BMJ Mental Health

Background: Substance use is common among individuals with depression. Transcranial magnetic stimulation (TMS) is an effective treatment for depression, but current clinical guidelines have discouraged TMS treatment for individuals with depression and co-occurring substance use given concerns for limited efficacy. However, limited data exists on whether substance use affects response to TMS. Methods: Using electronic health record data from patients who received a standard course of TMS for major depressive disorder at an academic medical center, we investigated associations between substance use frequency and response to TMS, defined as change in Patient Health Questionnaire-9 (PHQ-9) scores. Substance use frequency was extracted for alcohol, cannabis, nicotine, stimulants, benzodiazepines, opioids, inhalants, psychedelics, and other drugs. We performed ANCOVA and multiple regression analyses to predict change in PHQ-9 score based on substance use frequency, controlling for pre-TMS PHQ-9 score, age, sex, and number of TMS sessions received. Results: We extracted data from 219 TMS courses. Alcohol was the substance used most commonly (34.2%), followed by prescription benzodiazepines (28.3%), and prescription stimulants (21.0%). Across all substance categories, substance use was not associated with change in PHQ-9 score (all p > 0.05, Cohens d=0.00 to 0.30). In multiple regression models to compare individual levels of substance use frequency (e.g., daily use vs. no use), level of substance use was not associated with change in PHQ-9 score (all p > 0.05). The range of plausible effects of substance use frequency on PHQ-9 change was generally below the minimal clinically important difference for PHQ-9, suggesting substance use was unlikely to have a meaningful clinical effect on antidepressant response to TMS. Conclusions: Low to moderate substance use does not have a clinically significant effect on antidepressant response to TMS. Low-level substance use should not exclude individuals with depression from receiving TMS.

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.

Objective: Whether a scheduled antiseizure medication (ASM) continues on schedule across the ICU-to-floor transfer has not been characterized. We quantified ASM administration-gap frequency across this transfer and compared it with gap frequency during matched non-transfer intervals in the same patient and drug. Methods: In this retrospective MIMIC-IV (version 3.1) cohort study, we identified epilepsy and status-epilepticus admissions with an ICU stay followed by floor transfer and a scheduled ASM order active at ICU departure. A gap was defined as an interval exceeding 1.5 times the expected dosing interval between the last ICU dose and first floor dose, or no further dose before discharge, and compared with a matched non-transfer control interval in the same patient and drug (paired McNemar test). A multivariable model evaluated six prespecified clinical predictors; sociodemographic variables were summarized descriptively. Results: Among 2,469 ASM transition-by-drug observations (1,583 admissions, 1,335 patients), an administration gap occurred in 251 (10.2%; 95% CI, 8.7%-11.7%). Gap frequency across the transfer exceeded frequency during matched non-transfer control intervals in the same patient and drug: a paired rate difference of 5.8 percentage points (95% CI, 4.4-7.1; 7.5% vs 1.7%; P = 7.3 x 10^-22) before the transfer and 6.4 percentage points (95% CI, 4.9-7.9; 8.9% vs 2.5%; P = 1.9 x 10^-23) after. Gap rates were similar for intravenous-available (9.9%) and oral-only (11.4%) drugs (rate difference, 1.5 percentage points; 95% CI, -1.6 to 4.5; P = .34). None of six prespecified predictors reached significance after correction. Significance: An antiseizure medication administration gap occurred in approximately 1 of every 10 drug-transition observations at the ICU-to-floor transfer, exceeding matched non-transfer gap rates by 5.8 to 6.4 percentage points. This transfer-associated excess, rather than any single medication or patient characteristic, supports a structured medication-continuity check.

Background: Metabolomic studies of depression have yielded heterogeneous findings, potentially because metabolic correlates differ across symptoms and metabolic states. We examined symptom-specific metabolomic associations and whether body mass index (BMI) modifies these relationships. Methods: We analyzed 83,717 Estonian Biobank participants (70.6% female) with 249 Nightingale metabolite measures and 14 lifetime depressive symptoms. Logistic regression models progressively adjusted for sociodemographic, lifestyle, medication, and BMI factors. BMI-related attenuation and metabolite x BMI interactions were evaluated, followed by self-organizing map analyses of broader metabolic context. Results: Before BMI adjustment, 660 metabolite-symptom associations were Bonferroni-significant; 136 were significant after BMI adjustment, including 105 retained associations. Weight-related associations showed the strongest BMI dependence: none of 199 weight-gain associations and 2 of 115 weight-loss associations were retained. Among 691 preselected metabolite-symptom pairs, 211 (30.5%) showed significant metabolite x BMI interactions after false discovery rate correction. Six systemic metabolic profiles were identified, but only 3 of 211 BMI-sensitive pairs showed additional profile-dependent heterogeneity. Conclusions: Circulating metabolic correlates of depressive symptoms are heterogeneous and strongly dependent on symptom phenotype and BMI-related metabolic context. These findings suggest that metabolic biomarkers in depression should be interpreted in relation to both symptom presentation and metabolic state rather than as uniform correlates of the disorder.

