Transl Psychiatry [JOURNAL]
Sun
200 papers
Bridging molecules and connectome: network biomarkers guided by neurotransmitter architecture in major depressive disorder.
Lv Q, Dong D, Fang S … +6 more , Wang X, Lin P, ZIB Consortium, Feng J, Luo Q, Wang X
Transl Psychiatry · 2026 May · PMID 42129144 · Publisher ↗
Major depressive disorder (MDD) involves multiscale alterations ranging from molecular signaling to large-scale brain network dysfunction. However, how molecular topography constrains system-level connectome reorganizati...
Major depressive disorder (MDD) involves multiscale alterations ranging from molecular signaling to large-scale brain network dysfunction. However, how molecular topography constrains system-level connectome reorganization remains inadequately understood, limiting the development of biologically grounded diagnostic markers. We established a biologically grounded framework by integrating molecular organization with systems-level connectome analysis to characterize and classify MDD. Using resting-state functional magnetic resonance imaging data from a discovery cohort of 237 first-episode, medication-naïve MDD patients and 305 healthy controls (HC), as well as an independent multi-site validation cohort comprising 243 MDD patients and 340 HCs, we systematically mapped connectome-wide reconfigurations onto 14 normative neurotransmitter receptor and transporter density distributions. Our findings revealed widespread connectivity alterations (6.38% of edges). These alterations spatially correlated with normative densities of serotonin 1A (5-HT; ρ = -0.217) and dopaminergic markers, including the dopamine transporter (DAT) and dopamine receptors (D1 and D2; ρ range: -0.204 to -0.227). To translate these mechanistic insights into individual-level predictions, we developed the Neurotransmitter Transporter/Receptor-Annotated Connectome Classification Model (NTR-CCM), which incorporates molecular maps as biological priors to guide feature selection. The NTR-CCM achieved superior diagnostic performance in the discovery cohort (area under the curve [AUC] = 0.83-0.86) and maintained robust generalization in the external validation cohort (AUC = 0.73-0.75). These results indicate that macroscale connectome reorganization in MDD is spatially constrained by the brain's underlying neurochemical architecture. By bridging molecular and systems scales, the NTR-CCM provides a high-performing and mechanistically interpretable framework for precision psychiatry.
Acute placebo responsiveness predicts longitudinal expectation effects in antidepressant treatment.
Shim EJ, Schmidt L, Rauh J … +6 more , Leicht G, Gamer M, Bingel U, Büchel C, Rief W, Brassen S
Transl Psychiatry · 2026 May · PMID 42129142 · Full text
Positive treatment expectations are known to enhance antidepressant efficacy. Experimental placebo studies aim to provide mechanistic insights into this association, yet their findings have not been clearly linked to cli...
Positive treatment expectations are known to enhance antidepressant efficacy. Experimental placebo studies aim to provide mechanistic insights into this association, yet their findings have not been clearly linked to clinical expectation effects within individual patients. In a randomized crossover trial, 61 participants with major depressive disorder (31 women, 30 men) completed an emotion classification task and mood assessments after administration of a saline nasal spray labeled as either oxytocin (sham oxytocin treatment, deceptive placebo) or saline (control). Forty-five participants subsequently underwent antidepressant treatment and were monitored weekly for treatment expectations and depressive symptoms, with follow-ups extending to three months. Using linear mixed-effect models, we examined trajectories of clinical expectation effects and their prediction by experimental placebo-induced changes in emotional processing. Sham oxytocin treatment acutely induced positive expectations, improved mood, and shifted emotional processing toward positivity. Longitudinal modeling revealed that weekly reductions in depressive symptoms were predicted by higher treatment expectations reported the preceding week. These clinical expectation effects were most pronounced in individuals exhibiting strong acute placebo responses in emotional processing. Overall, our findings indicate that positive treatment expectations facilitate critical aspects of emotional processing in depression and that individual responsiveness generalizes across different treatments and time windows. Experimental placebo assessments offer an ecologically valid model for elucidating mechanisms and predictors of clinical expectation effects and highlight expectation sensitivity as a promising target for treatment optimization.
Application of escitalopram population pharmacokinetic repository: a step to precision dosing.
Liu L, Chen J, Ju G … +11 more , Qian C, Xie X, Song H, Gong Y, Luo Y, Nie W, Ouyang D, Chen L, Li J, Zhu X, Liu X
Transl Psychiatry · 2026 May · PMID 42129140 · Publisher ↗
Escitalopram is widely used to treat major depressive disorder, yet drug exposure varies substantially across patients, causing the inadequate response or toxicity probability. Individualized dosing supported by therapeu...
