Transl Psychiatry [JOURNAL]
Sun
200 papers
Neural mechanisms of fear memory precision and generalization: from auditory cortex to amygdala.
Manassero E, Cicciarelli F, Milano L … +3 more , Renna A, Giglio C, Sacchetti B
Transl Psychiatry · 2026 Jul · PMID 42401557 · Publisher ↗
Identifying neural networks that infer safety versus danger is of great interest across multiple disciplines. Recent research has started to elucidate the brain networks mediating fear discrimination and generalization....
Identifying neural networks that infer safety versus danger is of great interest across multiple disciplines. Recent research has started to elucidate the brain networks mediating fear discrimination and generalization. Here, we focus on the contribution of the auditory cortices to auditory fear memory and discrimination processes. We first review studies showing that the primary auditory cortex (Te1) is involved in fear memory for tones with complex perceptual features only. Conversely, Te1 is essential for fear discrimination across all types of acoustic stimuli. These studies support the idea that Te1 plays a key role in the precision of auditory fear memory and in discriminating between aversive sounds and other, non-aversive sounds. We also discuss potential neuronal mechanisms within Te1 that may support these functions. Next, we review studies showing that higher-order auditory cortices, particularly those located in the posterior auditory field, constitute a critical hub for the encoding of auditory fear memories, regardless of the physical characteristics of the tones. We present evidence suggesting that these cortices may be involved in encoding the emotional and motivational significance that sounds acquire through experience. We also summarize studies suggesting that these areas might contribute to fear discrimination, although more compelling evidence is needed. We then discuss how descending pathways from auditory cortices may influence neuronal processes within the basolateral amygdala that participate in fear discrimination. We conclude by proposing that a better understanding of these sensory cortical mechanisms may inform novel strategies to address pathological fear generalization in fear- and anxiety-disorders.
Maraviroc attenuates inflammation-exacerbated cognitive and amyloid pathology in an early-stage Alzheimer's disease mouse model.
Liu C, Zhang T, E ED … +7 more , Xu TY, Yang FR, Li JW, Shang Q, Zhang ZY, Shen HW, Zhang XQ
Transl Psychiatry · 2026 Jul · PMID 42401549 · Publisher ↗
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive decline, and increasing evidence indicates that systemic inflammation can accelerate disease progression. Marav...
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive decline, and increasing evidence indicates that systemic inflammation can accelerate disease progression. Maraviroc, a CCR5 antagonist approved for the treatment of human immunodeficiency virus (HIV) infection, has shown neuroprotective effects in several neurological contexts, but its role in AD-related pathology remains unclear. In this study, cognitive performance was assessed in 5 × FAD mice using the Y-maze, novel object recognition, novel location recognition, and social discrimination tests. Amyloid-related changes were evaluated by hippocampal APP/Aβ immunoblotting and plaque staining using 6E10 and Thioflavin S. Glial responses were examined by IBA1 and GFAP immunostaining, and inflammatory cytokines were quantified by ELISA. We found that 5 × FAD mice exhibited age-dependent cognitive impairments, with detectable deficits emerging at 3 months of age. Systemic administration of lipopolysaccharide (LPS) further exacerbated cognitive dysfunction, amyloid-related alterations, and neuroinflammatory responses in young 5 × FAD mice. Maraviroc treatment attenuated LPS-associated cognitive impairments, reduced amyloid-related measures, and dampened pro-inflammatory cytokine responses, with a trend toward reduced microglial cell density. Collectively, these findings demonstrate that systemic inflammation accelerates Alzheimer's-like pathology and cognitive decline, and suggest that pharmacological modulation of neuroinflammatory signaling by maraviroc may mitigate inflammation-driven disease exacerbation at early stages.Schematic diagram illustrating the effects of maraviroc on LPS-induced cognitive deficits in 3-month-old 5 × FAD mice. In this model, maraviroc is associated with modulation of glial inflammatory responses, reduced pro-inflammatory cytokine levels, and alleviation of amyloid pathology in the hippocampus, which together coincide with improved cognitive performance. Figure created with BioRender.com.
High-order brain interactions during ketamine-induced state changes: A functional marker of response in late-life treatment-resistant depression?
Shah K, Herzog R, Swann AC … +4 more , O'Brien B, Balakrishnan R, Mathew SJ, Murphy N
Transl Psychiatry · 2026 Jul · PMID 42401545 · Publisher ↗
Ketamine is a fast-acting intervention for treatment-resistant depression (TRD), yet only a subset of patients show robust clinical response, and the underlying neural mechanisms remain unclear. High-order interactions (...
