted a longitudinal observational study and systematically measured acute subjective effects in patients receiving esketamine for treatment-resistant depression after each administration across the induction phase. A total of 45 patients were included, from two independent centres, totalling 352 esketamine administrations. Principal Component Analysis (PCA) supported the validity of the Mystical Experience Questionnaire (MEQ-30) for assessing esketamine-induced subjective effects, with components recovering dimensions previously validated with classic psychedelics. Mystical experiences (MEQ-30 score above 60) occurred in 58% of patients, with high inter- and intra-individual variability in frequency, intensity, and phenomenology across sessions. Higher mean and peak MEQ scores were associated with greater improvement in Montgomery-Asberg Depression Rating Scale scores from pre- to post-treatment, whereas the intensity of dissociative or other non-mystical effects was not. Positive mood and mystical MEQ dimensions in particular predicted therapeutic outcomes. Baseline spirituality also significantly predicted treatment outcomes and peak MEQ scores in the first week of treatment. These findings add to the growing body of evidence suggesting that psychedelic-like mystical experiences may be associated to therapeutic efficacy, not only in classic psychedelic-assisted therapy, but also in esketamine treatment.

Importance: Conventional repetitive transcranial magnetic stimulation (rTMS) can be ineffective in individuals who have previously failed brain stimulation, ketamine and/or multiple lines of therapies. Modern accelerated rTMS protocols using image-guided targets have not been systematically investigated in these individuals. The goal of this study was to assess the feasibility and efficacy of personalized, connectivity-guided, accelerated intermittent theta-burst stimulation (iTBS) in patients with treatment-resistant depression (TRD) of varying refractoriness. Objective: To assess whether connectivity-guided, accelerated iTBS produces significant reductions in depression severity, and to what extent this benefit extends to ultra treatment-resistant depression (UTRD). Design: This was an open-label feasibility trial of connectivity-guided, accelerated iTBS in patients with TRD. Two distinct groups of participants were recruited from a neurosurgical-psychiatry clinic with UTRD and an interventional psychiatry clinic with TRD. Patients were stratified into a priori treatment-resistance subgroups. Patients received five days of open-label treatment. Outcome measures were collected immediately prior to and after treatment, as well as at 4- and 12-weeks post-treatment. Setting: This trial (NCT05813093) was conducted between November 2023 and July 2025 at Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada. Participants: Patients with major depressive disorder. A total of 96 participants were screened, with 73 meeting eligibility criteria (UTRD=30, TRD=43). One withdrew due to inability to tolerate the baseline MRI, and the other withdrew voluntarily prior to treatment. Intervention: Participants underwent a neuronavigated accelerated iTBS (600 pulses) protocol using personalized left dorsolateral prefrontal cortex (dlPFC) targets derived from functional magnetic resonance imaging (fMRI), comprising eight daily treatments, repeated over five days. Main Outcomes: Primary outcomes were i) change in Hamilton Depression Rating Scale (HAM-D17) from baseline to the end of the fifth day of treatment, and ii) the difference in change in HAM-D17 between UTRD and TRD subgroups. Results: Connectivity-guided fMRI targeting yielded personalized targets clustered around the anterolateral dlPFC. Accelerated iTBS elicited rapid antidepressant effects ({Delta}HAM-D17 -9.01 [SD 6.06], t = -12.45, p < 0.001) regardless of treatment-resistance group ({Delta}HAM-D17 -9.64 [SD 5.94] vs -8.10 [SD 6.12], t = -1.05, p = 0.299), which were sustained up to 12 weeks after treatment. Overall response and remission rates at the end of treatment were 40.8% and 16.9%. Self-report scales revealed broad symptomatic relief outside of core depressive symptoms. Conclusions & Relevance: This study demonstrated that fMRI connectivity-guided, accelerated iTBS induces sustained antidepressant effects and broader psychiatric benefits in patients across the spectrum of TRD. In a cohort unlikely to respond to most antidepressant therapies, connectivity-guided, accelerated iTBS offers a safe, well-tolerated option that can achieve benefit, or when ineffective, allow patients to expeditiously proceed with subsequent therapies than conventional rTMS. Trial Registration: This clinical trial was registered at clinicaltrials.gov with NCT05813093.

