Transl Psychiatry [JOURNAL]
Sun
200 papers
A corticostriatal circuit mediates the switching of defensive responses to an approaching threat.
Ge J, Ren P, Zhang Y … +8 more , Chen B, Deng Y, Xu J, Zang Y, Xue Q, Wu S, Qi C, Wang W
Transl Psychiatry · 2026 May · PMID 42161946 · Publisher ↗
Defensive responses are evolutionarily conserved adaptive behaviors that species exhibit in response to threats to protect themselves from harm or death. The selection of context-appropriate defensive strategies, particu...
Defensive responses are evolutionarily conserved adaptive behaviors that species exhibit in response to threats to protect themselves from harm or death. The selection of context-appropriate defensive strategies, particularly the transition between freezing and flight behaviors, constitutes a critical determinant of species survival. We first established a two pure tone serial-compound stimulus (TTSCS) paradigm to evaluate the dynamic transition of defensive behaviors evoked by conditioned stimuli. This paradigm minimizes potential confounding effects on defensive behavior caused by differences in tone. Using this approach, we found that as the threat stimulus approached more closely, mice exhibited increased escape behaviors characterized by shorter latencies and larger magnitudes of response. These behavioral changes were associated with the dynamic responses of dopamine receptor 1 expressing MSNs (D1 MSNs) and dopamine receptor 2 expressing MSNs (D2 MSNs) in the dorsomedial striatum (DMS). Following functional validation through manipulation of the PFC (prefrontal cortex)-DMS circuit, we found that activating the PFC-DMS pathway significantly shortened the response latency of mice to heightened threat stimuli, enabling faster defensive reactions. However, activation of D2 MSNs subtypes of PFC-DMS pathway resulted in no significant alterations in the defensive behaviors. In conclusion, D1and D2 MSNs in the DMS likely act in an antagonistic manner to regulate defensive behaviors, and furthermore, the PFC projection specifically to the direct pathway within the DMS mediates the shift in defensive responses to an approaching threat.
Xanomeline-trospium reverses phencyclidine-induced cognitive deficits through modulation of the gut microbiota-brain axis in mice.
Ding X, Murayama R, Cai Y … +3 more , Yue Y, Yang JJ, Hashimoto K
Transl Psychiatry · 2026 May · PMID 42161933 · Publisher ↗
Cognitive impairment in schizophrenia remains largely unaddressed by dopamine-based antipsychotics. Xanomeline-trospium (KarXT; Cobenfy), a combination of the muscarinic M1/M4 receptor agonist xanomeline and the peripher...
Cognitive impairment in schizophrenia remains largely unaddressed by dopamine-based antipsychotics. Xanomeline-trospium (KarXT; Cobenfy), a combination of the muscarinic M1/M4 receptor agonist xanomeline and the peripherally restricted antagonist trospium, effectively reduces psychosis but is associated with gastrointestinal adverse effects. Here, we tested whether KarXT reverses phencyclidine (PCP)-induced cognitive deficits through microbiota-associated mechanisms in adult male mice. Mice received saline or PCP (10 mg/kg/day, s.c.) on days 1-5 and 8-12, followed by vehicle or KarXT [xanomeline 2 mg/kg/day + trospium 1 mg/kg/day, intragastric] on days 15-28. Recognition memory was evaluated using the novel object recognition test (NORT), and lung and intestinal microbiota (small intestine, cecum, and colon) were profiled by 16S rRNA sequencing. KarXT significantly rescued PCP-induced recognition-memory deficits without exacerbating PCP-related reductions in weight gain or fecal output. Microbiome analyses revealed region-specific dysbiosis after PCP exposure, most pronounced in the small intestine and cecum. Several taxa elevated by PCP-including Bacteroides fragilis, Veillonella ratti, Megamonas funiformis, Cupriavidus numazuensis, and Acetanaerobacterium elongatum-were normalized following KarXT treatment. Notably, restoration of multiple pulmonary, cecal, and colonic taxa correlated positively with the NORT recognition index. These findings demonstrate that KarXT reverses PCP-induced cognitive dysfunction while modulating microbial composition in a region-specific manner. Elucidating these relationships may help optimize cognitive efficacy and reduce gastrointestinal adverse effects of muscarinic therapies for schizophrenia.
Stage-dependent reorganization of amyloid PET region-symptom bipartite networks in drug-naïve, amyloid-positive Alzheimer's disease.
Yang Y, Kwak YT
Transl Psychiatry · 2026 May · PMID 42161924 · Publisher ↗
Management of neuropsychiatric symptoms (NPS) is pivotal to care in Alzheimer's disease (AD), yet their alignment with amyloid topology may vary by stage. We examined whether the community (modular) structure of a brain-...
