Neuropsychopharmacology最新文献

{"title":"Targeting depression circuitry with H1 coil Transcranial Magnetic Stimulation: a retrospective circuit mapping study","authors":"Samantha Baldi, Nicole Chiulli, Stephan Palm, Summer Frandsen, Gaby S. Pell, Samuel Zibman, Josias Rodriguez-Ponde, Joshua C. Brown, Shan H. Siddiqi","doi":"10.1038/s41386-025-02157-5","DOIUrl":"10.1038/s41386-025-02157-5","url":null,"abstract":"The efficacy of transcranial magnetic stimulation (TMS) for depression may depend on targeting specific brain circuits. However, this has not been tested for TMS with the H1 coil, a widely used device believed to target more broadly and deeply than TMS with figure-of-8 coils. This study examined whether targeting a specific brain circuit with H1 coil TMS treatment may impact depressive symptom improvement. We retrospectively analyzed data from 97 patients at McLean Hospital, who received at least 19 TMS sessions and had incidentally completed an anatomical brain MRI. We modeled each patient’s electric (E-)field using SimNIBS and estimated the connectivity of the E-field using a normative connectome (n = 1000), which was correlated with depression improvement as measured by the Quick Inventory of Depressive Symptomatology. H1 E-fields improving depression were preferentially connected to a distinct brain circuit, validated with leave-one-out cross-validation (p = 0.0005). This circuit was significantly similar to a predefined causal depression circuit (spatial r = 0.59, p = 0.04) derived from TMS, deep brain stimulation, and lesion studies. E-fields with greater connectivity similarity to this circuit led to greater symptom improvement (r = 0.41, p < 0.001). Post-hoc analyses revealed that more posterior coil positioning increases H1 E-field overlap with the depression circuit, with high overlap at scalp locations 3–6 cm anterior to the motor hotspot. Thus, H1 coil stimulation sites that improve depression converge on a common causal depression circuit. Prospective studies are needed to validate these findings.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 11","pages":"1674-1682"},"PeriodicalIF":6.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02157-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532854","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":"Circulating endocannabinoids in children and adolescents: associations with anxiety and the impact of selective serotonin reuptake inhibitors","authors":"Hilary A. Marusak, Clara G. Zundel, Tehmina Shakir, Samantha L. Ely, Carmen Carpenter, MacKenna Shampine, Reem Tamimi, Mariya Matsko, Sarah Rogers, Jennifer Losiowski, Emilie O’Mara, Alaina M. Jaster, Kamakashi Sharma, Terri A. deRoon-Cassini, Cecilia J. Hillard, Heidi K. Schroeder, Jeffrey A. Mills, Jeffrey R. Strawn, Jeanne Barcelona","doi":"10.1038/s41386-025-02155-7","DOIUrl":"10.1038/s41386-025-02155-7","url":null,"abstract":"Anxiety disorders are prevalent psychiatric conditions that frequently emerge during adolescence. Among the neurobiological systems implicated in these disorders, the endocannabinoid (eCB) signaling system plays a crucial role, making it a promising target for therapeutic interventions. In addition to its direct effects on anxiety regulation, eCBs may also influence response to first-line pharmacologic treatments, such as selective serotonin reuptake inhibitors (SSRIs). However, little is known about developmental changes in eCB lipids—N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG)—or their relationship to anxiety symptoms and treatment response. Circulating AEA and 2-AG concentrations were measured in youth (aged 9–17, N = 199) with varying anxiety symptoms, assessed using the Screen for Child Anxiety-Related Disorders (SCARED). We evaluated how eCBs relate to developmental factors (e.g., demographics, biological variables) and anxiety symptoms (SCARED total). Additionally, we examined how eCB concentrations change in response to acute SSRI treatment in a subsample of adolescents (age 12–17, N = 41) with generalized anxiety disorder (GAD), who participated in an 8-week randomized placebo-controlled trial of escitalopram (15 mg/day, titrated to 20 mg/day). Body mass index (BMI) was positively correlated with circulating AEA, while 2-AG showed negative associations with age, female sex, and time-of-day. After adjusting for these variables, more severe anxiety symptoms were associated with higher AEA and lower 2-AG. Greater increases in 2-AG from baseline (without changes in AEA) were linked to improved treatment response in adolescents with GAD. Our study suggests that circulating eCBs may serve as biomarkers for anxiety severity and predictors of treatment response in youth. ClinicalTrials.Gov Identifier: NCT02818751.