Isolated rapid eye movement sleep behavior disorder (iRBD) is characterized by nigro-striatal deficits, comprising dopaminergic denervation of the striatum and loss of dopaminergic cells in the substantia nigra (SN), that may herald phenoconversion to clinically manifest synucleinopathy. While phenoconversion has repeatedly been shown to relate to pre-synaptic dopaminergic deficits in the striatum, potential involvement of loss of dopaminergic cells in the SN remain unclear. In addition, phenoconversion may independently relate to noradrenergic deficits, stemming from cell loss in the locus coeruleus/subcoeruleus (LC/LsC) complex. Fifty-six iRBD patients were included and clinically followed over an 11-years as part of the ICEBERG study. Putamen dopamine denervation was quantified using 123I-FP-CIT single-photon emission computed tomography. Cell loss in the SN and LC/LsC was quantified using neuromelanin-sensitive magnetic resonance imaging (MRI). SN cell loss was additionally characterized as free water, derived from diffusion-weighted MRI. The primary outcome was time to phenoconversion. Cox proportional hazards regression was used to investigate relationships between phenoconversion risk and imaging predictors, estimated as hazard ratios (HRs). Out of 56 patients, 24 (41%) converted to a clinically manifest synucleinopathy [PD=14 (58%), DLB=8 (33%), MSA=2 (8%)] over a maximum period of 11 years. We replicated the well-established finding that reduced putamen DaT confers an increased phenoconversion risk [HR (95%CI)=3.1 (1.7-5.5), P<0.001]. We extend on this by showing a similar relationship for SN neuromelanin [HR (95%CI)=2.5 [1.3-4.6], P=0.004], SN free water [HR (95%CI)=1.54 (1.06-2.24), P=0.025], and LC/LsC neuromelanin [HR (95%CI)=2.1 (1.2-3.7), P=0.011], demonstrating involvement of the broader nigro-striatal dopaminergic system along with potential involvement of noradrenergic neurotransmission. When adjusting for putamen DaT, the relationship between phenoconversion risk and SN neuromelanin was attenuated [P=0.16], suggesting partial overlap between the metrics. In contrast, when modelled together, SN neuromelanin [HR (95%CI)=2.8 (1.4-5.6), P=0.003] and LC/LsC neuromelanin [HR (95%CI)=2.3 (1.1-4.8), P=0.037] contributed to phenoconversion risk independently of each other, indicating a differential contribution of dopaminergic and noradrenergic neurotransmitter deficits to iRBD phenoconversion. We demonstrate that phenoconversion in iRBD relates similarly to dopaminergic denervation of the putamen and cell loss in the SN. This opens possibilities for using NM-MRI, which can simultaneously capture dopaminergic and noradrenergic deficits, as an alternative to nuclear imaging techniques when estimating phenoconversion risk in iRBD.

