Progress in Neuro-Psychopharmacology and Biological Psychiatry

BackgroundTheta-band oscillation is integral to fronto-parietal connectivity in the executive control network and its top-down regulation on subcortical areas. External frontoparietal synchronization using theta-frequency transcranial alternating current (tACS) is a technology to potentially engage this network. In this pre-registered, triple-blind, sham-controlled trial (NCT03907644), we tested this intervention targeting the right frontoparietal network in people with opioid use disorder (OUD) to measure network engagement and behavioral outcomes. MethodSixty male participants with OUD were randomized to receive 20 minutes of active or sham 6 Hz tACS (HD electrodes over F4 and P4). Structural, resting-state, task-based fMRI drug cue reactivity, and repeated cue-induced craving assessments were collected immediately before and after stimulation. Pre-registered outcome measures were analyzed using timexgroup interaction models to examine (1) modulation of drug cue-related brain activity, (2) changes in craving, (3) alterations in functional connectivity, and (4) relationship between electric field, neural responses, and craving behavior. Results(1) A significant Time x Group interaction revealed decreased post-stimulation opioid cue-related activity in the active group relative to sham, involving key nodes in reward processing (ventral striatum, amygdala and ventral tegmental area) (FWE corrected =0.05) (2) subjective craving did not differ significantly between groups (3) Group by time generalized psychophysiological interaction analyses showed increased right frontoparietal network engagement ({beta}=2.63, p=0.0308) following stimulation, and increased top-down inhibitory regulation of frontoparietal network on right ventral striatum ({beta}=1.99, p=0.037) and left medial amygdala ({beta}=1.97, p=0.039) (4) Electric field strength in the right frontal/parietal node predicted frontoparietal network engagement in the active group (r=0.43, p=0.02). ConclusionTogether, these findings demonstrate that theta-band frontoparietal tACS can modulate activity and task-dependent coupling within cortical-subcortical circuits in OUD, supporting network-targeted neuromodulation as a potential intervention for addiction. Significance StatementAddiction is linked to imbalances in cortico-subcortical brain circuits that control reward processing and craving. This study tested whether a non-invasive brain stimulation method-- theta-band transcranial alternating current stimulation (tACS)--can rebalance these circuits in people with opioid use disorder. Using advanced brain imaging, we found that tACS strengthened communication within frontoparietal brain regions involved in self-control while reducing their connections with reward and emotion centers. These brain changes were linked to reduced craving responses to drug cues. Our results demonstrate that dual-site, network-targeted tACS modulates neural activity and task-dependent engagement of brain circuits during drug cue reactivity in addiction, supporting its potential as a novel therapeutic approach.

Despite decades of clinical implementation of medications for opioid use disorder (OUD), overdose mortality rates remain high, underscoring a critical gap in treatments that target brain mechanisms driving addiction. Mindfulness-Oriented Recovery Enhancement (MORE) has demonstrated efficacy in reducing opioid use and craving, hypothetically by restructuring the salience of drug and natural rewards. Yet, to date, MOREs neurobiological mechanisms remain unclear. In this first functional magnetic resonance imaging (fMRI) randomized controlled trial (RCT) of MORE for OUD (NCT04112186), we tested whether compared with an active psychoeducational supportive therapy (PST) control group, MORE rebalanced neural responses to drug and natural reward cues in inpatients with OUD receiving standard of care including medications. Compared with PST, eight weeks of MORE significantly reduced drug-biased activity in the dorsolateral prefrontal cortex (dlPFC) and posterior regions of the default mode network including the precuneus during downregulation of responses to drug cues relative to upregulation of responses to natural reward cues (even when controlling for passive cue viewing). The shift from drug to natural reward responses in the lateral and ventromedial PFC was associated with lower cue-induced craving exclusively in the MORE group. MORE also reduced medial PFC synchronization to naturalistic drug-related movie scenes and significantly extended abstinence duration at follow-up ([~]4 months post-treatment) relative to PST. Together, this neuroimaging RCT demonstrates that MORE normalizes function in PFC nodes of the reward, salience, and control systems, positioning MORE as a biologically-grounded adjunct to pharmacotherapy for OUD.

Schizophrenia is a severe neuropsychiatric disorder characterized by positive and negative symptoms and cognitive impairments. The present study aimed to investigate the potential interference of ambient noise on the performance of executive function (EF) tasks in individuals with schizophrenia. The sample consisted of 40 participants, divided equally into two groups: a group of individuals with schizophrenia (SchG) and a healthy control group without neuropsychiatric disorders (HC). All participants did three EF assessment instruments: Trail Making Test, Corsi Block Test, and Maze Test. The experimental design included a test-retest procedure with order counterbalancing: half of the sample began the assessment in the noise condition and the other half in the no-noise condition, to control for order and learning effects. The results indicate that ambient noise has a negative impact on the cognitive performance of individuals with schizophrenia. Specifically, the SchG group performed significantly worse on the Maze Test in the noise condition compared to the no-noise condition. These findings contribute to the understanding of the interactions between sensory and cognitive processes underlying the symptoms of schizophrenia. In addition to their theoretical potential, the results have practical implications, as they support the development of intervention strategies and ambiental adaptations that can improve the functionality and quality of life of people with the disorder.

Neurological health score (NHS), indicating the health of brain and nervous system, helps in identifying high risk individuals, and in recommending lifestyle modifications. In the present study, we developed NHS based on genetic, lifestyle and biochemical variables associated with eight neurological disorders - dementia, stroke, Parkinsons disease, amyotrophic lateral sclerosis, schizophrenia, bipolar disorder, multiple sclerosis and migraine. UK Biobank data from Caucasian individuals was used to develop the model, and the data from individuals of Indian ethnicity was used to validate the model. Logistic regression and XGBoost algorithms were used in selecting the significant variables for the disorders. NHS developed from the selected variables was found to be very significant after adjusting for age and sex (AUC:0.6, OR: 0.95). Higher NHS was associated with a lower risk of neurological disorders and better social well-being. Highest NHS group (top 25%) showed 1.3 times lower risk compared to the rest of the individuals. Results of our study help in developing a framework for quantifying the neurological health in clinical setting.

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.

IntroductionSleep spindles are electroencephalographic elements characteristic of non-rapid eye movement sleep generated by thalamo-cortical interactions. Spindles have been linked to some of the cognitive benefits afforded by sleep and high spindle activity is associated with increased arousal threshold (deeper sleep). Here, we demonstrate that targeting the thalamus with Transcranial Electrical Stimulation with Temporal Interference (TES-TI) can enhance spindle activity. Methods24 participants (25.5 {+/-} 9.5 years; 69.6% F) underwent thalamic TES-TI stimulation during daytime naps. Three stimulation protocols were tested during stage 2 of non-rapid eye movement sleep (N2): fixed difference frequency of 10 Hz (TES15kHz-TI10Hz), difference frequency matched to individual spindle peak (TES15kHz-TIPeak), and carrier frequency only (TES15kHz). Spectral power in the spindle (sigma) band and integrated spindle activity (ISA) were compared before and during the stimulation, and across stimulation protocols. ResultsTES15kHz-TI10Hz stimulation was associated with a significant increase in sigma band power ({Delta}[x]STIM-PRE = 0.49 log10{micro}V2, p = 0.021) and ISA ({Delta}[x]STIM-PRE = 7.48 {micro}V/s, p = 0.042). Cluster-based analysis localized the increase in sigma power over the frontal and centro-parietal areas (p = 0.022). Linear mixed effects models showed that both sigma band power and ISA during stimulation increased significantly in TES15kHz-TI10Hz compared to the TES15kHz protocol ({beta} = 0.67 log10{micro}V2, p = 0.018; {beta} = 14.70 {micro}V/s, p = 0.0077), while the TES15kHz-TIPeak did not show the same effect. ConclusionsThis study provides evidence supporting the successful use of TES-TI targeting the thalamus to enhance sleep spindle activity. Stimulation at a fixed difference frequency of 10 Hz increased sigma band power and ISA, whereas neither stimulation matched to individual sigma band peak nor TES alone produced comparable effects. These promising results warrant further investigations into the cognitive and clinical impact of TES-TI, a non-invasive neuromodulation tool that can reach deep brain regions. Statement of significanceThis study provides evidence that thalamo-cortical networks, which are central to many physiological and pathological brain activities, can be modulated non-invasively in humans. More specifically, the findings show that transcranial electrical stimulation with temporal interference targeting the thalamus can selectively enhance sleep spindle activity. This work introduces a new strategy for precisely targeting sleep-generating mechanisms regulated by deep brain circuits without surgery or medication. Key next steps include determining how this increase in spindle activity can positively impact cognition and assessing the translational potential of this approach for clinical populations.

ObjectiveTo delineate the phenotype of juvenile myoclonic epilepsy (JME) with a focus on obsessive-compulsive personality disorder (OCPD) using multimodal psychiatric, neuropsychological, quantitative EEG (qEEG), and structural MRI markers within a predictive-processing/free-energy framework. MethodsWe prospectively studied 65 patients with JME and 68 matched healthy controls (HC). Participants completed DSM-IV SCID I/II interviews and a neuropsychological battery assessing working memory, psychomotor speed, mental flexibility, divided attention, inhibition, and phasic/tonic alertness; standard EEG and high-resolution structural MRI were acquired. Groups comprised HC and JME subgroups without psychiatric comorbidity, with non-OCPD Axis I/II diagnoses, and with OCPD. Welchs t-tests (FDR-corrected) and Hedges g quantified neuropsychological and alpha-band coherence differences. Surface-based analyses assessed cortical thickness/surface area. Exploratory regressions tested associations of OCPD, seizure freedom, and antiseizure medication (ASM) load with cognition; Kendalls tau tested coherence-cognition associations. ResultsCompared with HC, JME showed broad executive-attentional impairment, most pronounced in patients with psychiatric comorbidity. The OCPD subgroup exhibited particularly large slowing in psychomotor speed, inhibition (reaction time), and tonic alertness versus HC, while OCPD versus non-OCPD JME differences did not survive multiple-comparison correction. qEEG showed increased interhemispheric frontal and decreased temporal alpha coherence in JME, with temporal hypo-coherence strongest in those with psychiatric comorbidity; within JME, OCPD was linked to increased left fronto-temporal alpha coherence. In the MRI subsample, JME-OCPD demonstrated increased cortical thickness in left medial orbitofrontal and anterior cingulate regions (vs HC and vs JME without OCPD) and additional posterior occipito-temporal clusters versus HC. Regression and coherence-cognition associations were weak and non-significant after FDR correction. SignificanceJME features syndrome-level executive-attentional dysfunction and altered fronto-temporal network organization. Comorbid OCPD marks a subgroup with accentuated cognitive slowing and distinct medial prefrontal/cingulate structural and left fronto-temporal connectivity signatures, aligning with predictive-processing accounts of rigid, over-precise high-level priors. Key pointsJME is linked to broad executive-attentional impairment versus healthy controls. Psychiatric comorbidity amplifies cognitive deficits in JME. JME with OCPD shows particularly large slowing/inhibitory-control deficits versus controls, while OCPD vs non-OCPD differences within JME are modest. Alpha-band EEG coherence indicates altered network organization in JME and an OCPD-related increase in left fronto-temporal coherence within JME Surface-based MRI suggests an OCPD-related structural phenotype in JME, involving medial orbitofrontal/anterior cingulate cortical thickening

Objective: Posttraumatic stress disorder (PTSD) after a traumatic birth is a serious but overlooked maternal morbidity, affecting ~20% of women following medically complicated deliveries. PTSD can undermine maternal caregiving. Rapid screening tools suited to busy obstetric settings are lacking. We developed and evaluated a brief screener, derived from the 20-item PTSD Checklist for DSM-5 (PCL-5), to identify PTSD related to childbirth. Study Design: We enrolled 107 women with traumatic childbirth. Participants completed the PCL-5 and the gold-standard clinician diagnostic interview for PTSD (CAPS-5); depression was measured with the Edinburgh Postnatal Depression Scale (EPDS). Bootstrap resampling with LASSO regression identified PCL-5 items most associated with PTSD. Firth logistic regression models estimated diagnostic accuracy. Sensitivity, specificity, area under the ROC curve (AUC), and Youden's J statistic determined performance and optimal cut-off. Results: A six-item version of the PCL-5 (PCL-5 R6), statistically derived from the full scale, showed excellent discrimination for PTSD compared with clinician evaluation (AUC = 0.95; 95% CI, 0.89-1.00). A cut-off score of 7 yielded high sensitivity (0.96) and good specificity (0.83), with an overall diagnostic efficiency of 0.86, detecting most PTSD cases while minimizing false positives. The PCL-5 R6 correlated moderately with the EPDS (rho = 0.53), showing that a depression screen alone cannot reliably detect PTSD. Conclusions: A short, 6-item PCL-5 provides a valid, efficient tool for detecting childbirth PTSD. Its brevity and accuracy make it practical for integration into routine postpartum care, enabling timely mental health screening.

BackgroundInhaled combusted cannabis and co-use of combusted cannabis and nicotine electronic cigarettes (nECIGs) are on the rise, yet their long-term cardiovascular risk is unclear due to the high prevalence of confounders in observational human studies. Using primary plasma and monocytes and a novel ex vivo mechanistic model of two early steps in atherogenesis, this study examined whether chronic combusted cannabis use is associated with atherogenic changes, as estimated by 1) monocyte transendothelial migration (MTEM), and 2) monocyte-derived foam cell formation (MDFCF), and whether nECIG co-use further amplifies this risk. MethodsA cross-sectional parallel group comparison study was conducted in healthy adults (21-30 years) who chronically 1) used combusted cannabis, 2) co-used both combusted cannabis and nECIGs, and 3) were non-using controls. Using our ex vivo atherogenesis assay, primary outcomes of MTEM, MDFCF, and median fluorescence intensity (MFI) of the lipid-staining fluorochrome BODIPY were determined using primary plasma and autologous primary monocytes from participants. Using flow cytometry and the fluorochrome CELLROX, cellular oxidative stress (COS) in monocytes was determined. ResultsOf the 134 participants, 59 used cannabis, 26 co-used cannabis/nECIG, and 49 were non-using controls. The groups had similar age, sex, and race. Median MTEM was 1.13 fold greater in people who used cannabis compared to non-users 27.8% (IQR 26.1:29.2%) vs 24.5%, (IQR 22.9:27.4%), p<0.0001, and tended to be greater in people who co-used cannabis/nECIG by 1.22-fold 34.1%, (IQR 29.9:38.3%, p=0.17). Median MDFCF and MFI were also increased in people who used cannabis compared to non-users (MDFCF 36.3%, IQR 31.8:35.8%, vs 26.6%, IQR 23.8:25.8%, 1.36-fold and MFI 1163.8, IQR 1042.8:1155.0, vs 940.2 IQR 849.9:1101.4, 1.24-fold) and were further increased in people who co-used cannabis/nECIG (MDFCF 48.7%, IQR 37.3:52.4%, 1.34-fold, MFI 1433.7, IQR 1263.8:1686.4, 1.23-fold; all comparisons p<0.008). Foam cell formation, but not transendothelial migration, was strongly positively correlated with COS. All primary outcomes increased with greater frequency of cannabis and/or nECIG use. ConclusionsIn healthy young adults, exclusive cannabis use is associated with increased atherogenic properties of monocytes and plasma, and this atherogenic effect is further amplified by co-use of nECIGs.

Traumatic brain injury (TBI), particularly sports- and recreational activity related mild TBI (mTBI), is common in young adults and can be followed by persistent attentional and executive complaints. This study investigated chronic ([&ge;]6 months post-injury) structural brain alterations in gray matter (GM) and white matter (WM) and their associations with self-reported inattentive and hyperactive/impulsive symptoms, with a focus on sex-differentiated patterns. Structural brain properties in gray matter (GM) and white matter (WM) were acquired from 44 subjects with TBI and 45 matched controls, by utilizing structural MRI and diffusion tensor imaging techniques. Behavioral measures assessing severities of post TBI inattentive and hyperactive/impulsive symptoms were collected from each participant. Between-group and sex-specific differences of these brain and behavioral measures were conducted. Interactions among the TBI-induced significant brain- and behavioral-alterations, and their sex-specific patterns, were assessed as well. Male-dominated pattern of increased cortical thickness in superior parietal lobule (SPL) and female-dominated pattern of higher superior longitudinal fasciculus and superior fronto-occipital fasciculus (sFOF) fractional anisotropy (FA) were observed in the TBI group, when compared to controls. In males with TBI, greater SPL cortical thickness was significantly correlated with increased inattentive behaviors. In females with TBI, higher FA of sFOF was significantly correlated with decreased hyperactive/impulsive behaviors. Findings suggest that TBI-induced superior parietal cortical GM abnormalities may significantly cause attention deficits in patients with TBI, especially in males; while optimal post-TBI WM recovery in sFOF significantly contributes to maintenance of inhibitive control in patients with TBI, especially in females.

Background and HypothesisClozapine is the only antipsychotic with protective effects against suicide in schizophrenia (SCZ). Newer third-generation antipsychotics (TGA) have better tolerability and modulate serotonin, dopamine, and N-methyl-d-aspartate neurotransmission pathways implicated in suicide. We aimed to investigate the effects of TGAs on suicide in SCZ. MethodsWe searched seven databases up to December 2023 for SCZ studies that reported suicide data. The primary outcome was suicide deaths and attempts; suicidal ideation was added as a secondary outcome. Random effects meta-analyses quantified suicide risk in randomized controlled trials (RCT) while single proportion meta-analyses assessed longitudinal suicide risk in open label extension trials (OLE). For RCTs, sensitivity analyses were conducted and subgroup analyses explored the impact of dose, drug type, and comparator arm. Study ResultsTwenty articles were included; thirteen excluded higher suicide risk participants. Compared to placebo control, TGAs did not significantly change the risk of primary [RR = 0.65, p = 0.38] or secondary [RR = 0.63, p = 0.15] suicide outcomes. Subgroup and sensitivity analyses were not statistically significant. For OLEs, there was a significant increase in the incidence of primary [Ip = 0.004, p = 0.048] and secondary [Ip = 0.024, p = 0.0013] suicide outcomes, but there was marked study heterogeneity. ConclusionThere is no current trial evidence to show that TGAs significantly impact suicide outcomes in SCZ. The signal from OLEs should be interpreted cautiously due to heterogeneity and requires replication. An effective clozapine alternative is needed for suicide prevention in SCZ.

ObjectiveCognitive deficits are a leading cause of disability in schizophrenia and are linked to poor functional outcomes. There are no first line treatments for these deficits, and their neural basis is poorly understood. While schizophrenia is associated with widespread cognitive deficits, information processing speed is most profoundly impaired. Processing speed deficits have been associated with hyperconnectivity in the Default Mode Network (DMN). We therefore tested if modulating DMN connectivity with single or multiple sessions of transcranial magnetic stimulation (TMS) applied to an individualized DMN target would affect processing speed. MethodsIn the first study, 10 individuals with schizophrenia received single TMS sessions and underwent resting-state neuroimaging and processing speed assessment (Brief Assessment of Cognition in Schizophrenia digit symbol coding) acutely before and after each session. These sessions included excitatory (intermittent theta burst stimulation, iTBS); inhibitory (continuous theta burst stimulation, cTBS); and sham stimulation sessions. In the second study, 29 individuals (17 schizophrenia, 12 non-psychosis controls) received 5 accelerated sessions of cTBS with resting-state neuroimaging and processing speed assessment before and after the course of TMS sessions. ResultsIn the accelerated, multi-session DMN-targeted TMS trial, cTBS improved processing speed in the schizophrenia group (p=0.0124). In individuals with schizophrenia, reduction in DMN connectivity was linked to improvement in processing speed (p=0.021). These changes were dependent on age, where younger participants experienced greater processing speed improvements than older participants (p=0.006). ConclusionsIn sum, personalized network targeted TMS is a novel method for reducing cognitive impairment associated with schizophrenia.

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.

Tobacco use disorder (TUD) remains a leading cause of preventable mortality, and existing pharmacotherapies yield 12-month abstinence rates below 30%. As cannabis legalization expands, approximately 18-22% of people who use tobacco report concurrent cannabis use, yet the impact of co-use on cessation outcomes and the therapeutic potential of endocannabinoid system (ECS) modulation remain unclear. We conducted a translational systematic review and meta-analysis following PRISMA 2020 guidelines, searching Ovid MEDLINE, Embase, APA PsycInfo, and Web of Science through January 2026 (PROSPERO: CRD420250652724). Three study categories were eligible: observational studies of cannabis co-use and cessation outcomes; preclinical studies of cannabinoid modulators on nicotine-related behaviors; and human experimental studies of ECS-targeted interventions. Of 4,869 records screened, 52 studies met inclusion criteria. Meta-analysis of 18 observational studies (N=229,630) revealed that cannabis use was associated with 35% lower odds of achieving tobacco smoking cessation (OR=0.65; 95% CI: 0.55-0.78; p<0.0001; I{superscript 2}=88.1%). Preclinical evidence (15 studies) demonstrated that CB1 receptor antagonists robustly reduced nicotine self-administration and reinstatement, while cannabidiol (CBD) attenuated both nicotine intake and withdrawal without affecting food reinforcement. Clinical translation of CB1 receptor inverse agonists failed due to psychiatric adverse effects, but CBD showed promise by reducing cigarette consumption by 40%, reversing attentional bias to smoking cues, and alleviating withdrawal severity. These findings distinguish naturalistic cannabis exposure from potentially beneficial targeted ECS modulation, and support CBD as a promising candidate for adequately powered tobacco cessation trials.

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.

BackgroundEEG microstates provide a window into rapid, large-scale brain network dynamics. Despite showing alterations in schizophrenia, evidence in first-episode schizophrenia spectrum psychosis (FESSP) is limited. We assessed whether microstate temporal and transition features could identify a multivariate signature of FESSP, and whether these dynamics can track symptom severity. MethodsResting-state EEG was analysed in 69 participants (FESSP n=41, mean age: 22.49 years; healthy controls n=28, mean age: 21.33 years). Twenty-eight microstate temporal and transition features were extracted across microstate classes (A-D). Group classification accuracy was assessed using a linear support vector machine with stratified cross-validation and permutation testing. Within the FESSP group, we further assessed associations between microstate features and clinical scores using the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Positive Symptoms (SAPS), and Scale for the Assessment of Negative Symptoms (SANS). ResultsMultivariate microstate features provided above-chance discrimination of FESSP from controls (balanced accuracy=0.644; AUC=0.688; p=0.030). However, when comparing individual features between groups, no feature survived multiple-comparison correction consistent with characterisation of FESSP via a distributed multivariate pattern across correlated features. Within the FESSP group, microstate dynamics were most strongly linked to negative symptoms, with higher SANS scores associated with shorter microstate D durations ({rho}=-0.507, pFDR=0.020) and higher occurrence of microstates A and B ({rho}=0.434-0.443, pFDR=0.042). BPRS-18 and SAPS showed no associations with any features. ConclusionsUsing EEG microstate temporal and transition features with multivariate classification, we identified a pattern that differentiated FESSP from controls and showed selective associations with negative symptom severity.

ObjectivesElectroconvulsive Therapy (ECT) is an effective treatment for bipolar disorder, particularly in severe acute cases or for illness resistant to pharmacotherapy. However, the risk of relapse following ECT is high, necessitating intervention to reduce this risk. Based on findings from ECT studies in unipolar depression and its well-known mood-stabilizing properties, it is likely that lithium treatment may reduce the risk of relapse of bipolar disorder following ECT. Therefore, we conducted a target trial emulation using data from Danish nationwide registers to investigate whether lithium protects against relapse following ECT treatment of bipolar disorder. MethodsPatients discharged from their first psychiatric admission with a primary diagnosis of bipolar disorder between January 1, 2006, and June 1, 2024, who received at least six ECT treatments, were included. Follow-up began two weeks after discharge and continued until relapse, death, one year, or January 1, 2025. Patients were considered allocated to lithium treatment if they redeemed a prescription for lithium within the first two weeks after discharge from the index admission (ECT treatment). The outcome was time to relapse, defined by either psychiatric hospital admission or suicide. Cox proportional hazards regression, adjusted for potential confounders, was used to compare the outcome between patients allocated and not allocated to lithium treatment. ResultsAmong the 574 eligible patients (mean age 41.5 years, 61.3% women), 214 (37.3%) were allocated to lithium treatment and 360 (62.7%) were not allocated to lithium treatment. During follow-up, 56 patients (26.2%) in the lithium group and 135 patients (37.5%) in the non-lithium group experienced a relapse. Lithium treatment was associated with a substantially reduced risk of relapse (adjusted hazard rate ratio, 0.60, 95% CI=0.43-0.84). ConclusionLithium treatment after ECT may reduce the risk of relapse in patients with bipolar disorder. These findings should be followed up by a randomized controlled trial.

Oscillatory coupling between respiration, heart rate, and cortical function is fundamental to physiological regulation yet remains poorly characterized in humans. Diminished respiratory heart rate variability (RespHRV)--the rhythmic heart rate modulation accompanying respiration--has emerged as a transdiagnostic biomarker of mental and physical health, reduced in anxiety, depression, cardiovascular disease, and aging (Beauchaine & Thayer, 2015; Menuet & Gourine et al., 2025). However, the cortical substrates that coordinate rhythmic cardiovascular-respiratory coupling are not well understood. Our current findings highlight the involvement of the left orbitofrontal cortex (OFC) in oscillatory cardiorespiratory dynamics. In adults aged 50-70 (N = 55; mean age = 60.1 {+/-} 6.0 years; 29 female), across both a slow-paced breathing condition and a random-paced breathing condition, greater heart rate oscillatory power during 9-week breathing training sessions predicted OFC volume increases. OFC changes were most strongly linked with upper low-frequency range power during practice (0.09-0.13 Hz; p < 0.005, cluster-corrected) but were not tightly constrained by precise breathing frequency. These effects covaried with improved attentional and executive performance, including reduced pupil responses to distractors and enhanced working-memory and associative-memory scores. Our findings identify the orbitofrontal cortex as a key site of cortical plasticity linked to rhythmic cardiovascular-respiratory engagement. By delineating how oscillatory body-brain coupling supports cognitive control-related processes, including attentional filtering and memory updating, this work bridges mechanistic neuroscience and translational intervention science, suggesting a frequency-general pathway through which simple breathing practices may enhance neurovisceral integration and cognitive resilience in aging. SummaryO_LIGreater oscillatory heart rate power during breathing training, particularly within the upper low-frequency range (0.09-0.13 Hz), predicted increases in left orbitofrontal cortex (OFC) volume. C_LIO_LIOFC volume increases were associated with improved attentional and executive performance, including reduced pupil reactivity to distractors and enhanced working-memory and associative-memory scores. C_LIO_LIThese findings suggest that rhythmic cardiovascular-respiratory coupling supports cortical plasticity and cognitive resilience, providing a frequency-general mechanism through which breathing practices enhance neurovisceral integration in aging. C_LI

BackgroundTo clarify the working mechanisms of psychotherapy for obsessive-compulsive disorder (OCD), we studied the neural effects of two psychotherapies: cognitive behavioral therapy with exposure and response prevention (CBT-ERP) and inference-based cognitive behavioral therapy (I-CBT). MethodsFifty-five individuals with OCD completed an emotional processing task during fMRI before and after 20 weekly psychotherapy sessions, using general fear and OCD-related visual stimuli. Forty-two healthy controls performed the task once. We used Bayesian region-of-interest analyses to assess changes in brain activation in prefrontal, limbic, sensory, subcortical, and visual areas, and their association with symptom improvement. ResultsAfter treatment, the CBT-ERP group (N=28) showed strong credible evidence for decreased activation across all brain regions during fear (but not OCD) versus neutral stimuli, especially in treatment responders. Conversely, the I-CBT group (N=27) showed increased activation during fear versus neutral stimuli in the precentral gyrus and lateral occipital cortex (LOC), which correlated with symptom improvement. A similar but weaker pattern was observed for OCD-related stimuli. Across all ROIs, baseline fear-related activity was associated with symptom improvement in CBT-ERP, while lower baseline activity was associated with improvement in I-CBT in, amongst others, the precentral gyrus and dorsolateral prefrontal cortex. Lower baseline LOC activation during OCD-related stimuli was linked to symptom improvement after both psychotherapies. ConclusionsThe results support CBT-ERPs mechanism of fear reduction and I-CBTs mechanism of sensory engagement. Visual brain activity during emotional processing may predict treatment response across psychotherapies.

BackgroundMotor threshold (MT) estimation is fundamental to transcranial magnetic stimulation (TMS), guiding individualized stimulation intensity in research and therapy. Conventional methods such as the 5-out-of-10 rule require many stimuli, while adaptive approaches like Parameter Estimation by Sequential Testing (PEST) improve efficiency but can exhibit poor convergence under certain conditions. ObjectiveThis study introduces the Bayesian Uncertainty Dynamic Algorithm for Parameter Estimation by Sequential Testing (BUDAPEST), a Bayesian adaptive method for fast, accurate MT estimation with user-controlled uncertainty. The aims were to validate its accuracy in simulations and human data, promote usability through a MATLAB-based graphical interface, and evaluate experimental utility through resting and active MT comparisons and session-to-session reliability. MethodsBUDAPEST infers MT from binary MEP responses using sequential Bayesian updating and terminates when a user-defined uncertainty threshold is reached. Performance was evaluated in 10,000 virtual simulations and in human rMT and aMT measurements across two sessions per subject, including 3x5 cortical motor mapping to assess physiological spatial patterns. ResultsIn simulations, BUDAPEST achieved a mean absolute error of 1.9% MSO within ~10 pulses using a 2% uncertainty criterion while avoiding PEST misestimations. In human data, MT estimates were accurate within {+/-}4% MSO and robust to initialization; rMT showed strong session-to-session reliability (r = 0.78), whereas aMT exhibited greater variability. Motor mapping revealed coherent excitability gradients centered on the hotspot. ConclusionBUDAPEST enables rapid, reliable, and uncertainty-controlled MT estimation while reducing procedure time and participant burden. The accompanying GUI facilitates immediate adoption in research and clinical TMS environments. HighlightsO_LIIntroduces BUDAPEST, a Bayesian uncertainty-aware algorithm for rapid and reliable TMS motor threshold estimation. C_LIO_LIAchieves accurate MT estimates ({approx}2% MSO error) in ~10 pulses with user-controlled trade-offs between precision and procedure duration. C_LIO_LIDemonstrates robust performance in simulations and human data, with strong resting MT reliability and an open-source GUI enabling immediate adoption. C_LI