Management of neuropsychiatric symptoms (NPS) is pivotal to care in Alzheimer's disease (AD), yet their alignment with amyloid topology may vary by stage. We examined whether the community (modular) structure of a brain-region-symptom co-occurrence network differs by clinical stage, testing the hypothesis that modular organization is more pronounced in earlier AD and becomes less segregated with increasing severity. In a cross-sectional retrospective cohort from a tertiary dementia clinic, we included 301 consecutive, drug-naïve patients with probable AD and amyloid-positive PET (F-FC119S). Patients were stratified by Clinical Dementia Rating (CDR 0.5, n = 38; CDR 1.0, n = 107; CDR 2.0, n = 156). We built bipartite networks linking six cortical regions (bilateral frontal, temporal, parietal; PET positivity from automated SUVRs) to 12 Korean Neuropsychiatric Inventory (K-NPI) domains (presence = frequency × severity ≥ 1). Network density, community structure (Louvain modularity with 2000 within-symptom permutations), node strength/centralities, and stage-matched backbones were assessed. The pooled network was dense and non-modular. Stage-stratified analyses revealed significant modularity at CDR 0.5 only, with increasing density from CDR 0.5 to 2.0 and loss of community structure thereafter. Left temporal and left frontal cortices emerged as consistent regional hubs, while parietal contributions were minimal. On the symptom side, aggression and delusion carried the largest co-occurrence burdens, followed by disinhibition and anxiety; findings were robust across backbone and sensitivity analyses. These results support a stage-dependent reorganization from modest, symptom-specific modularity in early stage AD to diffuse, hub-centric coupling in later stages. Recognizing this transition may reconcile prior inconsistencies and inform clinical strategy: targeted, domain-focused interventions when modularity persists versus global stabilization as networks densify, with implications for enrichment and endpoint selection in NPS-focused trials.
Urinary copper is linked to regional cortical volume reductions in adolescents with major depressive disorder.
Jiang X, Wang W, Zhang J … +7 more , Chen H, Wan N, Wang T, Lei D, Zhu D, Li X, Zhou X
Transl Psychiatry · 2026 May · PMID 42156723 · Publisher ↗
Major depressive disorder (MDD) is highly prevalent among adolescents, but its neurobiological mechanisms remain unclear. Neuroimaging studies have shown cortical abnormalities in MDD, and emerging evidence suggests that...
Major depressive disorder (MDD) is highly prevalent among adolescents, but its neurobiological mechanisms remain unclear. Neuroimaging studies have shown cortical abnormalities in MDD, and emerging evidence suggests that trace elements may impact brain structure. This study aimed to investigate the association between urinary element concentrations and cortical alterations in adolescent MDD. Structural magnetic resonance imaging (sMRI) was conducted on 190 adolescents with MDD and 123 healthy controls (HCs), measuring cortical volume, cortical thickness, and urinary metal concentrations. Partial correlation analyses examined the associations between differential elements and cortical features, while mediation analyses tested whether cortical changes mediated the effects of elements on symptom severity. Furthermore, nine supervised machine learning models were trained using differential cortical and element features, and model performance was evaluated using cross-validation and stacking ensembles. The results revealed significant reductions in cortical volume in the left lateral orbitofrontal cortex (LLOF), left medial orbitofrontal cortex (LMOF), left rostral middle frontal gyrus (LRMFG), and left frontal pole (LFP), as well as reduced cortical thickness in the right pars triangularis (RPTRI), right pars orbitalis (RPORB), and right medial orbitofrontal cortex (RMOF) in adolescents with MDD compared with HCs. Urinary copper (Cu) levels were negatively correlated with LFP volume and positively associated with both depressive and anxiety symptom severity. In machine learning classification, the stacking ensemble demonstrated the best overall performance, indicating the discriminative value of combined cortical and urinary element features in distinguishing adolescents with MDD from HCs. This study suggests that trace elements, particularly Cu, are linked to structural brain alterations and symptom severity in adolescent MDD. The integration of neuroimaging and element data enhances predictive modeling and offers new insights into the pathophysiology of MDD.
Multimodal imaging reveals resilient memory networks in carriers of pathogenic ARID1B variants.
Fabre A, Aljabali K, Boisgontier J … +12 more , Fillon L, Guida L, Saitovitch A, Rio M, Amiel J, Michot C, Dangouloff-Ros V, Cabet S, Cormier-Daire V, Munnich A, Zilbovicius M, Boddaert N
Transl Psychiatry · 2026 May · PMID 42156711 · Publisher ↗
The phenotypic spectrum associated with pathogenic ARID1B variants is remarkably broad, ranging from classic Coffin-Siris syndrome to non-syndromic intellectual disability and autism spectrum disorders. While speech dela...
The phenotypic spectrum associated with pathogenic ARID1B variants is remarkably broad, ranging from classic Coffin-Siris syndrome to non-syndromic intellectual disability and autism spectrum disorders. While speech delay, motor impairments and learning difficulties are well documented, brain imaging investigations remain scarce in this population. We combined multimodal neuroimaging and neuropsychological assessments in 12 patients carrying pathogenic ARID1B variants (age = 13.8 ± 4.7 years) and 34 age-matched healthy controls. Whole-brain voxel-wise analyses included arterial spin labelling to measure cerebral blood flow (CBF) at rest and voxel-based morphometry to assess grey matter density. To investigate white matter abnormalities, we performed fixel-based analysis in a subgroup of 7 patients and 17 age-matched controls. While patients showed pronounced language, motor and social impairments, their memory performance ( + 5 SD) largely exceeded other cognitive and motor skills. Whole-brain voxel-wise analyses showed a significant bilateral increase of CBF at rest in several limbic structures, including hippocampi and visual areas. They also showed significant decrease in grey matter density and fibre density in the same limbic structures, language, motor and social circuits. This paradoxical coexistence of hyperperfusion and structural deficits within memory networks suggests functional resilience or compensatory mechanisms. These preserved visual and memory functions strongly contrasted with their impaired language, motor, and social abilities. Patients appeared to rely on visual cues and memory to compensate for deficits in verbal communication. These findings support the development of individualized and innovative interventions that build on preserved visual and memory abilities in children with pathogenic ARID1B variants.
