Molecular Psychiatry最新文献

{"title":"Npbwr1 signaling mediates fast antidepressant action.","authors":"Gregor Stein, Janine S Aly, Lisa Lange, Annamaria Manzolillo, Konstantin Riege, Anna Brancato, Christian A Hübner, Gustavo Turecki, Steve Hoffmann, Olivia Engmann","doi":"10.1038/s41380-024-02790-4","DOIUrl":"10.1038/s41380-024-02790-4","url":null,"abstract":"<p><p>Chronic stress is a major risk factor for depression, a leading cause of disability and suicide. Because current antidepressants work slowly, have common side effects, and are only effective in a minority of patients, there is an unmet need to identify the underlying molecular mechanisms. Here, we identify the receptor for neuropeptides B and W, Npbwr1, as a key regulator of depressive-like symptoms. Npbwr1 is increased in the nucleus accumbens of chronically stressed mice and postmortem in patients diagnosed with depression. Using viral-mediated gene transfer, we demonstrate a causal link between Npbwr1, dendritic spine morphology, the biomarker Bdnf, and depressive-like behaviors. Importantly, microinjection of the synthetic antagonist of Npbwr1, CYM50769, rapidly ameliorates depressive-like behavioral symptoms and alters Bdnf levels. CYM50769 is selective, well tolerated, and shows effects up to 7 days after administration of a single dose. In summary, these findings advance our understanding of mood and chronic stress and warrant further investigation of CYM50769 as a potential fast-acting antidepressant.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":"1828-1835"},"PeriodicalIF":9.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene-dose-dependent reduction of Fshr expression improves spatial memory deficits in Alzheimer's mice.","authors":"Funda Korkmaz, Steven Sims, Fazilet Sen, Farhath Sultana, Victoria Laurencin, Liam Cullen, Anusha Pallapati, Avi Liu, Ronald Chen, Satish Rojekar, Georgii Pevnev, Uliana Cheliadinova, Darya Vasilyeva, Guzel Burganova, Anne Macdonald, Mansi Saxena, Ki Goosens, Clifford J Rosen, Orly Barak, Daria Lizneva, Anisa Gumerova, Keqiang Ye, Vitaly Ryu, Tony Yuen, Tal Frolinger, Mone Zaidi","doi":"10.1038/s41380-024-02824-x","DOIUrl":"10.1038/s41380-024-02824-x","url":null,"abstract":"<p><p>High post-menopausal levels of the pituitary gonadotropin follicle-stimulating hormone (FSH) are strongly associated with the onset of Alzheimer's disease (AD). We have shown recently that FSH directly activates the hippocampal FSH receptors (FSHRs) to drive AD-like pathology and memory loss in mice. To unequivocally establish a role for FSH in memory loss, we depleted the Fshr on a 3xTg background and utilized Morris Water Maze to study deficits in spatial memory. 3xTg;Fshr^+/+ mice displayed impaired spatial memory at 5 months of age. The loss of memory acquisition and retrieval were both rescued in 3xTg;Fshr^-/- mice and, to a lesser extent, in 3xTg;Fshr^+/- mice-documenting clear gene-dose-dependent prevention of spatial memory loss. Furthermore, at 5 and 8 months, sham-operated 3xTg;Fshr^-/- mice showed better memory performance during the learning and/or retrieval phases, further suggesting that Fshr deletion prevents age-related progression of memory deficits. This prevention was not seen when mice were ovariectomized, except in the 8-month-old 3xTg;Fshr^-/- mice. There was also a gene-dose-dependent reduction mainly in the amyloid β40 isoform in whole brain extracts. Finally, serum FSH levels <8 ng/mL in 16-month-old APP/PS1 mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial memory deficits in mice and lay a firm foundation for the use of an FSH-blocking agent for the early prevention of memory loss in post-menopausal women.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":"2119-2126"},"PeriodicalIF":9.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12097745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APOE deficiency inhibits amyloid-facilitated (A) tau pathology (T) and neurodegeneration (N), halting progressive ATN pathology in a preclinical model","authors":"Sarah Vanherle, Art Janssen, Manuel Gutiérrez de Ravé, Bieke Janssen, Chritica Lodder, Pablo Botella Lucena, Sofie Kessels, Jana Hardy, Eline Vandeput, Yanyan Wang, Ilie-Cosmin Stancu, Andrei Segal, Markus Kleinewietfeld, Thomas Voets, Bert Brône, Suresh Poovathingal, Yeranddy A. Alpizar, Ilse Dewachter","doi":"10.1038/s41380-025-03036-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03036-7","url":null,"abstract":"<p>In AD, amyloid pathology (A) precedes