Neurotherapeutics最新文献

{"title":"Perfusion imaging predicts therapeutic cooling response and tracks cis-p-tau pathology in porcine brain injuries.","authors":"Olivia L H Tong, Zhixiong Li, Laura Morrison, Susan Tyler, Lise Desjardins, Jennifer Hadway, Marcus Flamminio, Lynn Keenliside, Kevin J Chung, Ruizhi Wang, Yitong Li, Xiao Zhen Zhou, Kun Ping Lu, Ting-Yim Lee","doi":"10.1016/j.neurot.2026.e01081","DOIUrl":"https://doi.org/10.1016/j.neurot.2026.e01081","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) and ischemic stroke cause substantial morbidity and mortality, yet effective neuroprotective therapies remain elusive. Although therapeutic hypothermia shows strong neuroprotection in lissencephalic rodent models, adult clinical trials have repeatedly failed, largely due to poor preclinical translatability and uniform cooling protocols that overlook patient heterogeneity. Using a large cohort of gyrencephalic porcine models (n = 89) of TBI and stroke, subjects were allocated to sham, injury, or therapeutic cooling groups administered via a custom-designed, non-invasive intranasal selective brain cooling device for pre-hospital and hospital settings. We combined clinical CT perfusion and neuropathology to identify biomarkers that predict cooling efficacy. Brain cooling significantly reduced mortality in TBI and stroke compared to untreated controls. We showed that concurrent hyperemia (elevated cerebral blood flow) and blood-brain barrier (BBB) leakage during cooling predicted intracranial hypertension, which may facilitate identification of high-risk subjects that require intervention. Sustained hyperemia was pathological. Neuropathological assessment revealed that cis-phosphorylated-tau (cis-p-tau), a major early driver of both TBI and stroke, is correlated with injury severity, treatment response, and BBB permeability. In TBI, mild selective brain cooling (∼1.3 °C reduction) was associated with reduced secondary brain damage, whereas deeper cooling (≥3 °C) offered no added benefit in this cohort. These findings suggest that integrating perfusion imaging and the early molecular driver cis P-tau can guide personalized hypothermia, advancing the field toward precision medicine in acute brain injury neuroprotection.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e01081"},"PeriodicalIF":7.4,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137553","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":"Chlorogenic acid attenuates TBI-induced neuroinflammation by suppressing cGAS–STING signaling","authors":"Xu Yang,&nbsp;Kun He,&nbsp;Yulian Zhang,&nbsp;Hanhan Dang,&nbsp;Zixi Wang,&nbsp;Yunsheng Zhang,&nbsp;Chuanpeng Zhang,&nbsp;Pengyu Chen,&nbsp;Tongbo Zhang,&nbsp;Li Zhang,&nbsp;Yanbing Yu","doi":"10.1016/j.neurot.2026.e01085","DOIUrl":"10.1016/j.neurot.2026.e01085","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) induces persistent neuroinflammation that contributes to secondary brain injury and neurological dysfunction. The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is a key regulator of post-traumatic innate immune responses. Although chlorogenic acid (CGA) possesses well-established anti-inflammatory properties, the mechanisms underlying its protective effects after TBI remain incompletely understood. CGA efficacy was evaluated using a murine controlled cortical impact model. Bulk and single-cell RNA sequencing, network pharmacology, and mouse-specific molecular docking simulations were combined to identify candidate pathways. The underlying mechanism was further investigated <em>in vivo</em> and in LPS-stimulated BV2 microglia using the STING agonist DMXAA. CGA treatment significantly improved neurological function, enhanced cognitive performance, and alleviated blood-brain barrier disruption after TBI. Integrated analyses implicated cGAS–STING signaling as a candidate pathway associated with CGA action, with single-cell transcriptomic analysis showing relatively high pathway activity in microglia and infiltrating myeloid populations. Mechanistically, CGA reduced cGAS expression, inhibited the phosphorylation of STING, TBK1, and IRF3, and decreased pro-inflammatory cytokine production <em>in vivo</em>. <em>In vitro</em>, CGA decreased the expression of inflammatory and interferon-stimulated genes in a concentration-dependent manner and reduced reactive oxygen species accumulation; these effects were largely reversed by DMXAA. CGA attenuates neuroinflammatory responses and improves neurological outcomes after TBI, with early suppression of cGAS–STING signaling potentially contributing to these effects. These findings support further investigation of cGAS–STING signaling as a potential therapeutic target in TBI.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 6","pages":"Article e01085"},"PeriodicalIF":7.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of brain-computer interface rehabilitation in stroke patients: A meta-analysis and restricted cubic spline analysis of randomized controlled trials","authors":"Yutian Xu,&nbsp;Ping Hu,&nbsp;Zhihui Long,&nbsp;Mingyu Liang,&nbsp;Senlin Du,&nbsp;Yanze Wu,&nbsp;Xingen Zhu,&nbsp;Tengfeng Yan","doi":"10.1016/j.neurot.2026.e01086","DOIUrl":"10.1016/j.neurot.2026.e01086","url":null,"abstract":"<div><div>Despite growing evidence supporting the benefits of brain-computer interface (BCI) rehabilitation in post-stroke motor recovery, this review aimed to evaluate its efficacy and determine optimal training intensity. Systematic searches were conducted across Medline, EMBASE and Web of Science from January 1, 1990, to January 30, 2026, to identify relevant RCTs. A random- or fixed-effects model was used to pool outcome data. The restricted cubic spline (RCS) method was applied to estimate the dose-response relationship between BCI training intensity and upper extremity motor function. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Twenty-six studies, encompassing 1100 stroke patients, were included in this meta-analysis. The number of studies and participants varied across outcomes. Compared with control interventions, BCI-based rehabilitation demonstrated significant improvement in FMA-UE (24 studies, 1042 participants; MD = 1.11, 95% CI = 0.63 to 1.60), ARAT (8 studies, 524 participants; MD = 0.21, 95% CI = 0.04 to 0.39), WMFT (5 studies, 425 participants; MD = 0.94, 95% CI = 0.32 to 1.55), MBI (4 studies, 153 participants; MD = 1.17, 95% CI = 0.29 to 2.06), and BBS (2 studies, 35 participants; MD = 0.54, 95% CI = 0.02 to 1.07), but not in FMA-LE (2 studies, 78 participants; MD = −0.12, 95% CI = −0.79 to 0.55) or TUGT (2 studies, 35 participants; MD = −0.40, 95% CI = −1.15 to 0.34). Dose-response analysis suggested a non-linear, inverted U-shaped relationship between BCI rehabilitation intensity and FMA-UE, with the peak effect estimated at approximately 48 min per session. BCI-based rehabilitation may be an effective therapeutic strategy for enhancing upper-extremity motor recovery in post-stroke patients, and this review further suggests a potential optimal session duration of approximately 48 min based on dose-response analysis. However, its efficacy for lower-extremity motor recovery remains inconclusive and warrants further investigation.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 6","pages":"Article e01086"},"PeriodicalIF":7.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From molecular precision to the whole patient: New developments and therapies in neuro-oncology","authors":"Mary Jane Lim-Fat,&nbsp;Patrick Y. Wen","doi":"10.1016/j.neurot.2026.e01102","DOIUrl":"10.1016/j.neurot.2026.e01102","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 6","pages":"Article e01102"},"PeriodicalIF":7.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterogeneous neuroimaging findings in obsessive-compulsive disorder converge to a common brain network using coordinate network mapping","authors":"Haohao Yan,&nbsp;Yiding Han,&nbsp;Wanjun Guo,&nbsp;Wenbin Guo,&nbsp;Hengyi Cao","doi":"10.1016/j.neurot.2026.e01089","DOIUrl":"10.1016/j.neurot.2026.e01089","url":null,"abstract":"<div><div>Neuroimaging studies in obsessive-compulsive disorder (OCD) have yielded heterogeneous findings, limiting efforts to localize OCD to specific brain regions or networks. This study applied coordinate network mapping (CNM) to test whether these distributed abnormalities converge onto a common brain network and to explore the biological substrates of this network through associations with neurotransmitter systems. We systematically reviewed and extracted coordinates of significant clusters from 66 Gy matter volume (GMV) and resting-state activity studies involving 3123 patients with OCD and 3116 healthy controls. Using CNM and functional connectome data from 1000 healthy individuals, we identified brain networks functionally connected to these abnormalities. Spatial correlations were examined between identified networks and 19 types of neurotransmitter maps acquired from over 1000 healthy subjects. The GMV and resting-state activity findings in OCD both converged to a common, functionally connected brain network involving the striatum, thalamus, cingulate, supplementary motor area, insula, and inferior frontal and superior temporal gyri. The identified networks derived from the two neuroimaging modalities were significantly correlated with the N-Methyl-D-Aspartate (NMDA) receptor distribution (r = 0.551 and r = 0.541, respectively; <em>p</em> &lt; 0.001). Findings were robust across different methodological parameters and demonstrated good test–retest reliability. This study identifies a robust and reproducible brain network underlying the heterogeneous neuroimaging abnormalities in OCD, helping to interpret previous inconsistencies. Furthermore, the alignment of this network with the cortico-striato-thalamo-cortical circuitry and NMDA receptor distribution underscores its biological and clinical relevance, thereby illuminating potential targets for future neuromodulation and pharmacological interventions.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 6","pages":"Article e01089"},"PeriodicalIF":7.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MuSK agonistic antibody has therapeutic potential for MuSK antibody-positive myasthenia gravis","authors":"Kentaro Yamamoto,&nbsp;Akiyuki Uzawa,&nbsp;Genta Narazaki,&nbsp;Yoshikazu Nezu,&nbsp;Mami Yamazaki,&nbsp;Hirofumi Kondo,&nbsp;Kozo Yoneda,&nbsp;Masaya Shimada,&nbsp;Chigusa Yoshimura,&nbsp;Yoko Nakano,&nbsp;Manato Yasuda,&nbsp;Hiroyuki Akamine,&nbsp;Yosuke Onishi,&nbsp;Hideo Handa,&nbsp;Etsuko Ogaya,&nbsp;Tomonori Kunikata,&nbsp;Ryutaro Nakashima,&nbsp;Hidenori Takahashi,&nbsp;Tomohiro Nishizawa,&nbsp;Satoshi Kuwabara,&nbsp;Kiyosumi Takaishi","doi":"10.1016/j.neurot.2026.e01090","DOIUrl":"10.1016/j.neurot.2026.e01090","url":null,"abstract":"<div><div>Muscle-specific tyrosine kinase (MuSK)-antibody-positive myasthenia gravis (MG) is caused by MuSK autoantibodies that disrupt acetylcholine receptor clustering at neuromuscular junctions, resulting in muscle weakness and often a severe myasthenic crisis. Given the limited efficacy of conventional treatments involving immunosuppressants and steroids for patients with MuSK-MG, novel treatment approaches have been actively explored. In this study, we investigated the potential of the MuSK agonistic antibody, a novel therapeutic tool, to recover MuSK signaling in the presence of varying levels of autoantibodies. We obtained MuSK agonistic antibodies that bind to the Fz domain of MuSK. The efficacy of the antibody was demonstrated in a MuSK-MG mouse model. The effect of MuSK signaling recovery by our MuSK agonistic antibody was evaluated in the presence of autoantibodies in sera collected from 12 patients with MuSK-MG. We found that a decreasing trend of MuSK signaling recovery by MuSK agonistic antibody was observed upon increasing the serum concentration in some cases. Our findings imply that, for the future clinical development of a MuSK agonistic antibody, there is a need to identify those who will respond well to such an antibody or to develop an add-on treatment to reduce autoantibody levels. This would mitigate the potential risk of insufficient efficacy of such an antibody in patients with MuSK-MG who have high autoantibody concentrations.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 6","pages":"Article e01090"},"PeriodicalIF":7.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporal interference stimulation for treating Wilson disease: A prospective clinical and functional MRI study","authors":"Nan Cheng,&nbsp;Yanming Wang,&nbsp;Huiyu Du,&nbsp;Guofang Yu,&nbsp;Xiaojing Han,&nbsp;Yangfei Huang,&nbsp;Chunsheng Xu,&nbsp;Bensheng Qiu,&nbsp;Ting Dong","doi":"10.1016/j.neurot.2026.e01097","DOIUrl":"10.1016/j.neurot.2026.e01097","url":null,"abstract":"<div><div>Wilson disease (WD) is an inherited disorder of copper metabolism caused by ATP7B mutations, and persistent neurological deficits, especially dystonia and motor disability, may remain despite standard anti-copper therapy. The putamen is a deep gray-matter nucleus frequently affected by copper deposition in WD and may therefore represent a plausible target for non-invasive neuromodulation. This prospective, single-arm, open-label study evaluated the clinical efficacy and neural mechanisms of right putamen-targeted temporal interference stimulation (TIS) in patients with WD. Twenty-five patients received right putamen-targeted TIS once daily for 10 sessions. Clinical outcomes were assessed using the Unified Wilson's Disease Rating Scale (UWDRS) total score and its neurological, hepatic, and psychiatric subscale scores. Resting-state functional magnetic resonance imaging (rsfMRI) was used to evaluate regional homogeneity (ReHo) and seed-based functional connectivity (FC) of the right putamen. Paired tests compared pre- and post-treatment changes, and Spearman correlation analysis examined associations between imaging changes and clinical improvement. After treatment, the UWDRS total score decreased significantly from 59.40 ± 30.54 to 44.12 ± 24.96, with concurrent improvements in neurological, hepatic, and psychiatric subscale scores. The rsfMRI analysis showed increased ReHo in the right putamen and enhanced FC between the right putamen and right Rolandic operculum. After correction for multiple comparisons, greater increases in right putamen ReHo correlated significantly with larger reductions in UWDRS total and neurological scores. In this exploratory study, these preliminary findings suggest that right putamen-targeted TIS may improve clinical symptoms in WD, potentially through enhanced local functional synchronization within the putamen.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 6","pages":"Article e01097"},"PeriodicalIF":7.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCR5 protects against permanent brain ischemia by suppressing neuronal ferroptosis through AMPK/ACC signaling","authors":"Minhuang Huang,&nbsp;Qilong Wu,&nbsp;Kefan Xie,&nbsp;Zejin Dong,&nbsp;Yijun Ge,&nbsp;Xiaoyang Luo,&nbsp;Wentao Fan,&nbsp;Yuan Chen,&nbsp;Suning Ping","doi":"10.1016/j.neurot.2026.e01088","DOIUrl":"10.1016/j.neurot.2026.e01088","url":null,"abstract":"<div><div>Ischemic stroke triggers devastating neuronal injury cascades, and ferroptosis acts as a key mediator of post-ischemic neuronal loss. Although C–C chemokine receptor type 5 (CCR5) has been traditionally implicated in post-stroke neuroinflammation, its cell-specific role in neuronal ferroptosis remains obscure. Here, we combined single-cell transcriptomic analysis, a permanent middle cerebral artery occlusion (pMCAO) mouse model, and in vitro hypoxia-ischemia-mimicking conditions to define an endogenous neuroprotective role for neuronal CCR5. Single-cell RNA sequencing revealed a marked upregulation of the CCL-CCR signaling pathway, with CCR5 identified as a prominent hub mediating intercellular interactions. In vivo, CCR5 was significantly elevated in peri-infarct neurons from 48 h up to one month after pMCAO, rather than microglia or astrocytes, suggesting an intrinsic stress response. In vitro, hypoxia-ischemia-mimicking conditions in SH-SY5Y cells and primary cortical neurons recapitulated this compensatory yet insufficient CCR5 induction alongside HIF-1α upregulation, GPX4 depletion, and severe lipid peroxidation. Functional studies demonstrated that CCR5 knockdown or pharmacological inhibition with maraviroc (MVC) further aggravated GPX4 reduction and lipid peroxide accumulation, whereas CCR5 overexpression substantially restored anti-ferroptotic capacity. CCR5 positively regulated AMPK and ACC phosphorylation, and inhibition of AMPK completely abolished CCR5-mediated GPX4 preservation and anti-ferroptotic defense. In vivo, MVC administration further accelerated peri-infarct iron deposition, reduced neuronal survival, and significantly worsened long-term motor deficits in pMCAO mice. Collectively, these findings identify a previously unrecognized endogenous adaptive mechanism whereby ischemia-induced neuronal CCR5 limits ferroptosis through AMPK/ACC-mediated GPX4 maintenance, providing a novel therapeutic conceptualization for strengthening endogenous protective cues in ischemic stroke.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 6","pages":"Article e01088"},"PeriodicalIF":7.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meningioma in the modern era: Updates in stratification and therapeutic approaches","authors":"Leeor S. Yefet,&nbsp;Gelareh Zadeh,&nbsp;Farshad Nassiri","doi":"10.1016/j.neurot.2026.e01098","DOIUrl":"10.1016/j.neurot.2026.e01098","url":null,"abstract":"<div><div>Meningioma is the most common primary intracranial tumor in adults. Most meningiomas have an indolent growth pattern, but some can grow quickly. The World Health Organization (WHO) classification system is the gold standard for tumor grading and relies predominantly on histopathology and limited molecular alterations. It is increasingly recognized that the variability in tumor behaviour is incompletely captured using traditional systems. Contemporary advances have expanded tumor stratification beyond starting WHO grading, providing a more comprehensive framework for understanding tumor biology. Molecular profiling has identified independent biological classification systems and molecular signatures that capture important prognostic information beyond histopathology. Magnetic resonance imaging-based analyses and radiomics have enabled non-invasive characterization of tumor phenotype and growth potential. Therapeutically, surgical resection and radiation therapy remain the foundation of management, with evolving paradigms emphasizing maximal safe resection and risk-adapted radiotherapy strategies informed by integrated tumor characteristics. Systemic therapies have historically shown limited efficacy; however, recent efforts are shifting toward biomarker-driven, precision approaches guided by molecular alterations. Future directions focus on integrating multimodal data into unified, clinically actionable models that more accurately predict recurrence, progression, and treatment response. Such approaches aim to move beyond parallel classification systems toward individualized management strategies, ultimately advancing meningioma care into a precision-based paradigm.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 6","pages":"Article e01098"},"PeriodicalIF":7.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electroconvulsive therapy shifting brain dynamics toward more adaptive and integrated states in treatment-resistant depression based on a hidden markov model","authors":"Tan Li,&nbsp;Leyi Zhang,&nbsp;Yiding Han,&nbsp;Zhiguo Guo,&nbsp;Ping Yao,&nbsp;Lixia Chen,&nbsp;Yonggui Yuan,&nbsp;Jingping Zhao,&nbsp;Yangpan Ou,&nbsp;Dongsheng Lv,&nbsp;Wenbin Guo","doi":"10.1016/j.neurot.2026.e01091","DOIUrl":"10.1016/j.neurot.2026.e01091","url":null,"abstract":"<div><div>Treatment-resistant depression (TRD) is characterized by persistent symptoms and poor response to conventional therapies, yet its dynamic neural mechanisms and treatment-related changes remain incompletely understood. This study applied a hidden Markov model (HMM) combined with neurotransmitter atlas mapping to investigate whole-brain spatiotemporal dynamics in TRD and their modulation by electroconvulsive therapy (ECT). Resting-state fMRI data were collected from 72 TRD patients (52 completing follow-up) and 63 healthy controls. HMM identified six recurring brain states defined by distinct patterns of functional connectivity and averaged functional activity. At baseline, TRD patients showed reduced occupancy and stability of globally coordinated states and increased engagement of subcortical-dominant states, indicating impaired global stability and disrupted cortical–subcortical balance. After ECT, clinical symptoms improved significantly, accompanied by increased occupancy of states characterized by higher activity within the default mode and frontoparietal networks, as well as a highly integrated whole-brain state. These changes suggest improved overall brain coordination and cortical engagement rather than full normalization of baseline abnormalities. In contrast, subcortical-dominant states persisted after treatment, consistent with trait-like features of TRD. Neurotransmitter mapping showed that treatment-responsive states were associated with serotonergic, dopaminergic, and glutamatergic systems, whereas persistent subcortical states were linked to noradrenergic and cholinergic markers. Overall, these findings suggest that ECT improves symptoms by shifting brain dynamics toward more adaptive and integrated states, rather than fully restoring baseline function. This dynamic perspective provides new insight into the neural mechanisms of TRD and its treatment.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 6","pages":"Article e01091"},"PeriodicalIF":7.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}