Escitalopram is widely used to treat major depressive disorder, yet drug exposure varies substantially across patients, causing the inadequate response or toxicity probability. Individualized dosing supported by therapeutic drug monitoring and published population pharmacokinetic models is promising, but independent evaluation of existing models and clinically usable decision-support tools remains limited. We systematically reviewed published population pharmacokinetic models for escitalopram and extracted key patient characteristics and model parameters. The models were evaluated in an independent real-world dataset from Chinese psychiatric patients using simulation-based or prediction-based metrics. The best-performing model was implemented in a web-based clinical decision-support tool. Ten published models were identified and evaluated using data from 309 Chinese patients, contributing 421 plasma concentrations. A priori predictions consistently underestimated observed concentrations, with median absolute prediction errors ranging from 37.97-64.62%. In contrast, Bayesian updating using TDM data markedly improved both accuracy and precision, reducing most of median absolute prediction errors to <30%. The best-performing model was implemented in an openly accessible Shiny application to support initial dose selection, TDM-guided dose individualization, and management of missed or delayed doses with remedial dosing recommendations (https://escitalopram-liux-v1.shinyapps.io/Escitalopram_MIPD_Tool/). This study provides a comprehensive external evaluation of escitalopram population pharmacokinetic models in a Chinese psychiatric cohort and presents a freely accessible, clinically oriented precision dosing tool to support individualized escitalopram therapy for Chinese patients.
Spatial lipidomic and neuron-specific transcriptomic signatures in the nucleus accumbens reveal phospholipid dyshomeostasis in depression-related maladaptations.
Camargo A, Kaya I, Sturchio A … +5 more , Saarinen M, Kurgina A, Liang T, Andrén PE, Svenningsson P
Transl Psychiatry · 2026 May · PMID 42129137 · Full text
Lipid systems play a substantial role in the pathophysiological mechanisms underlying several brain disorders. However, the mechanisms underlying the lipid profile in stress-induced maladaptations and how these changes c...
Lipid systems play a substantial role in the pathophysiological mechanisms underlying several brain disorders. However, the mechanisms underlying the lipid profile in stress-induced maladaptations and how these changes can impact distinct neuronal circuits and behavioral states remain to be fully elucidated. Here, we investigated the effects of p11 deficiency in combination with stress by using p11KO mice and chronic stress mouse models of depression to study spatial lipidomic and transcriptomic signatures in the mouse nucleus accumbens. Our results show that p11 deficiency and stress induce depression-related maladaptive phenotypes and provide novel evidence that these responses are associated with phospholipid dyshomeostasis in the nucleus accumbens. Phospholipid disturbances were predominantly related to phosphatidylethanolamine (PE) and ether PE metabolism, along with targets involved in the PE biosynthetic pathway. Moreover, chelerythrine administration, a compound reported to disrupt phospholipid balance, induces PE changes and depression-like behaviors. Altogether, the present study provides evidence that alterations in phospholipid-related pathways may alter reward/anti-reward circuits and how these changes might be implicated in stress-related disorders.
Functional system-specific brain aging across the Alzheimer's disease continuum.
Huo Y, Huang W, Liu Z … +11 more , Chen H, Bai T, Wang Y, Wang K, Zhang D, Cheng J, Sun Y, Ma G, Zhao C, Zhang Z, Shu N
Transl Psychiatry · 2026 May · PMID 42129136 · Publisher ↗
Accelerated brain aging is implicated in Alzheimer's disease (AD). However, the spatial heterogeneity of brain aging patterns across different functional systems along the AD continuum remains largely unexplored. We deve...
Accelerated brain aging is implicated in Alzheimer's disease (AD). However, the spatial heterogeneity of brain aging patterns across different functional systems along the AD continuum remains largely unexplored. We developed functional system-specific brain age models derived from structural magnetic resonance imaging in a healthy adult cohort (n = 22,672) and applied them to 1478 participants across the AD continuum. Using up to 6 years of retrospective longitudinal data before clinical AD conversion, we quantified predicted age differences (PADs) and their change rates, characterized heterogeneous brain aging trajectories, and examined their associations with AD biomarkers, cognitive performance, and clinical progression. Progressive mild cognitive impairment (MCI) individuals showed early PAD deviations in the default mode network and accelerated changes in attention and control networks. System-wise PAD dynamics mediated the effects of AD-related biomarkers on cognitive decline. Integrating PAD features can improve predictive accuracy of MCI-to-AD conversion (AUC = 0.95). Functional system-specific PADs can be sensitive biomarkers for early detection and monitoring of individualized AD risk.
Perineuronal nets in cerebellar nuclei neurons orchestrate social behaviour via regulation of neuronal activity in circuits innervated by the cerebellum.
