Neuroscience & Biobehavioral Reviews

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.

ObjectiveAlthough mental health and healthy lifestyle interventions are associated with functional outcomes in adolescence, the extent to which particular lifestyle factors explain relationships between mental health and outcome are unclear. Here we examined mediating effects of lifestyle factors on relationships between mental health and two functional outcomes measured 2-3 years later as well as the moderating effect of environmental risk factors on mediation strength in early adolescence. MethodsThis study analyzed data from 3 waves of the Adolescent Brain Cognitive Development Study (ages 10-11, 11-12, and 12-13). Mediating effects of sleep quality, screen time, physical activity and Mediterranean diet on the relationships between depression, anxiety, psychotic-like experience (PLE) distress, and total problems with two subsequent functional outcomes (academic functioning and social problems) were examined. Secondary analyses included environmental factors as moderators. ResultsSleep quality mediated 18.5%, 36.3%, 8.3%, and 3.4% of the relationships between depression, anxiety, PLE distress and total problems with academic functioning, respectively. Screen time was the second strongest mediating factor. For social problems, only sleep quality showed > 3% mediation (19.6% - 23.3%). Mediating effects of sleep and screen time on academic functioning decreased as financial adversity increased. Conversely, mediating effects of sleep quality on social problems increased with worsening family conflict, financial adversity, and school environment. ConclusionsThese results suggest that healthy lifestyle factors (in particular sleep quality) may partially explain the associations between mental health and functioning in adolescents and suggest that these effects are modulated by environmental factors. These results may have important implications for future intervention studies.

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

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.

Evidence-based psychotherapies are first-line treatments for psychiatric disorders, yet response rates remain suboptimal. Noninvasive brain stimulation (NIBS) may augment psychotherapy by modulating treatment-engaged circuits. We conducted a systematic review and meta-analysis of randomized controlled trials comparing active NIBS plus evidence-based psychotherapy versus sham NIBS plus psychotherapy. Following Cochrane methods, we searched six databases through February 2025, screening 1,017 records. Twenty-eight trials (31 treatment arms; 1,506 participants) met inclusion criteria. Active NIBS combined with psychotherapy produced significantly greater symptom improvement than sham NIBS with psychotherapy (standardized mean difference = -0.38, 95% confidence interval [-0.68, -0.08]), with substantial heterogeneity. Moderator analyses revealed critical implementation parameters: repetitive transcranial magnetic stimulation (rTMS) showed significant benefit while transcranial direct current stimulation did not. Non-concurrent delivery--stimulation before or after psychotherapy sessions--was significantly effective, whereas concurrent administration was not. Among psychotherapy modalities, cognitive behavioral therapy combined with NIBS produced significant benefit. Human-delivered psychotherapy, but not computerized formats, significantly enhanced outcomes. By diagnosis, significant effects were observed only for anxiety disorders. Secondary analyses revealed significant anxiety symptom reduction specific to rTMS. Treatment integrity was under-reported: only 39.3% of studies used fully manualized protocols and 10.7% documented therapist adherence. Non-concurrent rTMS paired with human-delivered, manualized cognitive behavioral therapy emerges as the most effective strategy, particularly for anxiety disorders. These findings provide an evidence-based framework for optimizing combined treatment protocols and highlight the need for standardized psychotherapy fidelity monitoring in future trials.