Cumulative exposure to cannabis and hippocampus MRI in middle age: results from the coronary artery risk development in young adults (CARDIA) study.
Schilling B, Pasquier B, Elbejjani M … +10 more , Reis J, Rana JS, Tal K, Launer LJ, Baggio S, Sidney S, Bryan N, Yaffe K, Auer R, Jakob J
Transl Psychiatry · 2026 May · PMID 42156373 · Publisher ↗
Cannabis was previously associated with worse memory function in men but not in women. As the hippocampus is crucial in the formation and retrieval of memory, we studied if cumulative exposure to cannabis is associated w...
Cannabis was previously associated with worse memory function in men but not in women. As the hippocampus is crucial in the formation and retrieval of memory, we studied if cumulative exposure to cannabis is associated with differences in the hippocampal tissue volume, fractional anisotropy (FA) and cerebral brain perfusion (CBF) by MRI, overall and by sex, stratified by ever tobacco smoking, in multivariable adjusted linear regression models in both sexes. We included participants of the CARDIA cohort, followed since 1985, with cannabis assessed during each follow up. Categories of self-reported cumulative exposure were never, <0.5, 0.5-<2, and >2 cannabis-years, where 1 cannabis-year=365 days of use. We included 648 participants: 52% were women; mean age was 55 years, 86% reported ever using cannabis and 48% ever smoking tobacco. There was no difference in mean hippocampal volume according to greater cumulative use of cannabis. The coefficient of hippocampal volume in participants never smoking tobacco reporting >2 cannabis-years was -37.99mm (95% CI -201.08-125.09) compared to never users. There was no significant difference when stratifying by sex or ever tobacco exposure, or for FA or CBF. Cumulative cannabis exposure over 30 years was not associated with hippocampal volume, integrity or blood flow in middle age. The differences in memory function in cannabis users are likely not attributable to the hippocampus only. Future studies should assess further neuronal mechanisms and social determinants associated with cognition in cannabis users.
Associations between residential segregation, ambient air pollution, and hippocampal features in recent trauma survivors.
Liang SS, Roeckner AR, Ely TD … +38 more , Lebois LAM, van Rooij SJH, Bruce SE, Jovanovic T, House SL, Beaudoin FL, An X, Neylan TC, Clifford GD, Linnstaedt SD, Germine LT, Rauch SL, Haran JP, Storrow AB, Lewandowski C, Musey PI, Hendry PL, Sheikh S, Pascual JL, Seamon MJ, Harris E, Pearson C, Peak DA, Merchant RC, Domeier RM, Rathlev NK, O'Neil BJ, Sergot P, Sanchez LD, Sheridan JF, Harte SE, Kessler RC, Koenen KC, McLean SA, Ressler KJ, Stevens JS, Webb EK, Harnett NG
Transl Psychiatry · 2026 May · PMID 42151109 · Publisher ↗
Residential segregation is associated with differential exposure to air pollution. Hippocampus structure and function are highly susceptible to pollutants and associated with posttraumatic stress disorder (PTSD) developm...
Residential segregation is associated with differential exposure to air pollution. Hippocampus structure and function are highly susceptible to pollutants and associated with posttraumatic stress disorder (PTSD) development. Therefore, we investigated associations between residential segregation, air pollutants, hippocampal neurobiology, and PTSD in recent trauma survivors. Participants (N = 278; 34% non-Hispanic white, 46% Non-Hispanic Black, 16% Hispanic) completed multimodal neuroimaging two weeks after trauma. Yearly averages of air pollutants (PM and NO) and racial/economic segregation (Index of Concentration at the Extremes) were derived from each participant's address. Linear models assessed if air pollutants mediated associations between segregation and hippocampal volume, threat reactivity, or parahippocampal cingulum fractional anisotropy (FA) after covarying for age, sex, income, and 2-week PTSD symptoms. Further models evaluated if pollutants or segregation prospectively predicted PTSD symptoms six months post-trauma. We found that non-Hispanic Black participants lived in neighborhoods with significantly greater segregation and air pollution compared to Hispanic and non-Hispanic white participants (ps < 0.001). PM concentration was positively correlated with threat reactivity (r(276) = 0.16, p < 0.006), while NO concentration was positively correlated with hippocampus volume (r(276) = 0.17, p < 0.005) and negatively correlated with white matter tract FA (r(276) = -0.18, p < 0.003). There was a significant indirect effect of NO between segregation and FA values (β = 0.08, 95% CI[0.01, 0.15]), and an indirect effect of PM between segregation and threat reactivity (β = -0.08, 95% CI[-0.14, -0.01]). There was no direct effect of segregation on hippocampal features. Pollutants and segregation were not associated with PTSD symptoms. In conclusion, residential segregation is associated with greater air pollution exposure, which is in turn associated with variability in hippocampal features among recent trauma survivors. Further research is needed to assess relationships between other environmental factors and trauma and stress-related disorders.