Fujita K, Zhu H, Tsuji C … +4 more , Kawamura A, Nishiyama M, Higashida H, Yokoyama S
Transl Psychiatry · 2026 May · PMID 42129135 · Full text
Certain types of neurons in the central nervous system are wrapped in extracellular matrix protein complexes named perineuronal nets (PNNs). While it is known that PNNs regulate neuronal activity by modulating synaptic p...
Certain types of neurons in the central nervous system are wrapped in extracellular matrix protein complexes named perineuronal nets (PNNs). While it is known that PNNs regulate neuronal activity by modulating synaptic plasticity, their pathophysiological role in psychiatric disorders has not been sufficiently clarified. Here, we demonstrate that the expression of PNNs in autism-spectrum-disorder (ASD)-associated mice, valproic acid-injected mice and chromodomain helicase DNA-binding protein 8 (Chd8) gene haploinsufficient mice was decreased in cerebellar nuclei neurons. The pharmacological disruption of PNNs by the enzyme chondroitinase ABC (ChABC) injection into the deep cerebellar nuclei was associated with an impairment of social interaction compared with sham-operated mice. In the large glutamatergic neurons, neuronal activity was increased during social behavior which was revealed by intracellular calcium dynamics and phosphorylation of cAMP responsive element-binding protein 1 (CREB1). The transcriptional factor aryl hydrocarbon receptor nuclear translocator 2 (ARNT2), which regulates neuronal activity, was increased in ChABC-injected mice and ASD-associated mice under the basal condition without any neuronal activity-dependent stimulation of gene expression. Moreover, the evaluation of neuronal activity by the increase of c-Fos in distal regions, including the red nucleus and ventromedial thalamic nuclei, revealed that ChABC injection into the deep cerebellar nuclei negatively affected the c-Fos induction after the social interaction test. The reduction of ARNT2 by injection of adeno-associated virus (AAV) carried shRNA-ARNT2 into the deep cerebellar nuclei, together with ChABC, rescued the impairment of social interaction and restored the induction of c-Fos expression in distal regions compared with scrambled-shRNA-injected mice. Therefore, the present results may imply a functional role of PNNs in the regulation of neuronal activity in the circuits innervated by the cerebellum that orchestrate social behaviour.
Structural imaging predictors of ketamine response in treatment-resistant depression: a machine learning approach.
Bryant L, Alexander L, Mena S … +12 more , Jacob Y, Jubeir J, Li M, Neukam PT, Morris LS, Murrough JW, Price R, Koutsouleris N, Mehta MA, Juruena M, Coutts F, Lalousis PA
Transl Psychiatry · 2026 May · PMID 42120872 · Publisher ↗
Ketamine has demonstrated rapid antidepressant efficacy in treatment-resistant depression (TRD), but clinical decision-making is challenging due to variability in individual response. Current trial-and-error prescribing...
Ketamine has demonstrated rapid antidepressant efficacy in treatment-resistant depression (TRD), but clinical decision-making is challenging due to variability in individual response. Current trial-and-error prescribing practices may expose patients to ineffective treatment and avoidable adverse effects, underscoring the need for reliable predictive tools to optimize treatment selection and support personalized, evidence-based care. We developed a machine-learning model (support vector classifier) to predict antidepressant response to ketamine using pre-treatment structural MRI data. The model was trained on 99 adults with TRD given a single intravenous ketamine infusion (0.5 mg/kg). Clinical response was defined as a ≥50% reduction in MADRS scores 24 h post-infusion. Internal validation used repeated nested cross-validation, and generalizability was tested in two independent ketamine-treated cohorts (n = 51) and a saline-treated control group (n = 49). Among ketamine-treated participants, 52 (52.5%) responded to treatment. The model achieved a balanced accuracy of 72.2% (sensitivity = 72.3%, specificity = 73.1%, AUC = 0.72) in the discovery sample and 60.0% (p = 0.01, AUC = 0.65) in external validation. Greater gray matter volume in frontal regions predicted response, whereas greater cerebellar volume predicted non-response. Performance dropped to chance in the saline cohort (BAC = 41.1%, AUC = 0.45), supporting pharmacologic specificity. These findings present the first machine-learning model for the prediction of ketamine response in TRD using structural neuroimaging and highlight its potential utility for stratified treatment planning and biomarker-informed interventions while providing mechanistic insight into neuroanatomical predictors of antidepressant response.
Fragmentomics features of cell free DNA in eating disorders.
Burova A, Verebi C, Lebrun N … +6 more , Nectoux J, Boutonnet A, Duriez P, Gorwood P, Ramoz N, Bienvenu T
Transl Psychiatry · 2026 May · PMID 42120358 · Publisher ↗
Eating disorders are lacking reliable biomarkers despite their severe psychiatric and medical burden. In this study, we examined plasma cell-free DNA (cfDNA) from patients with the restrictive (ANR), or binge-purge (ANBP...