Cognitive flexibility, switching behaviour responses to changing task demands, is classically attributed to the prefrontal cortex. Yet thalamocortical circuits involving the mediodorsal thalamus (MD) and thalamic nucleus reuniens (Re) are dysfunctional across a range of neurological conditions with cognitive flexibility deficits. Interventions involving thalamocortical interactions may offer therapeutic benefits. Here we examined the effects of MD or Re bilateral glutamatergic neurotoxic damage in rats on cognitive flexibility using the attentional set-shifting task. Rats must attend to a sensory dimension that reliably predicts reward (intradimensional shift, ID) followed by a shift in attention to a previously irrelevant sensory dimension when contingencies change (extradimensional shift, ED). We found MD rats required more trials to criterion in the ED, while Re rats showed significant impairments on the first of three ID subtasks (ID1) only. Both MD and Re rats required more trials to criterion to complete each subtask than Sham controls. Intraperitoneal noradrenaline (atipamezole 1mg/kg), given 30 minutes prior to the task reduced trials to criterion across all rats, improving cognitive flexibility even after thalamic damage. These findings demonstrate the influence MD and Re contribute to cognitive flexibility and support noradrenergic regulation of thalamocortical circuits as potential therapeutic targets for cognitive flexibility dysfunction.

Objective: Major depressive episodes frequently show limited response to first-line treatments, motivating the search for objective biomarkers. EEG/ECG-based support tools aggregating electrophysiological predictors may guide treatment selection. We examined whether antidepressant treatments concordant with an EEG/ECG-biomarker report were associated with higher response rates. Methods: We retrospectively analyzed adults with ICD-10 depressive disorder or bipolar depression treated with electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), (es)ketamine, or selective serotonin reuptake inhibitors (SSRIs) between 2022 and 2024. Resting-state EEG with simultaneous ECG generated individualized biomarker reports with modality-specific response likelihoods. Treatment chosen by clinical teams was classified as concordant or non-concordant; response was derived from routinely collected clinical scales. Results: Among 153 patients (ECT n=53, rTMS n=48, (es)ketamine n=36, SSRIs n=16), response rates were higher for concordant vs non-concordant treatments: ECT 70% vs 50%, rTMS 30% vs 13%, (es)ketamine 31% vs 10%, and SSRIs 100% vs 11%. Overall, 46% (42/92) of concordant vs. 26% (14/54) of non-concordant patients responded (absolute difference +20 percentage points; relative increase {approx}77%; number needed to treat {approx}5). Conclusion: Concordance with EEG/ECG biomarkers correlated with higher treatment response, warranting confirmation in prospective trials. Significance: EEG/ECG-based decision support may enhance antidepressant treatment response in everyday clinical practice.

Background. Major depressive disorder (MDD) is characterized by altered frontal alpha oscillations. Transcranial alternating current stimulation (tACS) can normalize aberrant oscillations in MDD, yet the daily dynamics of tACS target engagement of alpha oscillations in depression remain unclear. Methods. In a double-blind randomized controlled trial (NCT03994081), 20 participants with MDD received verum or sham 10 Hz tACS (40 min/day, 5 days) targeted to left and right dorsolateral prefrontal cortex (F3/F4). High-density EEG was collected pre/post-stimulation each day to quantify within-session and cumulative changes in alpha power and functional connectivity (wPLI). Results. Verum stimulation produced late-emerging, session-specific alpha power decreases compared to sham, with robust day (D)4 post-pre reductions at both IAF and 10 Hz across frontal and parietal regions (t=-2.42 to -3.82, p<0.05; parietal t=-3.82, pFDR<0.05). Whole-brain topographical analysis confirmed a distinct condition x D4 effect at left prefrontal cortex (t=2.9, pFWE<0.05, cluster permutation). Connectivity changes emerged earlier and more transiently, with D2 bilateral frontal wPLI reductions (t=-2.53, p<0.05). Cumulative analyses (change from D1) showed significant wPLI decreases on D2 and D3 (t=-2.65 and t=-2.46; p<0.05). Exploratory clinical correlations showed that the D4 IAF power decrease was associated with increased reward sensitivity (spearman rho= -0.6, p<0.05, cluster-corrected). Conclusions. Alpha-tACS produced a temporally distinct neural response: an early, transient decrease in functional connectivity on D2, which may have driven a later suppression of left prefrontal alpha power on D4, correlated with clinical and behavioral improvements. These results delineate target engagement and validation mechanisms in a multi-day tACS trial, supporting optimized dosing in future tACS interventions.