Ketamine is a fast-acting intervention for treatment-resistant depression (TRD), yet only a subset of patients show robust clinical response, and the underlying neural mechanisms remain unclear. High-order interactions (HOI) derived from multivariate information theory provide a framework for examining nonlinear dependencies among brain regions beyond pairwise connectivity. One such metric, the O-information, captures the balance between synergistic and redundant interactions across three or more variables. In this secondary analysis of a randomized, double-blind, midazolam-controlled trial (NCT02556606), we examined EEG-derived HOI in 30 late-life veterans with TRD following a single 40-minute intravenous infusion of ketamine (0.1, 0.25, 0.5 mg/kg; n = 18) or midazolam (0.03 mg/kg; n = 12). Resting state and mismatch negativity data were analyzed at baseline, 1 h, 24 h, and 7 d post-infusion. Ketamine induced temporally dynamic alterations in redundancy-dominant O-info, with maximal effects in the alpha-band at 1 h (Cohen's d = 2.57), attenuation at 24 h that shifted toward the theta-band, and partial resurgence in beta and gamma by Day 7. Linear mixed-effects modeling identified significant group effects across most band x metric families, with the strongest effects in alpha, beta, and gamma redundancy. Greater increases in 24-hour alpha-band redundancy were associated with greater improvement in depressive symptoms at Day 7 (β = 69.31, q = 0.05). HOI metrics also tracked acute dissociative states, with several 24-hour alpha and beta features remaining positively associated with symptom severity after correction. These findings extend prior HOI work in healthy samples to a controlled TRD cohort and suggest that ketamine induces temporally structured reorganization of higher-order brain interactions, with exploratory associations to clinical outcomes.
Immune-metabolic mediation of depression risk: Causal evidence from antibody and metabolite GWAS.
Zhang Y, Chen F, Song G … +4 more , Zhou L, Ren Y, Hua J, Wang H
Transl Psychiatry · 2026 Jul · PMID 42399632 · Publisher ↗
Depression is a major contributor to global disability, yet its underlying biological mechanisms remain incompletely understood. Immune activation and metabolic alterations, particularly involving lipid metabolism, have...
Depression is a major contributor to global disability, yet its underlying biological mechanisms remain incompletely understood. Immune activation and metabolic alterations, particularly involving lipid metabolism, have been implicated, but their roles in depression remain unclear. We used large-scale genome-wide association study (GWAS) summary statistics to examine the relationships among antibody responses, plasma metabolites, and depression. Mendelian randomization (MR) was applied to evaluate genetically predicted associations of antibody traits and metabolites with depression risk. Generalized summary-data-based Mendelian randomization (GSMR) was used as a complementary analysis, and two-step mediation analyses were performed to assess whether selected metabolites were compatible with mediating immune-related effects on depression. Higher Epstein-Barr virus (EBV) ZEBRA antibody levels were associated with increased depression risk, whereas arachidonate-enriched metabolites tended to show inverse associations with depression and several linoleoyl-related metabolites showed positive associations. Mediation analyses suggested that 1,2-dilinoleoyl-GPC showed a positive indirect effect, whereas 1-arachidonylglycerol showed a negative indirect effect. Two glycerolipid ratios also showed indirect effects consistent with partial mediation. Complementary GSMR analyses showed directionally concordant results for the principal associations. Overall, these findings support an immunometabolic interpretation in which EBV-related immune responses and plasma metabolite remodeling may be relevant to depression vulnerability, and they prioritize candidate metabolites and pathways for future mechanistic and clinical investigation.
DRD1 and DRD2 dopamine-sensitive neurons in the central amygdala respond differently to rewarding and aversive stimuli.
Bijoch Ł, Wiśniewska J, Szczypkowski P … +4 more , Pawłowska M, Hajdukiewicz K, Lapkiewicz R, Beroun A
Transl Psychiatry · 2026 Jul · PMID 42399629 · Publisher ↗
The ability to differentiate between rewarding and aversive stimuli is crucial for survival, yet the underlying neural mechanisms allowing animals to make such a distinction remain elusive. Here, using in vivo two-photon...