Eating disorders are lacking reliable biomarkers despite their severe psychiatric and medical burden. In this study, we examined plasma cell-free DNA (cfDNA) from patients with the restrictive (ANR), or binge-purge (ANBP) subtypes of anorexia nervosa, as well as from those with bulimia nervosa (BN), and controls, using the BIABooster electrophoresis method and shallow whole-genome sequencing to characterize cfDNA fragmentomics. While absolute cfDNA concentrations did not differ between groups, patients exhibited consistent qualitative alterations. Patients with BN showed increased cfDNA at the first nucleosomal peak, while all patient groups displayed shifts towards shorter fragments in the second and third nucleosomal peaks. End-motif analysis revealed higher motif diversity and trinucleotide sequence motifs TNN-type enrichment in ANR, together with a lower ratio of trinucleotide sequence motifs CGN to NCG, which has been correlated with hypomethylation. Multivariate analyses demonstrated that ANBP exhibits a distinct molecular profile that is not explained by combined effects of anorexia and bulimia. These findings suggest that cfDNA in eating disorders carries biologically meaningful signatures related to chromatin organization, nuclease activity, and methylation. This supports the potential of cfDNA as a minimally invasive biomarker for the clinical management of eating disorders.
Barriers and facilitators to implementing deep brain stimulation for psychiatric disorders: a systematic review.
Karaszewska DM, Beunk EMK, Mol GJJ … +7 more , Beudel M, Leentjens AFG, Schruers K, Schuurman R, van den Munckhof P, Denys D, Mocking RJT
Transl Psychiatry · 2026 May · PMID 42120357 · Publisher ↗
BACKGROUND: Deep brain stimulation (DBS) is effective in treating severe obsessive-compulsive disorder (OCD) and treatment-resistant depression (TRD). However, patient referrals for DBS remain lower than expected based o...
BACKGROUND: Deep brain stimulation (DBS) is effective in treating severe obsessive-compulsive disorder (OCD) and treatment-resistant depression (TRD). However, patient referrals for DBS remain lower than expected based on prevalence and eligibility. Understanding the factors behind this gap is crucial for improving DBS implementation. This study aimed to identify key barriers and facilitators influencing DBS use for OCD and TRD. Insights from this research may help policymakers and clinicians address challenges, ultimately enhancing DBS accessibility and effectiveness for psychiatric disorders. METHODS: A systematic review was performed using four electronic databases until May 1st 2024 following PRISMA and ENTREQ guidelines. Eligible for inclusion were quantitative and qualitative studies describing facilitators or barriers for implementing DBS in psychiatry. RESULTS: We included 28 studies, out of which 11 in TRD, 5 in OCD and 12 in both, and revealed a spectrum of barriers, including ethical concerns, safety issues, stigma and knowledge gaps. Promising facilitators include educational initiatives, specialized psychiatric DBS care and stakeholder engagement. DISCUSSION: This first systematic review provides a comprehensive overview of barriers and facilitators affecting DBS implementation for OCD and TRD. Key areas include establishing consensus on treatment resistance, refining referral guidelines, addressing knowledge gaps among clinicians-such as psychiatrists unfamiliar with neurosurgical psychiatric treatments-and improving DBS's media image to reduce stigma. Limitations include a large portion of included articles from the same contributors and a predominance of US-based studies, potentially affecting generalizability of findings. International perspectives should be included in future studies to ensure a more widely applicable understanding of DBS implementation challenges.
Functional connectivity density alterations in obsessive-compulsive disorder are associated with neurotransmitter and genetic profiles.
Chen K, Liu Y, Xiao Y … +14 more , Cao F, Zhu S, Pan W, Weng W, Hong Y, Hua Q, Wan K, Ye J, Li Z, Xiang S, Yu F, Wang K, Ji G, Zhu C
Transl Psychiatry · 2026 May · PMID 42120356 · Publisher ↗
Obsessive-compulsive disorder (OCD) is characterized by disrupted brain network organization, yet the molecular basis underlying this dysconnectivity remains elusive. Here, we applied voxel-wise functional connectivity d...
Obsessive-compulsive disorder (OCD) is characterized by disrupted brain network organization, yet the molecular basis underlying this dysconnectivity remains elusive. Here, we applied voxel-wise functional connectivity density (FCD) mapping to characterize brain network alterations across 145 patients with OCD and 168 healthy controls (HCs), while further evaluating its ability to support diagnostic classification and predict treatment response in OCD. Then, we examined the spatial correlations between FCD alterations, neurotransmitter distributions, and gene expression profiles. Relative to HCs, OCD patients showed increased FCD in the visual network and decreased FCD in the limbic and default mode networks. Support vector machine (SVM) and support vector regression (SVR) analyses demonstrated that FCD could efficiently discriminate OCD patients from HCs and predict treatment response. Additionally, the FCD alterations showed significant spatial correlations with four neurotransmitter distributions as well as gene expression patterns enriched in excitatory and inhibitory neurons, synaptic signaling, neuronal function, and cellular metabolism. By integrating neuroimaging, neurotransmitter profiles, and transcriptomics, this study reveals that aberrant FCD in OCD reflects both its clinical relevance and molecular basis, providing insights into the neurobiological mechanisms and potential targets for personalized intervention.