Endocannabinoid (eCB) signaling is a key regulator of reward-related dopaminergic signaling, particularly in response to drugs of abuse, such as cocaine. To date, our understanding of this mechanism has primarily been limited to male subjects. Prior work establishes that female cocaine users have more adverse outcomes, and female rats show greater sensitivity to cannabinoid type 1 receptor (CB1R) regulation of cocaine self-administration. Therefore, we hypothesize that female rats exhibit enhanced eCB regulation of cocaine-evoked dopamine (DA). We used in vivo fiber photometry recording of the dopamine biosensor, dLight 1.3b, in the nucleus accumbens medial shell (NAcms) in response to cocaine in male and female rats. Rats were pretreated with cannabinoid-targeting drugs to investigate the effects of CB1R inactivation or augmentation of the eCB 2-AG on cocaine-evoked DA. Our results revealed that CB1R inactivation attenuates cocaine-evoked DA in male and female rats, but females showed enhanced sensitivity for CB1R regulation of cocaine-evoked DA. Cocaine-evoked DA was enhanced by augmenting 2-AG levels, and females again showed increased sensitivity to this manipulation. Finally, females show greater cocaine-evoked DA when in a non-estrous cycle compared to estrous, reinforcing that estrous cycle is a determinant of cocaine-evoked DA. These data indicate that females show enhanced eCB regulation of cocaine-evoked DA signaling, underscoring the importance of sex as a biological variable in our understanding of endocannabinoid regulation of drug reward. HighlightsO_LICB1R inactivation attenuates cocaine-evoked DA in NAcms, preferentially in females C_LIO_LI2-AG augmentation via MAGL inhibition enhances cocaine-evoked DA, with female bias C_LIO_LIEstrous phase modulates the dopamine response to a high dose of cocaine in females C_LIO_LIMale and female rats show similar baseline DA and locomotor responses to cocaine C_LI

Background: Diminished Expression (DE) and Amotivation/Apathy (AA) are widely recognized as two main factors of negative symptoms. This study aimed to 1) examine the longitudinal stability of the DE-AA structure and its variation throughout a 5-year follow-up in people with first-episode psychosis (FEP), and 2) investigate whether DE and AA have distinct predictive value compared with the unitary construct of negative symptoms. Study Design: 227 participants from the EUropean Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) and Genetics and Psychosis (GAP) studies were included at FEP and were followed up 5 years later. One-factor (global negative symptoms), uncorrelated two-factor (DE-AA), and correlated two-factor structures were modelled using confirmatory factor analysis. Regression analyses were applied to examine the associations between these factors and negative symptom trajectories, functioning, and quality-of-life outcomes. Study Results: The correlated two-factor model composed of DE and AA best fitted the data and exhibited 5-year stability. The regression model adjusted for AA accounted for more variance (59.2%) than global negative symptoms (52.8%) in explaining the enduring course of negative symptoms. Baseline AA was the only negative symptom factor that significantly predicted individuals' functional outcome at follow-up (B=-1.76, p=0.037). All negative symptom dimensions negatively predicted employment status, whereas lower educational attainment was primarily related to AA severity at baseline. Conclusions: Our findings support the validity and longitudinal stability of the two-dimensional (DE-AA) approach to negative symptoms in individuals with FEP. AA in particular exhibited distinctive predictive value, underscoring its potential clinical utility for early identification and the development of targeted interventions.

BackgroundTranscranial alternating current stimulation (tACS) is a promising non-pharmacological intervention for major depressive disorder (MDD), but its effects on endogenous alpha oscillatory dynamics and their relationship to clinical improvement remain unclear. MethodsIn this double-blind, sham-controlled randomized clinical trial, 20 adults with MDD received five consecutive days of prefrontal 10 Hz tACS or sham. Resting 128-channel EEG was acquired before stimulation on Day 1 (D1), Day 5 (D5), and two-week follow-up. Changes in alpha power spectral density were quantified at the stimulation frequency (10 Hz) and at each participants individual alpha frequency (IAF), using prefrontal regions of interest and whole-head topographical analyses. Depression severity was assessed using the Hamilton Depression Rating Scale (HDRS-17). ResultsBetween-group comparisons revealed no significant differences in prefrontal alpha power changes at either 10 Hz or IAF during the intervention week or at follow-up, although right prefrontal 10 Hz power showed a trend-level reduction with tACS. In contrast, within the tACS group, greater reductions in prefrontal IAF power were associated with greater HDRS-17 improvement from D1 to follow-up, and early IAF power suppression during the intervention week predicted later symptom improvement. Whole-head analyses identified a posterior cluster of reduced 10 Hz power at follow-up in the tACS group relative to sham, whereas clinically relevant correlations were specific to IAF power and distributed across frontal-central and parietal electrodes. Depression scores improved over time in both groups, with greater reductions in HDRS-17 scores observed in the tACS group. ConclusionsFindings suggest that five days of 10 Hz tACS engages depression-relevant alpha mechanisms, with symptom improvement linked specifically to modulation of alpha power at IAF. Results support personalization of tACS in future trials.