Background: Shiftwork disrupts natural sleep-wake cycles, alters light exposure patterns, and contributes to circadian misalignment. Detrimental health consequences associated with shift work include elevated risk for metabolic disorders, cardiovascular disease, cancer and all-cause mortality. Healthcare workers have one of the highest rates of shift work exposure, yet there are relatively few non-pharmacological interventions (with good evidence) developed to improve sleep outcomes in this population. Objective: A pre-post pilot interventional study assessed the acceptability and perceived effectiveness of commercial noise-masking earbuds on improving subjective sleep characteristics among National Health Service (NHS) healthcare staff working fast rotating shifts. Methods: Noise-masking sleep earbuds (Kokoon NightBuds) were worn for a pilot six-week intervention by twenty-seven NHS nurses (aged 26-43 years, 88.9% female) working fast rotating shifts from the EClocker Study. Sensors inside the earbuds were paired with a smartphone app to monitor sleep. An audio library in the smartphone app delivered personalised relaxation exercises and sleep techniques drawn from cognitive behavioural therapy for insomnia (CBT-I). A pre-post two-week monitoring period with daily smartphone-based Experience Sampling Methods (ESM) captured perceived daily sleep patterns. Acceptability and perceived effectiveness of the earbuds in promoting better sleep outcomes was assessed. Results: Use of the noise-masking sleep earbuds over a six-week period was associated with positive sleep improvement trends and elicited promising acceptability. Almost two thirds of NHS fast rotating shift nurses (63%) subjectively reported reductions in general sleep disturbance symptoms (PSQI Global), one in four experienced perceived sleep quality improvements (SQ; 25.9%), one in five reported sleeping longer (TST; 22.2%), and a third perceived falling asleep faster (SOL; 33.3%), had better sleep efficiency (SE; 33.3%) and improved daytime dysfunction (33.3%) (PSQI subcomponent scores). Sleep diaries (CSD) collected daily using smartphone-based ESM also demonstrated small improvements post-sleep earbud use; nurses reported sleeping an average 18 minutes longer (TST) and fell asleep more easily, on average 11 minutes faster (SOL). Sleep earbuds were generally well tolerated; 56% of nurses reported the earbuds as (somewhat to very) helpful, 52% reported (somewhat to strongly) falling asleep more easily (SOL), 44% felt (somewhat to strongly) their sleep quality was improved (SQ) and 30% agreed (somewhat to strongly) they slept longer (TST) and had less disturbed sleep. Conclusions: To our knowledge, this is the first study in Europe to pilot noise-masking earbuds as a potential non-pharmacological aid to improve sleep-wake behaviours or mitigate fatigue for healthcare staff. Preliminary results showed promising acceptability and (small) perceived sleep improvement trends following a targeted six-week earbud intervention in NHS fast rotating shift nurses.

Major depressive disorder (MDD) is strongly associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, systemic inflammation, and gut microbiota dysbiosis. Although selective serotonin reuptake inhibitors such as escitalopram are standard treatments, their efficacy is often constrained by partial response and gastrointestinal adverse effects. In this 12-week, randomized, double-blind, placebo-controlled trial, we evaluated the clinical efficacy and microecological mechanisms of adjunctive Lactiplantibacillus plantarum PS128 (PS128; 6*1010CFU/day) in MDD patients on stable escitalopram therapy. Adjunctive PS128 significantly enhanced clinical response compared to placebo, yielding substantial reductions in HAMD-17 and MADRS, alongside a higher remission rate. 16S rRNA sequencing and PICRUSt2 profiling revealed that PS128 enriched key short-chain fatty acid producers (Faecalibacterium, Coprococcus), counteracting the Klebsiella expansion seen in placebo. Functionally, PS128 up-regulated neuroprotective cofactor, B vitamins, biosynthesis and down-regulated the neurotoxic kynurenine pathway. Network analysis demonstrated that PS128 maintained a resilient, integrated microbial co-occurrence topology, whereas the placebo network showed structural segregation. This stabilized ecosystem attenuated peripheral inflammatory signaling and normalized salivary cortisol levels. Overall, adjunctive PS128 augments escitalopram efficacy by enhancing gut network stability, supporting cellular energetics, and modulating neuroendocrine activity, offering a promising multimodal strategy for MDD.

This study investigated bidirectional associations between maternal sleep and depressive symptoms from preconception to postpartum, and whether infant sleep mediated or moderated these associations. We used data from the Generation R Next Study (N=2,294). Maternal sleep (specifically general sleep disturbance, latency, quality, duration, and midpoint) and depressive symptoms were prospectively assessed at five timepoints from preconception to 12-month postpartum. Sleep was self-assessed with the General Sleep Disturbance Scale and Munich Chronotype Questionnaire; depressive symptoms with the Adult Self Report depression/anxiety subscale and Edinburgh Postnatal Depression Scale. Infant sleep (specifically night awakenings, nocturnal sleep duration, and latency) was parent-reported at 1-month postpartum using the Brief Infant Sleep Questionnaire. Bidirectional associations were examined using Autoregressive Latent Trajectory Models with Structured Residuals. The role of infant sleep was examined using mediation and moderation analyses. We found that maternal sleep and depressive symptoms were both stable over time. For sleep quality and disturbance, bidirectional associations suggested slightly stronger effects from depression to sleep (sleep quality:{beta}depression[-&gt;]sleep quality=0.11, 95%CI:0.07 - 0.14; general sleep disturbance:{beta}depression[-&gt;]sleep disturbance=0.14, 95%CI:0.10 - 0.18) than from sleep to depression ({beta}sleep quality/disturbance[-&gt;]depression=0.07 for both, 95%CIs:0.03 - 0.11). For latency, effects were comparable in both directions ({beta}depression[-&gt;]sleep latency=0.06, 95%CI:0.03 - 0.09; {beta}sleep latency[-&gt;]depression=0.05, 95%CI:0.01 - 0.09). The association between depressive symptoms and sleep latency was both mediated (9.7%) and moderated (p<0.05) by infant sleep latency. In conclusion, general maternal sleep disturbance, sleep quality, and sleep latency showed bidirectional associations with depressive symptoms from preconception/early pregnancy onwards. Infant sleep latency may represent a potential modifiable factor within this cycle.

Background: Inequalities exist for many health outcomes, but there is limited evidence regarding menstrual symptoms despite their importance for health and wellbeing. We aimed to investigate inequalities in menstrual symptoms according to socioeconomic position and childhood adversity. Methods: In two generations (G0 mothers and G1 offspring) from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective cohort study, we examined associations of multiple indicators of socioeconomic position (SEP) and adverse childhood experiences (ACEs) with menstrual symptoms (pain, abnormal uterine bleeding, and premenstrual syndrome (PMS) measured 3-8-years post-birth in G0 and 17-21-years-old in G1), using multivariable logistic regression. Samples ranged from 4,828 to 9,335 G0 participants and 1,288 to 2,757 G1 participants depending on the exposure-outcome association. Missing data were addressed using multiple imputation and inverse probability weighting. Results: Financial difficulties were associated with greater odds of menstrual pain (G1 OR 1.41; 95% CI 1.07, 1.86: G0 OR 1.55; 95% CI 1.36, 1.76) and irregular cycles (G1 OR 1.60; 95% CI 1.12, 2.29: G0 OR 1.48; 95% CI 1.27, 1.72) in both generations, as well as with short/long cycle lengths in G0 only. Lower education and manual social class were also associated with these three menstrual symptoms in at least one generation. Conversely, higher SEP was associated with PMS in both generations. Higher cumulative ACEs were consistently associated with menstrual pain (4+ compared to none: G1 OR 2.15; 95% CI 1.48, 3.11: G0 OR 1.52; 95% CI 1.29, 1.80) and irregular cycles (G1 OR 1.92; 95% CI 1.20, 3.09: G0 OR 1.54; 95% CI 1.26, 1.87) but not cycle length. Lower parental education, financial difficulties, and cumulative ACEs were associated with heavy bleeding in G1 offspring only, whereas financial difficulties, own manual social class, and cumulative ACEs were associated with prolonged bleeding in G0 mothers only. Higher cumulative ACEs were also associated with PMS in G1 offspring only. Conclusions: We found evidence of inequalities according to socioeconomic disadvantage and childhood adversity for multiple menstrual symptoms, although some associations were only observed in one generation. Findings suggest that menstrual symptoms are disproportionately experienced by socially and socioeconomically disadvantaged women.

Background Sleep, mood, and affective states are mutually connected. There is a paucity of studies, however, that have considered bidirectional relationships between daily sleep-affective dyads in naturalistic settings, particularly for shift workers. Objective To evaluate the dynamic and temporal interplay of daily smartphone-based self-reported sleep measurements, dimensions of affective experience and cognitive processing in UK shift working nurses. Methods The EClocker Study prospectively monitored 102 National Health Service (NHS) nurses (aged 25-61 years, 83.3% female) working standard (day shift) and non-standard (fast rotating shifts) schedules over a two-week period. Smartphone-based Experience Sampling Methodology (ESM) recorded daily sleep, mood, momentary affect and cognitive attentional functioning. Self-reported burnout, emotional dysregulation, emotion reactivity and affective dimensions (positive and negative) were also collected. Findings Overall, NHS nurses reported a high prevalence of depressive symptoms, stress, burnout and sleep-circadian rhythm disturbances. Generalised Additive Modelling (GAMs) revealed that NHS nurses higher perceived sleep quality predicted better next-day mood state, while better daytime mood was associated with reduced sleep onset latency, such that participants reported falling asleep faster. In contrast, daytime mood or affect (positive and negative) had no substantial, direct impact on nurses subjective sleep parameters (sleep quality, sleep duration, sleep efficiency). Exposure to fast rotating night shifts across the two-week study was associated with more frequent response errors on a Choice Reaction Time (CRT) cognitive task, while daytime somnolence did not adversely influence nurses momentary reaction time speeds or attentional function. Conclusions Clinically relevant sleep impairments, insomnia-related symptoms, elevated stress, and poor mood were pervasive in a sample of UK NHS nurses, regardless of shift type. Sleep quality impacted next-day mood and daytime mood impacted sleep latency, while rotating shifts led to an increase in cognitive errors. Recognising the impact of shiftwork and designing interventions to promote better sleep quality offer potential to enhance mood and performance in healthcare professionals. Clinical implications We need to implement and evaluate interventions that regularise sleep patterns and promote sleep quality to alleviate mood symptoms among frontline NHS shift workers.