The ability to differentiate between rewarding and aversive stimuli is crucial for survival, yet the underlying neural mechanisms allowing animals to make such a distinction remain elusive. Here, using in vivo two-photon calcium imaging, we uncovered how the activity of dopamine-sensitive neurons in the medial nucleus of the central amygdala (CeM) is associated with appetitive and aversive experiences. We found that cocaine and sucrose strongly activated DRD1(+) neurons while suppressing DRD2(+) activity, whereas the aversive quinine stimulus predominantly engaged DRD2(+) neurons, particularly those not previously recruited by sucrose. Our findings suggest that DRD1(+) and DRD2(+) neurons differentially contribute to the processing of appetitive and aversive stimuli. Furthermore, by simultaneously monitoring facial expressions, we identified stimulus-specific behavioral responses to sucrose, quinine, and cocaine.
Neuroinflammation and depression: immune-brain interface mechanisms, biomarker stratification, and therapeutic strategies.
Santerre M, Shcherbik N, Sawaya BE
Transl Psychiatry · 2026 Jul · PMID 42399626 · Publisher ↗
Major depressive disorder is among the most prevalent and disabling conditions in global medicine, yet its biological underpinnings remain incompletely understood, and current pharmacological treatments fail to produce a...
Major depressive disorder is among the most prevalent and disabling conditions in global medicine, yet its biological underpinnings remain incompletely understood, and current pharmacological treatments fail to produce adequate responses in approximately one-third of patients. A rapidly accumulating body of evidence has not simply challenged the long-dominant monoamine deficiency hypothesis but has provided a mechanistic framework that may explain many of the observed monoaminergic alterations in depressive cohorts, including IDO1-driven serotonin depletion, cytokine-mediated AMPA receptor internalization, and HPA-immune feedback dysregulation. Neuroinflammation, particularly glial activation across microglial, astrocytic, and oligodendrocyte lineages, and its downstream consequences for tryptophan metabolism, glutamatergic transmission, synaptic plasticity, and neurotrophic signaling, represents a central pathophysiological mechanism in a substantial subgroup of depressed patients. Peripheral inflammatory markers, including C-reactive protein, interleukin-6, and tumor necrosis factor-alpha, are elevated in a significant proportion of individuals with major depressive disorder, and these elevations predict poor response to conventional antidepressants while identifying patients who may respond preferentially to anti-inflammatory strategies. Post-mortem studies, positron emission tomography imaging of translocator protein density, and transcriptomic analyses of brain tissue have collectively provided consistent, though not yet fully definitive, evidence that microglial activation is a neurobiological feature of depression rather than a consequence of comorbid physical illness. This review synthesizes current mechanistic understanding of the neuroinflammatory hypothesis of depression, examines the evidence base from epidemiological, biomarker, neuroimaging, and interventional studies, including null findings and methodological limitations, evaluates emerging therapeutic strategies targeting the immune-brain interface, and identifies the critical questions that will determine whether immunopsychiatry fulfills its promise as a precision medicine framework for treatment-resistant depression.
Operationalization drift in the construct of impulsivity: relevance to animal models of addiction.
Ginovart N, Dalley JW, Belin D
Transl Psychiatry · 2026 Jul · PMID 42399616 · Full text
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Kappa-opioid receptor activation promotes depression-like behaviors by suppressing Pax6-dependent adult hippocampal neurogenesis.
Peng HS, Chen RS, Ye RF … +9 more , Zhai CY, Jiang XC, Li PP, Ye JY, Han MM, Fu QQ, Shen YQ, Liu JG, Xu C
Transl Psychiatry · 2026 Jul · PMID 42399227 · Publisher ↗
Accumulating evidence indicates that adult hippocampal neurogenesis (AHN) undergoes heterogeneous alterations in depression, yet the underlying mechanisms remain incompletely understood. In this study, we established a c...
Accumulating evidence indicates that adult hippocampal neurogenesis (AHN) undergoes heterogeneous alterations in depression, yet the underlying mechanisms remain incompletely understood. In this study, we established a corticosterone (CORT)-induced mouse model of depression and combined pharmacological, molecular biological, and genetic approaches to investigate the mechanisms through which CORT suppresses AHN and induces depressive-like behaviors. Our results demonstrated that chronic CORT treatment led to depressive-like phenotypes in mice, including decreased sucrose preference and behavioral despair, accompanied by impaired AHN, manifested by a reduction in immature neurons (DCX⁺BrdU⁺) but an increase in proliferating cells (Ki67⁺). Further mechanistic studies revealed that CORT upregulates dynorphin A in the dentate gyrus (DG), leading to overactivation of the κ-opioid receptor (KOR). This subsequently inhibits the expression of Pax6 and its downstream targets Neurog2 and NeuroD1, thereby obstructing neuronal differentiation. The KOR antagonist nor-BNI effectively reversed both the depressive-like behaviors and AHN abnormalities induced by CORT. Moreover, overexpression of Pax6 alleviated depressive behaviors and restored neurogenesis, whereas knockdown of Pax6 was sufficient to induce depressive phenotypes and impair AHN. Our study unveils a central role of the KOR/Pax6 signaling axis in AHN suppression and depression pathogenesis, providing a theoretical foundation for antidepressant strategies targeting KOR or Pax6.
