Transl Psychiatry [JOURNAL]
Sun
200 papers
Prenatal valproic acid exposure alters striatal proteomic signatures associated with autism spectrum disorder in mice.
Jo EH, Choi Y, Kim HB … +8 more , Woo RS, Han D, Kim WC, Park SJ, Kang M, Choi Y, Kang KW, Kim HS
Transl Psychiatry · 2026 May · PMID 42204145 · Publisher ↗
Prenatal exposure to valproic acid (VPA), a widely prescribed antiepileptic and mood‑stabilizing drug, is a well-established environmental risk factor for autism spectrum disorder (ASD). Although behavioral and anatomica...
Prenatal exposure to valproic acid (VPA), a widely prescribed antiepileptic and mood‑stabilizing drug, is a well-established environmental risk factor for autism spectrum disorder (ASD). Although behavioral and anatomical abnormalities have been reported in VPA-exposed animal models, the underlying molecular mechanisms within specific brain regions remain unclear. In this study, we used tandem mass tag (TMT)-based quantitative proteomics to profile protein expression in the striatum of 9-10-week-old mice prenatally exposed to VPA. Behavioral assessment confirmed core ASD-like phenotypes, including reduced body and brain weights and increased repetitive self-grooming behavior. Proteomic profiling identified 101 differentially expressed proteins (DEPs), with 47 upregulated and 54 downregulated in VPA-exposed mice. Functional enrichment analysis revealed significant involvement of pathways related to synaptic transmission, neuronal development, metal ion homeostasis, oxidative stress response, and excitation/inhibition (E/I) balance. Notably, proteins such as parvalbumin (PVALB), NR2F1, and metallothioneins (MT1, MT2, MT3) were markedly downregulated, implicating impaired inhibitory signaling and redox regulation. Importantly, quantitative PVALB immunofluorescence analysis provided histological validation of the proteomic findings, revealing a significant reduction of PVALB immunoreactivity in the dorsolateral striatum, with a non-significant trend toward reduction in the dorsomedial striatum. Additionally, protein-protein interaction network analysis identified PVALB and MT2 as central hub proteins linking synaptic, glial, and oxidative stress-related modules, highlighting disrupted striatal network organization. Collectively, these findings provide subregion-specific molecular and histological insight into how prenatal VPA exposure alters striatal neurobiology and contributes to ASD-like behavioral phenotypes. Proteomic data are available via ProteomeXchange (PXD067574).
Hippocampal rhythm modulation via frequency-tuned trigeminal nerve stimulation.
Chen L, Majdi A, Asamoah B … +1 more , Mc Laughlin M
Transl Psychiatry · 2026 May · PMID 42203796 · Publisher ↗
Trigeminal nerve stimulation (TNS) is a non-invasive method for modulating brain activity through peripheral afferent pathways. Although pulse-based stimulation has been commonly used, the impact of sinusoidal alternatin...
Trigeminal nerve stimulation (TNS) is a non-invasive method for modulating brain activity through peripheral afferent pathways. Although pulse-based stimulation has been commonly used, the impact of sinusoidal alternating current stimulation of the trigeminal nerve (TN-ACS) on hippocampal network activity remains unclear. This study examined the effects of TN-ACS delivered at 8 Hz (theta) and 40 Hz (gamma) on neuronal activity in the rat hippocampus. We applied 3 min of TN-ACS at different frequencies in rats and recorded neural activity from the hippocampus using multi-channel electrophysiology. We analyzed spike-phase entrainment in CA1, spike rate, power spectral changes in local field potentials (LFP, focusing on off-frequency stimulation effects), and spike-field coherence between CA3 LFPs and CA1 spikes. Our results showed that TN-ACS modulated hippocampal dynamics in a frequency-specific manner. 40 Hz stimulation enhanced spike-phase locking in CA1, while 8 Hz did not. At the single neuron level, theta-band coherence between CA3 LFPs and CA1 spikes showed a wide range of effects. At the group level, theta-band coherence decreased during 8 Hz stimulation and increased during 40 Hz stimulation. Spike rates remained stable across all conditions. To our knowledge, this is the first study to demonstrate that TN-ACS can entrain hippocampal spike timing and modulate interregional coherence without affecting overall firing rates. These novel findings indicate that TN-ACS can selectively shape deep brain rhythms, highlighting 40 Hz TN-ACS as a promising intervention for targeting memory-related processes.
Excitatory paraventricular thalamus-posterior insular cortex circuit mediates pain-anxiety comorbidity in diabetic neuropathy.
Wei M, Shou J, Yang J … +14 more , Cai S, Bai Q, Hou J, Jiang Y, Shen S, Yu Z, Zhao X, Han Y, Cai J, Yang XW, Li Z, Ma D, Xing GG, Li M
Transl Psychiatry · 2026 May · PMID 42203788 · Publisher ↗
Painful diabetic neuropathy (PDN) is frequently accompanied by anxiety, yet the neural circuit mechanisms associated with nociceptive hypersensitivity to affective dysfunction remain unclear. Here we combined brain-wide...