progressive development of tau pathology (T) and neurodegeneration (N), with the latter (T/N) processes associated with symptom progression. Recent anti-amyloid beta (Aβ) clinical trials raise hope but indicate the need for multi-targeted therapies, to effectively halt clinical AD and ATN pathology progression. <i>APOE</i>-related putative protective mutations (including <i>APOE3Christchurch</i>, <i>RELN-COLBOS</i>) were recently identified in case reports with exceptionally high resilience to autosomal dominant AD. In these cases, Nature provided proof of concept for halting autosomal dominant AD and ATN progression in humans, despite a high amyloid load, and pointing to the APOE pathway as a potential target. This is further supported by the recent identification of <i>APOE4</i> homozygosity as genetic AD. Here we studied the role of APOE in a preclinical model that robustly mimics amyloid-facilitated (A) tau pathology (T) and subsequent neurodegeneration (N), denoted as ATN model, generated by crossing 5xFAD (<i>F</i> ^<i>+</i>) and TauP301S (<i>T</i> ^<i>+</i>) mice. We show that APOE deficiency, markedly inhibited progression to tau pathology and tau-induced neurodegeneration in this ATN model, despite a high Aβ load, reminiscent of the high resilience ADAD case reports. Further study identified, despite increased Aβ load (W02 stained), a significant decrease in compacted, dense core plaques stained by ThioS in APOE deficient ATN mice. Furthermore, single-cell RNA sequencing (scRNA-seq) showed a crucial role of APOE in microglial conversion beyond homeostatic microglia to reactive and disease associated microglia (DAM) in this ATN preclinical model. Microglial elimination significantly decreased amyloid-driven tau pathology, in the presence of APOE, but not in APOE deficient mice. Together the data demonstrate that APOE deficiency inhibits amyloid-driven tau pathology and subsequent neurodegeneration, by pleiotropic effects including prevention of dense core plaque formation and halting conversion of homeostatic microglia. We here present a model recapitulating inhibition of amyloid-facilitated tau pathology by APOE deficiency despite high Aβ load, important for understanding the role of APOE, and APOE-dependent processes in ATN progression and its therapeutic exploitation in AD.</p><figure></figure>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"11 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nutritional interventions to counteract the detrimental consequences of early-life stress","authors":"Jorine Geertsema, Hannah G. Juncker, Lars Wilmes, George L. Burchell, Susanne R. de Rooij, J. B. van Goudoever, Kenneth J. O’Riordan, Gerard Clarke, John F. Cryan, Aniko Korosi","doi":"10.1038/s41380-025-03020-1","DOIUrl":"https://doi.org/10.1038/s41380-025-03020-1","url":null,"abstract":"<p>Exposure to stress during sensitive developmental periods comes with long term consequences for neurobehavioral outcomes and increases vulnerability to psychopathology later in life. While we have advanced our understanding of the mechanisms underlying the programming effects of early-life stress (ES), these are not yet fully understood and often hard to target, making the development of effective interventions challenging. In recent years, we and others have suggested that nutrition might be instrumental in modulating and possibly combatting the ES-induced increased risk to psychopathologies and neurobehavioral impairments. Nutritional strategies are very promising as they might be relatively safe, cheap and easy to implement. Here, we set out to comprehensively review the existing literature on nutritional interventions aimed at counteracting the effects of ES on neurobehavioral outcomes in preclinical and clinical settings. We identified eighty six rodent and ten human studies investigating a nutritional intervention to ameliorate ES-induced impairments. The human evidence to date, is too few and heterogeneous in terms of interventions, thus not allowing hard conclusions, however the preclinical studies, despite their heterogeneity in terms of designs, interventions used, and outcomes measured, showed nutritional interventions to be promising in combatting ES-induced impairments. Furthermore, we discuss the possible mechanisms involved in the beneficial effects of nutrition on the brain after ES, including neuroinflammation, oxidative stress, hypothalamus-pituitary-adrenal axis regulation and the microbiome-gut-brain axis. Lastly, we highlight the critical gaps in our current knowledge and make recommendations for future research to move the field forward.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"41 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain circuits that regulate social behavior","authors":"Hao Li, Zhe Zhao, Shaofei Jiang, Haitao Wu","doi":"10.1038/s41380-025-03037-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03037-6","url":null,"abstract":"<p>Social interactions are essential for the survival of individuals and the reproduction of populations. Social stressors, such as social defeat and isolation, can lead to emotional disorders and cognitive impairments. Furthermore, dysfunctional social behaviors are hallmark symptoms of various neuropsychiatric disorders, including autism spectrum disorder (ASD) and post-traumatic stress disorder (PTSD). Consequently, understanding the neural circuit mechanisms underlying social behaviors has become a major focus in neuroscience. Social behaviors, which encompass a wide range of expressions and phases, are regulated by complex neural networks. In this review, we summarize recent progress in identifying the circuits involved in different types of social behaviors, including general social investigation, social preference, mating, aggression, parenting, prosocial behaviors, and dominance behaviors. We also outline the circuit mechanisms associated with social deficits in neuropsychiatric disorders, such as ASD, schizophrenia, and PTSD. Given the pivotal role of rodents in social behavior research, our review primarily focuses on neural circuits in these animals. Finally, we propose future research directions, including the development of specific behavioral paradigms, the identification of circuits involved in motor output, the integration of activity, transcriptome, and connectome data, the multifunctional roles of neurons with multiple targets, and the interactions among multiple brain regions.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"17 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissociable effects of psilocybin and escitalopram for depression on processing of musical surprises","authors":"Rebecca Harding, Neomi Singer, Matthew B. Wall, Talma Hendler, David Erritzoe, David Nutt, Robin Carhart-Harris, Leor Roseman","doi":"10.1038/s41380-025-03035-8","DOIUrl":"https://doi.org/10.1038/s41380-025-03035-8","url":null,"abstract":"<p>Psilocybin therapy (PT) is emerging as an effective intervention for Major Depressive Disorder (MDD), offering comparable efficacy to conventional treatments like selective serotonin reuptake inhibitors (SSRIs). Music, an emotionally evocative stimulus, provides a valuable tool to explore changes in hedonic and predictive processing mechanisms via expectancy violations, or ‘surprises’. This study sought to compare behavioural and functional magnetic resonance imaging (fMRI) responses to musical surprises in MDD patients treated with either PT or the SSRI, escitalopram. In this secondary analysis of a trial, 41 MDD patients (with usable fMRI data) were randomly assigned to either PT (<i>n</i> = 22) or escitalopram (<i>n</i> = 19) treatment groups. Participants listened to music during fMRI and tracked their emotional experience, both before and after a 6-week intervention. Surprise-related valence and arousal indices were calculated. Musical surprises were entered as regressors for whole-brain and region of interest fMRI analyses. PT caused a greater decrease in anhedonia scores compared with escitalopram. While escitalopram led to reductions in surprise-related affective responses, PT showed no significant change. Escitalopram was associated with increased activation in memory and emotional processing areas during musical surprises (versus control events) when compared with PT. Following PT, there was greater activation in the ventromedial prefrontal cortex and sensory regions, and reduced activation in the angular gyrus. PT may allow for the subjective response to musical surprises to be maintained through a lasting reduction in the salience of prediction errors, or, alternatively, by increasing hedonic priors. Contrastingly, escitalopram may diminish hedonic priors, highlighting fundamental differences in treatment mechanisms.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"16 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic approach uncovering the pathways between childhood maltreatment and suicide attempt","authors":"Diyang Qu, Xu Zhang, Yuhao He, Chang Lei, Yuanxia Han, Junkang Lin, Tongtong Cai, Xueping Zhu, Yize Mao, Runsen Chen","doi":"10.1038/s41380-025-02966-6","DOIUrl":"https://doi.org/10.1038/s41380-025-02966-6","url":null,"abstract":"<p>Childhood maltreatment significantly heightens the risk of suicide attempt, but the causal mechanisms and underlying pathways are not fully understood. Using genetic instruments for both childhood maltreatment (<i>n</i> = 185,414) and suicide attempt (cases = 29,782; controls = 519,961), we performed two-sample Mendelian randomization analyses. Our results show that higher level of childhood maltreatment is causally associated with an increased risk of suicide attempt (OR = 3.40; 95% CI, 2.34–4.96, <i>P</i> = 1.3e–10). We then conducted a two-step Mendelian randomization mediation analysis, identifying 11 out of 58 potential mediators between childhood maltreatment and suicide attempt. These mediators included neurobiological, psychopathological and behavioral factors. The psychopathological factors had the most significant impact, accounting for 10.4–50.2% the mediation. This study confirms the causal relationship between childhood maltreatment and suicide attempt, highlighting specific mediators-especially within the psychopathological dimension-that can guide targeted interventions to alleviate the adverse effects of childhood maltreatment and prevent suicide attempt.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"33 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunological drivers and potential novel drug targets for major psychiatric, neurodevelopmental, and neurodegenerative conditions","authors":"Christina Dardani, Jamie W. Robinson, Hannah J. Jones, Dheeraj Rai, Evie Stergiakouli, Jakob Grove, Renee Gardner, Andrew M. McIntosh, Alexandra Havdahl, Gibran Hemani, George Davey Smith, Tom G. Richardson, Tom R. Gaunt, Golam M. Khandaker","doi":"10.1038/s41380-025-03032-x","DOIUrl":"https://doi.org/10.1038/s41380-025-03032-x","url":null,"abstract":"<p>Immune dysfunction is implicated in the aetiology of psychiatric, neurodevelopmental, and neurodegenerative conditions, but the issue of causality remains unclear impeding attempts to develop new interventions. Using genomic data on protein and gene expression across blood and brain, we assessed evidence of a potential causal role for 736 immune response-related biomarkers on 7 neuropsychiatric conditions by applying Mendelian randomization (MR) and genetic colocalisation analyses. A systematic three-tier approach, grouping biomarkers based on increasingly stringent criteria, was used to appraise evidence of causality (passing MR sensitivity analyses, colocalisation, False Discovery Rate and Bonferroni thresholds). We provide evidence for a potential causal role of 29 biomarkers for 7 conditions. The identified biomarkers suggest a role of both brain specific and systemic immune response in the aetiology of schizophrenia, Alzheimer’s disease, depression, and bipolar disorder. Of the identified biomarkers, 20 are therapeutically tractable, including <i>ACE</i>, <i>TNFRSF17</i>, <i>SERPING1</i>, <i>AGER</i> and <i>CD40</i>, with drugs currently approved or in advanced clinical trials. Based on the largest available selection of plasma immune-response related biomarkers, our study provides insight into possible influential biomarkers for the aetiology of neuropsychiatric conditions. These genetically prioritised biomarkers now require examination to further evaluate causality, their role in the aetiological mechanisms underlying the conditions, and therapeutic potential.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"24 1 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic markers of disease risk and psychotherapy response in anxiety disorders – a longitudinal analysis of the DNA methylome","authors":"Katharina Domschke, Miriam A. Schiele, Óscar Crespo Salvador, Lea Zillich, Jan Lipovsek, Andre Pittig, Ingmar Heinig, Isabelle C. Ridderbusch, Benjamin Straube, Jan Richter, Maike Hollandt, Jens Plag, Thomas Fydrich, Katja Koelkebeck, Heike Weber, Ulrike Lueken, Udo Dannlowski, Jürgen Margraf, Silvia Schneider, Elisabeth B. Binder, Andreas Ströhle, Winfried Rief, Tilo Kircher, Paul Pauli, Alfons Hamm, Volker Arolt, Jürgen Hoyer, Hans-Ulrich Wittchen, Angelika Erhardt-Lehmann, Anna Köttgen, Pascal Schlosser, Jürgen Deckert","doi":"10.1038/s41380-025-03038-5","DOIUrl":"https://doi.org/10.1038/s41380-025-03038-5","url":null,"abstract":"<p>Epigenetic mechanisms such as DNA methylation are hypothesized to play a pivotal role in the pathogenesis of anxiety disorders and to predict as well as relate to treatment response. An epigenome-wide association study (EWAS) (Illumina MethylationEPIC BeadChip) was performed at baseline (BL), post-treatment (POST) and 6-month follow-up (FU) in the so far largest longitudinal sample of patients with anxiety disorders (<i>N</i> = 415) treated with exposure-based cognitive behavioral therapy (CBT), and in 315 healthy controls. Independent of comorbidity with depression, anxiety disorders were significantly (<i>p</i> ≤ 6.409E–08) associated with altered DNA methylation at 148 CpGs partly mapping to genes previously implicated in processes related to anxiety, brain disorders, learning or plasticity (e.g., <i>GABBR2</i>, <i>GABRD</i>, <i>GAST</i>, <i>IL12RB2</i>, <i>LINC00293</i>, <i>LOC101928626</i>, <i>MFGE8</i>, <i>NOTCH4</i>, <i>PTPRN2</i>, <i>RIMBP2</i>, <i>SPTBN1</i>) or in a recent cross-anxiety disorders EWAS (<i>TAOK1</i>) after pre-processing and quality control (<i>N</i> = 378 vs. <i>N</i> = 295). Furthermore, BL DNA methylation at seven and three CpGs, respectively, was suggestively (<i>p</i> &lt; 1E–5) associated with treatment response at POST (<i>ABCA7</i>, <i>ADRA2C</i>, <i>LTBR</i>, <i>RPSAP52</i>, <i>SH3RF3</i>, <i>SLC47A2</i>, <i>ZNF251</i>) and FU (<i>ADGRD1</i>, <i>PRSS58</i>, <i>USP47</i>). Finally, suggestive evidence for dynamic epigenome-wide DNA methylation changes along with CBT response emerged at four CpGs from BL to FU (<i>ADIPOR2</i>, <i>EIF3B</i>, <i>OCA2</i>, <i>TMCC1</i>). The identification of epigenetic biomarkers may eventually aid in developing environment-based preventive strategies aimed at increasing resilience by providing deeper molecular insights into the mechanisms underlying anxiety disorders. Defining epigenetic signatures as predictors or key mechanisms in exposure-based interventions could pave the way for more targeted and personalized treatments for anxiety disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"78 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-intensity transcranial focused ultrasound amygdala neuromodulation: a double-blind sham-controlled target engagement study and unblinded single-arm clinical trial","authors":"Bryan R. Barksdale, Lauren Enten, Annamarie DeMarco, Rachel Kline, Manoj K. Doss, Charles B. Nemeroff, Gregory A. Fonzo","doi":"10.1038/s41380-025-03033-w","DOIUrl":"https://doi.org/10.1038/s41380-025-03033-w","url":null,"abstract":"<p>Mood, anxiety, and trauma-related disorders (MATRDs) are highly prevalent and comorbid. A sizable number of patients do not respond to first-line treatments. Non-invasive neuromodulation is a second-line treatment approach, but current methods rely on cortical targets to indirectly modulate subcortical structures, e.g., the amygdala, implicated in MATRDs. Low-intensity transcranial focused ultrasound (tFUS) is a non-invasive technique for direct subcortical neuromodulation, but its safety, feasibility, and promise as a potential treatment is largely unknown. In a target engagement study, magnetic resonance imaging (MRI)-guided tFUS to the left amygdala was administered during functional MRI (tFUS/fMRI) to test for acute modulation of blood oxygenation level dependent (BOLD) signal in a double-blind, within-subject, sham-controlled design in patients with MATRDs (N = 29) and healthy comparison subjects (N = 23). In an unblinded treatment trial, the same patients then underwent 3-week daily (15 sessions) MRI-guided repetitive tFUS (rtFUS) to the left amygdala to examine safety, feasibility, symptom change, and change in amygdala reactivity to emotional faces. Active vs. sham tFUS/fMRI reduced, on average, left amygdala BOLD signal and produced patient-related differences in hippocampal and insular responses. rtFUS was well-tolerated with no serious adverse events. There were significant reductions on the primary outcome (Mood and Anxiety Symptom Questionnaire General Distress subscale; <i>p</i> = 0.001, Cohen’s <i>d</i> = 0.77), secondary outcomes (Cohen’s <i>d of</i> 0.43–1.50), and amygdala activation to emotional stimuli. Findings provide initial evidence of tFUS capability to modulate amygdala function, rtFUS safety and feasibility in MATRDs, and motivate double-blind randomized controlled trials to examine efficacy.</p><p>ClinicalTrials.gov registration: NCT05228964</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"2 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}