BackgroundParental genetics matters for childrens behavioural difficulties, but the extent to which this is due to direct genetic transmission versus environmentally mediated indirect genetic effects remains unclear. MethodsWe studied eight European birth cohorts with over 33,000 family-based trio samples. We analysed polygenic scores (PGSs) for 13 mental health and neurodevelopmental conditions and their composite indices (PC1 and mean) representing general neuropsychiatric liabilities, as well as educational attainment (EA) and alcohol and cigarette use, from children (PGSc), mothers (PGSm), and fathers. Child internalising, externalising, and total difficulties reported by mothers and/or fathers were examined at preschool and school ages. We then conducted multivariate meta-analyses to combine cohort-level results. FindingsWe observed several direct genetic effects on externalising difficulties, while indirect genetic influences were mainly identified for internalising difficulties. Specifically, child PGSs for attention-deficit/hyperactivity disorder (ADHD) and EA predicted higher and lower levels, respectively, of child externalising and total difficulties (all pFDR<0{middle dot}001; for school-aged externalising difficulties, PGSc-ADHD: {beta}=0{middle dot}121 [95% CI 0{middle dot}091 to 0{middle dot}151], pFDR<0{middle dot}0001; PGSc-EA: {beta}=-0{middle dot}095 [95% CI -0{middle dot}127 to -0{middle dot}063], pFDR<0{middle dot}0001), whereas maternal PGSs for major depressive disorder (MDD) and general neuropsychiatric liabilities were associated with internalising and total difficulties across parental raters and child ages (all pFDR<0{middle dot}05; for school-aged internalising difficulties, PGSm-MDD: {beta}=0{middle dot}049 [95% CI 0{middle dot}017 to 0{middle dot}081], pFDR=0{middle dot}016; PGSm-PC1: {beta}=0{middle dot}056 [95% CI 0{middle dot}022 to 0{middle dot}091], pFDR=0{middle dot}011). No statistically significant effects from paternal PGSs were identified. InterpretationIn this multi-cohort study, findings across multiple traits, raters, and ages supported several direct genetic effects of ADHD and EA on child externalising difficulties and indirect genetic effects on internalising difficulties, especially maternal depression and general neuropsychiatric liabilities. These suggest that child internalising difficulties are not solely driven by direct genetic transmission. More comprehensive research is needed to better understand the mechanisms involved, and ultimately how to ameliorate child behavioural difficulties. FundingEU, ERC, RCN, RCF, UKRI, SERI, DFG Research in contextO_ST_ABSEvidence before this studyC_ST_ABSIndirect genetic effects (IGEs) refer to the influence of parental genotypes on offspring outcomes beyond direct genetic effects (DGEs), for example via environmental pathways. While IGEs on offspring cognitive traits are well-established for educational attainment, evidence for IGEs of parental liabilities to mental health and neurodevelopmental conditions remains limited. To assess the current state of evidence, we conducted a systematic search of published studies applying trio-based polygenic score (PGS) designs to child and adolescent mental health outcomes. We identified 141 primary studies in MEDLINE, Embase, PsycInfo, and Web of Science, by 6 March 2025, after removing duplicates; following screening, 12 studies met inclusion criteria (see supplement for a full description including results). Ten out of the 12 studies focused on externalising outcomes, with little or inconsistent support for IGEs. When observed, IGEs were mainly driven by maternal liabilities to autism, educational attainment, and cognitive performance on child outcomes. The current evidence was too limited and heterogeneous to synthesize findings quantitatively, therefore a qualitative synthesis was conducted. Many studies were statistically underpowered, and the observed IGEs were in all cases sample-specific. There were no published multi-cohort studies. Added value of this studyWe integrated information across over 33,000 mother-father-child trios from eight European cohorts, investigating 18 PGSs from parents and children, using maternal and paternal ratings of offsprings internalising, externalising, and total difficulties as outcomes at both preschool and school age. We mainly observed DGEs on externalising difficulties, consistent with previous studies. Some evidence of IGEs was found for internalising and total difficulties. IGEs were often found to be maternally driven, with the most robust evidence across ages and raters emerging for maternal depression and general neuropsychiatric liabilities. Implications of all the available evidenceThe current evidence suggests that childrens behavioural difficulties, especially internalising difficulties, may be partly driven by the environment shaped by maternal neuropsychiatric liabilities. Ours and previous findings highlight a pressing need for more comprehensive studies across different cohorts, raters, outcomes, and time points to understand the true extent of IGEs in the intergenerational transmission of mental health.

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.

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.