Imbalance in excitation and inhibition in sgACC is associated with depression in dementia with Lewy bodies.
Gliaudelytė L, Rushton SP, Thomas AJ … +1 more , Morris CM
Transl Psychiatry · 2026 Jul · PMID 42399222 · Publisher ↗
Depression in dementia with Lewy bodies (DLB) is a common neuropsychiatric symptom associated with reduced quality in life. Structural, functional and neurochemical abnormalities in glutamatergic and GABAergic neurotrans...
Depression in dementia with Lewy bodies (DLB) is a common neuropsychiatric symptom associated with reduced quality in life. Structural, functional and neurochemical abnormalities in glutamatergic and GABAergic neurotransmission are implicated in the pathophysiology of depression, showing changes in regions involved in emotional processing, including the subgenual cingulate cortex (sgACC), which shows pathological changes in DLB. Using post-mortem tissue from DLB patients and controls, we assessed synaptic and neurochemical changes within the sgACC in relation to depression in DLB. We identified a reduction of layer V GABAergic neurones in depressed DLB cases, potentially indicating reduced inhibition of layer V pyramidal neurons, leading to altered excitation. High-resolution confocal imaging demonstrated a significantly increased volume of presynaptic glutamatergic synapses containing phosphorylated α-synuclein (s129) in DLB cases, and specifically in depressed DLB cases, potentially as a compensatory response to the accumulation of pathological s129. GABAergic synapses containing s129 were enlarged in both DLB groups showing no depression specific changes. Selective reductions in glutamatergic and GABAergic receptors were seen in depressed DLB cases, suggesting a role in the pathophysiology of depression in DLB, that may prove amenable to therapy with fast-acting antidepressants. Interactions with serotonergic and dopaminergic innervation were observed, where preserved 5HT3B receptor and calbindin characterised non-depressed DLB patients. In depressed DLB cases, this may lead to reduced inhibition of lower layer pyramidal neurones due to reduced dopaminergic coupling and enhanced excitatory activity within the cingulate. Overall, our findings suggest altered excitatory and inhibitory neurotransmission may contribute to the development of depression in DLB.
Distinct temporal neural dynamics of working memory in depressive patients: early encoding deficits and late maintenance correlates of rumination.
Wang X, Zou H, Zhao S … +2 more , Yao Z, Lu Q
Transl Psychiatry · 2026 Jul · PMID 42399221 · Publisher ↗
Working memory (WM) deficits and maladaptive rumination are hallmark features of major depressive disorder (MDD), yet the stage-specific electrophysiological mechanisms remain poorly understood. This study investigated n...
Working memory (WM) deficits and maladaptive rumination are hallmark features of major depressive disorder (MDD), yet the stage-specific electrophysiological mechanisms remain poorly understood. This study investigated neural dynamics during WM encoding and maintenance in individuals with depressive episode (DE) and their associations with rumination subfactors. A total of 59 DEs and 49 healthy controls (HCs) performed an n-back task (0-back and 2-back) while 64-channel electroencephalography (EEG) was recorded. Behavioral results demonstrated that the DEs exhibited impaired WM updating, characterized by significantly lower accuracy and slower reaction time (RT) under high cognitive load. Electrophysiological analyses revealed that during encoding, the DEs showed attenuated load-related modulation of the frontal N2 amplitude. During maintenance, the DEs demonstrated pathologically elevated occipital alpha power. Crucially, a significant group × alpha interaction (Wald χ² (1) = 9.258, p = 0.002) in predicting RT was observed. Higher alpha power was associated with slower RT in HCs (β = 0.006, p = 0.021), whereas this neurobehavioral coupling was disrupted and paradoxically reversed in the DEs (β = -0.003, p = 0.063). Within the DE group, alpha power was significantly negatively associated with brooding (β = -0.962, p = 0.006) and reflective pondering (β = -0.692, p = 0.035) independent of task load. Our findings reveal that impaired resource mobilization during encoding and disorganized functional inhibition during maintenance converge to drive WM deficits in depressive patients, with the latter uniquely tied to maladaptive rumination.
Fish oil-derived fatty acids during pregnancy and risk of neurodevelopmental disorders in children at age 10 - A randomized controlled trial.