Painful diabetic neuropathy (PDN) is frequently accompanied by anxiety, yet the neural circuit mechanisms associated with nociceptive hypersensitivity to affective dysfunction remain unclear. Here we combined brain-wide c-Fos mapping, viral tracing, in vivo fiber photometry, whole-cell recordings, and projection-specific opto/chemogenetics in a mouse model of streptozotocin-induced PDN to define a thalamo-cortex circuit for pain-anxiety comorbidity. Within the posterior insular cortex (pIC), CaMKIIα⁺ excitatory neurons were recruited in PDN mice with comorbid anxiety, exhibiting heightened neuronal excitability and enhanced excitatory synaptic input. Bidirectional chemogenetic modulation of pIC neurons oppositely regulated anxiety-like behavior and mechanical hypersensitivity without locomotor or glycemic confounds. Circuit mapping identified a monosynaptic excitatory projection from the paraventricular thalamus (PVT) to the pIC; PVT neurons were hyperactive in PDN, and projection-defined manipulation of the PVT to pIC pathway bidirectionally controlled the behavioral phenotypes. Cacna1c was upregulated in the PVT of PDN mice; its knockdown in pIC-projecting PVT neurons attenuated both pain and anxiety-like behaviors. Together, these results delineate a thalamo-cortex excitatory pathway that couples nociceptive and affective dimensions of PDN and suggest that selective targeting of the PVT to pIC circuit may provide coordinated relief of pain and anxiety-related symptoms.
Epigenome-wide association study of psilocybin-induced methylome changes in alcohol use disorder.
Urban MM, Zillich L, Rieser NM … +5 more , Herdener M, Spanagel R, Vollenweider FX, Preller KH, Meinhardt MW
Transl Psychiatry · 2026 May · PMID 42192100 · Full text
The serotonergic hallucinogen psilocybin has shown potential as a treatment for psychiatric conditions like alcohol use disorder (AUD) and depression in clinical studies. Epigenetic mechanisms, including DNA methylation,...
The serotonergic hallucinogen psilocybin has shown potential as a treatment for psychiatric conditions like alcohol use disorder (AUD) and depression in clinical studies. Epigenetic mechanisms, including DNA methylation, are hypothesized to contribute to its lasting therapeutic benefits. In this exploratory study, we present the first methylome-wide analysis of psilocybin-induced changes in a cohort of detoxified patients with AUD. The longitudinal study design included three assessment days in 37 patients with blood sampling and acquisition of psychometrics - at baseline, 24 h after administration of psilocybin (25 mg) or placebo (mannitol), and one month after treatment. As the primary endpoints (duration of abstinence and mean alcohol use) in this trial were not reached, our investigation included secondary psychometrics that differed significantly between groups: Beck's Depression Inventory and Beck's Hopelessness Scale. The epigenome-wide association study (EWAS) identified one CpG site in TLE4 (p = 1.1e-7) associated with psilocybin treatment. Screening for differentially methylated regions, we observed altered methylation in the gene RASGRP4 (pFDR = 3.2e-4). Network analysis revealed co-methylation modules related to psilocybin treatment, as well as modules associated with the reduction of depressive symptoms and drinking behavior. Gene ontology analysis indicated involvement of these modules in neuroplasticity and immune functions, suggesting that they may reflect abstinence-related recovery processes. Investigating candidate genes at nominal significance (p < 0.05) uncovered promoter-associated methylation changes in HTR2A and TNF. Interestingly, several of the reported analyses point to immunomodulatory actions of psilocybin. While the findings of this pilot study are limited by the modest sample size, they align well with previous literature and might provide starting points for further, large-scale investigations or hypothesis-driven experiments.
Sad emotion processing-related theta oscillation patterns link suicide attempt to childhood trauma in depression: evidence from MEG.
Xia Y, Du Y, Song M … +5 more , Sheng J, Yan R, Wang X, Yao Z, Lu Q
Transl Psychiatry · 2026 May · PMID 42191684 · Publisher ↗
Major depressive disorder (MDD) is a severe mood disorder with genetic and environmental interactions. Subtypes with childhood trauma (CT) tend to have higher rates of suicide attempt (SA). The amygdala (AMY) and medial...
Major depressive disorder (MDD) is a severe mood disorder with genetic and environmental interactions. Subtypes with childhood trauma (CT) tend to have higher rates of suicide attempt (SA). The amygdala (AMY) and medial prefrontal cortex (mPFC) are integral to the neurocircuitry underlying emotional processing, with dysregulation of these regions being posited as a pathophysiological hallmark both in CT and SA. However, the specific neural mechanisms linking CT and SA are unclear. Here, we examined local neural oscillatory patterns and interregional connectivity within mPFC and AMY during sad emotion processing. 88 MDD patients (44 with CT, 44 without CT) and 44 healthy control (HC) participants underwent an emotion recognition task during magnetoencephalography (MEG) recording. Time-frequency analysis was used to examine inter-trial phase coherence (ITPC) and neural oscillatory power at bilateral mPFC and AMY. In addition, directed connectivity between mPFC and AMY was examined using Granger causality. MDD without CT demonstrated less ITPC at bilateral mPFC and bottom-up dysconnectivity from the AMY.R to the mPFC.R compared to HC. Theta power (bilateral mPFC and left AMY), ITPC (bilateral AMY and mPFC) and top-down functional connectivity from the mPFC.L to the AMY.L were reduced in MDD with CT relative to MDD without CT. Furthermore, the mPFC.L theta ITPC mediated the association between SA and CT. Overall, the results suggest that abnormal theta power modulation, phase coherence, and hypo-connectivity between the mPFC and AMY may underlie impaired sad emotion processing in MDD with CT, partially explaining the increased SA rate in this subgroup.
Using deep learning to identify brain networks mediating cognitive and motor impairments in alcohol use disorder.
Wang Y, Müller-Oehring EM, Sassoon SA … +5 more , Salinas KZ, Pfefferbaum A, Sullivan EV, Zhao Q, Pohl KM
Transl Psychiatry · 2026 May · PMID 42185254 · Publisher ↗
Alcohol Use Disorder (AUD), with a lifetime prevalence of 29.1% in the U.S., is associated with functional impairment affecting visuospatial working memory, executive functions, and motor control. The objective of this s...
Alcohol Use Disorder (AUD), with a lifetime prevalence of 29.1% in the U.S., is associated with functional impairment affecting visuospatial working memory, executive functions, and motor control. The objective of this study was to distinguish people with AUD from controls on the basis of functional brain and neuropsychological measures that would contribute to identifying mechanisms of AUD-related dysfunction. A data-driven, deep-learning framework jointly analyzed 6105 region-to-region connections from resting-state functional MRI and 16 cognitive and motor performance scores. The deep learning method first derived 16 brain networks aligned with neuropsychological functions and then combined them into 14 functional units. After determining the most important functional unit for diagnostic classification, mediation analysis identified the neural pathways of that unit through which AUD affects neuropsychological performance. The Temporal Attention Network (TAN) fully mediated the effect of AUD diagnosis on spatial working memory (Visual Span). TAN also fully mediated the effects of AUD on visually guided attention, set-shifting, and motor performance (Trail Making Test), which, in parallel was mediated by a second network, the Sensorimotor Network (SMN). In conclusion, selective and dissociable brain functional and neuropsychological relationships differentiated individuals with AUD from controls. These relations, which were identified with deep learning technology and replicated on an independent dataset of people with HIV (with or without AUD comorbidity), provide support for brain functional substrates of commonly observed, AUD-related neuropsychological deficits.
Early Trajectories of Resting-State EEG power in autistic children: a longitudinal study across language profiles.
Latrèche K, Godel M, Flò A … +3 more , Journal F, Borghesani V, Schaer M
Transl Psychiatry · 2026 May · PMID 42185252 · Publisher ↗
Language development in autism spectrum disorder (ASD) is heterogeneous, ranging from subtle differences to significant delays. In previous work, we identified three autistic language profiles in early childhood: Languag...
Language development in autism spectrum disorder (ASD) is heterogeneous, ranging from subtle differences to significant delays. In previous work, we identified three autistic language profiles in early childhood: Language Unimpaired (LU), Language Impaired (LI), and Minimally-Verbal (MV). While these profiles show distinct vocabulary, grammar, and pragmatic development, understanding their underlying neural correlates is essential to predict outcomes and develop targeted interventions. Here, we examined whole-brain resting-state EEG power across five canonical frequency bands in a longitudinal sample comprising 66 typically developing (TD) children and 122 autistic children (ages 1.6-6.0 years), yielding 358 time points. Within the ASD group, 61 children belonged to the LU profile, 44 children to LI, and 17 children to MV. Compared to TD peers, autistic children showed increased power in low-frequency (delta, theta) and high-frequency bands (beta, gamma). Gamma power varied by autistic language profile, with the highest levels in MV children. Moreover, gamma power within ASD followed a quadratic trajectory in relation to word combination acquisition, peaking around the time of acquisition and decreasing afterward. This pattern suggests a dynamic, compensatory mechanism supporting the transition to phrase speech, which is a critical milestone toward functional speech that may predict language outcomes in ASD.
Social exclusion alters attention and autonomic regulation in adolescents with nonsuicidal self-injury.
Goreis A, Lozar A, List R … +9 more , Oehlke SM, Pfeffer B, Prillinger K, Klinger D, Zesch H, Marschik PB, Claes L, Plener PL, Kothgassner OD
Transl Psychiatry · 2026 May · PMID 42177212 · Publisher ↗
Nonsuicidal self-injury (NSSI) poses a growing clinical challenge in adolescence, while imagery of NSSI is increasingly embedded in everyday digital life. Prior research indicates that adolescents who engage in nonsuicid...
Nonsuicidal self-injury (NSSI) poses a growing clinical challenge in adolescence, while imagery of NSSI is increasingly embedded in everyday digital life. Prior research indicates that adolescents who engage in nonsuicidal self-injury orient more rapidly toward NSSI-related imagery and report heightened urges to self-injure after viewing such content. What remains unknown is how social stress shapes these attentional biases. In the present study, we tested whether experimentally induced ostracism modifies attention to NSSI images, urges to self-injure, and autonomic regulation in adolescents with recent NSSI. Fifty adolescents who engaged in recent NSSI (M = 16.40 years, SD = 1.33) were randomized to inclusion vs. exclusion in an in-person ball-tossing ostracism paradigm and then completed free-viewing eye-tracking (with stimuli durations of 500/1000 ms) and dot-probe tasks (200/500 ms) that included NSSI images. NSSI urges, perceived stress, heart rate, and heart rate variability (Root Mean Square of Successive Differences, RMSSD) were assessed throughout the experiment. Social exclusion produced sustained reductions in RMSSD relative to inclusion, with no reliable heart rate differences. During free-viewing, both groups preferentially fixated NSSI images, but exclusion reduced the probability of first fixations on NSSI. In the dot-probe task, exclusion amplified the slowing from congruent to incongruent trials for NSSI. After viewing NSSI images, both groups showed increased urges and stress, with larger increases after exclusion. Acute interpersonal rejection reorganized attention, dampening initial gaze capture yet impairing later disengagement, occurring in the context of vagal withdrawal. These dynamics may help explain how social stress potentiates NSSI risk in everyday digital environments and highlight interpersonal context and post-rejection coping as modifiable targets for intervention. Trial Registration: German Clinical Trials Register Identifier: DRKS00025905.
Brain age prediction in generalized anxiety disorder using a convolutional neural network.
Richier C, Zugman A, Harrewijn A … +88 more , Cardinale EM, Khosravi P, Aghajani M, Bruin WB, Hilbert K, Cardoner N, Porta-Casteràs D, Cano M, Gosnell S, Salas R, Jackowski AP, Pan PM, Salum GA, Blair KS, Blair JR, Milad MR, Burkhouse KL, Phan KL, Schroeder HK, Strawn JR, Beesdo-Baum K, Jahanshad N, Thomopoulos SI, Nielsen JA, Smoller JW, Soares JC, Mwangi B, Wu MJ, Zunta-Soares GB, Assaf M, Diefenbach GJ, Brambilla P, Maggioni E, Hofmann D, Straube T, Andreescu C, Price RB, Manfro GG, Agosta F, Canu E, Cividini C, Filippi M, Kostić M, Munjiza Jovanovic A, Benson B, Freitag GF, Leibenluft E, Ringlein GV, Werwath K, Zwiebel H, Grabe HJ, Van der Auwera S, Wittfeld K, Völzke H, Bülow R, Balderston NL, Ernst M, Mujica-Parodi LR, van Nieuwenhuizen H, Critchley HD, Makovac E, Mancini M, Meeten F, Ottaviani C, Fonzo GA, Paulus MP, Stein MB, Gur RE, Gur RC, Kaczkurkin AN, Larsen B, Satterthwaite TD, Harper J, Perino MT, Sylvester CM, Yu Q, McClure P, Pereira F, Lueken U, Veltman DJ, Thompson PM, Groenewold NA, Bas-Hoogendam JM, Stein DJ, Van der Wee NJA, Winkler AM, Pine DS, Sawyers CK
Transl Psychiatry · 2026 May · PMID 42177199 · Publisher ↗
Higher predicted brain age difference has been associated with several psychiatric disorders. Generalized anxiety disorder (GAD) is associated with markers of accelerated aging. In this study, we determined brain predict...
Higher predicted brain age difference has been associated with several psychiatric disorders. Generalized anxiety disorder (GAD) is associated with markers of accelerated aging. In this study, we determined brain predicted age difference (PAD) in individuals with GAD and healthy controls (HC) as well as group differences in PAD variability using voxel-wise structural MRI. The training dataset included 3511 controls, and the testing dataset included 1595 individuals with GAD and 4552 HC from the ENIGMA-Anxiety GAD Working Group. A convolutional neural network model using four input modalities per subject and a model ensemble approach was used to predict brain age. The PAD was then calculated by subtracting chronological age from the predicted age. Model performance was consistent with other image-based brain age prediction models with similar accuracy across the training set (mean absolute error (MAE) = 2.95 years) and HC in the testing set (MAE = 2.94). We found no evidence of accelerated brain aging in individuals with GAD compared to individuals without GAD, though we did find evidence for greater variation in PAD for individuals with GAD (Levene's test: W = 442.98, p < 0.001) and evidence for greater variability in PAD of those with GAD over 25 years of age. In several exploratory analyses, we found that symptom severity related significantly to PAD, even after controlling for medication and comorbid diagnoses, echoing previous brain age research. These findings underscore the need for consideration of heterogeneity and dimensionality of psychopathology when examining brain age predicted differences.
Multi-session CBM-I for social anxiety: examining psychopathology, cognitive, neural, and psychophysiological effects in a randomized controlled trial.
Abado E, Kunna M, Würtz F … +9 more , Laflör L, Blank L, Blackwell SE, Salemink E, Adolph D, Dietel FA, Wolf OT, Margraf J, Woud ML
Transl Psychiatry · 2026 May · PMID 42173859 · Full text
Cognitive Bias Modification - Interpretation (CBM-I) aims to alter maladaptive interpretations in social anxiety, yet effects are often small and outcome measures are diverse. Although CBM-I has shown promise, its underl...
Cognitive Bias Modification - Interpretation (CBM-I) aims to alter maladaptive interpretations in social anxiety, yet effects are often small and outcome measures are diverse. Although CBM-I has shown promise, its underlying mechanisms remain unclear and integration with psychophysiological and neural measures has been limited. In this randomized controlled trial, eighty-eight participants with high levels of social anxiety completed two lab sessions, an online training in between, and online follow-up. Participants filled out questionnaires, completed interpretation bias tasks, and underwent neuro-psychophysiological assessments. Active CBM-I trained positive resolutions of ambiguous social scenarios, while the sham version used neutral scenarios. The primary outcome, i.e., scores on the Liebowitz Social Anxiety Scale (LSAS), decreased across time in both groups, without group differences. However, the Brief Fear of Negative Evaluation decreased only in the active group. Interpretation bias shifted more strongly toward positive outcomes in the active group. Autonomic measures confirmed sensitivity to stress induction but did not differentiate between conditions. Electrophysiological results paralleled subjective ratings, as participants exhibited ambivalent responses to socially relevant stimuli but clearly differentiated responses toward neutral stimuli. Baseline correlations indicated strong convergence across self-report and interpretation tasks. Mediation analyses showed that reductions in negative interpretations mediated the effect of the training group on LSAS scores at follow-up. These findings identify interpretation bias as a modifiable mechanism underlying social anxiety and underscore its role as a transdiagnostic marker. Targeting interpretation bias through easily accessible and applicable online interventions may strengthen preventive and therapeutic approaches for social anxiety and related disorders.
Maternal brain alterations based on neurotransmitter and hormone receptor distributions over six months postpartum.
Losse EM, Daneshnia N, Dukart J … +2 more , Nehls S, Chechko N
Transl Psychiatry · 2026 May · PMID 42173858 · Full text
The long-term impact of pregnancy and post-childbirth hormonal changes on the maternal brain is yet to be fully understood. Here, we monitored 24 postpartum women longitudinally across six time points over the first 24 w...
The long-term impact of pregnancy and post-childbirth hormonal changes on the maternal brain is yet to be fully understood. Here, we monitored 24 postpartum women longitudinally across six time points over the first 24 weeks following childbirth. By means of structural MRI, we investigated how maternal brain volume, over time and compared to nulliparous women, is associated with receptor distribution maps. While appearing to slow down toward the later time points, the voxel-wise gray matter volumes (GMV) continued to increase for at least 24 postpartum weeks, showing, from the start, a significant association with GABA and glutamate receptor distributions. The most pronounced increase was observed at three weeks postpartum, compared to childbirth, when the changes were also strongly co-localized with the cortisol, estradiol, and progesterone receptor systems. The volumetric increase from 12 to 24 weeks co-localized with areas of higher oxytocin receptor density. Compared to nulliparous controls, the maternal brains exhibited persistently smaller GMV in the amygdala, the hippocampus, the putamen and the SMA across the entire observation period. In the later postpartum phase, smaller volumes in the left hippocampus, the parahippocampal gyrus and the amygdala were found to be linked to reduced hostility toward the infant. The sustained, receptor-specific brain adaptation throughout the postpartum period was found to be complemented by the experience of maternity, likely mediated by oxytocin release. Given the robust link between these brain alterations and the GABA and glutamate receptor distributions, our findings indicate a possible role of the excitation-inhibition balance in postpartum mood regulation.
White matter structure-function coupling in neonatal brain and its association with Autism-related traits in early childhood.
Zhang Z, Zhang C, Zhang X … +6 more , Zhang J, Xu Y, Dou W, Li M, Zheng W, Li B
Transl Psychiatry · 2026 May · PMID 42173856 · Publisher ↗
The neonatal brain undergoes a rapid maturation of white matter pathways, yet how structural refinement within these tracts drives concurrent functional reorganization remains poorly understood. Using multimodal MRI data...
The neonatal brain undergoes a rapid maturation of white matter pathways, yet how structural refinement within these tracts drives concurrent functional reorganization remains poorly understood. Using multimodal MRI data from 399 infants (348 term-born and 51 preterm-born) from the Developing Human Connectome Project, here we characterize the developmental trajectories of white matter structure-function coupling (SFC) and examine its associations with myelination (indexed by the T1w/T2w ratio), prematurity, and later autism-related traits. We find that SFC strength and its temporal variance develop heterogeneously across major fiber tracts, in which the inferior longitudinal and inferior fronto-occipital fasciculi exhibit a marked left-lateralized tendency, supporting the formation of nascent language and social cognition. The association between SFC and myelination is also dynamic, weakening over time in most tracts but strengthening selectively in the inferior longitudinal fasciculus. Preterm infants exhibit significantly reduced SFC across most tracts compared to term-born peers. Notably, reduced SFC in the right corticospinal tract partially mediates the association between prematurity and higher autism-related traits at 18 months. Furthermore, neonatal SFC predicts these traits only in preterm infants. These findings delineate a dynamic, tract-specific interplay between structure and function in early-life brain and establish neonatal SFC as a key link between prematurity and subsequent neurodevelopmental risk.
Towards disentangling the polygenic contribution of dyslexia to school performance.
Graell M, Bosch R, Soler Artigas M … +16 more , Alemany S, Llonga N, Carabí-Gassol P, Zubizarreta-Arruti U, Macias-Chimborazo V, Mitjans M, Pagerols M, Pagespetit È, Prat R, Puigbó J, Rivas C, Martinez L, Ramos-Quiroga JA, Casas M, Ribasés M, Cabana-Domínguez J
Transl Psychiatry · 2026 May · PMID 42173846 · Publisher ↗
Dyslexia is a neurodevelopmental disorder typically diagnosed in school-aged children and associated with poor school performance and lower levels of educational attainment (EA). Here, we aimed to test the shared genetic...
Dyslexia is a neurodevelopmental disorder typically diagnosed in school-aged children and associated with poor school performance and lower levels of educational attainment (EA). Here, we aimed to test the shared genetic architecture between dyslexia and EA, to dissect the polygenic contribution of dyslexia by its relationship with EA and to assess how these genetic partitions influence school performance, early manifestation of psychopathology and related traits. We first confirmed a negative genetic correlation between dyslexia and EA (rg = -0.186, SE = 0.019, P = 1.75E-22). Then, polygenic scores for EA and dyslexia were tested in a cohort of 4274 school-aged children, revealing opposite direction of the effect in school performance. Next, we dissected the genetic liability for dyslexia into components shared with, and independent of, EA. The results revealed similar patterns of association for performance in primary and foreign languages, but distinct patterns when comparing these language-related subjects with mathematics. The dyslexia-specific genetic component independent of EA was associated with poorer academic outcomes in language-related subjects and increased rates of psychopathology, supporting the existence of dyslexia-specific genetic effects beyond general cognitive or educational pathways. In contrast, the genetic load of dyslexia that overlaps with EA contributes to school performance in both language-related subjects and mathematics and displayed opposite patterns of association dependent on whether concordant and discordant genomic partitions were considered. The discordant partition was associated with poorer school performance and higher rates of behavioral and emotional problems, with these associations being partially mediated by the dyslexia diagnosis (accounting for a reduction in effect size ranging from 10.44-12.91%). Conversely, the concordant partition was only associated with better performance in mathematics. Overall, these findings highlight the polygenic contribution of dyslexia to both academic and psychopathological outcomes, support distinct genetic influences on language skills and mathematics, and underscore the usage of the genetic load for EA to deepen insight into the complex genetic relationship between dyslexia and school performance.
The glutamatergic NTS-PAG/PVN pathway underlies myocardial injury and anxiety-like behavior induced by myocardial ischemia-reperfusion.
Zhang F, Luo ZJ, Wei NX … +11 more , Yu JQ, Shao WJ, Liu W, Xu ZH, Shu Q, Zhou X, Wang J, Hu L, Shen GM, Cai RL, Yu Q
Transl Psychiatry · 2026 May · PMID 42173843 · Publisher ↗
For patients with myocardial ischemia-reperfusion injury (MIRI), cardiac dysfunction accompanied by anxiety is an extremely common comorbidity. Although the association between these two conditions has received some atte...
For patients with myocardial ischemia-reperfusion injury (MIRI), cardiac dysfunction accompanied by anxiety is an extremely common comorbidity. Although the association between these two conditions has received some attention, the underlying neural mechanisms remain unclear. Here, we functionally characterized two distinct glutamatergic (Glu) neural pathways in the nucleus tractus solitarius (NTS) of male mice, a pathway from the NTS to the periaqueductal gray (PAG) that mediates anxiety-like behaviors in MIRI mice, and a pathway from the NTS to the paraventricular nucleus of the hypothalamus (PVN) that influences cardiac dysfunction following MIRI. Chemogenetic inhibition of these two pathways simultaneously ameliorated both the anxiety-like behaviors and cardiac dysfunction in MIRI mice. Thus, our study reveals that the distinct circuits NTS-PAG and NTS-PVN separately encode anxiety-like emotions and cardiac dysfunction after myocardial ischemia-reperfusion, thereby providing insights at the neural circuit level for improving both cardiac dysfunction and anxiety-like emotions following MIRI.
Lonely minds, inflamed guts: metabolic and circulating protein pathways linking social isolation and loneliness to inflammatory bowel disease.
Zhao J, Ye J, Zhang M … +10 more , Yu G, Ji H, Zhou S, Jiang F, Xue E, Li K, Yu Z, Yang H, Wu H, Li X
Transl Psychiatry · 2026 May · PMID 42173842 · Publisher ↗
Mounting evidence suggests that psychosocial stressors, such as social isolation and loneliness, contribute to gastrointestinal disorders by disrupting gut-brain interactions. We aim to investigate the associations of so...
Mounting evidence suggests that psychosocial stressors, such as social isolation and loneliness, contribute to gastrointestinal disorders by disrupting gut-brain interactions. We aim to investigate the associations of social isolation, loneliness, and their related alterations in metabolism and circulating proteins with the risk of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). 275,157 adults from the UK Biobank were analyzed, including metabolomic data from 68,362 participants and proteomic profiling from 29,339 participants. The exposures included social isolation, loneliness, and their related metabolites and circulating proteins, with incident IBD as the outcome. Cox regression and two-sample Mendelian randomization (TSMR) analysis were utilized to examine the associations. Over a mean follow-up of 13.49 years, this cohort study identified 1565 incident IBD cases, comprising 1063 UC cases and 492 CD cases. Social isolation and loneliness showed significant associations with an elevated risk of IBD (social isolation: hazard ratio [HR]: 1.31, 95%CI: 1.01-1.70; loneliness: 1.29, 95%CI: 1.04-1.60). Social isolation and loneliness jointly increased the risk of IBD by 85%, with an HR of 1.85 (95% CI: 1.02-3.36). TSMR analyses further indicated that more sports or gym activity reduced IBD and CD risk, more religious activity lowered UC risk, while fewer leisure/social activities increased UC risk. For the metabolomic analysis, eight and five metabolites were identified to be associated with social isolation and loneliness, respectively. Additionally, 22 circulating proteins consistently associated with both loneliness and social isolation were identified, predominantly enriched in cytokine-related pathways. The derived protein scores were positively associated with an increased risk of IBD. This study demonstrates social isolation and loneliness significantly raise IBD risk, with related metabolite and circulating proteins shedding light on underlying biological mechanisms.
Hypoactivity, abnormal development of dendrites relevant to impaired synaptic transmission of calretinin-expressing interneurons in the medial prefrontal cortex underlies social deficits of mouse model in autism.
Chen M, Zhao K, Gao C … +11 more , Mei D, Shi S, Wang L, Sun L, Guo J, Bin G, Zhao S, Yan X, He M, Zhang Y, Wang X
Transl Psychiatry · 2026 May · PMID 42168170 · Full text
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms including impairments in social behavior and communication. The impaired excitatory and inhibitory signals have been implicat...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms including impairments in social behavior and communication. The impaired excitatory and inhibitory signals have been implicated in the pathophysiology of social behavior deficits. Altered calretinin (CR)-containing GABAergic interneurons have been observed in ASD, but their roles and underlying mechanisms remain unveiled. Here, using valproic acid (VPA)-exposed mice for CR-Cre and R26::LS-tdTomato (Ai14) model of ASD, we prove that a decreased number of CR interneurons in the mPFC of an animal model for ASD. Double-staining experiments demonstrated the decreased number of CR interneurons stained for c-Fos. Also, reduction in GCaMP7s fluorescence intensity was elicited in sociability and social novelty preference using in vivo fiber photometry, manifesting VPA-induced suppression of CR-positive cell activation. Additionally, we observed the abnormalities of dendrites in CR interneurons including lower dendritic arbors, decreased dendrite complexity, and spine density, paralleled by abnormal development of spine morphology. Intriguingly, the electrophysiological recordings of tdTomato-labeled interneurons revealed that exposure to VPA depressed intrinsic neuronal excitability by decreasing spontaneous and evoked action potential frequencies. These changes were concomitant with impairments of glutamatergic and GABAergic synaptic transmission of CR interneurons. Strikingly, chemogenetic silencing of mPFC CR-expressing interneurons induced social interaction deficits in mice. These sociability impairments can be rescued by optogenetic activation of CR activity in VPA-exposed mice. Our study indicates that prenatal exposure to VPA induced reduced activities, abnormalities in morphological development, and decreased intrinsic excitability as well as accompanying impaired synaptic transmission of CR interneurons. Our findings provide strong evidence for the notion that the CR interneurons has a critical role in the regulation of social behavior in mice and manifest that CR interneurons dysfunction may be implicated in social impairments in ASD.
Superior colliculus modulates the compulsion in a model of addiction with foot-shock.
Yang MD, Chen JG, Wang F … +4 more , Wu N, Li J, Long LH, Song R
Transl Psychiatry · 2026 May · PMID 42168166 · Publisher ↗
Compulsive drug use despite negative consequences is a core addiction feature and key therapeutic target. Animal models utilize footshock to screen for mice exhibiting compulsive-like addiction traits. Following the admi...
Compulsive drug use despite negative consequences is a core addiction feature and key therapeutic target. Animal models utilize footshock to screen for mice exhibiting compulsive-like addiction traits. Following the administration of aversive stimuli, compulsive animals persist in drug-seeking, suggesting that addicted individuals may have impaired innate defensive responses, thereby exacerbating addictive behaviors. However, little is known about the neural mechanisms behind this behavior. The superior colliculus (SC), a multisensory integration hub, plays a crucial regulatory role in innate fear and defense. This study employed an optical intracranial self-stimulation (oICSS) addiction-like model. Using footshock to screen for mice with compulsive-like behavior, fiber photometry recordings revealed significant differences in neuronal activity within the SC. Specifically, SC neurons in compulsive-like mice showed significantly lower responses to footshock stimuli compared to non-compulsive mice. Subsequently, chemogenetic inhibition of SC neuronal activity in non-compulsive mice significantly reduced their resistance to footshock, inducing a compulsive-like state. Conversely, chemogenetic activation of SC neurons in compulsive-like mice significantly decreased their oICSS behavior. These findings indicate that mice exhibiting compulsive-like addiction behavior, identified through footshock, exhibit significant functional abnormalities in SC neurons. The SC is implicated in regulating compulsive addictive behaviors, providing novel insights into the mechanisms of compulsivity and identifying a promising new target for addiction intervention.
"Intranasal clozapine sol-gel formulation induces an antipsychotic effect at a fraction of a comparable oral therapeutic dose".
Eyles DW, Parekh HS, Alexander S … +6 more , Pandey P, Siskind D, Ali M, Langguth M, Lohman R, Cui X
Transl Psychiatry · 2026 May · PMID 42168165 · Publisher ↗
Clozapine is arguably the most effective antipsychotic in the treatment of schizophrenia. However, clozapine comes with a substantial and even sometimes lethal side-effect burden. The vast majority of side-effects are pe...