Altered flow of information in attention-deficit/hyperactivity disorder.
Keshmiri S, Wang S, Kuhn B
Transl Psychiatry · 2026 May · PMID 42115201 · Full text
Growing evidence suggests that alterations in the connectivity profile of the large-scale brain networks underpin attention-deficit/hyperactivity disorder (ADHD). However, the impact of the brain's asymmetric flow of inf...
Growing evidence suggests that alterations in the connectivity profile of the large-scale brain networks underpin attention-deficit/hyperactivity disorder (ADHD). However, the impact of the brain's asymmetric flow of information on these alterations is unknown. Here, we investigate the brain's asymmetric flow of information in ADHD (N = 355; Control = 189, age = 11.74(2.32); ADHD = 166, age = 11.16(2.20)) using transfer entropy (TE). We report that ADHD is associated with two distinct patterns of the brain's flow of information: the one in which the flow of information is decreased in ADHD and the other in which the flow of information is increased in ADHD. Whereas the first pattern converges on the right visual cortex and the right ventral anterior thalamus as its brain target regions, the second pattern converges on the right frontal operculum. These patterns correlate with the core symptoms and behavioral traits in ADHD, as quantified by the Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Scale (SWAN). They include SWAN - Inattention, SWAN - Hyperactive, and SWAN - Total scores, among the others. These alterations further distinguish the individuals with ADHD from the general population. The present study advances the view of the brain's altered functional pathways in ADHD symptomatology by showing the impact of the brain's flow of information on their directionality. It allows for conceptualizing ADHD in terms of alteration in the brain's capacity for the information flow optimization. This should encourage further investigation of this flow of information in neurodevelopmental conditions. This can have implications for the development of the therapeutic strategies which prioritize targeting the brain regions that play pivotal roles in this condition.
Gut microbiota dysbiosis drives depression-like behavior in adolescent rats via lysine-regulated mTOR autophagy pathway.
Zhang J, Chen F, Xu X … +13 more , Zhang L, Zhang L, Qin B, Li K, Liu Q, Hou H, Li Y, Liu C, Li Y, Shi J, Teng T, Wang C, Zhou X
Transl Psychiatry · 2026 May · PMID 42115187 · Full text
The prevalence of major depressive disorder (MDD) is increasing globally, particularly among adolescents. Although gut-brain axis dysfunction has been implicated in adolescent depression, the mechanisms by which gut micr...
The prevalence of major depressive disorder (MDD) is increasing globally, particularly among adolescents. Although gut-brain axis dysfunction has been implicated in adolescent depression, the mechanisms by which gut microbiota dysbiosis drives depressive behaviors and potential antidepressant targets remain unclear. In this study, fecal microbiota transplantation (FMT) was performed from either healthy controls (HCs) or adolescents with MDD into antibiotic-treated adolescent rats. FMT from MDD adolescents induced depressive-like behaviors in recipient rats. Metagenomic sequencing revealed that FMT from MDD adolescents led to alterations in gut microbiota in recipient rats. While qPCR, Western blotting, immunofluorescence, and transmission electron microscopy (TEM) confirmed that these rats exhibited prefrontal cortex (PFC) autophagy hyperactivation, evidenced by a reduction in SQSTM1/p62 levels, an elevation in the LC3-II/LC3-I ratio, upregulated Beclin1, and increased numbers of autolysosomes. Similar autophagy-related transcriptional changes were observed in peripheral blood from MDD adolescents. Furthermore, ELISA showed reduced plasma lysine levels in MDD adolescents and decreased lysine concentrations in the PFC of FMT-MDD rats. The antidepressant effect of lysine and its interaction with autophagy were explored in a chronic unpredictable mild stress (CUMS) rat model with or without rapamycin (the autophagy activator, RAPA). Lysine supplementation alleviated depressive-like behaviors and suppressed PFC autophagy hyperactivation, while these effects were abolished by RAPA co-treatment. These findings reveal lysine deficiency as a metabolic bridge between gut microbiota imbalance and neuronal autophagy dysregulation, suggesting a gut microbiota-lysine-autophagy axis as an innovative mechanism and therapeutic focus for adolescent depression.