Rosenberg JB, Sevelsted A, Jepsen JRM … +13 more , Vinding R, Mohammadzadeh P, Hernández Lorca M, Horner D, Sørensen ME, Fagerlund B, Bilenberg N, Pantelis C, Glenthøj BY, Chawes B, Stokholm J, Ebdrup BH, Bønnelykke K
Transl Psychiatry · 2026 Jul · PMID 42393063 · Publisher ↗
Fish oil-derived omega-3 fatty acids (ꙍ-3 FA), particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are critical for early brain development, but evidence of causal effects from supplementation during...
Fish oil-derived omega-3 fatty acids (ꙍ-3 FA), particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are critical for early brain development, but evidence of causal effects from supplementation during pregnancy is limited. In the prospective COPSAC cohort of 700 mother-child pairs, we investigated whether i) maternal DHA + EPA blood concentrations in mid-pregnancy and ii) fish oil supplementation in a randomized trial in late pregnancy influence neurodevelopmental outcomes at age 10. Maternal blood DHA + EPA concentrations were measured at 24 weeks gestation, followed by randomization to 2.4 g daily fish oil (37% DHA, 55% EPA) or placebo until one-week postpartum. Psychopathology was assessed in the children at age 10 using the Kiddie Schedule for Affective Disorders and Schizophrenia -Present and Lifetime version and parental-rated questionnaires Statistical analyses included logistic and linear regression models. Higher maternal DHA + EPA concentrations were associated with reduced ADHD risk (OR 0.71, p = 0.03) and ADHD symptom load (β = -1.14, p < 0.001) in unadjusted analyses but not after confounder adjustment (OR 0.82, p = 0.24; β = -0.49, p = 0.21). Similar trends were observed for autistic traits (β = -1.96, [-1.11; -0.24] p = 0.01), but not significant after confounder adjustment. Fish oil supplementation showed no significant reduction in ADHD (OR 0.79, p = 0.37) or ASD risk (OR 0.56, p = 0.42). A secondary analysis suggested a protective effect for ADHD Predominantly Inattentive Presentation, although it did not hold significance after correction for multiple testing (OR 0.41; p = 0.03; FDRp=0.12). Thus, potential effects on inattentive ADHD symptoms should be explored in future studies.
Cerebellar hypermetabolism disrupts fronto-cerebellar resting-state functional connectivity and associated executive compensation.
Ritz L, Morand A, Laniepce A … +3 more , Cabé N, Segobin S, Pitel AL
Transl Psychiatry · 2026 Jul · PMID 42393033 · Publisher ↗
Cerebellar hypermetabolism measured with FDG-PET is interpreted as maladaptive plasticity, while increased cerebellar functional connectivity reported in fMRI studies indicates a compensatory role. Using Alcohol Use Diso...
Cerebellar hypermetabolism measured with FDG-PET is interpreted as maladaptive plasticity, while increased cerebellar functional connectivity reported in fMRI studies indicates a compensatory role. Using Alcohol Use Disorder (AUD) as a neurobiological model, the combination of PET and fMRI examinations can extend our understanding of cerebellar mechanisms underlying brain reorganization within the fronto-thalamo-cerebellar circuit (FCC) supporting executive functions. The aim of the present study was to investigate resting-state functional connectivity (rs-FC) of the cerebellum and to examine its relationship with cerebellar metabolism, thalamic grey matter volume (GM) as a key node of the FCC, and executive functioning. In AUD patients, stronger negative rs-FC was found between the cerebellar lobule VIII seed and voxels in the left superior frontal gyrus compared with HC. Path analysis conducted in AUD patients indicated that cerebellar hypermetabolism was positively related to fronto-cerebellar rs-FC, and that fronto-cerebellar rs-FC was positively related to inhibition performance. In this model, after controlling for thalamic GM abnormalities, cerebellar hypermetabolism negatively impacted inhibition performance through rs-FC. Cerebellar hypermetabolism disrupts negative fronto-cerebellar rs-FC, resulting in desynchronization within the fronto-cerebellar loop that compromises compensation for executive deficits. Cerebellar hypermetabolism may represent a biomarker of alcohol-related brain dysfunction, as an initial mechanism in the cascade linking fronto-cerebellar desynchronization and executive impairment.
Medium-intensity aerobic exercise can relieve mice anxiety by activating cannabinoid type 1 receptors on medial prefrontal cortex GABAergic neurons.
Li H, Yang M, Yang Y … +9 more , Ren H, Wang H, Huang J, Zhou H, Hu X, Yuan Z, Qi G, Zhanmu O, Li M
Transl Psychiatry · 2026 Jul · PMID 42393030 · Publisher ↗
Anxiety disorders are highly prevalent, yet current pharmacological treatments often have limited efficacy and adverse effects. As a safe and accessible non-pharmacological intervention, physical exercise has shown promi...
Anxiety disorders are highly prevalent, yet current pharmacological treatments often have limited efficacy and adverse effects. As a safe and accessible non-pharmacological intervention, physical exercise has shown promise in alleviating anxiety; however, its precise neural mechanisms remain unclear. This study aimed to elucidate how moderate-intensity aerobic exercise reduces anxiety, with a specific focus on the role of distinct cell populations within the medial prefrontal cortex (mPFC). Using a chronic restraint stress (CRS) mouse model, we combined behavioral tests, protein analysis, pharmacological interventions, and optogenetics to systematically examine the effects of exercise on anxiety-like behaviors and the associated molecular and cellular mechanisms in the mPFC. Moderate-intensity aerobic exercise significantly alleviated stress-induced anxiety-like behaviors. Further investigation revealed that exercise enhanced endocannabinoid system (ECS) activity in the mPFC, specifically by activating cannabinoid type 1 receptors (CB1Rs) located on local inhibitory neurons. Cell type-specific manipulation demonstrated that CB1Rs on GABAergic neurons are essential for the anxiolytic effect of exercise, whereas CB1Rs on other neuronal subtypes were not involved. Our findings indicate that moderate-intensity aerobic exercise reduces anxiety by selectively enhancing CB1R function on GABAergic neurons in the mPFC, thereby restoring circuit balance. This study not only advances the understanding of exercise-induced neurobiological benefits but also offers a novel theoretical basis for developing targeted antianxiety strategies.
Aberrant multivariate mapping between behavioral profiles and cortical morphological brain networks in children with autism spectrum disorder.
Liao Y, Pan N, Qiu X … +4 more , Jing J, Lin L, Wang X, Wang J
Transl Psychiatry · 2026 Jul · PMID 42393028 · Publisher ↗
Understanding how human behavior relates to brain structure and function is a central goal of neuroscience. Autism spectrum disorder (ASD) is increasingly conceptualized as a disorder of connectome dysfunction; however,...
Understanding how human behavior relates to brain structure and function is a central goal of neuroscience. Autism spectrum disorder (ASD) is increasingly conceptualized as a disorder of connectome dysfunction; however, how morphological brain networks relate to behavioral profiles in children with ASD remains unclear. In this study, we collected a comprehensive battery of behavioral assessments and structural MRI data from 101 children with ASD and 67 typically developing (TD) children. Individual morphological brain networks were constructed by integrating four cortical features to estimate morphological connectivity (MC). We then applied sparse canonical correlation analysis (sCCA) to identify multivariate brain-behavior associations within each group. Using group-specific MC features, four distinct association modes were identified in TD children, none of which generalized to the ASD group. In ASD children, three modes were detected that captured comparable behavioral dimensions with three TD modes but were supported by largely distinct neural architectures. Within a unified MC framework, an autistic trait mode emerged in both groups; however, it was primarily supported by MC between the default and control networks in TD children, versus MC between the default and dorsal attention networks in ASD children. Notably, the prosociality mode present in TD children was consistently absent in the ASD group, regardless of the MC features used in sCCA. These findings reveal a reorganization of brain-behavior relationships in children with ASD and provide evidence for a neurodiverse neural architecture, in which similar behaviors arise from divergent neurodevelopmental pathways, moving beyond a simple continuum model of typical development.
In the Search for Suicide Signatures, Phenotype Matters.
Punzi G
Transl Psychiatry · 2026 Jul · PMID 42393027 · Full text
Abstract loading — click title to view on PubMed.
Early life social defeat in mice reduces prefrontal innervation of downstream structures in a regionally specific manner.
Mayeaux M, Shantha-Raman S, Hisey EE
Transl Psychiatry · 2026 Jul · PMID 42393026 · Publisher ↗
Physical abuse in childhood and adolescence results in long lasting effects on mental and physical health in adulthood. The prefrontal cortex of adults exposed to abuse in childhood shows both functional and structural a...
Physical abuse in childhood and adolescence results in long lasting effects on mental and physical health in adulthood. The prefrontal cortex of adults exposed to abuse in childhood shows both functional and structural abnormalities in comparison to healthy controls. However, the changes in prefrontal innervation of specific downstream targets as a result of early life abuse are unclear. Here we used a novel abbreviated early adolescent chronic social defeat stress paradigm (5 day eaCSDS) to assess changes to prefrontal innervation in adult male and female C57BL/6 J mice. We injected control and defeated mice with virally encoded GFP in the prelimbic region of prefrontal cortex (PL) and examined axon density in basolateral amygdala (BLA), nucleus accumbens (NAc) and ventral tegmental area (VTA). We find that both male and female mice show robust but seemingly opposing changes in social interaction after 5 day eaCSDS. We found significantly decreased PL innervation of BLA and increased fragmentation of PL axons in BLA. Males, but not females, also show increased fragmentation of PL axons in NAc. Interestingly, PL innervation of BLA significantly correlates with adult social behavior in males and females. Our findings suggest that PL innervation of downstream targets is dramatically affected by early life social defeat in both a regional and sex-specific manner. This differential change in innervation across regions and sexes may underlie the social behavioral deficits seen after early life social defeat.
Natural flavonoid dihydroquercetin blocks Trim14-JAK1-STAT3 signaling and relieves pain-depression comorbidity in rheumatoid arthritis.
Ni XW, Chai B, Li ZM … +7 more , Li XP, Sun C, Yuan XL, Zhang YB, Zhang Y, Qian WJ, Zhang HL
Transl Psychiatry · 2026 Jul · PMID 42393024 · Publisher ↗
Rheumatoid arthritis (RA) is frequently complicated by chronic pain, anxiety and depression, yet the neuroimmune mechanisms linking peripheral inflammation to central affective dysfunction remain elusive. Here we demonst...
Rheumatoid arthritis (RA) is frequently complicated by chronic pain, anxiety and depression, yet the neuroimmune mechanisms linking peripheral inflammation to central affective dysfunction remain elusive. Here we demonstrate that the natural flavonoid dihydroquercetin (DHQ) blocks Trim14 and relieves pain-depression comorbidity in RA. Serum Trim14 is elevated in RA patients and correlates with clinical symptom severity. We identify Trim14 as a contributing factor of JAK1/STAT3 signaling in spinal dorsal horn neurons, promoting both nociceptive sensitization and affective symptoms in collagen-induced arthritis (CIA) mice. Intrathecal Trim14 siRNA attenuates synovial inflammation, inflammatory pain and anxiety-depressive behaviors. Molecular docking and molecular dynamics simulations reveal that DHQ occupies the Trim14 PRYSPRY substrate-recognition pocket with sub-micromolar affinity. Long-term DHQ treatment improves both nociceptive and affective symptoms by inhibiting spinal Trim14-JAK1-STAT3 axis in CIA mice. These findings suggest Trim14 as a potential neuroimmune target and DHQ as a natural medicine modulator for pain-depression comorbidity in chronic inflammatory disease.
Clock gene signature predicts insomnia and links to sleep/circadian parameters.
Carvalhas-Almeida C, Alves J, Davi T … +9 more , Santos B, Gaspar L, Ribeiro RFN, Serra J, Ferreira M, Moita J, Sehgal A, Cavadas C, Álvaro AR
Transl Psychiatry · 2026 Jul · PMID 42386720 · Publisher ↗
Chronic Insomnia is a prevalent sleep disorder that remains difficult to diagnose due to subjective symptoms and heterogeneous presentations. The most severe form, insomnia with short sleep duration (ISSD), is defined by...
Chronic Insomnia is a prevalent sleep disorder that remains difficult to diagnose due to subjective symptoms and heterogeneous presentations. The most severe form, insomnia with short sleep duration (ISSD), is defined by a total sleep time of less than six hours on polysomnography. However, objective assessments are rarely recommended in diagnostic guidelines, highlighting the need for alternative biomarkers. Disruptions in the circadian clock system may contribute to chronic insomnia, though the extent of these effects remains unclear. In this study, we investigate sleep and circadian rhythm-related alterations in chronic insomnia and its subtypes, ISSD and insomnia with normal sleep duration (INSD), by assessing plasma cortisol, wrist and axillary temperature, and clock gene expression in peripheral blood mononuclear cells (PBMCs). Additionally, we use machine learning to identify the most relevant clock genes for detecting insomnia and classifying its subtypes. Chronic insomnia patients exhibited reduced body temperature rhythms, elevated cortisol levels during wake before sleep, and significant alterations in clock gene expression, including in BMAL1, PER1-2, REV-ERBα, and REV-ERBβ, compared to controls. Most alterations were more significant in the ISSD group. Moreover, associations between clock gene expression, sleep-related parameters and Insomnia Severity Index (ISI) scores were identified. Using machine learning, we identified three genes as sensitive biomarkers distinguishing chronic insomnia from controls and differentiating between ISSD and INSD subtypes. Our findings suggest that circadian markers and machine learning could improve understanding of chronic insomnia and aid biomarker discovery for diagnosis.