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

Background and HypothesisAbnormal default mode network (DMN) connectivity was observed in both tobacco use and psychotic spectrum disorders, but it remains unknown how psychosis impacts the relationship between connectivity and tobacco use. Interventions targeting the left lateral parietal DMN node (LLPDMN) have modulated DMN connectivity and nicotine craving in psychosis. We aimed to investigate relationships between DMN connectivity, psychotic illness, and tobacco use. Study Design336 participants (psychosis: n=161, control: n=175) reported their tobacco use history and underwent resting-state functional magnetic resonance imaging. We calculated connectivity within DMN and salience network (SN), between DMN-SN, and from LLPDMN to other DMN and SN nodes. Logistic and LASSO regression with bootstrapping were performed to investigate diagnosis-by-connectivity interactions on lifetime tobacco use. Exploratory brainwide analysis was conducted by regressing brainwide connectivity to LLPDMN against daily cigarette use. Study ResultsWe observed a significant diagnosis-by-DMN connectivity interaction for lifetime tobacco use (p=0.0281, coefficient=0.457, OR=1.579, 95% CI=[1.063, 2.411]); in the psychosis group, higher DMN connectivity was associated with higher odds of lifetime tobacco use. LASSO regression yielded four predictors of lifetime tobacco use: age, diagnosis, LLPDMN connectivity to a prefrontal SN node, and the interaction between diagnosis and LLPDMN connectivity to a right parietal DMN node. Brainwide analysis identified bilateral somatomotor clusters where higher connectivity to LLPDMN correlated with higher daily cigarette use (voxel-wise p<0.001, cluster p<0.05). ConclusionsPsychosis diagnosis modified relationship between DMN connectivity and tobacco use. Modulating DMN connectivity may provide a psychosis-specific treatment target for tobacco dependence.

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.

BackgroundSubstance use disorders (SUD) are associated with a high global burden of disease, with 5.4% of all disability-adjusted life years lost due to alcohol and illicit drugs. Highly prevalent multimorbidity includes polysubstance use, mental health conditions, and other non-communicable and infectious diseases. Where traditional treatments are insufficient alone, music therapy (MT) is highly engaging and improves motivation and reduces craving; however, its long-term effects are unknown. The present study aims to examine long-term effects of active music groups (AMG) and music listening groups (MLG) versus treatment as usual (TAU) on addiction severity, recovery, and other outcomes in people with SUD Immediate and short-term effects, as well as mechanisms of these interventions, will also be examined. MethodsIn individuals with SUD across a wide range of age, gender, socioeconomic, and cultural backgrounds, a parallel 3-arm assessor-blinded pragmatic multinational randomised controlled trial (RCT) with embedded exploratory trials and mechanistic studies will determine long-term effects of AMG and MLG versus TAU on addiction severity (primary endpoint: 1 year), recovery, and other outcomes. Embedded trials will examine immediate effects of AMG or MLG combined with individual components of TAU combined to determine the best combinations of interventions. Experimental studies will examine mechanisms using cognitive testing and brain imaging. With 600 participants in 7 countries randomised, the trial will have 80% power on the primary outcome. Patient representatives, health technology assessment (HTA) bodies, and interventionists have been involved from conception and will ensure feasibility and applicability of the intervention across Europe. DiscussionThis document describes the FALCO RCT, the main part of the FALCO project, which aims to reduce disease burden through innovative, effective, and affordable treatment, and will strengthen research and innovation expertise. Recommendations from FALCO will inform intervention delivery across Europe and beyond, leading to increased safety, effectiveness, and cost-effectiveness, and improved quality of life for individuals with SUD. Stakeholders will be involved in communicating findings across all European countries and regions and ensuring that findings are effectively implemented. Trial registrationClinicalTrials.gov, NCT07028983, registered 11th of June 2025. https://clinicaltrials.gov/study/NCT07028983

New-onset chronic pain is a common and debilitating symptom of Long COVID (LC) that remains not fully understood in terms of pathophysiology and therapeutic targets. A growing body of evidence in chronic pain syndromes similar to LC demonstrates an association between EEG alpha oscillatory activity and the experience of pain, with clinical studies showing maladaptive changes in oscillatory activity, particularly a slowing of alpha activity. This study aims to investigate the association between EEG alpha oscillatory activity and pain perception in new-onset LC-chronic pain. We recruited 31 individuals (20 females) with a clinical diagnosis of LC reporting new-onset chronic pain and 31 healthy pain-free age-and sex-matched controls. Participants completed questionnaires regarding symptoms and psychological functioning prior to recording eyes-open resting-state EEG. Peak alpha frequency (PAF) and spectral power within the alpha band (8-13 Hz) were extracted from EEG signals. Lower PAF over the posterior scalp region was significantly associated with higher LC-chronic pain severity when controlling for age and depression. This observation was consistent across PAF estimation methods. PAF was significantly increased, particularly in the posterior region, in the moderate pain LC subgroup compared to both severe pain subgroup and controls, while alpha power did not differ between the three groups and was not associated with pain severity. Our findings highlight associations between PAF and pain symptoms in a new post-infection chronic pain syndrome. PAF can thus be explored as a potential biomarker and therapeutic target for EEG-based neuromodulation interventions in LC-chronic pain. These results may have implications for other similar chronic pain syndromes. SummaryLower resting-state EEG peak alpha frequency in posterior scalp region is associated with higher severity of new-onset Long COVID chronic pain.