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1606-1614"},"PeriodicalIF":6.6,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513069","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":"Anti-seizure effects of WS-3, a TRPM8 agonist, on focal onset seizure mouse model via reduction of extracellular glutamate levels","authors":"Hiroshi Moriyama, Sadahiro Nomura, Hirochika Imoto, Yuichi Maruta, Naomasa Mori, Natsumi Fujii, Kohei Haji, Michiyasu Suzuki, Hideyuki Ishihara","doi":"10.1038/s41386-025-02143-x","DOIUrl":"10.1038/s41386-025-02143-x","url":null,"abstract":"The development of novel anti-seizure drugs targeting novel mechanisms is crucial, especially for patients with intractable epilepsy. Previous studies using focal onset seizure rodent models have demonstrated that Icilin and WS-3, agonists of the transient receptor potential melastatin 8 (TRPM8) channel, suppress drug-induce epileptiform discharges (EDs) and seizures (ESs). In contrast, TRPM8 deficiency exacerbates EDs and ESs. This study investigated the mechanism underlying the anti-seizure effects of the TRPM8 agonist, WS-3, using a focal onset seizure mouse model. Mice were injected with WS-3 either before or after administering the seizure inducer, penicillin G potassium. EDs, ESs, and glutamate levels were subsequently evaluated. In wild-type (WT) mice, WS-3 injected after the seizure inducer reduced glutamate levels and ED power by 44% and 60%, respectively, with a positive correlation between WS-3 efficacy and these parameters. WS-3 injection before seizure induction suppressed the increase in glutamate levels and the development of ED and ES, with positive correlations observed among the three parameters. Conversely, TRPM8-knockout mice showed no anti-seizure effects from WS-3. TRPM8 deficiency led to a further increase in the glutamate levels, ED power, and ES severity after the seizure inducer injection. Additionally, TRPM8-deficient mice experienced EDs with fewer glutamate exposures and shortened latency to ED development following seizure induction. These findings suggest that TRPM8 agonists suppress the development of EDs and ESs by reduction of extracellular glutamate levels, indicating that TRPM8 channels may represent a promising treatment option for epilepsy.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 12","pages":"1855-1863"},"PeriodicalIF":6.6,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02143-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144510469","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":"Using causal network mapping to clarify pre-clinical brain stimulation results","authors":"Ryan D. Webler, Diana King, Nicholas L. Balderston, Shan H. Siddiqi","doi":"10.1038/s41386-025-02153-9","DOIUrl":"10.1038/s41386-025-02153-9","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 11","pages":"1752-1753"},"PeriodicalIF":6.6,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500301","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":"The mesolimbic reward pathway is necessary for disruptions in cocaine-seeking behavior following mediated devaluation","authors":"Bingxin Mo, Victoria K. Fex, Alice McQueney, Doris I. Olekanma, Christopher A. Reeves, Luciano S. Voutour, Sarah Simmons, A. J. Robison, Amy A. Arguello, Alexander W. Johnson","doi":"10.1038/s41386-025-02119-x","DOIUrl":"10.1038/s41386-025-02119-x","url":null,"abstract":"We developed an approach to disrupt cocaine-seeking behaviors using mediated devaluation. Male rats underwent cocaine self-administration training in which active lever responses led to cocaine infusions and the presentation of a tone-light conditioned stimulus (CS). Subsequently, during mediated devaluation rats received non-contingent presentations of the cocaine-associated CS in a second distinct context, which led to the cue-evoked retrieval of associated memories. This was immediately followed by an intraperitoneal injection of lithium chloride (LiCl) and served to pair the memory of cocaine reward with gastric malaise. Consequently, this led to a substantial reduction in cocaine-seeking behavior during extinction training, relative to rats that received CS-saline or LiCl alone during mediated devaluation. Cue- and cocaine-evoked reinstatement testing indicated that the manipulations did not devalue the CS or the reinforcing properties of cocaine. A separate cohort of rats received a dual-viral chemogenetic strategy that permitted circuit-specific inactivation of midbrain ventral tegmental area (VTA) cells projecting to the nucleus accumbens (NAc). Inactivation of VTA→NAc circuitry during mediated devaluation prevented the subsequent reduction of cocaine-seeking behavior during extinction training. Overall, these findings suggest that intact mesolimbic signaling is required to enable disruptions in cocaine-seeking behavior following mediated devaluation.