Postoperative delirium in hip fracture patients linked to epigenetic alterations in inflammatory and immune pathways: a genome-wide DNA methylation study.
Seki T, Nishitani S, Nishizawa Y … +16 more , Yamanishi K, Shimura A, Nishiguchi T, Ishii T, Aoyama B, Santiago TA, Phuong NJ, Gorantla N, Nguyen HD, Takeda R, Kameoka T, Inoue T, Sugiyama D, Ueda K, Yamanashi T, Shinozaki G
Transl Psychiatry · 2026 May · PMID 42143058 · Publisher ↗
Delirium is a common yet underdiagnosed condition in elderly hospitalized patients. The lack of effective diagnostic and therapeutic methods can be attributed to the limited understanding of its pathophysiology. Delirium...
Delirium is a common yet underdiagnosed condition in elderly hospitalized patients. The lack of effective diagnostic and therapeutic methods can be attributed to the limited understanding of its pathophysiology. Delirium has recently been reported to be linked to neuroinflammation and epigenetic changes. The aim of this study was to validate the pathways in a larger cohort with a uniform type of surgery, while rigorously adjusting for potential covariates. This study primarily investigated DNA methylation (DNAm) changes before and after surgery in postoperative delirium (POD) among older adults having undergone femoral fracture surgery. After propensity analysis, 65 subjects were divided into 2 subgroups; one consisted of subjects who had blood samples collected preoperatively and on postoperative day 0, and the other consisted of those who had samples collected preoperatively and on postoperative day 3. We performed differential methylation analysis and enrichment analysis on each subgroup. Enrichment analysis using CpGs that exhibited substantial DNAm changes between pre- and postoperative day 0 samples in POD cases showed inflammation- and immunity-related pathways such as "leukocyte mediated immunity" and "NF-kappa B signaling pathway." Inflammation- and immunity-related pathways became less noticeable between pre- and postoperative day 3 samples. Inflammation- and immunity-related pathways showed in this study align with previous studies across diverse populations, reinforcing the role of inflammation- and immunity-related epigenetic mechanisms in delirium including POD. Notably, these DNAm changes were potentially transient, corresponding to the typical onset of delirium, suggesting their potential as biomarkers for early diagnosis.
A depression-like phenotype is associated with discrete defects in the primary hippocampal circuit.
Gunn BG, Yang CC, Lauterborn JC … +5 more , Pruess BS, Quintanilla J, Ge K, Gall CM, Lynch G
Transl Psychiatry · 2026 May · PMID 42143033 · Publisher ↗
Major depressive disorder is known to disturb the hippocampus, but how this impacts signal processing performed by the structure remains poorly understood. Here, we report that single housing (7-10 days) promotes a depre...
Major depressive disorder is known to disturb the hippocampus, but how this impacts signal processing performed by the structure remains poorly understood. Here, we report that single housing (7-10 days) promotes a depression-like phenotype in young adult mice that is associated with a robust, yet surprisingly discreet defect in information flow across the primary hippocampal circuit. In addition to sociability disturbances and despair-like behavior, single housing eliminated preference for novelty and impaired episodic memory encoding. Additionally, the lateral habenula, an epithalamic structure critically involved in depression, was hyperactive. Although the CA1 waveform and associated spike output elicited by single-pulse lateral perforant path (LPP) activation of hippocampus was largely unaffected by single housing, pronounced disturbances emerged when the circuit was activated with physiologically relevant frequencies and patterns. The characteristic 'theta/gamma' pattern was distorted such that a pronounced facilitation was present in the single-housed group, while the filtering of CA1 output to brief beta (25 Hz) and gamma (50 Hz) frequency LPP stimulation evident in group-housed slices was absent. Within field CA3, the recruitment of inhibitory interneurons suppresses spike output, and subsequent signal propagation to CA1, in response to beta frequency LPP inputs but not those arriving at gamma frequencies. This CA3 beta filter was significantly impaired following single housing. These results suggest that a depression phenotype is associated with a highly selective and partial loss of inhibition within the CA3 and CA1 links of the hippocampal circuit, providing new insights into the relationship between depression and hippocampal function.
Neural Responses to Affective Sentences Reveal Signatures of Depression.
Kommineni A, Jeong W, Avramidis K … +13 more , McDaniel C, Hughes M, McGee T, Kaiser E, Lerman K, Blank IA, Byrd D, Habibi A, Cahn BR, Kadiri S, Medani T, Leahy RM, Narayanan S
Transl Psychiatry · 2026 May · PMID 42140957 · Publisher ↗
Major Depressive Disorder (MDD) is a highly prevalent mental health condition, and a deeper understanding of its neurocognitive foundations is essential for identifying how core functions such as emotional and self-refer...