There is a predicted increase in older adults presenting with mild to severe cognitive impairment. Screening tools with high sensitivity are the first frontier in identifying a cognitive pathology; however, to ensure that they are measuring the intended concept or criterion, thorough psychometric procedures should be followed. In this study, convergent criterion validity of Riga Cognitive Screening Task was measured, using cortical thickness of regions of interest as the criterion. 106 older adults (Mage = 70.49, SD =8.08, 35.8% male) with varying levels of cognitive functioning were involved in the study. All participants underwent cognitive assessment with the screening task and a 3T MRI. Cortical thickness of selected temporal and parietal regions was used as a brain measure. Behavioural Partial Least Squares Correlation was conducted and one latent variable was extracted. The results confirmed that Riga Cognitive Screening Task shows good criterion validity, suggesting successful use for screening.

BackgroundThe present study examines the link between DNA methylation at the nerve growth factor-induced protein A (NGFI-A) binding domain of the NR3C1 1F promoter and later cognitive functions in children from families living in disadvantaged psychosocial conditions. MethodsParticipants were 132 children who took part in a Swiss Parents as Teachers (PAT) randomized controlled trial (72 in the intervention group, 60 in the control group). DNA methylation was quantified from saliva samples collected at age three using sodium bisulfite next-generation sequencing (NGS). Cognitive functions were assessed at age five using the SON-R 2.5-7 Intelligence Test. Results(a) DNA methylation at age three predicted lower IQ at age five through increased concentration problems; (b) participation in the three-year PAT program predicted lower methylation levels at the end of the intervention; and (c) early life stressors predicted lower IQ through increased methylation and concentration problems with descriptively stronger effects in the control group. ConclusionsThese findings demonstrate a link between early DNA methylation at the NGFI-A binding site of the NR3C1 1F promoter and later cognitive functions in children and highlight the role of early life stressors and the PAT intervention in shaping these associations.

BackgroundLight plays a critical role in mental health, as the primary input to the circadian system, which regulates mood, energy, and the sleep-wake cycle. Altered light sensitivity is a potential mechanism in circadian-associated mental disorders. MethodsActigraphy-derived sleep, physical activity, and circadian rhythm correlates of the pupillary light reflex were explored in young people with emerging mental disorders. Participants were 27 healthy controls (Mean age=25.67 {+/-} 2.83, 52% female) and 155 young people from the Neurobiology Youth Follow-up Study (Mean age=25.48 {+/-} 5.65; 60% female), recruited from an early intervention mental health service. 32% of the latter group were re-assessed over 12 months. Pupil constriction, average and maximal constriction velocity, and constriction latency were recorded by the PLR-3000 monocular pupillometer in response to dim ([~]10 lux) and bright ([~]1500 lux) pulses. ResultsCompared to healthy controls, young people with emerging mental disorders had a smaller change in pupil diameter (p=0.037) and a slower maximal constriction velocity (p=0.018) in response to dim light. In the full sample, decreased dim light sensitivity was correlated with later timing of actigraphy-derived sleep midpoint. Within the clinical cases, increased genetic risk for bipolar disorder was correlated with increased dim light sensitivity, and higher insomnia clinical scores were correlated with decreased dim light sensitivity. Pupillometry measures were stable across time and seasons. ConclusionAltered light sensitivity may be associated with the emergence of mood disorder in young people and with altered sleep-wake timing.

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.

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.

Background At present, there are no approved pharmacological treatments for people at clinical high risk for psychosis (CHR-P). We sought to assess the acceptability of cannabidiol (CBD): a promising candidate treatment for this population. Methods CHR-P individuals completed a survey which assessed their views on the acceptability of CBD, its expected effectiveness and side effects, and on formulation preferences. Results The sample comprised 55 CHR-P individuals (24.3 years and 69% female). Most (91%) were familiar with CBD, and had previously used cannabis (64%), and around half (42%) had tried over-the-counter CBD. 75% were willing to take CBD as an intervention for mental health problems. Most participants anticipated fewer side effects with CBD than with existing medications, and preferred tablet or capsule formulations over liquids. Discussion CBD is perceived as a highly acceptable treatment among CHR-P individuals.

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.