Genome-wide pleiotropic analysis identifies shared genetic architecture within the cognition-immune nexus.
Yu T, Zhao G, Zhang Y … +10 more , Sun Y, Lu Z, Yuan R, Zhu Y, Kang Z, Feng X, Sun J, Guo J, Yang Y, Yue W
Transl Psychiatry · 2026 Jul · PMID 42386713 · Publisher ↗
Increasing evidence supports associations between cognitive function and autoimmune disorders, yet the underlying genetic mechanisms remain unclear. Using large-scale genome-wide association statistics for seven cognitiv...
Increasing evidence supports associations between cognitive function and autoimmune disorders, yet the underlying genetic mechanisms remain unclear. Using large-scale genome-wide association statistics for seven cognitive traits and fifteen autoimmune disorders, together with two independent cohorts comprising 522 healthy individuals and 80 patients with schizophrenia, we performed multi-level pleiotropic analyses. Genetic correlation analyses identified nine significant cognition-immune linkage pairs, whereas Mendelian randomization (MR) analyses suggested that these associations were largely driven by shared genetic architecture rather than causality. Using PLACO, colocalization analysis, and MAGMA analyses, we identified 46 pleiotropic loci and 169 pleiotropic genes across the linkage pairs. Polygenic risk scores derived from pleiotropic variants were associated with cognition in healthy adults and showed nominal associations in schizophrenia. Enrichment analyses linked these genes to cognition-immune-related tissues, pathways, and biological processes, while multi-trait colocalization highlighted CD33 as a potential key mediator. Finally, summary-based MR analyses of both pleiotropic genes and anti-inflammatory drug target genes highlighted AMT, CRAT, ERAP2, ERBB3, GNL3, IRF3, MST1R, RPS26, SH2B1, SULT1A1, SULT1A2, TMEM258, CYP2D6 and MAPK3 as promising therapeutic targets for both cognitive function and autoimmune disorders. This study delineates the shared genetic architecture underlying the cognition-immune nexus and identifies novel candidate targets, highlighting the value of integrative genetic approaches for advancing diagnosis and treatment.
Theta burst stimulation of extrastriate body area for body perception in anorexia nervosa: a randomized controlled trial.
Boehme R, Kaldewaij R, Frost-Karlsson M … +13 more , Wold A, Enmalm A, Khoure I, Tell J, Käll J, Salerud M, Rimhagen E, Jackleus C, Barsjö S, Thordstein M, Gustafsson PA, Olausson H, Zetterqvist M
Transl Psychiatry · 2026 Jul · PMID 42386712 · Full text
Anorexia nervosa is a severe and potentially life-threatening psychiatric disorder characterized by self-starvation, intense fear of weight gain, and a distorted body perception. Treatment remains challenging, and effect...
Anorexia nervosa is a severe and potentially life-threatening psychiatric disorder characterized by self-starvation, intense fear of weight gain, and a distorted body perception. Treatment remains challenging, and effective interventions for adults are limited. The extrastriate body area (EBA), a cortical region involved in body representation, may contribute to the body perception disturbances. In this double-blind, placebo-controlled, randomized proof-of-concept trial, we investigated the therapeutic potential of targeted theta burst transcranial magnetic stimulation (TMS) of the EBA in patients with anorexia nervosa (n = 40). Participants received four weeks of active (n = 10) or sham (n = 10) TMS combined with body perception training, while a treatment-as-usual group (n = 20) and a healthy control group (n = 40) served as comparators. Improvements in the primary outcome measure, the Body Shape Questionnaire, differed across groups over time, with active TMS showing faster improvement (after 4 weeks) relative to both control groups, that was sustained at 6 months follow-up. Moreover, active stimulation was associated with changes in EBA responses to self- versus non-self touch, shifting neural activity patterns more closely to those of healthy individuals. These findings provide preliminary evidence that individualized neuromodulation targeting a disorder-relevant neural substrate combined with behavioral training shows potential for effectively recalibrating disturbed body perception. By integrating brain stimulation with behavioral training, this study exemplifies a precision psychiatry approach that links neurobiological mechanisms to personalized therapeutic interventions in anorexia nervosa.
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