Progress in Neuro-Psychopharmacology and Biological Psychiatry

Despite extensive epigenetic reprogramming, induced pluripotent stem cells (iPSC) from schizophrenia patients (SZ) retain several molecular and functional features of this disease. Transcriptomic and epigenomic analyses were performed in iPSC of SZ and healthy control subjects (HC). Transcriptional profiles were largely similar between SZ and HC iPSC, whereas pronounced differences emerged following neural differentiation, with SZ NSC exhibiting dysregulation of genes involved in neurodevelopment and synaptic function. ZNF5c0 was identified as a uniquely and consistently upregulated gene in SZ iPSC, robustly discriminating SZ from HC iPSC. Epigenomic profiling revealed increased chromatin accessibility and reduced DNA methylation at the ZNF5c0 promoter in SZ iPSC. ChIP-seq data suggested that ZNF560 can bind to promoters of genes implicated in synaptic signaling and neuronal development. Moreover, a subset of these genes was found to be differentially expressed in SZ neural stem cells. Together, our results identify ZNF5c0 as a reprogramming-resistant epigenetic marker of schizophrenia and suggest an altered KRAB-ZNF-mediated regulation in early neurodevelopmental pathways underlying this disorder.

The social anxiety disorder (SAD) is one of the most common mental health disorders, often developing in adolescence. It can severely impair educational achievement, career progression, and social functioning. Certain individuals within the Chinese Kunming dog (CKD) population display spontaneous, SAD-like behaviors towards strangers, offering a valuable model for genetic investigation. Using whole-genome sequencing data, we conducted a genome-wide association study on this SAD-like behavior in 100 CKDs, identifying several genes previously linked to human psychiatric disorders. Notably, SLC6A3 reached genome-wide significance, whereas CADPS2 exceeded only the suggestive threshold and is therefore considered a network-supported candidate locus. By integrating weighted gene co-expression network analysis with public RNA-seq data from the VTA of 38 mice (after quality control), we further showed that Slc6a3 and Cadps2 are part of a co-expression network module associated with the dopamine system. These findings suggest that this specific module may play a functional role in the stranger-directed anxiety-related behaviours in CKDs. Furthermore, we identified Nrip3 as a key candidate transcriptional coregulator in this specific module. Subsequent virus-mediated overexpression and behavioural experiments showed that Nrip3 regulates gene expression within this network and induces a spectrum of behavioural alterations in mice, including social avoidance, anhedonia, and increased locomotor activity. Collectively, this study highlights the involvement of dopamine system genes in canine social anxiety and suggests Nrip3 as an upstream regulator of Slc6a3 associated with anxiety. The identification of conserved anxiety-related signatures between humans and dogs further supports the dog as a valuable translational model for psychiatric research.

Background: Substance use disorders (SUDs) remain common worldwide and inadequately treated. Neuromodulation targets neural circuits involved in reward, craving, and cognitive control. However, the primary research literature has not been systematically mapped regarding the relative contributions of clinical and preclinical studies. Methods: We conducted a multi-database bibliometric analysis of primary studies on neuromodulation for SUD. Web of Science, Scopus, and PubMed were searched covering 2000-2025. After scope classification and exclusion of secondary literature, 810 primary research documents remained. Performance analysis and science mapping were performed with bibliometrix and VOSviewer. Results: Scientific output grew at a compound annual growth rate of 14.16% (2001-2025), accelerating after 2015. Of 810 studies, 82.8% were clinical, 12.5% preclinical, and 4.7% mixed/translational. Alcohol (31.5%) and nicotine/tobacco (25.7%) dominated the literature and were overwhelmingly clinical (>92%), whereas cocaine and opioids retained larger preclinical shares (24-27%). Repetitive transcranial magnetic stimulation (rTMS) was the leading modality (31.6%), followed by deep brain stimulation (24.9%) and transcranial direct current stimulation (24.2%). Keyword co-occurrence revealed three clusters: a clinical neuromodulation core, a nicotine/tobacco axis, and a preclinical reward-circuitry module. The United States and China led in output. Conclusions: Neuromodulation research for SUD is expanding rapidly and is heavily skewed toward clinical investigations. A persistent clinical-preclinical asymmetry and limited explicitly translational work constitute structural features of the field. Greater integration between mechanistic and clinical research is needed to advance definitive trials.

Animals experience stressors in a variety of contexts that result in activation of neuroendocrine and cellular stress responses. Release of stress hormones can disrupt or restore redox homeostasis, and the resulting changes in oxidative states, physiology and behavior vary by an individuals stress coping style. However, oxidative stress can also directly modulate neuroendocrine stress signaling. To what extent individual differences in brain antioxidant levels alter behavioral stress levels is not well understood. The present study investigated how N-acetylcysteine amide (NACA), an antioxidant and glutamate-modulating compound, regulates stress behavior across zebrafish (Danio rerio) with different stress coping styles (proactive, reactive). Following 24-hour exposure to NACA or control conditions, we quantified individual and composite stress behaviors using a Light-Dark Test (LDT). As expected, both proactive fish and NACA-treated fish showed significantly lower stress behaviors compared to reactive and control animals, respectively. Notably, stress-reducing effects of NACA were only seen in those with a reactive stress coping style. Overall, our data suggest that antioxidant mechanisms (e.g., glutathione system) may be key in facilitating the distinct behavioral and physiological responses to stressors that characterize alternative stress coping styles. The results underscore how individual differences in stress coping style and redox state can influence behavioral responses to stress.

RationalePsychedelic compounds such as psilocybin have attracted growing interest for their potential therapeutic effects in psychiatric disorders, with improvements in cognitive flexibility proposed as a possible mechanism of action. However, the effects of psychedelics on cognitive flexibility remain poorly understood. ObjectiveThis study aimed to examine the acute and post-acute effects of psilocybin (0.1, 0.3, 1 mg/kg) and lysergic acid diethylamide (LSD, (0.02, 0.04, 0.08 mg/kg) on cognitive flexibility in male rats. MethodsThis was tested using two variants of the probabilistic reversal learning task (PRLT): a touchscreen-based operant task and a more ethological foraging-based task. ResultsIn the touchscreen PRLT, acute psilocybin disrupted task engagement, with animals completing fewer trials and showing increased trial initiation latency, although psilocybin also showed a trend toward faster initial rule acquisition. However, psilocybin did not significantly alter the number of rule changes achieved, a canonical measure of cognitive flexibility, or feedback sensitivity. LSD similarly produced limited acute effects, although the highest dose reduced lose-shift probability, suggesting decreased sensitivity to negative feedback under some conditions. Post-acute effects of psilocybin were minimal in both PRLT variants and, where LSD effects were observed these occurred across different doses and timepoints without a consistent pattern. ConclusionsOverall, these findings suggest that serotonergic psychedelics do not robustly enhance reversal learning in these paradigms and that apparent learning effects may reflect transient disruptions in task engagement rather than improvements in cognitive flexibility. These results also highlight potential limitations of these PRLT paradigms for detecting psychedelic-induced changes in cognitive flexibility in rodents.

Background. Serotonergic psychedelics show promise for treating psychiatric disorders, with symptom improvements lasting for weeks after a single dose. Clarifying the neural basis of these effects would benefit from an identification of empirical biomarkers of such lasting shifts in brain function. Resting state EEG offers a rapid (<5 minute), low-cost window into functional brain networks. However, connectivity is not static, but cycles between recurring semi-stable patterns that vary across frequency bands. Here we employed a dynamic function connectivity (dFC) framework to identify frequency-specific connectivity states and examine how they change in the weeks following psychedelic use. Methods. We collected resting-state EEG from individuals who had used one of two serotonergic psychedelic subclasses within the prior three weeks, psilocybin/LSD (typical; n=14) or 5-MeO-DMT (atypical; n=12), and age- and sex-matched controls (n=16). Frequency-band-specific spatial connectivity states (phase-lag index) were estimated across the full sample (5 per band). Groups were compared on proportion and dwell-time (per state) and state-to-state transitions. Results. A right frontoparietally-distributed beta synchrony state was dominant after both typical and atypical psychedelics use (proportion/dwell-time). This effect correlated with the number of days since using psychedelics. A globally-distributed theta-band state was prominent in recent users of typical psychedelics but occurred less often in atypical users. In contrast, neural entropy (Lempel-Ziv complexity; known to increase acutely during psychedelic dosing) was not altered in recent users of either subclass. Conclusion. These results reveal a beta-band signature of altered neural dynamics in the week following a psychedelic dose, consistent with a relaxation of brain network hierarchy after psychedelics.

