Neuroscience & Biobehavioral Reviews

Neighbourhood deprivation is one of the few potential policy-modifiable risk factors for psychiatric and neurological disorders, but the neurobiological pathways underlying these associations remain unclear. We investigated these relationships across three cohorts spanning the life span: the Healthy Brain and Child Development (HBCD) Study (n = 84, aged 0 to 4 weeks postnatal), the Adolescent Brain Cognitive Development (ABCD) Study (n = 4,792, aged 9 to 10 years), and the UK Biobank (UKB; approximately 500,000 adults, aged 44 to 87 years). Neighbourhood deprivation was associated with elevated disease risk, and individual lifestyle factors accounted for only a small fraction of this burden, indicating that the much larger residual effect reflects broader contextual characteristics of deprived environments rather than individual behaviours alone. Across all cohorts, greater deprivation consistently predicted lower cortical and subcortical brain volume, with effects detectable in early development and substantially stronger in adulthood. Across disorders, regional brain volume emerged as a consistent neuroanatomical mediator linking neighbourhood deprivation to neuropsychiatric disease. We further showed that deprivation preferentially affects brain regions intrinsically vulnerable to neuropsychiatric disorders. Spatial decoding analyses implicated dopaminergic and serotonergic neurotransmitter systems together with specific excitatory and inhibitory neuronal classes. Importantly, both the deprivation effects and their neuroanatomical mediation patterns were replicated across independent populations. Our study delivers a translational framework linking neighbourhood deprivation to brain health, which could inform public health policies and preventive interventions.

Background: In Denmark, perioperative high-dose glucocorticoid treatment were step-wisely implemented for total hip arthroplasty (THA), total knee arthroplasty (TKA), and unicompartmental knee arthroplasty (UKA). We aimed to estimate the effect of a single high dose of glucocorticoids on opioid consumption following primary THA, TKA, and UKA. Methods: This was a prespecified analysis of a multicenter natural experiment using electronic health record data. We included elective THA, TKA, or UKA surgeries performed in Eastern Denmark from 2017-2025. At each center, surgeries before implementation of high-dose glucocorticoids served as controls, whereas surgeries after implementation comprised the intervention group. The primary outcome was the between-group difference in cumulative 0-24h opioid consumption, which included preemptive end-of-surgery doses. The predefined minimal important difference was set at 5 mg IV morphine equivalents. Secondary outcomes were maximum 0-10 numerical rating scale (NRS) pain score and incidence of opioid-related adverse events within 24 hours, hospital length of stay, and days alive and out of hospital at 30 days. Results: A total of 47,317 surgeries performed at nine centers were analyzed: 13,010 controls and 34,307 in the intervention group. During the study period, five centers implemented high-dose glucocorticoids for THA patients, two for TKA/UKA patients. High-dose glucocorticoids were administered to 6% of patients before implementation versus 92% after. High-dose glucocorticoids resulted in a mean reduction of 3.8 mg intravenous (IV) morphine equivalents (95% CI 3.3;4.3). The intervention also reduced the maximum 0-24h NRS pain score by 0.8 points (99% CI 0.7;0.9), but there was no difference in adverse events, length of stay, or days alive and out of hospital. Conclusions: Implementation of high-dose glucocorticoids reduced 0-24-hour opioid consumption by 3.8 mg IV morphine equivalents after elective hip and knee arthroplasty. This difference was below the prespecified minimal important difference threshold. Online registration: https://doi.org/10.1101/2025.11.11.25339982