Major Depressive Disorder (MDD) is a highly prevalent mental health condition, and a deeper understanding of its neurocognitive foundations is essential for identifying how core functions such as emotional and self-referential processing are affected. We investigate how depression symptoms alters the temporal dynamics of emotional processing by measuring neural responses to self-referential affective sentences using surface electroencephalography (EEG) in healthy and depressed individuals. Our results reveal significant group-level differences in neural activity during sentence viewing, suggesting disrupted integration of emotional and self-referential information in depression. Deep learning model trained on these responses achieves an area under the receiver operating curve (AUC) of 0.72 in distinguishing healthy from depressed participants, and 0.65 in differentiating depressed subgroups with and without suicidal ideation symptoms. Spatial ablations highlight anterior electrodes associated with semantic and affective processing as key contributors. These findings suggest stable, stimulus-driven neural signatures of depression symptoms that may inform future screening tools.
Tomentosin selectively targets microglial pyroptosis to overcome fluoxetine-resistant depression: a network-based therapeutic discovery.
Lee JS, Kang JY, Lee WY … +3 more , Gu JY, Woo TW, Son CG
Transl Psychiatry · 2026 May · PMID 42140921 · Publisher ↗
Treatment-resistant depression (TRD), a clinically challenging issue of major depressive disorder (MDD), affects up to one-third of patients and is associated with elevated suicide risk and limited treatment options. Cum...
Treatment-resistant depression (TRD), a clinically challenging issue of major depressive disorder (MDD), affects up to one-third of patients and is associated with elevated suicide risk and limited treatment options. Cumulative evidence highlights pathological microglial state and inflammasome-derived pyroptosis as key contributors to TRD pathophysiology. This study aimed to validate tomentosin as a network-based identified antidepressants and anti-microglial candidate and to define its mechanisms in suppressing microglial pyroptosis. Through a network-based multiscale interactome screening of a large terpenoid library exceeding 170,000 compounds, we identified tomentosin, a brain-penetrant sesquiterpene lactone with favorable drug-likeness and network relevance. In mice unresponsive to fluoxetine (called as FRD, fluoxetine-resistant depression), tomentosin (20 mg/kg) significantly alleviated depressive behaviors and normalized reactive microglial states in the anterior cingulate cortex (ACC). These pharmacological effects were observed in systemic and intracerebral inflammation-induced depressive mice models. We found that tomentosin mechanistically targeted the suppression of microglial NOD-like receptor protein-3 (NLRP3)/caspase-1/gasdermin D (GSDMD) signaling pathway. This inflammasome-specific suppressive effect was confirmed by the absence of pharmacological effects in caspase-1 knockout (Casp1 KO) mice. Underlying mechanisms were further validated through molecular interaction analyses, comparative studies with inhibitors, and overexpression vector transfections. Our findings suggest that tomentosin is a novel agent that selectively modulates inflammasome-associated microglia in FRD, primarily by suppressing pyroptosis in the ACC.
The development of FEDUPP: feeding experimentation device users processing package to assess learning and cognitive flexibility.
Yao M, Libster AM, Desfor S … +4 more , Malhotra F, Castorena N, Montilla-Perez P, Telese F
Transl Psychiatry · 2026 May · PMID 42140909 · Publisher ↗
Cognitive flexibility, the ability to adapt behavior in response to changing contingencies, is a key component of adaptive decision-making and is impaired in multiple neuropsychiatric disorders. Traditional rodent assays...
Cognitive flexibility, the ability to adapt behavior in response to changing contingencies, is a key component of adaptive decision-making and is impaired in multiple neuropsychiatric disorders. Traditional rodent assays of cognitive flexibility are conducted in experimenter-controlled sessions in restrictive environments, limiting ecological validity and temporal resolution. Here, we developed a fully automated, home-cage paradigm using the Feeding Experimentation Device 3 (FED3) and a companion open-source analysis pipeline, the Feeding Experimentation Device Users Processing Package (FEDUPP), to assess learning and cognitive flexibility with minimal experimenter intervention. The paradigm combines a single-day fixed-ratio 1 (FR1) task with a multi-day, reversal learning task in which active port assignment switches every 25 pellets collected. FEDUPP implements multi-scale learning metrics, including overall accuracy, an 80% accuracy milestone, and a machine learning-based classification of meal accuracy to capture motivated, goal-directed feeding. In wild-type mice, the paradigm detected rapid FR1 acquisition and progressive within-block adaptation during reversal. Application to mice with dorsal hippocampal knockdown of the scaffolding protein CASK revealed faster FR1 acquisition and higher accuracy. In addition, a faster onset of the first accurate meal after reversal suggests an improvement in updating goal-directed feeding behavior. These findings demonstrate that FEDUPP enables high-resolution, continuous assessment of learning and cognitive flexibility in ethologically relevant settings, and that meal-based accuracy provides a sensitive metric for detecting subtle changes in flexibility not captured by traditional measures.
Neural imbalance between feedback sensitivity and motor inhibition in compulsivity and negative urgency.
Wüllhorst R, Overmeyer R, Dück K … +2 more , Wüllhorst V, Endrass T
Transl Psychiatry · 2026 May · PMID 42140895 · Full text
Compulsivity and emotional impulsivity (negative urgency) are considered transdiagnostic risk factors for compulsive-impulsive psychopathology that is linked to a neural imbalance between executive and motivational-emoti...
Compulsivity and emotional impulsivity (negative urgency) are considered transdiagnostic risk factors for compulsive-impulsive psychopathology that is linked to a neural imbalance between executive and motivational-emotional systems. However, existing evidence does not derive from within-subjects designs, leaving it unclear whether imbalance occurs with high expressions in compulsivity and negative urgency. To address this gap, we conducted a preregistered analysis to examine how feedback sensitivity and motor inhibition interact as a function of compulsivity and negative urgency.Participants (n = 205; collected 2018-2019) expressing a wide range in compulsivity and impulsivity performed two motor inhibition and two feedback tasks during electroencephalography. We examined how the relationship between neural correlates of motor inhibition (nogo/stop>go) and feedback sensitivity (loss>gain) was moderated by compulsivity and negative urgency. Compulsivity emerged as the most robust moderator. Across multiple tasks, feedback sensitivity was associated with motor inhibitory activity in participants with mild, but not severe, compulsivity. A similar effect was observed in low versus high negative urgency. The moderation by compulsivity remained when controlling for negative urgency, and vice versa. These results suggest a neural imbalance between systems tied to motor inhibition and feedback sensitivity in transdiagnostic risk. This imbalance manifests such that strong motivational-emotional sensitivity is insufficiently compensated by motor inhibitory resources. It could drive repetitive or rash behaviors in response to distress in compulsivity and negative urgency, respectively. Whereas shared mechanisms may underlie compulsivity and negative urgency, the current interactions appear to also reflect processes unique to each construct.
Long-term risk of depression after sevoflurane versus propofol anesthesia: a global propensity score-matched cohort study.
Zhang J, Miao M, Wang Y … +10 more , Jiang L, Zhu R, Mao T, Lu Z, Wang J, Zhao L, Fu S, Chen WM, Wu SY, Sun M
Transl Psychiatry · 2026 May · PMID 42135318 · Publisher ↗
Preclinical studies indicate that volatile anesthetics such as sevoflurane induce neuroinflammation and oxidative stress-mechanisms implicated in the pathophysiology of depression-whereas propofol exhibits neuroprotectiv...
Preclinical studies indicate that volatile anesthetics such as sevoflurane induce neuroinflammation and oxidative stress-mechanisms implicated in the pathophysiology of depression-whereas propofol exhibits neuroprotective properties. However, whether these pharmacological differences translate into distinct long-term psychiatric outcomes in humans remains unclear. We conducted a multinational propensity score-matched cohort study using the TriNetX Global Federated Network (2005-2024) to determine whether sevoflurane anesthesia is associated with a higher risk of long-term depression compared with propofol. To isolate the effect of anesthetic choice, we applied a new-user design with a one-year latency washout, excluding patients with preexisting depression or antidepressant use. The primary outcome was new-onset depression diagnosed more than one year after anesthesia. The matched cohort included 37,936 patients balanced across more than 100 covariates. Sevoflurane exposure was associated with a higher risk of new-onset depression compared with propofol (adjusted hazard ratio [aHR], 1.51; 95% CI, 1.41-1.61). The association remained consistent across severity strata (aHR, 1.51 for moderate-to-severe depression) and surgical subgroups. Notably, we observed a graded dose-response relationship, where repeated sevoflurane exposures conferred progressively higher risk (aHR, 1.75 for ≥2 exposures), consistent with a biologic gradient. In this large multinational cohort, sevoflurane use was associated with a higher long-term risk of incident depression compared with propofol. These findings align with preclinical evidence of anesthetic-related neuroinflammatory mechanisms and indicate that anesthetic selection may have implications for long-term neuropsychiatric risk. Further mechanistic and prospective studies are warranted.
1-deoxysphinganine promoted microglial glycolytic reprogramming and neuroinflammation in alzheimer's disease.
Ye T, Lv X, Fang Z … +10 more , Li Q, Chen F, Dong Y, Xiang K, Yang Y, Dai C, Do QL, Sun J, Su KP, Liu J
Transl Psychiatry · 2026 May · PMID 42135307 · Publisher ↗
Recent evidence suggests that microglial activation, driven by a metabolic shift towards glycolysis, was involved in the pathogenesis of Alzheimer's disease (AD). Although sphingolipid (SL) dysregulation has been linked...
Recent evidence suggests that microglial activation, driven by a metabolic shift towards glycolysis, was involved in the pathogenesis of Alzheimer's disease (AD). Although sphingolipid (SL) dysregulation has been linked to AD, the role of 1-deoxysphinganine (deoxySO), an atypical and neurotoxic SL, on microglial glycolytic reprogramming remains unclear. We measured serum deoxySO levels in AD patients and evaluated their association with cognitive performance. In APP/PS1 mice, we examined cerebral deoxySO level and the effects of deoxySO supplementation on cognitive function, neuropathology, and microglial activation. In vitro, BV2 microglia were used to assess inflammatory and metabolic changes via qPCR, western blot, ELISA, and RNA-seq analyses. The serum deoxySO levels were significantly elevated in AD patients, which was positively correlated with cognitive impairment. APP/PS1 mice exhibited increased cerebral deoxySO level, and supplementation with deoxySO could exacerbate cognitive deficits and Aβ plaque accumulation. Moreover, deoxySO supplementation increased microglial activation and enhanced inflammation in vivo and in vitro AD models. qPCR analysis identified disease-associated microglia (DAM) as a key deoxySO-responsive subpopulation, while RNA-seq revealed significant enrichment of genes related to glycolytic metabolism and inflammatory responses. Subsequently, qPCR confirmed that deoxySO promoted glycolytic metabolic reprogramming, which promoted DAM activation, thereby aggravating AD pathology. These findings identify deoxySO as a critical metabolic driver that links to microglial glycolytic activation and neuroinflammation, suggesting that targeting deoxySO-mediated metabolic pathways may offer a novel therapeutic strategy for AD.
The paternal brain: longitudinal insights into structural and functional plasticity and attachment over 24 weeks postpartum.
Daneshnia N, Losse EM, Kurz A … +2 more , Chechko N, Nehls S
Transl Psychiatry · 2026 May · PMID 42135294 · Full text
Over the last two decades, interest in the neurobiological basis of parenthood has grown, with the primary focus being on maternal neuroplasticity. However, research on paternal brain adaptations remains limited and inco...
Over the last two decades, interest in the neurobiological basis of parenthood has grown, with the primary focus being on maternal neuroplasticity. However, research on paternal brain adaptations remains limited and inconclusive. This longitudinal study investigated gray matter volume (GMV) and resting-state functional connectivity (rsFC) changes in 25 fathers immediately after childbirth and at 3, 6, 9, 12, and 24 weeks postpartum. Morphological changes were most evident as reductions in GMV within the bilateral occipital, frontal, temporal and parietal cortices, as well as the temporo-parietal junction, and the insular and hippocampal regions during the first six weeks, followed by gradual stabilization. From 12 weeks onward, local GMV increases were observed in the frontal and cerebellar regions. Connectivity analysis revealed significant reorganization within the Salience, Default Mode, and Frontoparietal Networks, with peak changes during the first 9 weeks marked by a shift from sensory processing to enhanced cognitive and affective processing. Additional rsFC analysis identified increased amygdala-cingulate and amygdala-hippocampal connectivity, indicating a significant link between the amygdala and paternal attachment during the first 12 weeks. These findings outline a clear trajectory of paternal neuroplasticity and adaptation during the early postpartum period, followed by maintenance and fine-tuning processes that likely facilitate paternal caregiving behaviors. Clinical Trial Registration: The study was registered at the German Clinical Trials register (DRKS; ID: DRKS00024875).
Clozapine disrupts the gut-lung microbiota axis, linking gastrointestinal hypomotility to increased respiratory vulnerability.
Cai Y, Eguchi A, Murayama R … +8 more , Ding X, Yue Y, Niitsu T, Oda Y, Futamura T, Yang JJ, Nakamura H, Hashimoto K
Transl Psychiatry · 2026 May · PMID 42129154 · Publisher ↗
Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but its clinical use is limited by serious gastrointestinal and respiratory adverse effects, including constipation, ileus, and pneumon...
Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but its clinical use is limited by serious gastrointestinal and respiratory adverse effects, including constipation, ileus, and pneumonia. The mechanisms linking these complications remain poorly understood. We tested the hypothesis that clozapine disrupts the gut-lung microbiota axis and that this disruption contributes to systemic toxicity. Adult male and female C57BL/6J mice received oral clozapine (5 mg/kg/day) or vehicle for 14 days. Clozapine significantly reduced body weight and fecal output, indicating gastrointestinal hypomotility. 16S rRNA sequencing revealed region-specific and sex-dependent alterations in microbial communities across the lungs, small intestine, cecum, and colon. Untargeted plasma metabolomics identified systemic metabolic changes in both sexes, including increased D-pyroglutamic acid and glutathione, consistent with oxidative and metabolic stress. Correlation analyses demonstrated coordinated associations among reduced fecal output, altered intestinal taxa, and circulating metabolites, indicating disruption of an integrated microbiota-metabolite network. Functionally, clozapine pretreatment significantly decreased survival following lipopolysaccharide-induced acute lung injury, indicating increased pulmonary vulnerability. Together, these findings suggest that clozapine disrupts the gut-lung microbiota-metabolite axis, linking gastrointestinal hypomotility with heightened respiratory susceptibility. This microbiota-centered framework provides mechanistic insight into clozapine-associated systemic toxicity and highlights microbiota-targeted strategies as potential approaches to improve the safety of clozapine therapy in treatment-resistant schizophrenia.
Circadian instability following mass trauma predicts PTSD risk.
Magal N, Netzer O, Eldar E … +5 more , Mandelblit N, Sagi N, Oren M, Salomon R, Admon R
Transl Psychiatry · 2026 May · PMID 42129153 · Publisher ↗
Trauma exposure can lead to posttraumatic stress disorder (PTSD) in a subset of vulnerable individuals. Circadian rhythm disturbances have emerged as a candidate pathway of vulnerability, yet mean circadian levels often...
Trauma exposure can lead to posttraumatic stress disorder (PTSD) in a subset of vulnerable individuals. Circadian rhythm disturbances have emerged as a candidate pathway of vulnerability, yet mean circadian levels often show limited discriminability. We tested whether circadian instability at trauma aftermath prospectively predicts long-term PTSD risk, and what behavioral and physiological indices are most predictive. For that, 211 survivors of the Supernova music festival mass-trauma event and 113 matched comparison participants were monitored in real-world settings for one-month, two-to-six months post-event, using wearable sensors that tracked their heart rate (HR), activity, and sleep-wake cycles. PTSD symptoms were assessed before and after the recording period, as well as at follow-up eight-to-eleven months post-event. Linear regression models compared circadian metrics between trauma survivors and comparison participants, and tested associations between circadian measures two-to-six months post-event and PTSD status and severity at follow-up. Results revealed that trauma survivors exhibited reduced circadian stability relative to comparison participants, characterized by greater sleep interday instability and higher variability in daily HR acrophase, as well as elevated rhythm-adjusted mean HR (MESOR). Further, circadian instability at two-to-six months post-event was particularly elevated among survivors with PTSD at follow-up and predicted their symptom severity. Finally, hierarchical models highlighted sleep instability at trauma aftermath as the most significant circadian predictor of long-term PTSD risk, above and beyond initial PTSD severity. Together, specific behavioral and physiological metrics of circadian instability at trauma aftermath prospectively index PTSD risk, highlighting circadian regulation as a target for vulnerability monitoring and early intervention.
Chronic alcohol exposure contributes to postoperative cognitive dysfunction via NR2B upregulation in the hippocampus of adult mice.
Ma L, Li S, Dong W … +8 more , Wan J, Li Z, Zhang C, Zhou X, Wang Z, Zhou C, Wu Y, Zheng H
Transl Psychiatry · 2026 May · PMID 42129152 · Publisher ↗
Postoperative cognitive dysfunction (POCD) is a common perioperative complication of the central nervous system, and patients with chronic alcohol exposure frequently require surgery under anesthesia. However, the contri...
Postoperative cognitive dysfunction (POCD) is a common perioperative complication of the central nervous system, and patients with chronic alcohol exposure frequently require surgery under anesthesia. However, the contribution of chronic alcohol exposure to POCD and its underlying mechanisms remains unclear. In this study, eight-week-old female and male mice were subjected to chronic alcohol exposure using the intermittent access two-bottle choice (IA2BC) paradigm. Compared with controls, mice with chronic alcohol exposure exhibited greater susceptibility to POCD. Specifically, chronic alcohol exposure increased NR2B expression in hippocampal CA1 glutamatergic neurons, enhancing A/S-induced hyperexcitability, which led to neuronal apoptosis and cognitive impairment. Notably, knockdown of NR2B or chemogenetic inhibition of CA1 glutamatergic neurons in IA2BC mice could reduce neuronal apoptosis and rescue A/S-induced cognitive dysfunction. These findings demonstrate that chronic alcohol exposure heightens susceptibility to POCD in young adult mice through NR2B-mediated excitotoxicity, revealing a mechanistic link between chronic alcohol exposure and POCD that warrants further investigation.
Thalamic nuclei volumes across psychiatric and neurological disorders: a multi-site magnetic resonance imaging study.
Mäki-Marttunen V, Nerland S, Jørgensen KN … +33 more , Høgestøl EA, Rokicki J, Alnæs D, Borgwardt S, Boye B, Buitelaar J, Bøen E, Cervenka S, Conzelmann A, Erhardt S, Franke B, Celius EG, Harbo HF, Hilland E, Hoekstra P, Hartman CA, Jonassen R, Jönsson EG, Landrø NI, Lesch KP, Maglanoc LA, Pauli P, Sellgren CM, Nygaard GO, Oosterlaan J, Schmidt A, Schwarz E, Ziegler GC, Agartz I, Westlye LT, Andreassen OA, Kaufmann T, Elvsåshagen T
Transl Psychiatry · 2026 May · PMID 42129147 · Publisher ↗
The human thalamus is an integrative hub for multiple cortical and subcortical circuits involved in sensory processing and higher cognitive functions. Thalamic volume differences have been reported across multiple psychi...
The human thalamus is an integrative hub for multiple cortical and subcortical circuits involved in sensory processing and higher cognitive functions. Thalamic volume differences have been reported across multiple psychiatric and neurological disorders, but previous studies have typically relied on small samples, focused on one or a limited number of disorders, or investigated the thalamus as a whole without considering its functional subdivisions. In this multi-site study, we compared thalamic nuclei volumes across mild cognitive impairment (MCI), dementia (DEM), major depressive disorder, schizophrenia spectrum disorder (SCZ), clinical high risk for schizophrenia, bipolar spectrum disorder, autism spectrum disorder, attention-deficit/hyperactivity disorder, Parkinson's disease, multiple sclerosis (MS), and healthy controls (N > 8000). Using structural MRI, we segmented 25 bilateral thalamic nuclei, corresponding to six anatomical groups. Linear models revealed that anterior, medial and lateral regions of the thalamus were significantly smaller in several conditions, with largest effects observed for MCI, DEM, SCZ and MS. In contrast, the ventral and intralaminar groups were relatively normal. This pattern of effects largely corresponds to the canonical functional subdivision of the thalamus into higher-order and sensory regions. At the level of individual nuclei, the clinical conditions were associated with distinct patterns of alterations, while left and right lateral geniculate nuclei were implicated in six of the disorders, suggesting a possible relation with circadian and sleep disturbances. Together, the results highlight a role for the higher-order thalamus in common brain disorders and a differential involvement at the nuclei level, refining our understanding of thalamic pathology across common brain disorders.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe