Progress in Neuro-Psychopharmacology & Biological Psychiatry最新文献

{"title":"Lateral septum activation as a central hub for reversing chronic stress-induced novelty-avoidance","authors":"Chih-Hua Chang ,&nbsp;Sheng-Feng Sung ,&nbsp;Chi-Sheng Chen ,&nbsp;Kuan-Chin Sung ,&nbsp;Hsi-Chien Wang ,&nbsp;Ya-Hsin Hsiao","doi":"10.1016/j.pnpbp.2025.111436","DOIUrl":"10.1016/j.pnpbp.2025.111436","url":null,"abstract":"<div><div>Chronic stress is a major risk for mental disorders, particularly major depression, leading to behavioral impairments such as reduced novelty-seeking behavior. This study investigates the neurobiological mechanisms underlying chronic stress-induced deficits in novelty-driven exploratory behavior. Using a chronic unpredictable stress (CUS) model in mice, we observed significant reductions in novelty-seeking behavior during Y-maze and object location tasks, accompanied by decreased dorsal hippocampal activity. Chemogenetic activation of the dorsal hippocampus restored these behaviors, highlighting its critical role in novelty-seeking. In contrast, the ventral hippocampal activation failed to reverse the deficits, emphasizing a spatially specific function of the dorsal hippocampus. Further investigation revealed that activation of the ventral tegmental area (VTA) in CUS mice increased c-Fos expression in the lateral septum (LS) and alleviated CUS-induced novelty-avoidance. Furthermore, the LS received convergent projections from the dorsal hippocampal CA1 and VTA. Selective activation of LS-projecting pathways from the dorsal hippocampus and VTA drove novelty-seeking behavior in CUS mice. These findings suggest that LS activation is a pivotal node in enhancing novelty-seeking behavior impaired by chronic stress. By integrating spatial signals from the dorsal hippocampus with motivational inputs from the VTA, the LS emerges as a promising therapeutic target for interventions aimed to counteract chronic stress-induced novelty-avoidance. This study provides comprehensive insights into the neural underpinnings of exploratory behavior under chronic stress and underscores the translational potential of targeting the LS in stress-related disorders.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"140 ","pages":"Article 111436"},"PeriodicalIF":5.3,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144579328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Esketamine disinhibits brain networks in depression: Evidence from oscillatory and aperiodic activity","authors":"Verina Guirguis ,&nbsp;Sanvi Korsapathy ,&nbsp;Francesca Pupillo ,&nbsp;Robert K. McClure ,&nbsp;David Zarzar ,&nbsp;Mengsen Zhang ,&nbsp;Flavio Frohlich ,&nbsp;Tobias Schwippel","doi":"10.1016/j.pnpbp.2025.111438","DOIUrl":"10.1016/j.pnpbp.2025.111438","url":null,"abstract":"<div><h3>Background</h3><div>Nasal Esketamine is a rapid-acting intervention for depression, hypothesized to exert its effects through cortical disinhibition. However, the spatio-temporal dynamics of brain network activity and their relationship to the subjective drug experience following Esketamine administration remain elusive. This observational study aims to delineate brain network-level effects of Esketamine by analyzing changes in oscillatory and aperiodic EEG activity within 90 min following nasal Esketamine treatment in depression.</div></div><div><h3>Methods</h3><div>Eight individuals with major depressive disorder undergoing regular Esketamine treatment participated in the study. High-density, eyes-open resting state EEG was recorded before and subsequently five times up to 90 min post-administration. Before each recording, individuals completed ratings of individual drug experience. EEG spectral features were separated into canonical frequency bands and aperiodic exponent. Primary outcomes were changes in neural activity and their association with individual drug experience.</div></div><div><h3>Results</h3><div>Following Esketamine administration, we observed a marked decrease of frontoparietal alpha power and central beta and a significant increase of frontal midline delta and low gamma power, indicative of cortical disinhibition and reduction of top-down control. Correspondingly, the aperiodic exponent decreased, suggestive of a shift of the excitation/inhibition balance towards excitation. These electrophysiological changes were accompanied by an increase in subjective ratings of highness and happiness, and a decrease in tension. Further analyses revealed significant relationships between changes in neural activity and subjective drug experience.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that Esketamine induces brain network disinhibition and reduces top-down control. These neurophysiological changes closely correlate with individual drug experience, providing valuable insights into the neural mechanisms underlying Esketamine's immediate behavioral effects.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"140 ","pages":"Article 111438"},"PeriodicalIF":5.3,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144585631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"lnc15qD3 expression in the NAc shell regulates the reconsolidation of opioid reward memories","authors":"Xiaojie Li ,&nbsp;Bing Xie ,&nbsp;Yixiao Luo ,&nbsp;Yun Lu ,&nbsp;Minglong Zhang ,&nbsp;Xiaoli Wang ,&nbsp;Hailei Yu ,&nbsp;Ludi Zhang ,&nbsp;Bin Cong ,&nbsp;Di Wen ,&nbsp;Chunling Ma","doi":"10.1016/j.pnpbp.2025.111433","DOIUrl":"10.1016/j.pnpbp.2025.111433","url":null,"abstract":"<div><div>Following memory retrieval, permanent drug memories become unstable and easily disrupted, followed by reconsolidation; this pattern holds promise for treating substance use disorder (SUD). Recent research has demonstrated that epigenetic modifications, including long noncoding RNA (lncRNA) regulation, participate in learning and memory. However, the role of lncRNAs in drug-memory reconsolidation remains unclear. Here, we found that in conditioned place preference (CPP) and self-administration (SA) mouse models of drug abuse, lnc15qD3 expression was substantially upregulated after contextual cue exposure in the nucleus accumbens (NAc) shell but not in the core. Furthermore, after retrieval, viral-mediated knockdown of lnc15qD3 disrupted the reconsolidation of morphine-induced CPP memories in the NAc shell but not in the core. Additionally, the inhibitory effect cannot be reversed by time or morphine priming. Similarly, using a heroin SA protocol, lnc15qD3 knockdown in the NAc shell after retrieval long-term suppressed heroin-seeking behaviors. We further investigated the molecular events downstream of lnc15qD3 mediating the reconsolidation of opioid reward memories in rescue assays and in vitro experiments. Our results indicated that lnc15qD3 binds to endogenous miR-7118-5p/miR-6914-5p, which alters the expression of Notch2 and regulates opioid addictive memory reconsolidation. Consequently, lnc15qD3 may be applied as a target for anti-relapse therapy.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"140 ","pages":"Article 111433"},"PeriodicalIF":5.3,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144534785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High allostatic status impairs cognitive function in patients with first-episode drug-naive bipolar disorder","authors":"SuJuan Li ,&nbsp;XiuShan Chen ,&nbsp;Yan Qiu ,&nbsp;ZiWei Teng ,&nbsp;JinDong Chen ,&nbsp;BaoYan Xu ,&nbsp;JianZhong Mo ,&nbsp;HaiPing Liu ,&nbsp;HuaLin Cai ,&nbsp;HaiShan Wu","doi":"10.1016/j.pnpbp.2025.111434","DOIUrl":"10.1016/j.pnpbp.2025.111434","url":null,"abstract":"<div><h3>Objective</h3><div>Patients with bipolar disorder (BD) are often experience cognitive impairment. Allostatic load (AL) represents the cumulative physiological burden on the body resulting from prolonged or chronic stress, which plays a key role in the pathophysiology of BD. This study aimed to investigate the relationship between AL and cognitive function in first-diagnosed, drug-naïve BD patients.</div></div><div><h3>Methods</h3><div>Patients with BD (<em>n</em> = 113) recruited from March 2019 to August 2022, along with healthy controls (HCs, <em>n</em> = 115) recruited during the same period. Body mass index (BMI), waist-to-hip ratio (WHR), high-density lipoprotein cholesterol (HDL), total cholesterol (TC), blood glucose, C-reactive protein (CRP), cortisol and serum dehydroepiandrosterone (DHEA) levels were measured to calculate AL. Clinical symptoms were assessed using the Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Young's Mania Rating Scale (YMRS). Cognitive function was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Stroop Word Test. Differences in AL, eight biological indicators, and cognitive performance were compared between the BD and HC groups. Covariate analyses were conducted to examine correlations between AL and cognitive function, with further gender subgroups analysis to explore specific factors affecting cognition in BD.</div></div><div><h3>Results</h3><div>AL levels were significantly higher in the BD group (U = 5096, <em>P</em> = 0.004) compared to HC. Cognitive performance, as measured by RBANS (<em>t</em> = 6.359, <em>P</em> &lt; 0.0001) and Stroop test (<em>t</em> = 4.516, P &lt; 0.0001) scores, was significantly lower in BD patients. Cortisol levels were positively correlated with delayed memory performance (<em>r</em> = 0.29, <em>P</em> = 0.027), whereas CRP levels were negatively correlated with delayed memory performance (<em>r</em> = −0.31, <em>P</em> = 0.020). In the male subgroup, a negative correlation was observed between AL and RBANS scores (<em>r</em> = −0.48, <em>P</em> = 0.009).</div></div><div><h3>Conclusion</h3><div>Elevated AL may contribute to the pathophysiology of BD and the observed reduction of cognitive performance.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"140 ","pages":"Article 111434"},"PeriodicalIF":5.3,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144555870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imbalance of thalamocortical structural connectivity in adolescents with early-onset schizophrenia","authors":"Yonghui Xiang ,&nbsp;Shuting Chen ,&nbsp;Jinqiang Zhang ,&nbsp;Guowei Wu ,&nbsp;Xuan Ouyang ,&nbsp;Zhening Liu ,&nbsp;Chen Tan ,&nbsp;Can Xu ,&nbsp;Lange Zheng ,&nbsp;Xinran Xu ,&nbsp;Lena Palaniyappan ,&nbsp;Weidan Pu","doi":"10.1016/j.pnpbp.2025.111423","DOIUrl":"10.1016/j.pnpbp.2025.111423","url":null,"abstract":"<div><h3>Background</h3><div>Thalamocortical circuit imbalance, characterized by decreased prefrontal-thalamic connectivity and increased sensorimotor-thalamic connectivity, has been well-documented in adult-onset schizophrenia. We have previously demonstrated functional imbalance of this circuit in adolescents with early-onset schizophrenia (EOS). We now investigate whether this functional imbalance stems from the thalamocortical structural connectivity in EOS, thereby further establishing its relevance to the neurodevelopmental modeling of psychosis.</div></div><div><h3>Methods</h3><div>The study included 212 adolescents (145 EOS patients and 67 healthy controls). To further control the medication effect, the patients were divided into two subgroups (drug-naive vs drug-treated). Fourteen bilateral cortical regions of interest and bilateral thalamus were used as targets and seeds respectively for probabilistic tractography to quantify structural connectivity of the thalamocortical circuit.</div></div><div><h3>Results</h3><div>Compared to healthy controls, in EOS, structural connectivity of the thalamus with the dorsolateral prefrontal (dlPFC) and parietal cortices was decreased, while connectivity with the sensorimotor cortices was increased. We also observed an unexpected increase in connectivity of the medial prefrontal cortex (mPFC) with thalamus in EOS. The imbalance pattern was replicated in two subgroups regardless of medication status. Further correlation analysis showed that the thalamic hypoconnectivity with the dlPFC and the hyperconnectivity with the mPFC were both related with higher individual symptom burden in patients.</div></div><div><h3>Conclusions</h3><div>The functional thalamocortical circuit imbalance in adolescents with schizophrenia is underwritten by a similar imbalance in the structural connectivity. A specific thalamocortical structural hyperconnectivity involving the mPFC, previously unobserved in adult-onset patients, may contribute to the distinct clinical manifestations in EOS.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"140 ","pages":"Article 111423"},"PeriodicalIF":5.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144531140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel multidimensional, perinatal social and material deprivation paradigm induces aggressive behavior and cortical gene expression reprogramming in young adult mice","authors":"Bruno G. Berardino ,&nbsp;María Belén Cardillo ,&nbsp;Rocío Priegue ,&nbsp;Hugo C. Perez ,&nbsp;Sergio I. Nemirovsky ,&nbsp;Micaela Salvochea ,&nbsp;Verónica Cantarelli ,&nbsp;Marina F. Ponzio ,&nbsp;Mariela Chertoff ,&nbsp;Eduardo T. Cánepa","doi":"10.1016/j.pnpbp.2025.111432","DOIUrl":"10.1016/j.pnpbp.2025.111432","url":null,"abstract":"<div><div>Poverty is a complex, multidimensional stressor that affects both physical and mental health outcomes. Current animal models often isolate single aspects of socioeconomic adversity, limiting their translational relevance. This study introduces a novel murine model of social and material deprivation (SMD) designed to simulate the co-occurrence of environmental impoverishment and social stress observed in real-world settings.</div><div>During gestation and lactation pregnant mice and their litters were exposed to a combination of reduced nesting/bedding material, lack of cage enrichment, maternal separation with early weaning, and threat from a dominant male. Behavioral tests, brain morphology assessments, and prefrontal cortex gene expression analyses were performed in the offspring, considering sex as a biological variable throughout.</div><div>SMD dams displayed increased depressive-like behavior and maladaptive coping strategies, along with reduced maternal care. Offspring exhibited delayed neurodevelopment, increased anxiety-like behavior and aggression in males, and structural brain alterations, including reduced dorsal (females) and ventral (both sexes) hippocampal area, and increased prefrontal cortex width in both sexes.</div><div>Transcriptomic analyses of the prefrontal cortex revealed sex-specific patterns: in males, genes involved in neuronal development and immune function were predominantly upregulated; in females, chromatin remodeling genes were upregulated, while immune-related genes were downregulated.</div><div>The SMD model recapitulates key behavioral, morphological, and molecular features associated with early-life adversity and socioeconomic disadvantage, offering a valuable tool to investigate sex-specific neurobiological responses to complex stress exposure during sensitive developmental windows.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"140 ","pages":"Article 111432"},"PeriodicalIF":5.3,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-chain fatty acids in mood and schizophrenia spectrum disorders: Evidence in the field and translational perspectives","authors":"Julia Karska ,&nbsp;Karolina Skonieczna-Żydecka ,&nbsp;Natalia Jakubiak ,&nbsp;Wiktoria Czarnecka ,&nbsp;Błażej Misiak","doi":"10.1016/j.pnpbp.2025.111430","DOIUrl":"10.1016/j.pnpbp.2025.111430","url":null,"abstract":"<div><div>The etiology of mood and schizophrenia spectrum disorders remains largely unknown. In recent years, several studies have focused on the role of the microbiome-gut-brain-axis (MGBA) in its etiology, providing several novel insights. The communication within MGBA involves various pathways leading through the vagus nerve and the bloodstream mediators. The latter are represented by short-chain fatty acids (SCFAs), produced by gut microbiota from dietary fiber. To date, several physiological and pathophysiological roles in the periphery and the central nervous system for SCFAs have been suggested. Studies investigating gut microbiota have consistently reported a decreased abundance of bacteria-producing SCFAs in people with mood and schizophrenia spectrum disorders. Yet, studies investigating faecal and blood levels of SCFAs have provided mixed findings. The present article provides a narrative review of studies examining the physiological roles of SCFAs, along with animal model and human studies addressing the involvement of SCFAs in mood and schizophrenia spectrum disorders, formulates future directions and provides translational perspectives.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"140 ","pages":"Article 111430"},"PeriodicalIF":5.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144469940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-lasting behavioral, molecular and functional connectivity alterations after chronic THC exposure during adolescence in mice","authors":"Laura Gómez-Acero ,&nbsp;Federico Varriano ,&nbsp;Nuria Sánchez-Fernández ,&nbsp;Francisco Ciruela ,&nbsp;Guadalupe Soria ,&nbsp;Ester Aso","doi":"10.1016/j.pnpbp.2025.111422","DOIUrl":"10.1016/j.pnpbp.2025.111422","url":null,"abstract":"<div><div>Heavy and daily use of cannabis with high contents of Δ⁹-tetrahydrocannabinol (THC) during adolescence is associated with an increased risk of developing psychotic disorders later in life. Here, we treated mice with THC during adolescence and found that this exposure impaired social interaction and increased vulnerability to develop sensorimotor gating deficiencies comparable to those previously described among heavy cannabis consumers. Importantly, we provide evidence on long-term cortico-striatal dysconnectivity induced by exposure to THC during adolescence and its correlation with impaired social interactions occurring later in adulthood. Moreover, we have observed long-lasting molecular alterations in key elements that regulate the mesolimbic dopaminergic system, namely on the balance between dopamine D₂, adenosine A_2A, and cannabinoid CB₁ receptors in the striatum of treated mice. Together, these findings contribute to a better understanding of the neurobiological bases of the deleterious effects associated with cannabis abuse during adolescence.