Development of the brain networks is highly vulnerable to stressful events. Early life stress (ELS) has been linked to multifaceted cognitive and emotional deficits in adulthood. Despite a growing body of evidence showing ELS-induced structural and functional changes in the prefrontal cortex (PFC) and basolateral amygdala (BLA), a circuit crucial for emotional processing, our knowledge of the resulting changes in the network dynamics is incomplete. Here, we investigate how maternal separation (MS) affects prefrontal-amygdala network in terms of neuronal avalanches, spatiotemporal clusters of activity, using simultaneous multielectrode recordings in the medial PFC (mPFC) and the BLA of urethane-anaesthetized juvenile (postnatal day (p) 14 - p15) and young adult (p50 - p 60) rats. Firstly, we show that MS leads to an intensified spread of activity within both regions as reflected in the higher mean branching ratios of the avalanches. Next, we demonstrate that most of the avalanches occur locally in one region, however, a small percentage of avalanches has clusters of activity in both regions simultaneously. We show that in MS animals prefrontal clusters followed by activity in the amygdala tend to be larger compared to controls and each event in the mPFC is followed by smaller number of events in the BLA, pointing towards impaired spread of activity from the mPFC to the BLA. Interestingly, avalanche spread from the BLA to the mPFC remains unaffected by MS. Abovementioned effects manifest only in adulthood and, intriguingly, only in males highlighting prolonged developmental and sex-dependent nature of ELS outcome. Significance statementBrain criticality implies that the brain self-organizers towards critical state, characterized by sustained activity propagation reflected in the unitary branching ratios of neuronal avalanches. Here we show how adverse events during early periods of network maturation, namely ELS, can disrupt developmental trajectories of the critical dynamics in the mPFC-BLA circuit in a sex-specific manner. This study broadens our understanding of the critical dynamics emergence in the prefrontal-limbic network and highlights ELS as a potential criticality control parameter.

Perceptual learning is a temporally dynamic process involving the acquisition and integration of sensory information necessary for adaptive decision making. Resolving the neural basis of perceptual learning could uncover new therapeutic targets for schizophrenia and other neurodevelopmental disorders that implicate impaired perceptual acuity. In the present study, we developed a novel touchscreen task which utilizes orientation discrimination to assess visual perceptual learning (VPL) in male and female rats. Based on previous evidence we hypothesised that VPL would depend on inhibitory neurotransmission mediated by {gamma}-amino butyric acid (GABA). Segregating subjects based on poor learning (lower tertile) and good learning (upper tertile) revealed dose-dependent improvements in VPL in poor learners following the administration of a GABA-B agonist (R-baclofen) and an 5 subunit specific GABA-A (GABRA5) positive allosteric modulator (alogabat) administered early in learning. Poor VPL performance was associated with a significant reduction in GABRA5 expression in dorsal regions of the prefrontal cortex (PFC), most notably the prelimbic cortex. Reduced GABRA5 expression in this region was co-localized to somatostatin- and parvalbumin-expressing interneurons. These findings indicate that inter-individual variation in the expression of GABRA5 in selective PFC populations of inhibitory interneurons may determine the speed and acuity of VPL. Based on these findings, interventions that restore GABRA5 signalling in the PFC may hold therapeutic relevance for neuropsychiatric disorders involving deficits in perceptual learning.

Background: Bipolar disorder (BD) is increasingly conceptualized as a heterogeneous condition with a neurodevelopmental phenotype (NDP) identifying a subgroup with early neurodevelopmental vulnerability and poorer clinical outcomes. Sensory processing (SP) abnormalities are a core feature of neurodevelopmental disorders but remain poorly characterized in BD and may reflect underlying neurodevelopmental liability. We examined whether NDP load is associated with specific SP alterations in euthymic BD patients and whether NDP-based stratification explains SP variability better than conventional BD subtype (BD 1/2). Methods: We assessed 102 euthymic BD patients and 45 healthy controls (HC) using the Adolescent/Adult Sensory Profile (AASP). NDP load (0-3) was computed from nine clinical variables grouped into neonatal, comorbidity, and neurodevelopmental clusters; a median split defined BD without NDP (BD) and BD with NDP (BD-ND). Associations between NDP load and AASP quadrants were analyzed using Spearman correlations with FDR correction. Group differences (BD, BD-ND, HC) were assessed using Welch ANOVA and post-hoc tests. Nested and multivariable linear regressions examined whether NDP classification explained SP variance beyond BD subtype, adjusting for age, sex, anxiety, and residual mood symptoms. Results: Higher NDP load correlated with greater low registration (rho=0.35, p<0.001, q=0.004), sensory sensitivity (rho=0.30, p=0.001, q=0.004), and sensation avoiding (rho=0.23, p=0.014, q=0.040), but not sensation seeking. BD-ND showed higher low registration, sensory sensitivity, and sensation avoiding than BD and HC (all qs<0.01). NDP classification explained more SP variance than BD subtype; with robust associations after adjustment. Conclusions: Sensory processing alterations in BD are dimensionally associated with neurodevelopmental load and more accurately captured by NDP-based stratification than diagnostic subtype. SP alterations may represent a transdiagnostic marker of neurodevelopmental liability within BD, supporting biologically informed stratification approaches.