Optogenetic activation of liver-innervating vagal sensory neurons increases anxiety-like behavior in mice.
Lee S, Hwang J, Jo YH
Transl Psychiatry · 2026 May · PMID 42115167 · Full text
The liver plays a central role in energy balance, glucose homeostasis, and lipid metabolism through neural and humoral pathways. Intriguingly, impaired hepatic lipid metabolism has been also associated with an increased...
The liver plays a central role in energy balance, glucose homeostasis, and lipid metabolism through neural and humoral pathways. Intriguingly, impaired hepatic lipid metabolism has been also associated with an increased risk of anxiety and depression in rodents and humans. However, the mechanisms by which it affects mood behaviors via neural pathways remain poorly understood. This study investigated whether activation of the liver-brain axis can modulate anxiety-like behavior in mice. Advillin (Avil); channelrhodopsin-tdTomato mice and wireless optogenetics were used to selectively stimulate Avil-positive vagal sensory neurons that innervate the liver in freely moving mice. Acute optogenetic stimulation of their nerves in the liver activated neurons in the nodose ganglia, the dorsal motor nucleus of the vagus, and the nucleus of the solitary tract (NTS). Behavioral assessments revealed that acute optogenetic stimulation of these liver-innervating vagal sensory nerves increased anxiety-like behavior in male and female mice during open field, elevated plus maze, and light/dark box tests. Retrograde viral tracing revealed that neurons in the NTS sent projections to the locus coeruleus (LC), and optogenetic stimulation of liver-innervating vagal sensory nerves resulted in significant activation of norepinephrine-expressing neurons in the LC. Chemogenetic inhibition of LC norepinephrine (NE) neurons completely abolished the anxiogenic effect of stimulating Slc6a2‑positive vagal sensory neurons, demonstrating that LC NE neuron activity is essential for this behavioral response. Therefore, these findings reveal a novel liver - NTS - LC circuit that plays a role in the regulation of anxiety-like behavior through vagal sensory neurons. Unlike the traditional top-down neuronal circuits associated with the liver, this newly identified liver-brain axis is essential for regulating not only systemic energy homeostasis but also emotional behaviors.
Animal models of delirium: a narrative review.
Barichello T, Simon CS, Dominguini D … +4 more , Ritter C, Nishiguchi T, Shinozaki G, Dal-Pizzol F
Transl Psychiatry · 2026 May · PMID 42115158 · Full text
Delirium is an acute cognitive failure characterized by an acute onset and psychomotor disturbances. It is associated with poor outcomes in hospitalized patients, resulting in prolonged hospital stays, elevated rates of...
Delirium is an acute cognitive failure characterized by an acute onset and psychomotor disturbances. It is associated with poor outcomes in hospitalized patients, resulting in prolonged hospital stays, elevated rates of mortality, and cognitive dysfunctions after hospital discharge. The pathophysiology of delirium remains poorly understood, making the development of animal models a promising avenue for researchers to elucidate the mechanisms underlying human delirium. These models not only aid in understanding the pathophysiology and etiology of the disease but also enhance the efficacy of nonpharmacological interventions and identify pharmacological therapies. This review aims to present the most relevant and translational animal models of delirium available in the literature and to provide a critical appraisal of these models using contemporary translational benchmarks. In preclinical models, delirium-like behavior is induced in various methods to reproduce the fundamentals of human delirium, including anesthesia, surgery, sepsis, and drug interventions. However, researchers must select a model encompassing face, construct, predictive, and target validity. Delirium currently lacks pharmacological therapies, and this review is to encourage more researchers to delve deeper and shed light on this medical condition, which is highly prevalent in vulnerable and hospitalized patients.
ARHGAP39 plays an essential role in anxiety-like behavior and stress response.
Deng SM, Chen YJ, Hung WC … +5 more , Wu KY, Chang WC, Cheng IH, Chang MS, Huang GJ
Transl Psychiatry · 2026 May · PMID 42106334 · Full text
Anxiety is a common mental health disorder marked by heightened stress responses and impaired emotional regulation. While the hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis play key roles in regulating anx...