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"140 ","pages":"Article 111422"},"PeriodicalIF":5.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144313861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A review of nonhuman primate models of depressive disorder","authors":"Yu Bao ,&nbsp;Di Luan ,&nbsp;Zhiqiang Meng","doi":"10.1016/j.pnpbp.2025.111421","DOIUrl":"10.1016/j.pnpbp.2025.111421","url":null,"abstract":"<div><div>Major depressive disorder (MDD) is a common mental disorder that affects people worldwide. It has been challenging to apply findings from basic research using rodents to clinical research. Many treatments that target the monoamine system are not effective. Nonhuman primates (NHPs) play an important role in both basic and translational research, but their use in research has been limited, and it is difficult to measure moods or thoughts in NHPs. In this evaluation, we focus on the depression model and behavior assessments in NHPs to understand their unique contributions to depression research. We also examine depression-like behavior in NHPs that aligns with the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) and provide an overview of insights from studies using nonhuman monkey models and behavioral assessments in the development of new and effective treatments for depression.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"140 ","pages":"Article 111421"},"PeriodicalIF":5.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-dependent effects of cumulative methylphenidate exposure on brain structure and symptom amelioration in youth with ADHD: A longitudinal MRI study","authors":"Jung-Chi Chang ,&nbsp;Hsiang-Yuan Lin ,&nbsp;Susan Shur-Fen Gau","doi":"10.1016/j.pnpbp.2025.111429","DOIUrl":"10.1016/j.pnpbp.2025.111429","url":null,"abstract":"<div><div>Methylphenidate is known to alleviate attention-deficit/hyperactivity disorder (ADHD) symptoms. However, methylphenidate's age-dependent effects on brain structure have not been well studied. This longitudinal MRI study investigated the effect of cumulative methylphenidate exposure on brain structure and ADHD-related symptoms. Eighty-nine individuals with DSM-5 ADHD and 91 typically developing controls (TDC) were assessed with MRI for brain structure and the parent-rated SNAP-IV questionnaire for ADHD-related symptoms at baseline and follow-up. The average follow-up interval was 4.86 years. Participants were divided into two age-based groups at a baseline age cutoff of 12 years. In the early-exposure subgroup (baseline age &lt; 12 years), distinct developmental differences were noted between the ADHD and TDC groups in various frontal regions. Increased cumulative methylphenidate dosage was associated with increased gray matter volumes in several frontal areas, such as the right paracentral, caudal middle frontal, superior frontal, lateral orbitofrontal, rostral middle frontal, precentral cortices, left pars opercularis, paracentral, and superior frontal cortices in the early-exposure subgroup. Additionally, greater volumetric increases in specific frontal regions, including the right rostral middle frontal, right paracentral, right superior frontal, and left paracentral cortices, correlated with more significant improvements in oppositional symptoms. Conversely, the late-exposure subgroup (baseline age &gt; 12 years) showed no significant differences in cortical development or associations between methylphenidate and brain structure. Our findings indicate that early methylphenidate exposure may affect frontal brain morphology and its association with symptom improvement in ADHD. These age-dependent patterns of psychostimulants on brain structure provide further insight into treatment response and disorder progression monitoring.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"140 ","pages":"Article 111429"},"PeriodicalIF":5.3,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144318732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}