Translational Psychiatry最新文献

Diffusion imaging techniques have been widely used to investigate alterations in brain microstructure associated with major depressive disorder (MDD). Due to its technical limitations, diffusion tensor imaging (DTI)-based studies have often been restricted to evaluating white matter (WM), and analyses of gray matter (GM) microstructural changes using advanced diffusion models remain insufficient. Additionally, many of these studies concentrate on region-specific associations with symptoms rather than a comprehensive assessment of broader microstructural changes. In this study, we employed neurite orientation dispersion and density imaging (NODDI) and DTI to investigate GM and WM microstructural changes at both whole-brain and regional levels. Data were collected from 159 MDD patients and 112 healthy controls across multiple centers. Our findings revealed significantly increased mean free water fraction (FWF) in GM, elevated mean orientation dispersion index (ODI) in WM, and decreased fractional anisotropy (FA) in WM among MDD patients compared to healthy controls. Furthermore, the mean FA of WM exhibited a negative correlation, and the mean ODI of WM showed a positive correlation with illness duration. No significant correlations were observed between diffusion indices and Hamilton Depression Rating Scale (HAMD-17) scores. Gray matter-based spatial statistics demonstrated increased FWF in several GM regions, including the frontal lobes, temporal lobes, and limbic system. Tract-based spatial statistics revealed widespread reductions in FA across WM in MDD patients. These findings suggest that microstructural tissue disorganization may underlie the pathophysiology of MDD, emphasizing the need for future research to link neuroimaging findings with underlying biological mechanisms.

Previous work suggests people with anorexia nervosa (AN) display reduced facial expression of emotion. This may influence illness progression as blunted emotional reactions can negatively impact social relationships and increase isolation. The present study aimed to replicate and further build on previous findings by examining facial and brain responses to naturalistic, emotional films. In total, 141 women (71 AN/weight restored AN, 70 healthy comparison) completed two tasks in a fixed order: 1.) facial affect task and 2.) functional magnetic resonance imaging (fMRI) task. In both tasks, participants reacted to positive, neutral, and negative films, and rated their mood after each one. The effects of group and film category on facial expressions, brain responses, and mood ratings were examined. The AN group displayed reduced positive facial affect over time and lower self-reported mood in response to positive but not negative or neutral films. The fMRI task revealed no significant group differences in response to positive, neutral, or negative films. However, there was widespread activation of occipital, parietal, temporal, and frontal regions in response to the emotional films across groups. The behavioural findings replicate previously reported altered reactivity to positive films in AN. Additionally, task-related brain activation was observed in regions typically associated with the processing of naturalistic emotional stimuli, suggesting the task was valid. However, the lack of group differences during the fMRI task raises questions about whether the behavioural differences could be related to slower warming up to the task among those with AN.

Many psychiatric disorders are heritable, but the molecular consequences of genetic risk remain difficult to resolve, in part due to environmental confounds and the complexity of transcriptomic data. This challenge impedes therapeutic development, which relies on integrating genetic and genomic insights. Here, we integrate diagnosis, toxicological exposure, and gene expression to clarify disease-associated transcriptomic patterns in the subgenual anterior cingulate cortex (sgACC), a brain region implicated in affective regulation and psychiatric illness. We applied group regularized canonical correlation analysis (GRCCA)-a multivariate regression method that models interdependent features-to deeply sequenced bulk RNA-seq data from individuals with bipolar disorder (BD; N = 35), major depression (MDD; N = 51), schizophrenia (SCZ; N = 44), and controls (N = 55). Toxicology data from 17 known compounds were included to assess the relative contribution of known environmental exposures. Case-control expression changes were also analyzed using traditional differential gene expression (DGE) analysis to compare biological interpretability across methods. Gene set enrichment analyses evaluated enrichments for neuropsychiatric risk genes, gene ontology pathways, and cell type markers. GRCCA identified a latent variable significantly associated with schizophrenia (p_perm = 0.001). This expression pattern was enriched for upregulated neuronal pathways, downregulated immune processes, and genes within loci associated with schizophrenia by GWAS. While DGE results were correlated (r = 0.43; p_perm = 1.0 × 10^-4) and enriched for similar functional pathways, GRCCA showed stronger alignment with schizophrenia risk genes implicated by genome-wide association studies. Together, these findings define a schizophrenia-associated expression gradient in the sgACC and illustrate how multivariate integration can refine transcriptomic signals in the context of complex psychiatric disease.

During the past decade, our group has induced electroconvulsive seizures (ECS) in rodent models of early-life stress to prove clear differences in antidepressant-like efficacy mainly driven by sex and age, with females and adolescents showing diminished responses (as opposed to males and adult rodents). Moreover, we have proven a role for sex hormones in this response, since letrozole, an inhibitor of the biosynthesis of estrogens, improved the antidepressant-like efficacy of ECS in adolescent female rats. In this follow-up study, we utilized selective estrogen receptor modifiers (tamoxifen and clomiphene) to evaluate how they interact with the antidepressant-like response induced by ECS in male and female adolescent rats. Early-life stressed Sprague-Dawley rats through maternal separation were treated during adolescence with tamoxifen (1 mg/kg, 7 days) or clomiphene (10 mg/kg, 5 days) and/or with ECS (95 mA, 0.6 s, 100 Hz, 1 session/day, 5 days). Antidepressant-like responses were measured behaviorally under the stress of the forced-swim test, and through hippocampal markers (cell proliferation and neurogenic differentiation, and BDNF protein level). The main results proved that tamoxifen improved the expected antidepressant-like response of ECS in adolescent rats, as observed in the forced-swim test, while boosted hippocampal proliferation and neurogenic differentiation. Contrarily, clomiphene did not alter ECS' response at the behavioral level and even showed some negative signs on the neuroplasticity markers evaluated (decreased neurogenic differentiation and BDNF content). Therefore, when considering an estrogen receptor modifier to enhance the antidepressant-like potential of ECS in adolescence, tamoxifen emerges as a promising option due to its positive behavioral and neuroplastic effects.

Internet gaming disorder (IGD) has been recognized as a serious mental illness and is often accompanied by depression (IGD-D). An ideal treatment strategy should have effects on both the conditions. Mindfulness meditation (MM) has attracted substantial attention for the treatment of psychiatric diseases; however, its effects on IGD-D and the underlying mechanisms remain unknown. A total of 70 patients with IGD-D were randomly divided into the MM and progressive muscle relaxation (PMR) groups. Of these patients, 61 completed the 1-month study (MM group, n = 34; PMR group, n = 27), including pre- and post-resting-state functional magnetic resonance imaging (fMRI) and 8 training sessions. Regional homogeneity and degree centrality were calculated, and overlapping brain regions were selected as seed points for functional connectivity (FC) analysis. The correlation of FC with behavioral data and neurotransmitters was subsequently evaluated. Compared with the PMR group, the MM group had less severe depression, addiction, and cravings. FC analysis showed that MM increased FC in the executive control, frontal-striatal, and default mode networks. FC was significantly correlated with 5-Hydroxytryptamine 1 A receptor, serotonin transporter, vesicular acetylcholine transporter and dopamine receptors D1 and D2. This study demonstrated that MM was effective in the treatment of IGD-D. MM altered the default mode network, enhanced top-down control, and emotion regulation, and disrupted negative reinforcement mechanisms. These phenomena were supported by the correlation between FC and behavioral as well as biochemical measures, suggesting that MM is a promising therapy for IGD-D.

Lockdowns and social restrictions imposed in response to the Covid-19 pandemic intensified the proximity and reciprocal exposure among members of nuclear families. It is unclear how variation in mental distress during this period is attributed to potential influences of family members. This study used genetic data from adolescents (n = 4 388), mothers (n = 27 852) and fathers (n = 25 953), to disentangle the contributions of parent-driven, child-driven, and partner-driven components to mental distress during the first two months of the Covid-19 lockdown. Separate models also included adolescents' non-pandemic mental distress as outcomes (n = 13 484). Trio genome-wide complex trait analyses separated two types of genetic components; direct-how an individual's genotype is associated with their own mental distress, and indirect-how an individual's genotype is associated with the mental distress of family members. A trio polygenic score (PGS) design was used to investigate associations of specific genetic liability factors with mental distress, and whether these changed over time (PGS×time). Results suggest that family-level genetic factors contribute to mental distress; variance components capturing indirect genetic effects accounted for 10% of adolescent mental distress (mother-driven), 2-3% of maternal (partner-driven), and 5% of paternal mental distress (child-driven). Mothers' depression and ADHD PGS were positively associated with fathers' mental distress. No PGS×time interactions were found. Direct genetic effects accounted for 9-10% variance in mental distress across family members, partly explained by genetic variants associated with anxiety, depression, ADHD and neuroticism. These findings highlight the importance of family dynamics and emphasize the potential value of including family members in mental health interventions.

Serum albumin, a reverse acute-phase protein, tends to decrease in response to acute clinical conditions. We hypothesized that albumin levels would exhibit state-dependent dynamics, with distinct patterns between acute episodes and remission states in schizophrenia. To test this, we conducted a retrospective longitudinal study to investigate the dynamic serum albumin levels in 148 schizophrenia patients, starting from their first episode through remission and subsequent relapse. A matched general population sample served as the control group. Classification models were developed using albumin levels (Albumin _current) and changes (ΔAlbumin₁ = Albumin _current-Albumin _{previous remission}, and ΔAlbumin₂ = Albumin _current-Albumin _{previous acute episode}) to distinguish clinical states. Model performance was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). Serum albumin levels were significantly lower during acute episodes (first episode: 45·6, standard deviation (SD) 4·0 g/L; relapse: 44·9, SD 4·0 g/L) compared to remission (48·6, SD 2·9 g/L) and matched controls (48·6, SD 3·4 g/L). Patients in remission showed albumin levels comparable to controls. These findings remained consistent after adjustment for potential confounders using mixed-effects model and in sex-stratified analyses. The classification model incorporating ΔAlbumin₁ and ΔAlbumin₂ achieved an AUC of 0·88 (95% CI: 0·84, 0·92) in distinguishing acute episodes from remission. These findings highlight serum albumin's potential as a clinically useful biomarker of illness activity/state and mental stress in schizophrenia, with utility in differentiating between acute and remitted states.

Social isolation, characterized by a lack of social connections with family, friends, and others, is associated with adverse health outcomes. However, the genetic contribution to the susceptibility to social isolation remains unclear. This study aimed to identify genetic loci associated with social isolation using the Lubben Social Network Scale (LSNS-6) in a Japanese population. The Tohoku Medical Megabank Community-Based Cohort Study was conducted between 2013 and 2016. The participants were genotyped using the Affymetrix Axiom Japonica Array. The LSNS-6 was used to assess familial and friend ties through six questions and social isolation statuses were defined using the total scale, family subscale, and friend subscale. Genome-wide association studies (GWASs) were conducted using a generalized linear mixed model, adjusting for age, sex, 10 genetic principal components and batch effects. In total, 63,497 participants who completed genotyping and the LSNS-6 were included. The mean age was 59.4 ± 11.9 years, and 41,126 (64.8%) were female. Significant genetic loci were identified in GWASs for the total scale (rs10736933 near ACADSB and HMX3) and friend subscale of LSNS-6 (rs1778366 near LINC02315 and LRFN5). This study provides the first genome-wide evidence of social isolation in the Japanese population, suggesting associations with ACADSB, HMX3, LINC02315, and LRFN5. These findings could enable personalized prevention and intervention for social isolation and related psychiatric disorders.

Synaptic dysfunction is a candidate mechanism in psychotic disorders, yet the precise underlying substrates remain elusive. We investigated how combining in vivo electroencephalography (EEG) and in vitro human cortical spheroid (hCS)-based methods can further our understanding of psychosis pathophysiology during fetal stages of neurodevelopment. Ten individuals with schizophrenia (SZ) or bipolar disorder (BD; 5 males and 5 females) and five controls (CTRL; 3 males and 2 females) underwent EEG assessments, including long-term potentiation (LTP)-like cortical plasticity and mismatch negativity (MMN). hCS were generated from induced pluripotent stem cells of all participants, and immunohistochemistry, Seahorse bioenergetics and patch-clamp recordings were performed. EEG-based LTP-like plasticity was reduced in individuals with SZ and BD. Basal respiration was decreased in BD hCS and VGLUT1 levels were reduced in both SZ and BD hCS. There was a positive association between EEG-based LTP-like plasticity and hCS basal respiration which survived correction. Our data provide further support for roles of mitochondrial and glutamatergic impairments in the synaptic dysfunction of psychosis and demonstrate the potential of combining EEG- and hCS-based methods for early development mechanistic studies of brain disorders.

Recent evidence shows a strong correlative link between sleep disturbances and intrusive memories after traumatic events, presumably due to insufficient (nocturnal) memory integration. However, the underlying mechanisms of this link and the role of specific neural activities during sleep are poorly understood so far. Here, we investigated how the intra-individual affective response to an experimental trauma predicts changes in oscillatory activity during subsequent sleep and how these changes predict the processing of the experimental trauma. In a randomized within-subject comparison, twenty-two female, healthy participants (23.14 ± 2.46 years) watched a well-validated film clip including "traumatic" contents and a neutral film clip before bedtime on two separate nights. Heart rate was recorded during the film clips and nocturnal brain activity was recorded using 64-channel high-density EEG during subsequent nights. Intrusive memories were assessed via a six-day diary and negative affect was assessed using experimental trauma film reminders one week after the trauma film. An increased intra-individual heart rate during the trauma film predicted higher intra-individual sleep spindle envelope the following night. Increased theta activity (4.25 - 8 Hz) during rapid eye movement (REM) sleep after the trauma film predicted fewer trauma film related intrusive memories and negative affect. Likewise, an increase in sleep spindles after the trauma film predicted fewer trauma film related intrusive memories. Our findings suggest that an experience-dependent up-regulation of these nocturnal oscillatory activity patterns, which are known to be involved in adaptive memory consolidation processes, serves as a protective factor against trauma-related intrusive memory development. Particularly, increased theta activity during REM sleep and sleep spindle activity seem to be of importance here.