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1515-1523"},"PeriodicalIF":6.6,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02119-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144487743","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":"Fatty acid amide hydrolase in major depressive episodes: A [11C]CURB positron emission tomography study","authors":"Dorsa Rafiei, Michelle De Pol, Jeffrey H. Meyer, Kimberly Desmond, Ruth Ross, Isabelle Boileau, Jerry Warsh, Pablo Rusjan, Neil Vasdev, Ryan Aloysius, Lauren Gray, Nathan J. Kolla","doi":"10.1038/s41386-025-02150-y","DOIUrl":"10.1038/s41386-025-02150-y","url":null,"abstract":"The role of the endocannabinoid system (ECS) in major depressive disorder (MDD) is under-investigated despite reports of increased activity and/or concentration of fatty acid amide hydrolase (FAAH), a key ECS enzyme, in fronto-limbic brain regions in some animal models of depressive behavior. We hypothesized that [11C]CURB λk3, an index of FAAH density, would be elevated in the prefrontal cortex, hippocampus, and anterior cingulate cortex in major depressive episodes of MDD compared to healthy controls. Fifteen unmedicated MDD participants and 15 age- and sex-matched healthy controls underwent [11C]CURB positron emission tomography and FAAH genotyping. Psychological tests of depressive severity, apathy, and anxiety were administered and measurements were assessed as covariates in exploratory analyses. No significant group differences in [11C]CURB λk3 were observed between MDD participants and controls (F1,27 = 0.32; p = 0.58). A mixed effects model revealed that Marin Apathy Evaluation Scale scores in the MDD group had a significant main effect on [11C]CURB λk3 binding across the collective regions of medial prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, ventral striatum, and midbrain (F1,11 = 6.75; p = 0.02). Depressive severity and anxiety did not have a significant relationship to [11C]CURB λk3 binding. The relationship of greater fronto-limbic [11C]CURB λk3 to greater apathy along with the metabolic role of FAAH in the ECS, the latter which supports maintaining feelings of interest, initiative, and motivation, has important implications for the pathophysiology of apathy in MDD.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1536-1543"},"PeriodicalIF":6.6,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02150-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478549","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":"Inflammatory pain in mice induces light cycle-dependent effects on sleep architecture","authors":"Dominika J. Burek, Khairunisa Mohamad Ibrahim, Andrew G. Hall, Ashish Sharma, Jessica A. Cucinello-Ragland, Erik S. Musiek, Jose A. Morón, William A. Carlezon Jr.","doi":"10.1038/s41386-025-02152-w","DOIUrl":"10.1038/s41386-025-02152-w","url":null,"abstract":"Pain syndromes include physical, sensory, emotional, and cognitive symptoms such as disability, negative affect, feelings of stress, and fatigue. Experimental induction of long-term inflammatory pain in rodents by hindpaw injection of complete Freund’s adjuvant (CFA) produces anhedonia and dysregulated naturalistic behaviors, similar to the effects of unregulated stress. We examined whether these similarities extend to changes in sleep and rhythms, such as those induced by chronic social defeat stress, using actigraphy and wireless EEG in mice. Comparisons were made between groups that received injections at the onset of the light or dark phase. We found that CFA-induced inflammatory pain alters sleep architecture in both sexes; most notably, it increased sleep duration in the dark phase—when mice are normally more likely to be awake—while also increasing sleep bout length and reducing wake bout length. In contrast, during the light phase, it decreased sleep bout length, indicating fragmentation. Similarly, CFA-induced increases in REM and SWS duration and bouts were largest during the dark phase. Dark-phase effects were remarkably consistent regardless of whether the mice had been injected at darkness onset or 12 h earlier, whereas light-phase effects were more dependent on time since injection. Injections also produced non-specific alterations in circadian rhythmicity. Our findings indicate that inflammatory pain prominently increases sleep during normally active phases as well as transitions between sleep and wakefulness throughout the day. These effects align with clinical observations and establish a basis for mechanistic studies and use of these procedures to better predict outcomes in humans.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1595-1605"},"PeriodicalIF":6.6,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02152-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340803","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":"Unraveling time-dependent genetic components underlying alcohol response","authors":"Keiko Hikino, Ikuo Otsuka, Shunji Oshima, Akitoyo Hishimoto, Kouichi Ozaki, Xiaoxi Liu, Yuki Ishikawa, Taisei Mushiroda, Sachio Matsushita, Chikashi Terao","doi":"10.1038/s41386-025-02147-7","DOIUrl":"10.1038/s41386-025-02147-7","url":null,"abstract":"While numerous studies have examined the subjective response to alcohol as an intermediate phenotype to understand its variability, heritability, and predictive capacity for alcohol-related disorders, in-depth analyses linking alcohol reactivity indicators to genetic factors within a large cohort have been absent. Our study aimed to quantify the exact contribution of each genetic variant relevant to the alcohol metabolism to the variability in alcohol response. Specifically, we focused on two primary genes involved in alcohol metabolism (ALDH2 and ADH1B) and three additional loci (ALDH1B1, ALDH1A1, and GCKR) that have been shown to have significant associations with drinking behaviors in Japanese individuals. We conducted the first study to assess the relationship between subjective response to alcohol (SR), evaluated by various assessment subscales, and genetic factors using an intravenous clamp technique in 429 healthy Japanese young adults. By reducing the dimensionality of the data to assess similarity structures, we identified three distinct clusters of SRs and participants. Each participant cluster exhibited a distinct alcohol response profile shaped by specific genetic contributions. Participant cluster 1 demonstrated the strongest response, followed by participant cluster 2, and then participant cluster 3. Participant cluster 1 may also be the most strongly influenced by the allelic status of ALDH2 and ADH1B. SR patterns varied accordingly, and the enrichment of the ALDH2*2 and ADH1B*2, differed across both participant and subscale clusters. Notably, the three participant clusters closely aligned with the three subscale clusters, highlighting a consistent genotype–phenotype relationship. Furthermore, the proportion of variance explained by these genes also varied across subscale clusters. Contrary to known functions, ADH1B showed associations at later timings when ALDH2 associations attenuate. Our three-cluster classification may improve prevention by enabling early identification of individuals at health risk.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 11","pages":"1665-1673"},"PeriodicalIF":6.6,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02147-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340804","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":"The new normal: neural network adaptations in late-life depression","authors":"Ebrahim Haroon, Andrew H. Miller","doi":"10.1038/s41386-025-02145-9","DOIUrl":"10.1038/s41386-025-02145-9","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1469-1471"},"PeriodicalIF":6.6,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144337447","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":"Correction: Four dimensions of individualization in brain stimulation for psychiatric disorders: context, target, dose, and timing","authors":"Ghazaleh Soleimani, Michael A. Nitsche, Colleen A. Hanlon, Kelvin O. Lim, Alexander Opitz, Hamed Ekhtiari","doi":"10.1038/s41386-025-02134-y","DOIUrl":"10.1038/s41386-025-02134-y","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1615-1615"},"PeriodicalIF":6.6,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02134-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328485","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}