Anxiety is a common mental health disorder marked by heightened stress responses and impaired emotional regulation. While the hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis play key roles in regulating anxiety, the molecular mechanisms remain incompletely understood. In this study, we identified a strong link between ARHGAP39 function and anxiety using brain-specific Arhgap39 conditional knockout (cKO) mice. ARHGAP39 is a brain-enriched Rho GTPase-activating protein implicated in neurodevelopment and synaptic regulation. Arhgap39 cKO mice exhibited ectopic progenitor cells in the hilus of the hippocampus during early postnatal development, along with impaired adult neurogenesis in dentate gyrus (DG). Behaviorally, adult cKO mice demonstrated pronounced anxiety-like phenotypes without cognitive impairments, whereas aged cKO mice exhibited persistent anxiety accompanied by learning and memory deficits. Molecular profiling revealed that cKO mice exhibited significantly elevated RNA expression levels of glutamatergic and glucocorticoid receptor-related genes in the hippocampus. In addition, cKO mice exhibited more stress-activated neurons in the DG. Mechanistically, Arhgap39 deficiency disrupted Rho GTPase-related actin pathways, leading to elevated Cofilin-1 and Arp3 expression and reduced PSD-95 levels, suggesting disruption of synaptic organization. Finally, hippocampal overexpression of Arhgap39 in C57BL/6 mice did not affect baseline behavior but alleviated chronic stress-induced anxiety in light-dark box test. In conclusion, our findings demonstrate that ARHGAP39 plays a critical role in modulating anxiety, hippocampal neurogenesis, and synaptic stability, highlighting it as a promising target for developing anxiolytic therapies.
Comprehensive behavioral profiling in male spontaneously hypertensive rats: latent trait mapping supports a valid multidomain ADHD model.
Kim HB, Kim YJ, Lim HM … +6 more , Lim J, Kang S, Kim EM, Cheon GJ, Choi Y, Woo RS
Transl Psychiatry · 2026 May · PMID 42106332 · Full text
Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder marked by inattention, impulsivity, and hyperactivity. Although the spontaneously hypertensive rat (SHR) is widely used to mo...
Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder marked by inattention, impulsivity, and hyperactivity. Although the spontaneously hypertensive rat (SHR) is widely used to model ADHD, intra-strain behavioral heterogeneity and its neurobiological relevance remain insufficiently defined. We conducted a comprehensive multidomain behavioral assessment of male adolescent SHR and Wistar-Kyoto (WKY) rats spanning locomotion/exploration, anxiety- and risk-related behavior, compulsive-like activity, cognition, and sensorimotor gating. Across tasks, SHR rats exhibited increased impulsive and repetitive exploratory behaviors, context-dependent alterations in anxiety-related measures, reduced spontaneous alternation, and impaired prepulse inhibition. Exploratory factor analysis of 26 behavioral variables identified five interpretable latent dimensions, including exploratory-attentional engagement and impulsivity/disinhibition, and revealed substantial heterogeneity within the SHR population. Using WKY-referenced factor-score deviation, SHR were stratified into normative-range and combined-deviant subtypes. The combined-deviant subtype exhibited convergent circuit-level alterations, including reduced parvalbumin (PV)/glutamate decarboxylase 67 (GAD67)-associated inhibitory features and decreased synaptic marker signals in prelimbic and infralimbic medial prefrontal cortex, together with increased dopamine transporter expression (DAT) in the striatum without changes in tyrosine hydroxylase (TH). Complementary principal axis factoring, bootstrap resampling, and split-sample analyses supported the robustness of the factor structure. These findings link multidimensional behavioral subtypes in SHR to distinct prefrontal-striatal signatures, strengthening the translational utility of SHR-based ADHD research.
Identifying novel gene dysregulation associated with opioid overdose death: a meta-analysis of differential gene expression in human prefrontal cortex.
Carter JK, Quach BC, Willis C … +9 more , Minto MS, Hancock DB, Montalvo-Ortiz J, Corradin O, Logan RW, Walss-Bass C, Maher BS, PGC-SUD Epigenetics Working Group, Johnson EO
Transl Psychiatry · 2026 May · PMID 42103735 · Publisher ↗
Only recently have human postmortem brain studies of differential gene expression (DGE) associated with opioid overdose death (OOD) been published; sample sizes from these studies have been modest (N = 40-153). To increa...
Only recently have human postmortem brain studies of differential gene expression (DGE) associated with opioid overdose death (OOD) been published; sample sizes from these studies have been modest (N = 40-153). To increase statistical power to identify OOD-associated genes, we leveraged human prefrontal cortex RNA-seq data from four independent OOD studies and conducted a transcriptome-wide DGE meta-analysis (N = 272). Using a unified gene expression data processing and analysis framework across studies, we meta-analyzed 20, 098 genes and found 335 significant differentially expressed genes (DEGs) by OOD status (false discovery rate < 0.05). Of these, 66 DEGs were among the list of 303 genes reported as OOD-associated in prior prefrontal cortex molecular studies (e.g., genes/gene families OPRK1, NPAS4, DUSP, EGR). The remaining 269 DEGs were not previously reported (e.g., NR4A2, SYT1, HCRTR2, BDNF). There was little evidence of genetic drivers for the observed differences in gene expression between opioid addiction cases and controls. Enrichment analyses for the DEGs across molecular pathway and biological process databases highlight an interconnected set of genes and pathways linked to orexin and tyrosine kinase receptors through MEK/ERK/MAPK signaling to affect neuronal plasticity.