Stress-related experiences alter glutamatergic signaling and neuronal excitability, but the mechanisms that couple experience to dentate granule cell function remain incompletely understood. Here, we examined how protein kinase N1a (PKN1a), a protein kinase C-like serine/threonine kinase, and repeated swim exposure regulate mouse hippocampal dentate granule cell excitability, with a focus on the neuronal glutamate transporter excitatory amino acid transporter 3 (EAAT3) and group I metabotropic glutamate receptors (mGluRs). Five days of repeated swim exposure increased spike firing in mature dentate granule cells from wild-type mice. PKN1a knockout produced a similar increase, and repeated swim did not further enhance firing in knockout mice. The enhanced firing observed after repeated swim exposure and in PKN1a knockout mice was reduced by co-application of an mGluR1 antagonist (LY367385) and an mGluR5 antagonist (MPEP). Inhibition of glutamate transporters with DL-TBOA increased granule cell firing in control wild-type mice but did not further increase firing in repeated-swim wild-type or PKN1a knockout mice, suggesting occlusion of transporter-dependent regulation of excitability. Repeated swim exposure and PKN1a knockout also reduced total and surface expression of EAAT3 in the hippocampus, whereas expression of the glial glutamate transporter EAAT2 was not significantly altered. Finally, PKN1a knockout and repeated swim exposure reduced anxiety-related behavior in the elevated plus maze test. Thus, PKN1a-dependent regulation of EAAT3 may restrain group I mGluR-dependent excitability in dentate granule cells, whereas repeated swim exposure and PKN1a knockout shift this system toward a lower-EAAT3, higher-excitability state accompanied by reduced anxiety-related behavior.

Post-traumatic stress disorder (PTSD) is a highly prevalent, debilitating psychiatric condition. Existing treatments are ineffective for many patients. 3,4- methylenedioxymethamphetamine (MDMA)-assisted psychotherapy has demonstrated substantial clinical efficacy but relies on prolonged, resource-intensive therapeutic protocols that limit scalability and accessibility. Here, we investigated whether combining MDMA with exposure-based intervention could enhance therapeutic efficiency in a preclinical model of PTSD-like behavior. Using a learned helplessness paradigm in mice, we identified trauma-susceptible individuals based on persistent escape failures following inescapable stress. Traumatised mice subsequently received brief treatment regimens consisting of MDMA or saline vehicle administered with or without exposure to the traumatic cue. Behavioral outcomes were tracked longitudinally using active avoidance performance as the primary endpoint, complemented by assays of anxiety- like, depressive-like, cognitive, and social behaviors. MDMA treatment markedly reduced trauma-associated behavioral deficits. MDMA combined with exposure produced rapid and sustained recovery compared to control conditions. Statistical analyses revealed significant treatment- and time-dependent effects on avoidance behavior, indicating accelerated resilience acquisition in MDMA-treated groups. Additional behavioral assays demonstrated dose-dependent effects of MDMA on anxiety- and depression-related measures. Together, these findings provide proof-of-principle that pharmacological modulation with MDMA can enhance exposure-driven behavioral recovery, supporting a strategy to integrate MDMA into more efficient and accessible PTSD treatment frameworks. This work establishes a preclinical foundation for clinical studies aimed at optimizing MDMA-assisted interventions to improve scalability and patient access.

BackgroundConcurrent cocaine and alcohol use is one of the most prevalent forms of polysubstance consumption and is associated with poorer clinical outcomes than cocaine use alone. However, the regional molecular adaptations induced by combined exposure remain poorly understood. Here, we used matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) to characterize peptide/protein alterations in addiction-related brain regions following cocaine and cocaine-alcohol self-administration. MethodsYoung adult male and female Wistar rats underwent intravenous self-administration of saline, cocaine (1 mg/kg/infusion) or cocaine plus ethanol (1 mg/kg cocaine and 133 mg/kg ethanol per infusion), followed by extinction of drug-seeking behaviour. Coronal brain sections containing the anterior cingulate cortex (ACC) and ventral hippocampus (vHPC) were analysed by MALDI-IMS. Differential molecular features were identified using an exploratory statistical approach (FDR q < 0.20) and subsequently subjected to MS/MS analysis. ResultsThe ACC exhibited a substantially greater number of treatment-associated molecular alterations than the vHPC, suggesting a higher regional susceptibility to cocaine-induced molecular remodelling. Several molecular features were shared between the cocaine and cocaine-alcohol groups, indicating persistent cocaine-driven neuroadaptations. In contrast, additional signals were selectively associated with combined cocaine-alcohol exposure, while others present after cocaine alone were absent following alcohol co-exposure, supporting a modulatory effect of alcohol on specific cocaine-induced molecular responses. Overall, combined exposure generated a distinct regional molecular profile rather than simply reproducing the effects of cocaine alone. ConclusionsThis exploratory study demonstrates that MALDI-IMS enables the identification of region-specific peptide/protein alterations associated with cocaine and cocaine-alcohol exposure while preserving their spatial distribution within the brain. These findings highlight the ACC as a particularly responsive region and provide a framework for future studies aimed at validating molecular pathways involved in cocaine-alcohol polysubstance use.

BackgroundSocial dysfunction is a major source of disability in schizophrenia, yet the neural mechanisms that contribute to impaired social understanding remain poorly understood. Converging evidence points to the role of the default mode network (DMN) in integrating social information over time to construct interpretations of social behaviors. Here, we tested the hypothesis that individuals with schizophrenia show reduced stimulus-driven coordination between brain regions within the DMN during free viewing of naturalistic social stimuli. MethodsA sample of 124 adults (schizophrenia: n=63; healthy controls: n=61) viewed naturalistic video clips during fMRI. Inter-subject functional connectivity (ISFC) was computed within the two groups. Group differences were identified via permutation testing. We also explored group differences in other brain networks to examine whether effects were specific to the DMN. ResultsIndividuals with schizophrenia showed weaker stimulus-driven coupling within the DMN compared to healthy controls, specifically between areas such as the parahippocampal gyrus, precuneus, and medial prefrontal cortex. Group differences in ISFC were specific to the DMN. Furthermore, no between-group differences emerged for within-participant functional connectivity in the DMN, suggesting that the observed effects reflect reduced stimulus-driven coordination among DMN regions when processing social stimuli rather than a more general decline in DMN connectivity. ConclusionsSchizophrenia is characterized by impaired coordination within the DMN as it dynamically integrates social information over time, which could contribute to difficulties in constructing coherent interpretations of real-world social situations. These findings suggest that disrupted stimulus-driven network coordination might underlie social cognitive impairments in schizophrenia, highlighting the value of naturalistic paradigms for revealing network-level dysfunction under conditions that closely approximate real-world experience.

Background Children of parents with schizophrenia (SZ) or bipolar disorder (BP) show elevated rates of mental disorders. Longitudinal studies comparing offspring at familial risk with the background population are lacking. Method This study is an eight-year follow-up of the Danish High Risk and Resilience study. We examined four-year prevalence from age 11 to age15 (n=416), cumulative incidence by age 15 (n=516), persistency of mental disorders from age 11to age 15 (n=396) and global functioning in 15-year-old adolescents with familial high risk of SZ (FHR-SZ) or BP (FHR-BP) compared to population-based controls (PBC). We assessed mental disorders and global functioning with the Kiddie Schedule for Affective Disorders and Schizophrenia - Present and Lifetime Version (K-SADS-PL) and the Childrens Global Assessment Scale (CGAS). Results Four-year prevalence of any mental disorder was higher in FHR-SZ (51.3%, OR=2.39, 95% CI 1.49-3.83) and FHR-BP (45.9%, OR=1.98, 95% CI 1.16-3.37) compared with PBC (30.5%). Cumulative incidence of mental disorders by age 15 was higher in FHR-SZ (67.2%, OR=3.19, 95% CI 2.11-4.82) and FHR-BP (64.4%, OR=2.82, 95% CI 1.75-4.54) than in PBC (39.1%). Adolescents with FHR-SZ showed the highest rate of persistent mental disorders (33.3%), followed by FHR-BP (24.5%), and PBC the lowest (12.9%). Global functioning at age 15 was lower in FHR-SZ than in both FHR-BP and PBC, and FHR-BP showed lower scores compared with PBC. Between-group differences in cumulative incidences of mental disorders and in global functioning scores remained stable across ages 7,11 and 15. Conclusion Adolescents at FHR-SZ or FHR-BP show elevated risks of a range of mental disorders, psychiatric comorbidity, and lower global functioning from childhood to mid-adolescence, not confined to the disorders for which they carry familial risk. This vulnerability underscores the need for early detection and support for FHR offspring and their families.

Objective: This study examined the prevalence of psychotic experiences (PE) and how early onset and persistence of PE contribute to risk and severity of mental disorders in adolescents at familial high-risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) and adolescents from a population-based control group (PBC). Methods: This is the second follow-up of a nationwide cohort study including 522 children at FHR-SZ (N=202), FHR-BP (N=120), and PBC (N=200). Participants were assessed at ages 7, 11, and 15 using a semi-structured interview to evaluate PE and mental disorders. Results: At age 15, adolescents at FHR-SZ reported more PE than PBC over the past six months (current) and the past four years, while adolescents at FHR-BP only reported more current PE. PE reported at two or three timepoints (persistent PE) predicted any Axis I disorder in mid-adolescence, corresponding to three- (OR 2.9, 95% CI [1.5-5.7]) and 21-fold (OR 21.4, 95% CI [2.8-162.3]) increased risks, respectively. Persistent PE also predicted multimorbidity, with three- (OR 2.8, 95% CI [1.0-7.6]) and four-fold (OR 4.1, 95% CI [1.2-14.1]) increased risks, respectively. This was after adjustment for sex, early mental disorders, and familial risk. Conclusions: This study demonstrates a strong link between persistent PE and mid-adolescence mental disorders. Our findings emphasize PE as important risk markers for mental disorders during mid-adolescence and highlight the importance of monitoring children with PE before age 7 who develop persistent symptoms.

BackgroundHigh-frequency heart-rate variability (HF-HRV) is a downstream marker of cortico-autonomic regulation linked to executive function. A recent proposal suggests it indexes regulatory processes because it is both a product of and contributor to neural organization within the prefrontal cortex. The oscillatory phase of HF-HRV has been reported to modulate fronto-central EEG amplitude at rest, and this coupling is attenuated in individuals with schizophrenia relative to healthy controls. We evaluated this brain-body correspondence in relation to anxiety symptomatology, which is likewise associated with autonomic dysregulation. MethodsConcurrent EEG and electrocardiography (ECG) were recorded in 22 nonclinical adults at rest and during a mental arithmetic task. Participants rated anxiety severity using the Generalized Anxiety Disorder 7-item scale (GAD-7). We evaluated between-person associations between anxiety severity and HF-HRV-EEG coupling, as well as within-person differences in coupling between rest and mental arithmetic. ResultsAnxiety symptomatology was associated with decreased resting-state phase-amplitude coupling between HF-HRV phase and fronto-central theta amplitude, independent of EEG and HRV covariates. Relative to rest, HF-HRV-theta coupling increased during a cognitive task, independent of condition-related changes in EEG, HR, or respiration. Anxiety severity moderated the task-evoked changes in heart-brain coupling such that more anxious individuals exhibited larger condition-related differences. Simple-slope analyses indicated anxietys effect on coupling at rest was absent when engaged in a task. ConclusionsHF-HRV-theta phase-amplitude coupling captured anxiety-related and state-dependent variance not evident in conventional cardiac or neural indices. This coupling may index a state-sensitive component of cortico-autonomic regulation, although its putative functional role requires direct testing.

Behavioral test batteries are increasingly used to characterize multiple functional domains in zebrafish, yet the potential impact of test sequence on behavioral outcomes remains poorly defined. Here, we systematically evaluated whether test order influences behavioral responses in a three-assay battery comprising the novel tank test (NTT), mirror-induced aggression (MIA), and social preference (SP) test. Adult zebrafish (Danio rerio) were exposed to all possible permutations of the three assays in a fully counterbalanced design, allowing assessment of order effects across locomotor, anxiety-like, aggression-related, and social behaviors. Test order produced modest and parameter-specific effects, primarily affecting locomotor activity in the NTT and social proximity in the SP assay. Time-course analysis revealed within-test behavioral dynamics, with limited evidence that test order modulates early adaptation or late engagement with the testing environment but does not alter overall temporal response profiles. Sex-dependent effects were assay-specific and most pronounced in the NTT, with no consistent sex differences observed in MIA or SP. To evaluate the global structure of behavioral variation, Principal Component Analysis (PCA) was performed across assays. Despite localized effects of test order, no clear multivariate separation between test sequences was observed, indicating that sequential testing does not produce distinct baseline phenotypes. Together, these findings support the robustness and reproducibility of multidomain behavioral batteries while highlighting the importance of standardized test-order reporting to improve cross-study comparability.

Valproic acid/sodium valproate (VPA) is a widely prescribed anticonvulsant and has also been used against certain tumor cells. It is a potent modulator of gene expression. Its ability to induce apoptosis has been well documented in HeLa cells. However, another form of cell death - mitotic catastrophe - has not yet been explored in VPA-treated HeLa cells. Here, we investigated the effects of VPA treatment on mitotic catastrophe characteristics, including morphological features and their frequencies, fluorescence intensity signals of caspase-2 and p53, and the expression and abundance of DNMT1 and DNMT3B. An increased frequency of mitotic catastrophe was observed not only morphologically, but also through enhanced induction of caspase-2, involvement of p53, at least under more drastic VPA treatment, but without a decrease in DNMT1 or DNMT3B levels. Additionally, enhancement of mitotic catastrophe coincided with a reduction in mitotic chromosome abnormalities. Increased DNMT3B expression following VPA action, may be favored by previously reported chromatin decondensation induced by this drug. Enhanced CpG methylation of specific DNA sites could thus be promoted. In conclusion, VPA was shown to trigger metabolic pathways linked to different forms of cell death in HeLa cells, supporting its oncosuppressive potential.

The cerebellar nuclei (CN) has demonstrated its influence on cognitive behavior via the cerebello-cortico circuit, yet the role of CN critical period mechanisms and how they may influence cognitive behavior, such as parvalbumin (PV) expressing interneurons enwrapped by perineuronal nets (PNNs), is still unclear. Therefore, we investigated the role of the lateral CN (LCN) PV cell calcium activity while animals performed a visual discrimination touchscreen cognitive task. All animals received the PV cell calcium indicator GCaMP6f at postnatal day 21 (P21). We targeted the LCN critical period by manipulating neural activity in male mice using the inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) from postnatal day 21 to 35 or by injecting an Hapln1-AAV vector to selectively target LCN PNN development. After animals completed the visual discrimination task, cerebellar tissue was collected for viral recovery and antibody staining for PNN components, Hapln1 and aggrecan. Results revealed DREADD animals showed improved reversal learning, an increase in calcium response to learning-related activity and altered PNN expression (Hapln1 and aggrecan). Hapln1 treated animals displayed a decrease in final day acquisition performance, lower reversal performance compared to DREADD groups, a decrease in reversal calcium learning-related activity, and an increase in PNN expression (Hapln1). Together, these data provide further evidence of LCN mechanisms associated with learning as well as the importance of understanding region-specific critical periods of plasticity.