Background: Fluctuations in pain intensity are intrinsic to non-specific chronic low back pain (nsCLBP). Nevertheless, pain fluctuations have rarely been considered when investigating pathophysiological mechanisms. Therefore, a novel study protocol was developed and implemented to systematically assess the impact of fluctuating pain states on pain-related measures. Methods: The final study cohort consisted of 45 nsCLBP patients and 47 age- and sex-matched healthy controls (HCs). Patients participated in three visits, conducted during different pain states (i.e. clinically relevant pain, low-intensity clinical pain / pain-free, clinically irrelevant pain induced using a Qutenza 8% capsaicin patch). Pain fluctuations were monitored through online assessments every four days and guided the pseudorandomized visit scheduling. HCs participated in a single visit. Each study visit comprised a multimodal battery of pain-related measures. Results: 93.33% of patients completed all three visit types in a pseudorandomized order (chi-squared=1.50, p=0.826). Visit scheduling was possible due to the high self-report adherence (median=93.48%), unrelated to self-report burden (rho=-0.097, p=0.53). Study visits were conducted during different pain states, as indicated by: i) the significantly higher low back pain intensity in the clinically relevant pain visit (mean[SD]: 3.98[0.90]), compared to the low-intensity clinical pain (1.03[0.86]) and clinically irrelevant pain (1.13[0.82]) visits (p-values<0.001), as well as by ii) the successful induction of a moderate-to-high clinically irrelevant pain across assessments. Conclusion: Despite scheduling complexity and pain state transition uncertainty, a pain state-dependent pseudorandomized study design is feasible and could improve the understanding of nsCLBP mechanisms.

Background: Storage symptoms after stroke-isolated urgency, urgency with frequency, and isolated frequency are common but traditionally attributed to a single overactive bladder mechanism via suprapontine disinhibition. However, clinical heterogeneity in symptom presentation suggests distinct underlying mechanisms. We aimed to characterize the neural substrates of three storage symptom subtypes after stroke using comprehensive lesion-symptom mapping. Methods: We prospectively evaluated 1,498 consecutive subacute stroke patients admitted for inpatient rehabilitation (1,105 men, 73.8%; median age 61 years). Storage symptoms were classified into three subtypes: isolated urgency (n=109), urgency with frequency (n=32), and isolated frequency (n=19). Multivariable logistic regression models with Bonferroni correction identified independent predictors across demographic, clinical, white matter hyperintensity (WMH), brain atrophy, and lesion location variables. Results: The three subtypes demonstrated largely distinct sets of independent predictors. The left genu of the corpus callosum (aOR=20.06, 95% CI 7.78-51.74, P<0.001) and the inferior frontal gyrus (aOR=3.48, 95% CI 1.81-6.67, P<0.001) were independently associated with isolated urgency and survived Bonferroni correction, together with a right IFG-insula synergistic effect (OR=21.46, 95% CI 10.49-43.88, P<0.001). Urgency with frequency was associated with a broad fronto-cingulate network-the IFG (aOR=11.45, 95% CI 3.10-42.33, P<0.001, surviving Bonferroni correction) and the ACC (aOR=11.53, 95% CI 2.40-55.49, P=0.002) with diffuse right-hemisphere dominance, older age and brain atrophy. Isolated frequency was associated with anterior corona radiata involvement (aOR=5.46, 95% CI 1.92-15.54, P=0.002) and male sex (aOR=10.62, 95% CI 1.36-82.98, P=0.024), though none reached the strict Bonferroni threshold. Conclusions: These findings identify three mechanistically distinct post-stroke storage symptom subtypes with separable neural substrates, lateralization profiles, and clinical determinants. The triple dissociation across subtypes supports a discrete pathway model over the traditional unitary OAB framework, providing a neuroanatomically grounded basis for subtype-stratified treatment Keywords: storage symptoms; subacute stroke; hemispheric lateralization; structural synergy; lesion-syndrome mapping

Mitochondria are central hubs for cellular metabolism and mitochondrial dysfunction is a hallmark of many chronic diseases. Consequently, changes in mitochondrial DNA copy number (mtDNA-CN), the number of mtDNA genomes per cell or tissue sample, are associated with diseases ranging from cancer and obesity to psoriasis and all-cause mortality. MtDNA-CN especially holds promise as a biomarker for neurodegenerative diseases, but whether and how mtDNA-CN changes with neurodegeneration is controversial. Here, we performed a systematic review and meta-analysis of 76 studies including 156 comparisons of mtDNA-CN in populations with or without a neurodegenerative disease to identify overall trends and potential moderators that explain variation among studies. Overall, mtDNA-CN was not statistically different with neurodegeneration, but heterogeneity among studies was extreme (I2 = 99.5%). The diagnosed disease explained the most variation. For example, Alzheimer's patients showed a 21% decrease in mtDNA-CN, but there was no change in mtDNA-CN with Parkinson's disease. Decreases in mtDNA-CN during neurodegeneration were also more extreme at older ages. Surprisingly, the tissue sampled for mtDNA-CN was not particularly influential, except for certain diseases. Studies published in earlier years also showed more extreme decreases in mtDNA-CN with neurodegeneration. Excessive heterogeneity persisted even after accounting for all moderators and their interactions (I2 = 85.7%). We conclude that the general perception of decreased mtDNA-CN with neurodegeneration is a vast oversimplification that may stem from legacy effects of early studies. However, mtDNA levels offer great promise as biomarkers for neurodegeneration, other diseases, and general health metrics, assuming appropriate complications can be considered.

Background: Endometriosis is a chronic pain condition in which hormonal therapies form the cornerstone of long-term management. Treatment tolerability is critical for adherence and therapeutic success, but most comparative studies and reviews have focused on their ability to reduce menstrual pain, while their impact on non-menstrual pelvic pain (NMPP), bleeding patterns, adverse events (AEs), treatment discontinuation and quality of life (QoL) remain poorly characterised. This systematic review and meta-analysis evaluate these outcomes across currently available hormonal therapies, providing practical evidence for clinical decision-making. Methods: PubMed/MEDLINE, Scopus, and Embase were searched up to November 2025 for randomised controlled trials comparing at least two active first- or second-line hormonal treatments for endometriosis. Studies without confirmed endometriosis, treatment duration less than three months and comparing therapies to placebo only were excluded. Data were extracted by two reviewers from reports. Pain outcomes were pooled as mean differences (MD, 95% CI), with bleeding patterns, AEs, and discontinuations as proportions. Analyses were performed in R. PROSPERO: CRD420251137785. Findings: Of 1892 records screened, 48 trials (5583 women) met our inclusion criteria. Overall pelvic pain (0-10 scale) was significantly reduced across all treatment categories (p<0.001): combined oral contraceptives (COCs) (MD 3.17), oral and long-acting progestogens (MD 3.83; MD 4.29), and GnRH-analogues (MD 3.81). Sensitivity analyses restricted to studies reporting NMPP yielded comparable results. GnRH-agonists showed the most favourable bleeding profile, followed by continuous COCs. However, all regimens reported class-specific AEs, including mood changes, nausea, headache, weight gain, and decreased libido (pooled proportions >10%). Overall discontinuation due to AEs was 7.7%, and vaginal bleeding was the leading cause. Heterogeneity across meta-analyses was high. Risk of bias (RoB2) was moderate to high. Interpretation: Given similar reductions in overall pelvic pain across hormonal therapies, treatment decisions should prioritise differences in bleeding profiles, therapy-specific AEs, and QoL. Funding: None.

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.

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.

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.

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.

Generalization is a key cognitive process that allows humans to flexibly apply prior knowledge to guide new behaviors. Difficulties with generalization and flexibility are observed across neurodevelopmental disorders, especially autism, limiting adaptive function and quality of life. Cognitive-behavioral treatment benefits some but not all autistic individuals. As treatment requires application of learned skills to everyday life, variability in generalization ability may limit intervention success in autism. While cognitive substrates of learning and generalization are well established, their potential for explaining clinical outcomes is not known. Here, we combined a category learning task with computational modelling to distinguish two learning strategies underlying generalization -- prototype abstraction vs. exemplar memorization -- and tested whether individual differences in these learning strategies predicted real-world intervention outcomes in autistic youth. Fifty-four participants completed the category learning task at two pre-intervention timepoints, and then completed Unstuck and On Target:14-22 intervention targeting flexible problem solving, goal setting, and planning. We found that participants who consistently relied on prototype abstraction (N=26) were subsequently more likely to benefit from the intervention, showing improvement in parent- and self-reported flexibility. These findings identify prototype abstraction as a clinically relevant cognitive capacity that may help explain individual differences in intervention response and support the tailoring of interventions. More broadly, they demonstrate the value of linking basic cognitive mechanisms to clinical outcomes and may inform strategies to enhance the effectiveness of cognitive-behavioral interventions for youth with developmental disabilities.

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.

Background: The Centiloid (CL) scale standardizes global amyloid PET quantification and is widely used to define amyloid positivity. As a global summary measure, however, CL may not fully reflect the regional distribution of amyloid deposition, which can carry additional prognostic information about the rate of cognitive decline. Objective: To develop and externally validate a fixed, regional amyloid PET composite score that complements CL for predicting cognitive decline in Alzheimer's disease. Methods: The Regional Amyloid PET Score (RAPS) was derived from 82 FreeSurfer regions using machine learning with bootstrap stability selection to predict the rate of change in CDR-Sum of Boxes (CDR-SB) in 433 amyloid-positive ADNI [18F]florbetapir participants. The fixed nine-region weights were applied without retraining in a cross-tracer ADNI [18F]florbetaben subset (N = 71; largely overlapping the discovery participants) and two external validation cohorts, NACC SCAN (N = 1531; four tracers) and OASIS-3 (N = 428). Results: RAPS comprised nine regions. In ADNI, RAPS correlated more strongly with CDR-SB slope than CL and showed higher discrimination of rapid decliners (AUC 0.813 vs 0.713). Performance was directionally consistent across validation cohorts; in NACC SCAN, RAPS and CL independently predicted clinical progression. Cross-cohort meta-analysis of the three independent cohorts supported incremental discrimination beyond CL (pooled {Delta}AUC +0.066; I2 = 0%). Conclusions: RAPS, a fixed regional amyloid PET-derived score, may complement CL for prognostic stratification in Alzheimer's disease research.

Objective To measure the accuracy of clinical coding, clinician review, and a locally deployed large language model (LLM) in identifying alcohol, drug, and self-harm involvement in emergency department (ED) attendances, and quantify prevalence. Design Two-phase diagnostic accuracy study. In a validation week, the identification strategies were assessed against a conflict-adjudicated reference standard (n=2,256); the LLM was then applied to n=105,096 annual attendances at the same site. Setting UK Type 1 Emergency Department treating patients [&ge;]16yrs. Main outcome measures Prevalence quantification compared with the reference standard; sensitivity, specificity, and balanced accuracy of each strategy; monthly identification rates and adjusted annual prevalence. Results The reference standard identified 12.1% of attendances as involving alcohol, drugs, or self-harm (coding 6.0%; clinician 10.0%, LLM 15.6%). LLM balanced accuracy matched or outperformed clinician review in all three domains (alcohol 0.942 v 0.930, p=0.635; drug 0.959 v 0.791, p<0.001; self-harm 0.982 v 0.908, p=0.004). Coding recorded 1.07 domains per identified patient against 1.32 in the reference standard. Adjusted annual prevalence corresponded to 12,890 domain involvements per year not identifiable in coded data. Subdomain classification found at least 81.6% of self-harm attendances required medical assessment for injury or overdose before psychiatric review. Conclusions Clinical coding identified fewer than half of presentations involving alcohol, drugs, and self-harm and rarely captured co-occurring domains; under-recording was present across a full year. A locally deployed LLM generated more complete structured data from existing clinical text within NHS infrastructure, at a scale which is not feasible for manual review.

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.

Major depressive disorder (MDD) has been associated with accelerated structural brain aging, yet whether this reflects a pre-existing neurobiological vulnerability, a dynamic acute state effect, or an accumulating biological residual remains unresolved. Across two longitudinal cohorts (N=3220), including a unique sample of 78 initially healthy individuals who transitioned into their first depressive episode during the study course, we systematically tested all three hypotheses. Patients with diagnosed MDD showed elevated MRI-derived brain age relative to healthy controls (1.4 and 2.5 years across cohorts). For the vulnerability hypothesis, individuals scanned prior to their first episode showed no baseline elevation, despite already demonstrating subclinical elevations in self-reported symptom severity, indicating that advanced brain age does not precede illness onset. For the state hypothesis, we found no acceleration of brain aging following the first depressive episode, and longitudinal brain age trajectories were independent of acute clinical symptom severity. Finally, neither episode duration nor recurrence scaled with brain age. Accelerated brain aging in depression is therefore neither an antecedent vulnerability nor an acute state marker of the first episode, but rather a stable biological feature of a long term illness course.

Background: Major depressive disorder (MDD) is a severe mental illness associated with severe clinical consequences and substantial societal burden. It's characterized by immune-inflammatory dysregulation and immune sensitization. Objective: To determine whether in vitro ketamine attenuates phytohemagglutinin (PHA)/lipopolysaccharide (LPS)-induced immune sensitization in patients with MDD and healthy controls (HCs). Methods: Whole blood from 18 patients with MDD and 18 HCs was stimulated with PHA/LPS and exposed to ketamine (0.3 M, 0.6 M, and 6 M) for 72 hours. Cytokines, chemokines, growth factors, and composite immune profiles, including M1/M2 macrophages, T helper (Th)1/2/17, the immune-inflammatory response system (IRS), and compensatory immunoregulatory system (CIRS), were synthesized and determined. Results: Under PHA and LPS stimulation in vitro, the MDD group exhibited markedly elevated immune profiles, including M1, M2, Th1, Th2, Th17, IRS, CIRS, chemokines, and growth factors, consistent with immune sensitization. Significant group-by-treatment interactions were observed for Th1-Th2, M2, growth factors, IL-12(p70), M1, and chemokines. Ketamine produced minimal changes in HCs but broader suppression in MDD, particularly at the highest concentration, without normalizing the sensitized immune phenotype. Among the immune markers with no notable group-by-treatment interactions, ketamine exerted diagnosis-independent effects, decreasing MIP-1{beta}, IL-1&{beta}, Th1, TNF-{beta} IRS, IFN-{gamma}, and IL-2 compared to the control condition. Conclusions: Ketamine exhibited two distinct immunoregulatory patterns: selective, disease-dependent attenuation of sensitized immune pathways and broader, diagnosis-independent suppression of the stimulated immune response, predominantly at higher concentrations. However, these effects were insufficient to normalize the immune-sensitized phenotype of MDD.

Psychosis has long been conceptualized as a disorder of disrupted hierarchical integration across distributed brain systems, yet it remains unclear whether alterations in macroscale cortical hierarchy are already present before illness onset and are associated with subsequent transition to psychosis. Using connectome gradient mapping, we characterized baseline cortical hierarchical architecture along the unimodal-to-transmodal axis in 580 participants from the NAPLS-3 cohort, including converters (CHR-C, n = 56), non-converters (CHR-NC, n = 434), and healthy controls (HC, n = 90). Group differences were assessed at regional, network, and global levels. Group comparisons revealed that CHR-C individuals, relative to the other two groups, exhibited bidirectional alterations selectively along the sensorimotor-to-association gradient, with reduced values in the visual network alongside elevated values in the default mode network, indicating greater separation between sensory and transmodal systems along the gradient. At the global level, CHR-C showed increased explained variance, range, and variation of this gradient, collectively indicating hierarchical expansion. Notably, greater explained variance of this gradient was associated with a shorter time to conversion to psychosis, while increased gradient range and variation were associated with higher positive symptom severity across CHR individuals. These findings indicate that expansion of the sensorimotor-to-association connectome hierarchy is already present before psychosis onset in individuals who subsequently convert to psychosis. This altered hierarchical organization may reflect greater decoupling between sensory and transmodal systems and may characterize neurobiological changes associated with progression from a clinical high-risk state to psychotic illness.

Background Understanding the mechanisms underlying brain aging and age-related pathological changes is essential for advancing brain health research. Our group previously developed a mechanistic mathematical model of healthy brain, Chamberland et al. (2024) that integrates key biological processes involved in normal aging, from which Alzheimer's disease (AD) related changes may emerge naturally. Objectives To characterize and validate this brain model by evaluating its sensitivity, calibrating its parameters, and assessing generalizability in independent populations. Methods The model represents the evolution of key biological processes associated with brain aging, including amyloid beta (A{beta}), tau pathologies, neuroinflammation, and neuronal death. After identifying the 30 most influential parameters, we calibrated the model using cognitively normal (CN) participants from the AD Neuroimaging Initiative (ADNI) database (n = 211) by minimizing a loss function composed of three outcomes (AB) plaques, tau tangles, and neuronal density). The calibrated model was then applied to the UK Biobank cohort (n = 35,899) of normal controls (aged 44-82 years). The effects of sex and APOE were evaluated using stratified simulations. Results Parameter calibration significantly reduced the prediction errors for A{beta} and tau. Neuronal density predictions showed strong agreement in the UK Biobank cohort. The variance decomposition identified APOE status as a major contributor to variability in A{beta}. Conclusion Our validated brain health model links mechanistic pathways with population data and reproduces neuronal density patterns in an independent cohort. These findings support its use as a framework for studying brain aging and investigating how Alzheimer's disease related pathological changes may emerge with aging.

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.