Distinct sensory atypicalities bridge the gap between brain chemistry and motor dysfunction in autism.
Shi M, He JL, Powell H … +9 more , Lack O, Oeltzschner G, Deronda A, Crocetti D, Wodka EL, Edden RA, O'Muircheartaigh J, Mostofsky SH, Puts NAJ
Transl Psychiatry · 2026 May · PMID 42103716 · Full text
Sensory and motor difficulties are common in autism. Altered excitation-inhibition (E-I) balance is a putative framework for understanding atypical sensory and motor function. We investigated whether sensory differences...
Sensory and motor difficulties are common in autism. Altered excitation-inhibition (E-I) balance is a putative framework for understanding atypical sensory and motor function. We investigated whether sensory differences of autism mediate motor difficulties of autism via differences in E-I balance. 106 children were included in the study (Autism n = 44, Typical development children (TDC) n = 62, age 10.32 ± 1.49). E-I balance was assessed through magnetic resonance spectroscopy (MRS), quantifying Glutamate and Glutamine (Glx) and Gamma-Aminobutyric Acid (GABA) in primary sensorimotor cortex (SM1) and thalamus (Thal). Sensory function was evaluated using both objective vibrotactile perceptual sensitivity assessments and subjective parent ratings via the Sensory Experience Questionnaire (SEQ). Motor ability was assessed objectively through the Movement Assessment Battery for Children-second edition (MABC-2) and the Physical and Neurological Examination for Subtle Signs (PANESS). Our findings reveal that lower sensory reactivity and lower tactile thresholds are both predictive of better motor ability (R range between 0.32 and 0.57) with higher sensory scores reflecting poorer sensory filtering predicting worse motor function (R range -0.22 and -0.63). We identified significant associations between MRS-measured Glx and GABA+ levels and sensory reactivity (p < 0.001). Importantly, sensory reactivity sub-scores were found to fully mediate E-I balance to motor associations in domain-specific patterns: Hyper-reactivity mediated the impact of SM1 Glx levels, while hypo-reactivity mediated the impact of SM1 GABA levels. Additionally, sensory seeking mediated the impact of Thalamic GABA levels with all indirect paths ab p < 0.01. These results propose a model where regional metabolite-specific markers of E-I balance explain patterns of autism-associated sensory and motor difficulties, and where subsequently, distinct sensory phenotypes differentially mediate metabolite-motor associations (see Graphical Abstract for detail).
Correction: The blood lipidome fatty acid profile predicts the disease risk and clinical phenotypes of Alzheimer's disease: associations from two prospective cohort studies.
Liu WZ, Huang LY, Chi S … +5 more , Ma YH, Tan CC, Tan L, Alzheimer’s Disease Neuroimaging Initiative, Alzheimer’s Disease Metabolomics Consortium, Xu W
Transl Psychiatry · 2026 May · PMID 42086543 · Full text
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Diminished variability of alpha and beta band-limited power as a neural signature in schizophrenia.
Racz FS, Farkas K, Becske M … +4 more , Molnar H, Fodor Z, Mukli P, Csukly G
Transl Psychiatry · 2026 May · PMID 42069713 · Full text
Spectral features of the electroencephalogram (EEG) are essential for providing clinically relevant biomarkers in schizophrenia (SZ). Despite literature indicating altered short-scale neural dynamics in SZ, however, band...
Spectral features of the electroencephalogram (EEG) are essential for providing clinically relevant biomarkers in schizophrenia (SZ). Despite literature indicating altered short-scale neural dynamics in SZ, however, band-limited power (BLP) indices are rarely assessed in a time-resolved manner. To address this, here we evaluated static and dynamic BLP indices in a sample of 30 SZ patients and 31 healthy control (HC) individuals. Guided by recent findings on power spectral dynamics in SZ, we estimated total, and decomposed fractal and oscillatory BLP in a sliding window manner from resting-state EEG recordings collected in eyes-closed resting-state. The SZ cohort was characterized by elevated baseline of total fractal power (p = 0.0015, |r| = 0.4073), while its temporal variability was comparable between the two study groups. On the other hand, spectral power in the alpha (p < 10, d = 1.0503) and beta (p = 0.0022, |r| = 0.3925) regimes exhibited reduced fluctuation in SZ compared to HC, with no between-group differences in their baselines. Furthermore, alpha variability could be attributed to alterations in isolated oscillatory activity, while variability in beta-BLP over the dorsal attention network was found correlated with negative symptoms in SZ (Spearman r = -0.4994, p = 0.0055). Finally, surrogate data testing indicated altered phase dynamics in SZ as a potential mechanism for diminished BLP fluctuations.
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