Background: Individuals receiving buprenorphine treatment for opioid use disorder (OUD) remain at high risk for treatment discontinuation and return to opioid use. Transcranial magnetic stimulation (TMS) has shown efficacy in reducing craving and substance use in other substance use disorders, but its application in OUD remains limited and the neural mechanism underlying its therapeutic effects is poorly understood. Determining the feasibility and generalizability of TMS in patients receiving buprenorphine - the most commonly prescribed medication for OUD - is therefore critical. This protocol aims to address these issues in a clinical trial of weekly TMS sessions for OUD. Methods: We will enroll up to 120 individuals with OUD taking buprenorphine in a randomized, single-blind, sham-controlled trial of left dorsolateral prefrontal cortex (DLPFC)-targeted intermittent theta burst stimulation (iTBS). Participants will receive active or sham iTBS weekly (2 sessions of 1800 pulses each applied once per week x 8 weeks, 16 sessions total) with pre- and post-iTBS assessments (10, 12, 20 weeks) of craving, opioid use, and treatment retention. A subset of individuals will undergo optional pre- and post-iTBS neuroimaging. The study will be conducted at an academic medical center and a private outpatient TMS clinic. Aims: Our primary aim is to determine whether 16 sessions of active iTBS applied to the left DLPFC results in reduced craving and opioid use, and higher treatment retention, relative to sham. In a secondary aim, we will also examine whether iTBS-related changes in craving are associated with changes in functional connectivity between the left DLPFC and both the dorsal striatum and anterior cingulate cortex. Discussion: By evaluating the feasibility and efficacy of a weekly TMS protocol that aligns with routine care and focuses on patients maintained on buprenorphine, this study addresses key limitations of prior TMS research in OUD. Furthermore, the inclusion of neuroimaging will help characterize the neural mechanisms underlying TMS-related changes in craving. Trial registration: This clinical trial is registered at ClinicalTrials.Gov; ID NCT07457489; date of registration: 03/02/2026.

Cannabis is the most common illicit drug abused worldwide, and its consumption has substantially increased among pregnant women. We previously demonstrated that male preadolescent offspring prenatally exposed to {Delta}9-tetrahydrocannabinol (THC), a model of prenatal cannabinoid exposure (PCE), exhibit a mesolimbic dopamine (DA) neuron dysfunction contributing to at-risk psychotic-like (endo)phenotypes that are unmasked by acute THC exposure at preadolescence. Dysregulation of mesocortical DA signaling along with prefrontal cortex (PFC) function is also a central feature of psychotic disorders. Furthermore, studies investigating the impact of PCE on PFC in the offspring at preadolescence, a window of heightened plasticity and vulnerability, are limited. To fill this gap, we applied a multiscale analysis of mesocortical DA transmission and PFC function in PCE preadolescent offspring by integrating behavioral, neurochemical, electrophysiological, and molecular approaches. PCE enhanced spontaneous repetitive behaviors in a male-specific manner. PCE also abolished sex differences in the intrinsic excitability of PFC pyramidal neurons and Netrin-1 expression. In addition, PCE altered the expression of genes associated with endocannabinoid signaling without changing basal and THC-induced extracellular levels of DA in the PFC. Collectively, these findings demonstrate that prenatal THC exposure disrupts both proper maturation and sexual differentiation of PFC circuitry, thus extending the impact of PCE from previously described mesolimbic abnormalities to mesocortical pathway. Finally, our data identify early cortical molecular and cellular alterations that may contribute to neuropsychiatric vulnerability later in life. Highlights* Preadolescent male rats exposed in utero to THC display repetitive behavior * Prenatal cannabinoid exposure (PCE) does not alter dopamine transmission in the PFC * PCE potentiates AMPA-mediated transmission in male pyramidal cells * PCE abolishes sex differences in Netrin-1 expression levels in the PFC

Objective: Disruption of the excitation/inhibition balance may contribute to the pathophysiology of bipolar disorder, with post-mortem studies reporting abnormalities in GABA-receptors, interneurons and inhibitory signaling in prefrontal areas. Transcranial magnetic stimulation with electroencephalography (TMS-EEG) enables in vivo assessment of cortical excitability/inhibition. This study examined short-latency intracortical inhibition (SICI) after left- and right-dorsolateral prefrontal cortex (DLPFC) stimulation in bipolar depression (BDep, n=10) and healthy controls (HC, n=22). Methods: SICI (paired-pulse TMS) and excitability (single-pulse TMS) were quantified using local- and global-mean-field-power. Associations with lithium use and between-group differences in TMS-evoked potential amplitudes were also explored. Results: For left-DLPFC stimulation, BDep showed weaker SICI than HC (local: 3.7%{+/-}12.5 vs 9.0%{+/-}20.3, p=0.05; global: 1.5%{+/-}11.7 vs 8.8%{+/-}20.6, p=0.10), driven by larger ppTMS responses (weaker inhibition). For right-DLPFC stimulation, BDep showed stronger SICI than HC (local: 17.3%{+/-}16.1 vs 0.75%{+/-}27.1, p=0.36; global: 16.2%{+/-}14.6 vs -1.0%{+/-}21.8, p=0.03), driven by a larger spTMS response (enlarged excitability). Stronger right-hemispheric global-SICI was most pronounced in BDep patients not using lithium (17.9%{+/-}7.0) vs lithium users (3.9%{+/-}11.9) and HC (pFDR=0.03). Conclusions: BDep is characterized by reduced cortical inhibition after left DLPFC stimulation and enlarged cortical excitability after right DLPFC stimulation; the latter partly normalized by lithium. Significance: To our knowledge, this is the first study to apply TMS-EEG to the bilateral DLPFC in BDep, revealing distinct patterns of hemispheric dysfunction. These findings warrant replication in larger samples, to further elucidate the underlying pathophysiology and inform the mechanisms of action of neuromodulation treatments, such as rTMS.

BackgroundThe pre-supplementary motor area (preSMA) is increasingly being explored as a neuromodulation target for impulsive behaviour in several clinical populations. Treatment effects are generally interpreted as improvements in inhibitory control. However, healthy studies report improved/impaired/unchanged inhibitory control following identical preSMA stimulation protocols, and few studies examine accompanying neurophysiological changes. We therefore investigated whether preSMA stimulation influences downstream corticomotor excitability to modify a general stopping mechanism, other components of action control, or wider cue-dependent attentional processes relevant to impulsive behaviour. MethodsIn a preregistered, double-blind crossover study, 18 healthy adults received active and sham continuous theta burst stimulation (cTBS) over right preSMA. Motor-evoked potentials (MEPs), anticipatory response inhibition task measures, and alcohol dot-probe reaction times were collected before and after stimulation and analysed with linear mixed models. ResultsMEPs increased during sham (p = .028) but not after active cTBS (p = .741). Active cTBS did not affect complete or partial stopping on the response inhibition task. Instead, active cTBS slowed the continuing response after partial stopping (p < .001) whereas response execution sped up across the sham session (p < .001). No alcohol attentional bias or stimulation effect was detected. ConclusionsPreSMA cTBS did not impair general inhibitory or attentional control. Instead, it attenuated session-related corticomotor facilitation and selectively slowed reinitiation of a partially inhibited action. These findings suggest that clinical effects to impulsive behaviour from preSMA neuromodulation are primarily rooted in changes to motor preparation and action updating rather than a unitary stopping mechanism.