A body of research suggests that autistic individuals are less likely to drink alcohol than neurotypicals. However, emerging studies support a link between autism and alcohol use. This complex relationship is also reflected in studies that have examined the genetic overlap between the two traits. However, it is unclear whether there is a direct causal relationship between them. To explore this, we applied a combination of polygenic score and Mendelian randomisation analyses using publicly available genome-wide summary statistics and phenotypic measures of autism and alcohol consumption from UK Biobank. LD score regression analyses did not provide evidence of a genetic correlation between genetic liability for autism and drinks consumed per week (rg=-0.08; CI95%=-0.19, 0.03). Further, findings from polygenic score analyses did not support an association between genetic liability for autism and overall monthly alcohol intake. Univariable Mendelian randomisation analyses showed little evidence for a total effect of autism, attention deficit hyperactivity disorder (ADHD) or depression on overall monthly alcohol consumption. Multivariable Mendelian randomisation analyses also showed little evidence of a direct effect of autism on drinks per week when controlling for ADHD and depression. It is plausible that genetic liability for autism does not directly increase the amount of alcohol consumed but instead operates via commonly co-occurring difficulties in the autistic community. However, our findings may be due to methodological shortcomings, including weak instruments biasing effects towards to the null. Consequently, results should be interpreted with caution and further research conducted to address these issues.

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factor for Parkinson's disease (PD). G2019S, the most common pathogenic variant, has been linked to milder motor symptoms, but the effects of other LRRK2 variants on disease trajectory remain incompletely characterized. R1441G, the second most common pathogenic variant, co-occurs with the PD risk variant M1646T on a shared haplotype. Whether this haplotype confers a distinct rate of motor progression has not been established. Methods: We analyzed up to 12 years of longitudinal data from 603 participants in the Parkinson's Progression Markers Initiative (PPMI) with PD and available whole-genome sequencing data: 394 sporadic PD, 169 G2019S carriers, 20 R1441G+M1646T carriers, and 20 M1646T carriers. Motor symptom progression (MDS-UPDRS III) was assessed using linear mixed-effects models with genotype-by-time interactions, adjusted for age at onset, disease duration at baseline, sex, race, baseline score, and levodopa equivalent daily dose. Results: R1441G+M1646T carriers exhibited 76% slower progression in OFF-state MDS-UPDRS III than sporadic PD (0.50 vs. 2.04 points/year; {beta}=-1.54 [95% CI: -2.48, -0.60]; p=0.001). G2019S carriers exhibited 26% slower progression (1.52 points/year; {beta}=-0.52 [-0.99, -0.06]; p=0.03). M1646T carriers did not differ from sporadic PD (p=0.60). Slower progression in R1441G+M1646T carriers was characterized by attenuated bradykinesia (64% slower; p=0.008), axial decline (76% slower; p=0.002), and a lack of orofacial symptom progression (p<0.001). R1441G+M1646T carriers also exhibited 55% slower self-reported motor decline (MDS-UPDRS II; p=0.04) Conclusions: R1441G+M1646T carriers exhibit substantially slower motor progression than sporadic PD while M1646T carriers do not.

Parkinsons disease (PD) arises through disruption of multiple interconnected cellular processes, but the genetic contributions to these processes may differ across ancestries. We investigated functional convergence among genes harboring pathogenic or likely pathogenic (P/LP) variants and variants of uncertain significance (VUS) in a multicenter Indian cohort recruited through the Genetics of Parkinsons Disease in India Young Onset Parkinsons Disease project (GOPI YOPD). The cohort included 668 participants (463 males 69.3%) with a mean age at motor onset of 39.4+/-8.8 years. P/LP variants and VUS identified through previously reported whole-exome or whole genome sequencing were retained as separate evidential categories. The P/LP-associated gene set comprised 11 unique genes and the VUS associated set comprised 40 unique genes. Separate STRING functional-enrichment analyses evaluated Gene Ontology Biological Process, Molecular Function and Cellular Component terms, KEGG pathways, WikiPathways and STRING local network clusters. Terms meeting a Benjamini Hochberg false discovery rate threshold of <0.05 were organized into eight non-mutually-exclusive ontology/pathway categories. Gene to pathway mappings were subsequently projected to individual participants to estimate pathway representation and examine clinical associations. At least one reportable P/LP variant or VUS was identified in 336/668 participants (50.3%): 35 had a P/LP variant alone, 282 had VUS alone and 19 had a P/LP variant together with VUS in one or more additional genes. The most frequently represented categories were mitochondrial organization (247/336, 73.5%), autophagy related processes (228/336, 67.9%) and regulation of synaptic vesicle transport (201/336, 59.8%). PRKN was the most frequent P/LP-associated gene, occurring in 29/54 P/LP carriers, followed by PLA2G6 and PINK1. Lysosomal transport was represented exclusively by VUS-associated genes, particularly GBA1, VPS13C and LRRK2. Among P/LP carriers, additional VUS in distinct genes were not associated with age at onset (P = 0.81) or family history (52.6% versus 31.4%; P = 0.15). No pathway phenotype association remained significant after correction for multiple testing. Genetic findings in this Indian cohort converged across an interconnected mitochondrial autophagic lysosomal vesicular network, with different contributions from P/LP-associated and VUS associated gene sets. This study provides the first pathway resolved South Asian genetic profile and a framework for comparative studies across populations.

Background: Cognitive impairment is the leading cause of disability in schizophrenia with limited treatments. A major barrier to treatment development is the absence of reproducible, mechanistically grounded neural targets. Cross-sectional studies have identified dorsomedial prefrontal cortex (DMPFC)-somatomotor connectivity as a neural marker of cognitive performance on the Auditory Continuous performance task (ACPT), a measure of attention. To test the stability of this marker, we tested the relationship between DMPFC-somatomotor connectivity and ACPT performance in a longitudinal psychosis sample. Methods: Individuals with early psychosis (n=251) and matched controls (n=90) were enrolled and underwent resting-state neuroimaging and neurocognitive assessment. A subset completed longitudinal assessments over 2-4 years. We calculated DMPFC-somatomotor resting-state functional connectivity using a previously identified DMPFC region and a seed in the somatomotor cortex. We performed linear mixed effects models to predict ACPT performance based on connectivity, time, psychosis type, and their interaction. Results: In the psychosis sample, time (p=.0037) and affective psychosis diagnosis (p<.0001) predicted better ACPT performance. In a model predicting ACPT performance, we observed a significant interaction effect of DMPFC-somatomotor connectivity*psychosis subtype (p=.0079) such that DMPFC-somatomotor connectivity predicted ACPT performance only in individuals with non-affective psychosis (p=.0051). We then tested the specificity of this connectivity-cognitive performance relationship. In a model predicting DMPFC-somatomotor connectivity, only ACPT performance (p=.017), but not fluid cognition, was a significant predictor. Conclusions: DMPFC-somatomotor connectivity is longitudinally associated with cognitive performance in early psychosis. This relationship is strongest in nonaffective psychosis, suggesting a novel, reliable target for intervention for cognitive deficits in early psychosis.

Background: Unruptured intracranial aneurysms (UIAs) are increasingly identified incidentally, and management balances rupture risk against treatment risk. UIA diagnosis has been linked to psychological distress, but psychotropic medication initiation after UIA discovery has not been compared across the full UIA management spectrum. Methods: We conducted a retrospective cohort study using IBM MarketScan claims (CCAE, MDCD, and MDCR; 2009-2023) among adults with a UIA diagnosis, continuous enrollment for 365 days before and after the index date, and no SAH/rupture on or before the index date. We compared the prevalence of 6 mental-health diagnoses before versus after UIA discovery and used adjusted logistic regression to examine psychotropic medication initiation within 365 days by management strategy (untreated observation as the reference). Results: Among 54,945 patients (untreated, 78.5%; endovascular, 11.3%; clipping, 3.0%; other/uncertain, 7.2%), prevalence of every mental-health diagnosis was higher after UIA discovery, most for depression (+4.6 percentage points) and anxiety (+4.5 points). Medication initiation was most common for benzodiazepines (8.7%). Endovascular treatment was associated with higher adjusted odds of benzodiazepine (aOR, 1.21), SSRI (aOR, 1.20), and sedative-hypnotic (aOR, 1.25) initiation.Surgical clipping demonstrated the broadest association, with higher odds across 5 of 6 classes, including benzodiazepines (aOR, 1.71) and sedative-hypnotics (aOR, 1.86). Benzodiazepines had the lowest 1-year persistence (10.5%) despite being the most commonly initiated class. Findings were consistent across sensitivity analyses, with the exception of the increase in panic disorder, which was no longer observed after applying a 30-day post-index lag. Conclusions: Mental-health diagnoses and psychotropic medication initiation increased after UIA discovery, and medication initiation was most pronounced among patients treated with surgical clipping. These findings support psychological assessment as part of aneurysm management regardless of strategy.

Aim: The Patient Safety Screener-3 (PSS-3) is a brief suicide-risk screening tool. Item 1 of this scale assesses depressive mood but is not included in the total score. We examined the association of item 1 with depressive symptom severity and characterized the suicide-related risk captured by PSS-3 total positivity. Methods: We conducted a nationwide cross-sectional survey among resident physicians in Japan. Associations between PSS-3 item 1 endorsement and Patient Health Questionnaire-9 (PHQ-9) scores were evaluated using the Wilcoxon rank-sum test. Diagnostic performance of item 1 was evaluated using PHQ-9 positivity ([&ge;]10) as reference standard. We also compared Short-form Scale for Suicide Ideation (SIS-6) scores according to PSS-3 total positivity and PHQ-9 item 9 positivity. Results: A total of 1,844 participants were included. PSS-3 item 1 was endorsed by 443 physicians (24.0%), and 47 (2.5%) met the criteria for PSS-3 total positivity. Item 1 showed 79.3% sensitivity and 79.5% specificity for PHQ-9 positivity. SIS-6 scores were higher in the PSS-3 total-positive group than in the total-negative group (median [IQR], 6 [5-9] vs 0 [0-1]; p<0.001). The SIS-6 showed a higher area under the receiver operating characteristic curve (AUC) and Youden index using PSS-3 total positivity (AUC, 0.961; optimal cutoff, 3) than PHQ-9 item 9 positivity (AUC, 0.907; optimal cutoff, 2). Discussion: PSS-3 may support brief, simultaneous screening for depressive symptoms and suicide-related risk. Compared with PHQ-9 item 9, PSS-3 may capture a more severe spectrum of suicide-related risk. PSS-3 may facilitate identification of individuals requiring further mental health assessment.

Dopamine replacement therapy (DRT) alleviates motor symptoms in Parkinson's disease (PD) but can trigger hallucinations in a subset of patients, yet the neural basis of this selective vulnerability is unknown. Hallucinations are among the most disabling non-motor symptoms of PD, linked to social isolation, dementia and institutionalization. Using a validated robotic paradigm to induce and quantify hallucinations in real-time, combined with resting-state fMRI in a crossover On/Off DRT design, we studied patients with PD with (PD-H) and without (PD-nH) hallucinations. DRT selectively amplified sensitivity to robot-induced hallucinations in patients with pre-existing hallucinatory phenotype (PD-H, but not PD-nH) and was accompanied by cortico-striatal and large-scale network hyperconnectivity. Rather than supporting a uniform hallucinogenic effect of dopamine in PD, these findings indicate that DRT interacts with an intrinsic neural vulnerability that varies in patients. Prospective studies will establish whether this pharmacological-behavioural signature identifies patients at risk before clinical hallucinations emerge.

Objective: Cognitive impairment is a common comorbidity among people with epilepsy (PWE) and is associated with disability and reduced quality of life. We characterized the burden of cognitive impairment and identified factors associated with cognitive performance in a large, population-based cohort of PWE living in Northern Peru, a region highly endemic for Taenia solium where neurocysticercosis (NCC) is a common cause of acquired epilepsy. Methods: PWE enrolled in a population-based cohort in Northern Peru between 2007 and 2020 completed the Mini-Mental State Examination (MMSE) at enrollment. Cognitive impairment was defined as an MMSE score <24. Demographic and clinical data, including epilepsy characteristics and NCC status, were collected. Negative binomial regression was used to identify factors associated with the number of MMSE errors. Results: Among 764 participants, the mean MMSE score was 26.4 (SD 4.2), and 16.4% met criteria for cognitive impairment. Memory and attention were the most affected domains. In multivariable analysis, older age and lower educational attainment were independently associated with poorer cognitive performance. Conclusion: In this large, community-based cohort from Northern Peru, approximately 1 in 6 PWE had abnormal global cognition on the MMSE, with memory and attention most affected. These findings underscore the importance of incorporating cognitive evaluation and management into comprehensive epilepsy care, particularly in resource-limited settings where cognitive morbidity may be underrecognized. Given the potential for cognitive difficulties to compound disability and adversely affect quality of life, identifying and addressing cognitive morbidity may be especially important in populations already facing substantial barriers to epilepsy care.

Background: As cannabis policy changes in the United States, secondhand cannabis smoke (SCS) is increasingly common, including within families. However, prevalence of exposure and clinical correlates over time in adolescents are not fully understood. Objectives: (1) To estimate the prevalence of SCS and personal cannabis use in US-based teens exposed to SCS, and (2) examine the cognitive trajectories of adolescents exposed to SCS compared to non-exposed peers. Methods: Data from the Adolescent Brain Cognitive Development (ABCD) Study was used. Participants (n=11,316 of full cohort with follow-up data; n=776 with self-reported family SCS exposure) attended yearly visits from ages 11-17, completing substance use interviews, toxicological testing, and the NIH Toolbox Cognitive battery. Youth with SCS but no personal cannabis use (n=419; 47% female) were matched on prenatal substance exposure, family substance use history, and sociodemographics to non-SCS exposed and non-cannabis-using youth with a 1:2 ratio (Controls n=838). Linear mixed-effects models assessed cognitive performance by SCS*age interactions, accounting for random effects of subject and family. Covariates included sex and alcohol, nicotine, and other substance use. Secondary models analyzed performance by cumulative waves of reported SCS exposure interacting with age. Results: Of the full cohort, 6.9% (n=776) reported exposure to SCS. Of these individuals, 46% endorsed lifetime personal cannabis use by age 17, relative to 20% of non-SCS exposed youth (OR=3.83[95%CI:3.29,4.44]). Within matched participants, SCS*age demonstrated a significant interaction on attention and inhibitory control ({beta}=-0.32, p=.028), with SCS demonstrating reduced improvement over time. More waves of exposure were also associated with worse performance over time ({beta}=-0.39, p=.057). Discussion: Almost half of those who had been exposed to SCS endorsed personal cannabis use. Cognitive findings were domain specific, similar to findings in secondhand tobacco: SCS exposed youth showed restricted improvement in attention and inhibitory control by age 17. Public health and policymakers should make efforts to curb youth SCS exposure, given the potential for risk which has not been fully explored to date.

Background: Bipolar disorder is associated with persistent social, cognitive, and functional impairment during euthymia, yet the neural mechanisms underlying these deficits remain unclear. Alterations to self-referential processing are a candidate mechanism, but existing electrophysiological studies rely on emotionally valenced paradigms that potentially confound self-processing with emotional biases. Methods: We analysed electroencephalography from 28 patients with bipolar disorder (type I or II) and 28 age- and sex-matched healthy controls during an emotionally neutral colour judgment task with self-related (preference) and non-self-related (similarity) conditions. Late positive potentials, temporal generalisation decoding, and frequency band decoding (theta, alpha, beta) were used to characterise the temporal dynamics and oscillatory correlates of self versus non-self processing. Results: Controls showed higher overall event-related potential amplitudes and greater self versus non-self differentiation than patients (condition by group interaction, 337 to 946 ms). Broadband temporal generalisation decoding revealed extensive cross-temporal generalisation of the self versus non-self representation in controls, spanning most of the trial, but no significant generalisation in patients. Frequency analyses showed that alpha and beta carried self versus non-self information in both groups, with broader extent in controls, and that anterior theta carried this information in patients but not controls. Exploratory correlations linked decoding measures to rumination and anxiety but not to manic symptoms. Conclusions: The neural representation distinguishing self-referential from externally guided processing was both smaller in amplitude and less temporally sustained in bipolar disorder. Reduced persistence is not detectable by conventional amplitude analyses, and may bear on the self-related and social cognitive difficulties reported in this population.