Alzheimers disease (AD) is a neurodegenerative disorder characterised by progressive dementia, brain atrophy, and ultimately death. Using cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) carrying the familial PSEN1 A246E variant, we investigated the temporal relationship between amyloid-{beta} (A{beta}) dysregulation and spontaneous neuronal activity. Multielectrode array recordings from the differentiation day 60 (DD60) to at least DD130 revealed that AD organoids exhibited transient hyperexcitability and hypersynchrony compared with wild-type (WT) controls, followed by a gradual decline in activity. During the enhanced excitability stage, both elevated A{beta}42/40 and A{beta} aggregate size showed positive correlations with the percentage of active electrodes and the global synchrony index (GSI) in AD organoids. These findings indicate that A{beta} dysregulation might contribute to transient network hyperexcitability in early AD. The results also suggest that patient-derived cerebral organoids may serve as a translational model to examine early network dysfunction and inform future investigations of potential A{beta}-induced changes in excitability during the preclinical stages of AD.

BackgroundNegative symptoms are core features of schizophrenia that relate strongly to functional impairment, yet interventions targeting these symptoms remain largely ineffective. Emerging theoretical work highlights how environmental factors may shape and maintain negative symptoms. Although racial disparities in schizophrenia diagnosis among Black Americans are well documented and linked to racial stress and psychosis, the impact of racial stress on negative symptoms has not been examined. This study provides an initial test of a novel theory proposing that racial stress - here measured by racial discrimination - influences negative symptom severity through exacerbation of negative cognitions about the self, particularly defeatist performance beliefs (DPB). Study DesignParticipants diagnosed with schizophrenia-spectrum disorder (SSD) (N = 208; 80 Black, 128 White) completed the Positive and Negative Syndrome Scale (PANSS), the Defeatist Beliefs Scale, and self-report measures of subjective racial and ethnic discrimination (Racial and Ethnic Minority Scale and General Ethnic Discrimination Scale). Relationships among variables were tested using linear regression and mediation analysis. Study ResultsBlack participants exhibited significantly greater total and experiential negative symptoms than White participants with no group difference in DPB. Racial discrimination explained 46% of the relationship between race and negative symptoms. Among Black participants, higher DPB were associated with greater negative symptom severity. Discrimination was positively related to both DPB and negative symptoms. DPB partially mediated the relationship between discrimination and negative symptoms. ConclusionsFindings suggest that racial stress contributes to negative symptom severity via defeatist beliefs among Black individuals, highlighting potential targets for culturally informed interventions.

Stressors are commonly used in rats to induce models of anxiety or depression. The effectiveness of these stressors is often evaluated using specific behavioural tests. In a previous meta-analysis of chronic variable stress (CVS) procedures, we predicted that longer and more intensive stress procedures would result in larger effect sizes in behavioural tests. However, we found that the duration or intensity of CVS procedures did not correlate strongly with the magnitude of the effect sizes reported in behaviouraltests. In that study, we were concerned that the large and unexplained diversity in CVS procedure design, both in terms of duration and the types of stressors used, made it challenging to detect the factors that were influencing effect size. In an effort to address this, we explore here the use of a much simpler stress procedure - chronic restraint stress (CRS) - to study the relationship between the duration of CRS procedures and the effect sizes obtained in subsequent behavioural tests. We searched PubMed for articles using CRS procedures with rats, systematically documented the total duration of restraint, and carried out a meta-analysis of the effect sizes obtained in four behavioural tests: the forced swim test (FST), the sucrose preference test (SPT), the elevated plus maze (EPM) and the open field test (OFT). We found that chronic restraint stress increased immobility in the FST, decreased sucrose preference in the SPT, decreased time spent in the open arms of the EPM but had no effect on time spent in the centre of the OFT. However, the effect sizes in all behavioural tests, except the SPT, were not moderated by the duration of the CRS procedure, indicating that longer CRS procedures are associated with larger effect sizes in the SPT but not in the FST or EPM.