Clozapine is arguably the most effective antipsychotic in the treatment of schizophrenia. However, clozapine comes with a substantial and even sometimes lethal side-effect burden. The vast majority of side-effects are peripherally induced, requiring additional pharmacotherapy. An approach to diminishing such debilitating side-effects would be to minimize drug access to the periphery through consideration of other dosage forms and routes of administration. Although a number of intranasal formulations have been developed for clozapine, their antipsychotic potential and distribution across the brain remains unknown. We have developed a poloxamer-based clozapine-infused sol-gel engineered for sustained and controlled nose-to-brain drug delivery. Here in rats, we show that intranasal clozapine delivered via sol-gel achieves high concentrations in brain with minimal distribution to blood. Importantly, we also show that an industry-standard antipsychotic effect is achieved at a fraction (3.5%) of the dose required orally to achieve the same effect. These studies also show a greatly reduced potential of clozapine-infused sol-gel administered intranasally, to elevate blood glucose. The substantive reduction in dose achieved, through olfactory mucosa resident sol-gel restricts drug access to the periphery and therefore associated metabolic side-effects, making intranasal clozapine sol-gel an attractive option for further clinical investigation.
Differential alterations in peripheral tryptophan pathways in methamphetamine versus MDMA users are linked to their contrasting psychiatric symptoms.
Bavato F, Steuer A, Jacobsen AM … +8 more , Zacher A, Zimmermann J, Cole DM, Opitz A, Baumgartner MR, Stock AK, Beste C, Quednow BB
Transl Psychiatry · 2026 May · PMID 42168162 · Publisher ↗
Methamphetamine (METH, "Crystal Meth") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") are two types of substituted amphetamines that share structural-chemical similarities but exhibit contrasting acute and chron...
Methamphetamine (METH, "Crystal Meth") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") are two types of substituted amphetamines that share structural-chemical similarities but exhibit contrasting acute and chronic effects including addictive liability. Tryptophan (TRY) pathways are involved in pleiotropic physiological functions at the interface of brain-body connections. Preclinical evidence suggests that amphetamines may modulate these pathways and, thus, indirectly influence brain functions via persistent alterations of peripheral metabolites. However, little is known about alterations of TRY-related metabolites in the blood and their clinical implications in chronic users of MDMA and METH. Hence, we characterized serum levels of TRY-related metabolites in a comparative cross-sectional study including n = 36 chronic MDMA users, n = 33 chronic METH users, and n = 71 sex-matched, healthy controls. An ultra-high performance liquid chromatography-mass spectrometry method was used to determine TRY metabolites. Combining metabolite levels, metabolic ratios, and network analysis we found robust evidence of divergent pathway alterations between METH and MDMA users. Chronic METH use was particularly associated with a depletion of serum TRY and serotonin levels, and a general activation of kynurenine pathways, while chronic MDMA use was linked to a selective activation of the OH-kynurenine metabolic branch. Metabolite changes were associated with the severity of psychopathology in the depression and psychosis domains across groups. Altogether, our findings demonstrate differential changes of serum TRY pathways in chronic MDMA and METH users. Persistent alterations of these pathways might contribute to the contrasting clinical profile of the substances and constitute a peripheral dimension of neurochemical plasticity with relevant implications for therapeutic targets.
Inhibitory control deficits and ventral attention network alterations linked to apathy in schizophrenia.
Deng W, van Tol MJ, Marsman JC … +3 more , Kos C, Servaas MN, Aleman A
Transl Psychiatry · 2026 May · PMID 42168148 · Publisher ↗
Individuals with schizophrenia demonstrated impaired inhibitory control and apathy symptoms, which are characterized by a reduction in self-initiated voluntary activities. However, whether deficits in inhibitory control...
Individuals with schizophrenia demonstrated impaired inhibitory control and apathy symptoms, which are characterized by a reduction in self-initiated voluntary activities. However, whether deficits in inhibitory control are linked to apathy remains unclear. Here we investigated inhibitory control-related neural networks and associations with interview-based apathy and actigraphy-derived motor activity, an objective measure of apathy. Twenty-three patients with schizophrenia underwent 3T-fMRI scans during Go/No-Go task. Task-related networks were identified via independent component analysis. Behavioral performance was examined using a drift diffusion model. Correlation and regression analyses examined relationships between apathy severity scores, motor activity, behavioral parameters, task-related networks engagement and connectivity. Patients with higher levels of apathy showed reduced motor activity levels, lower overall accuracy rate in inhibitory control, particularly more inhibitory errors, lower Go-condition processing efficiency, and reduced stimulus sensitivity. On the neural level, higher apathy correlated with weaker ventral attention network (vAN) engagement during successful inhibition, and weaker default mode network (DMN) engagement during failed inhibition, although the latter association was influenced by age and depressive symptoms. Stronger left posterior cingulate cortex spatial contribution to DMN and weaker vAN-DMN coupling were associated with higher apathy in patients with schizophrenia. Motor activity levels were unrelated to inhibitory-related networks. Higher apathy in schizophrenia was related to worse inhibitory control performance and decreased vAN and DMN recruitment and connectivity during response inhibition, indicating impairments in sustaining attention on the task and allocating cognitive resources in response to external demands. Dysfunctional neural networks underpinning inhibition may contribute to reduced goal-directed behavior. Motor activity appears to be related to apathy in terms of auto-activation, but not in terms of cognitive inhibitory control.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe