Neuropsychopharmacology最新文献

{"title":"Nutritional state-dependent changes in subcortical limbic structures in anorexia nervosa are linked to leptin, ghrelin, and neurofilament light","authors":"Marie-Louis Wronski, Klaas Bahnsen, Fabio Bernardoni, Maria Seidel, Arne Doose, Inger Hellerhoff, Milena Schimack, Jonas L. Steinhäuser, Giulia Lombardo, Johanna L. Keeler, David M. Poitz, Tjalf Ziemssen, Kerstin Weidner, Veit Roessner, Joseph A. King, Carmine M. Pariante, Stefan Ehrlich","doi":"10.1038/s41386-026-02435-w","DOIUrl":"10.1038/s41386-026-02435-w","url":null,"abstract":"Anorexia nervosa (AN) involves limbic dysfunction, yet its neurobiology remains unclear. Examining morphological alterations in subcortical limbic regions across AN’s nutritional states and associations with neuroendocrine markers may improve understanding. We hypothesized that subcortical limbic volumes would be reduced in AN, normalize partially following short-term weight-restoration, and fully after long-term recovery. We examined whether leptin, ghrelin, neurofilament light (NFL), and brain-derived neurotrophic factor (BDNF) predict subcortical limbic dynamics. We studied 547 female individuals (aged 12–30 years): 168 with acute AN, 113 reassessed after ≈3 months of weight-restoration (>14% BMI increase), 80 long-term weight-recovered individuals, and 299 healthy controls. Ten subcortical limbic structures were segmented with FreeSurfer. Blood concentrations of leptin, ghrelin, NFL, and BDNF were measured. Group comparisons and marker associations were analyzed with mixed-effects models. Mediation was tested via regression-based mediation models. Most subcortical limbic volumes were reduced in AN (mean = −5.3%; Cohen’s d-range = 0.24–0.76) but normalized after short-term weight-restoration (longitudinal change: mean = +5.8%; d-range = 0.30–0.56), except residual hypothalamic reductions. Rising leptin mediated weight gain-related volumetric increases in the left inferior tubular hypothalamus (proportion mediated = 52.8%) and left (96.7%) and right (156.8%) nucleus accumbens. Declining ghrelin mediated volumetric increase of the right nucleus accumbens (77.8%). Decreasing NFL following weight-restoration predicted increases in two hypothalamic subunits, the fornix, and right nucleus accumbens (d-range = 0.56–0.98). BDNF was unrelated to limbic dynamics. Subcortical limbic alterations in AN exceed other mental disorders, highlighting neuroplasticity. Neuroendocrine recovery (leptin and ghrelin) may reverse, and reduced axonal damage (NFL) may indicate neurostructural alterations in homeostatic and reward-related regions, with prognostic and therapeutic relevance in AN.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"1932-1945"},"PeriodicalIF":7.6,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02435-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147990821","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":"An opioid-withholding human laboratory paradigm during opioid agonist treatment for opioid use disorder and chronic pain: Phase- and dose-dependent effects of cannabidiol","authors":"Gabriel P. A. Costa, Mehmet Sofuoglu, Peggy Compton, Mohini Ranganathan, Brian Pittman, Joao P. De Aquino","doi":"10.1038/s41386-026-02443-w","DOIUrl":"10.1038/s41386-026-02443-w","url":null,"abstract":"Even during opioid agonist treatment (OAT) for opioid use disorder (OUD), chronic pain remains common and unrelieved, as opioids impair endogenous pain modulation. Cannabidiol (CBD) may represent a non-opioid adjunct, but its effects among persons with co-occurring OUD and chronic pain receiving OAT are unknown. We conducted a randomized, double-blind, placebo-controlled crossover study evaluating acute oral CBD (400, 800, 1200 mg) effects on pain modulation, craving, and cognition among 23 participants (11 female) with co-occurring OUD and chronic pain receiving methadone (mean dose 85.7; SD: 29.7 mg/day). An opioid withholding model assessed CBD effects during two phases: Pre-OAT (delayed methadone dosing) and Post-OAT (following methadone administration). Primary outcomes included conditioned pain modulation (CPM; descending inhibition) and temporal summation of pain (TSP; ascending facilitation) assessed via quantitative sensory testing. Secondary outcomes included heat pain threshold and tolerance, and exploratory outcomes included cue-induced craving and cognitive performance. Pre-OAT, CBD was associated with a significant linear dose-response for enhanced descending pain inhibition (p = 0.034; d’=0.34 at 800 mg, d’=0.59 at 1200 mg). Post-OAT, CBD 1200 mg was associated with significant reduction of heat pain threshold relative to placebo (d’=-0.63, p = 0.017). CBD showed no significant effects on opioid craving. Cognitive performance was preserved across doses and CBD demonstrated a favorable safety profile. Among persons with co-occurring OUD and chronic pain receiving OAT, CBD demonstrated phase-dependent effects on pain modulation—dose-dependent enhanced descending inhibition Pre-OAT but worsened pain sensitivity Post-OAT at higher doses. These findings highlight OAT timing as a critical consideration for CBD-based pain interventions.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"2280-2289"},"PeriodicalIF":7.6,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13213852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147984389","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":"Good vibrations: Sternal vibration enhances white matter density and interoceptive awareness","authors":"Alexa Kondas, Timothy J. McDermott, Vishwadeep Ahluwalia, Greg J. Siegle, Alfonsina Guelfo, Travis M. Fulton, Aziz Elbasheir, Maya C. Karkare, Timothy D. Ely, Amanda Johnston, Rebecca Krawczak, Robert T. Krafty, Negar Fani","doi":"10.1038/s41386-026-02430-1","DOIUrl":"10.1038/s41386-026-02430-1","url":null,"abstract":"Vibration-based therapies are understudied but promising methods for alleviating psychiatric symptoms, particularly when paired with behavioral practices. The potential neuroplastic changes associated with a novel neurostimulation method, sternal vibration, and associations with clinical change remain unknown. We examined effects of sternal vibration paired with mindfulness meditation on change in white matter microstructure and dissociation using neurite orientation dispersion and density imaging (NODDI) in trauma-exposed adults with elevated dissociative symptoms. A total of 116 trauma-exposed adults with elevated dissociation completed MRI before/after eight mindfulness meditation sessions. Approximately half (n = 60) received sternal vibration augmentation whereas n = 56 had no augmentation. Self-reported dissociation was measured at each session with the Scale of Bodily Connectedness. Significant time-by-intervention type interactions showed vibration-specific improvements in body awareness (p = 0.032; ηp2 = 0.139) and increased neurite density index (NDI) in a region within the corticospinal tract (CST), the left cerebral peduncle (CP, p < 0.01, ηp2 = 0.102). This finding replicated in tractography analyses showing increased NDI in left (p = 0.007; ηp2 = 0.066) and right CST (p = 0.004; ηp2 = 0.075). Decreased body dissociation was associated with increased CP NDI in those who received vibration (p = 0.011, ηp2 = 0.058); no associations between clinical and white matter change were observed with non-vibration interventions. Findings indicate that brief sternal vibration in the context of mindfulness meditation enhanced body awareness and neurite density in a tract of relevance to somatosensory integration, with white matter changes corresponding with enhanced interoceptive awareness. Findings reveal the promise of sternal vibration as a low-cost, non-invasive neurostimulation method for enhancing interoception via neuroplastic alterations, with applications for various psychiatric populations.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 8","pages":"1369-1377"},"PeriodicalIF":7.6,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02430-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147960653","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":"Simvastatin rescues cognitive impairment in an Aβ1-42-induced model of Alzheimer’s disease through the HDAC2-BDNF signaling pathway","authors":"Chengyun Cai, Yee Song Chong, Haiying Liang, Yimin Hu, Qi Hu, Jiamin Chen, Sreedharan Sajikumar, Fang Liu","doi":"10.1038/s41386-026-02440-z","DOIUrl":"10.1038/s41386-026-02440-z","url":null,"abstract":"Statins, renowned for their efficacy in treating cardiovascular diseases, have emerged as potential therapeutic agents for the prevention of Alzheimer’s disease (AD). Among them, simvastatin (SV) has attracted considerable attention for its reported cognitive benefits in AD. However, the precise mechanisms by which SV modulates spatial cognitive function in AD remain unclear. In the present study, we used an AD model induced through intracerebroventricular administration of Aβ1-42 in male C57BL/6 mice. The cognitive performance were assessed using the Morris Water Maze (MWM) test, the Y-maze and the Novel Object Recognition (NOR) test. HDAC2 and BDNF expression levels were analyzed by Western blotting. Chromatin immunoprecipitation (ChIP) assays were performed to examine histone H4 acetylation (Ac-H4K5) at Bdnf promoters. Our results showed that SV treatment reversed cognitive impairments induced by Aβ1-42. Aβ1-42 administration increased HDAC2 expression, reduced histone H4 acetylation, and decreased BDNF levels in the dorsal hippocampus (dHPC), all of which were restored by SV treatment. Notably, viral overexpression of HDAC2 abolished the beneficial effects of SV, underscoring the critical role of HDAC2 in mediating its actions. Furthermore, blockade of BDNF signaling using TrkB-Fc attenuated the behavioral improvements induced by SV. In addition, SV treatment ameliorated Aβ1–42-induced deficits in neurogenesis and long-term potentiation (LTP). Together, these findings highlight the therapeutic role of SV in AD through epigenetic and synaptic mechanisms, and support further investigation into its clinical applicability.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"1946-1957"},"PeriodicalIF":7.6,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147950719","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":"Acute fentanyl induces opposing directions of changes in tonic and phasic dopamine release patterns and impairs Pavlovian task performance","authors":"Oliver P. Culver, Ren E. Thigpen, Thomas C. Jhou","doi":"10.1038/s41386-026-02437-8","DOIUrl":"10.1038/s41386-026-02437-8","url":null,"abstract":"Mu opioid receptor (MOR) agonists are recognized to disinhibit tonic dopamine (DA) in the ventral striatum (VS), contributing to opioid addiction and euphoria. However, MOR agonists can also inhibit non-drug reward-seeking, a phenomenon not readily explained by tonic DA disinhibition. We hypothesized that this effect could be due in part to disruption of phasic DA responses to conditioned stimuli (CS) which critically shape and maintain behaviors to obtain rewards. Because MOR effects on CS-evoked phasic DA are largely unexamined, we used fiber photometry in water-deprived male and female mice to examine acute fentanyl’s effects on CS-evoked DA responses to two distinct auditory CS predicting either a liquid sucrose unconditioned stimulus (US), or non-reward. Behaviorally, we observed that acute fentanyl (0.1 or 0.2 mg/kg subcutaneous) increased generalized locomotion while dose-dependently reducing CS-driven anticipatory nose poke entries into the reward port during water deprived states. In parallel with these behavioral changes, acute fentanyl at either dose increased tonic DA while reducing phasic DA responses to the reward CS. In contrast to fentanyl’s effects, during water-sated states we observed decreased DA responses to both the reward CS and US. Overall, our findings suggest that MOR agonists reduce cue-driven motivational behavior for non-drug rewards, and influence tonic and reward cue-evoked DA in opposite directions, but in a manner different from the effects of satiation.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"2175-2183"},"PeriodicalIF":7.6,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147944454","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":"Prenatal serotonin reuptake inhibitor exposure and maternal depression symptoms are associated with altered fetal brain and placental development","authors":"Yao Wu, Nickie Andescavage, Katherine L. Wisner, Kushal Kapse, Jonathan Murnick, Julius S. Ngwa, Catherine Limperopoulos","doi":"10.1038/s41386-026-02436-9","DOIUrl":"10.1038/s41386-026-02436-9","url":null,"abstract":"Maternal mental health is associated with fetal neurodevelopment. Identifying effective treatments for maternal psychiatric conditions is a public health priority. SRIs (SSRIs and SNRIs) are commonly prescribed for prenatal mental health conditions; however, their impact on fetal brain development remains understudied. In this observational cohort study, we compared fetal brain and placental structures between SRI-exposed and unexposed pregnancies divided by categories of maternal depressive symptom severity from the Edinburgh Postnatal Depression Scale (EPDS). Pregnant women treated with SRIs and controls without mental illness or antidepressant exposure underwent fetal MRI studies between 20-40 weeks’ gestation. Fetal brain motion correction and 3D reconstructions were performed using slice-to-volume registration. Fetal brain volumes (cortical gray matter, white matter, deep gray matter, cerebellum, brainstem, and hippocampi) were quantified using deep learning-based segmentation with manual correction. Cerebral cortical folding measures included local gyrification index, sulcal depth, curvedness, and surface area. Placental volume and microstructure were assessed with T2-weighted and diffusion-weighted MRI, respectively. EPDS scores were categorized as low ( ≤ 4), moderate (5–9), and high ( ≥ 10). A total of 182 pregnant women were included [62 SRI-exposed (59 SSRIs, 3 SNRIs); 120 controls]. Notably, 29% of SRI-exposed women continued to report elevated depression. SRI-exposed fetuses had smaller hippocampal volumes and reduced cortical gyrification, curvedness, and surface area. Subgroup analysis of stratification by EPDS scores revealed that SRI-exposed fetuses had reduced hippocampal volumes compared to unexposed fetuses with low and moderate, but not high, EPDS scores, and reduced cortical curvedness compared to unexposed subgroups. Among unexposed subgroups, fetuses exposed to high maternal EPDS scores had smaller hippocampal volumes compared to those with low scores. Placenta volume and microstructural diffusion were increased in the SRI-exposed compared to the unexposed group. Larger placental volume was associated with larger total fetal brain volume, and higher placental diffusion was associated with larger fetal white matter and cerebellar volumes in the SRI-exposed group. These findings suggest that prenatal SRI exposure may be associated with altered fetal hippocampal volumes, cerebral cortical maturation, and placental volume and microstructural diffusion. The clinical significance and long-term neurodevelopmental consequences of these structural alterations remain unknown and are currently under study.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"1999-2007"},"PeriodicalIF":7.6,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02436-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147864662","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":"PET imaging of FAAH in chronic Cannabis users: longitudinal assessment during short-term abstinence","authors":"Claudia Poluga, Shahtaj S. Dheda, Nadia Boachie, Tina McCluskey, Lucas Narciso, Maia Zilberman, Cassie Côté, Marilyn A. Huestis, Rachel F. Tyndale, Stefan Kloiber, Nathan J. Kolla, Pablo M. Rusjan, Bernard Le Foll, Jerry J. Warsh, Tony P. George, Isabelle Boileau","doi":"10.1038/s41386-026-02438-7","DOIUrl":"10.1038/s41386-026-02438-7","url":null,"abstract":"Cannabis withdrawal in cannabis use disorder (CUD) increase the risk of relapse and lacks effective treatments. The endocannabinoid enzyme fatty acid amide hydrolase (FAAH) may influence cannabis use and withdrawal, but the relationship between FAAH levels and withdrawal symptoms remains unclear. This study aims to investigate changes in FAAH levels during short-term abstinence from cannabis and their relationship with withdrawal symptoms. FAAH levels were measured in whole-brain regions of interest using positron emission tomography (PET) with the FAAH-specific probe [11C]CURB. An irreversible two-tissue compartment model determined [11C]CURB binding. Participants with CUD were scanned once after overnight abstinence (T1) and ~3–7 days after monitored last use (T2). FAAH polymorphism (rs324420) was determined from blood samples, and mood, cognition, withdrawal symptoms, and craving were assessed. In a sample of 14 participants (N = 17 prior to attrition) who completed both scans, FAAH binding in whole-brain increased between T1 and T2 (n = 14; %ΔFAAH = 10%; p = 0.003), with the largest change in the ventral striatum (11%, p = 0.026). Increases in FAAH (%ΔFAAH whole-brain) were significantly associated with longer cannabis abstinence, greater baseline depression severity, and tendency to act without thinking (p < 0.001). Short-term cannabis abstinence is associated with increases in brain FAAH levels. These changes are linked to traits and symptoms associated with relapse vulnerability, including negative mood and impulsivity. These preliminary findings suggest that FAAH may play a key role in the neurobiological response to short-term abstinence and could represent a potential target for interventions.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"2124-2131"},"PeriodicalIF":7.6,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02438-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147864512","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":"Sex-specific role of microglia in Δ9-tetrahydrocannabinol-induced disruption of fear memory reconsolidation","authors":"Ana Maria Raymundi, Nathalie Carla Cardoso, Gabriel Costa Lourenço, Ruliam Queiroz, Maressa D. Dolzan, Luciano Vitali, Erika Meyer, Sabrina Francesca Lisboa, Francisco Silveira Guimarães, Graziano Pinna, Leandro José Bertoglio, Cristina Aparecida Jark Stern","doi":"10.1038/s41386-026-02434-x","DOIUrl":"10.1038/s41386-026-02434-x","url":null,"abstract":"In PTSD, microglia are more engaged in fear-related circuits, where they participate in fear memory processing responses. The reconsolidation-impairing effect of Δ⁹-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis, is typically linked to cannabinoid type-1 receptor (CB1) signaling. THC also engages peroxisome proliferator-activated receptor gamma (PPARγ), and both CB1 and PPARγ modulate neuroimmune processes, including microglial activity. This dual mechanism suggests that THC’s impact on fear memory reconsolidation may extend beyond classical cannabinoid signaling. We hypothesize that THC disrupts contextual fear memory reconsolidation via microglial recruitment in the dorsal hippocampus (DH) through a sex-specific engagement of CB1 and PPARγ. Adult male and female Wistar rats underwent contextual fear conditioning, followed by THC (0.002 mg/kg, i.p.) or vehicle administration immediately after memory retrieval. Microglial involvement was assessed using immunofluorescence and pharmacological and chemogenetic inhibition in DH. The role of CB1 and PPARγ receptors was assessed via intra-DH selective antagonist infusion. THC impaired reconsolidation in males and females. In males, fear memory retrieval increased microglial engagement in the DH CA1 subfield, which THC further enhanced. Pharmacological and chemogenetic inhibition of microglia, as well as selective CB1 and PPARγ antagonism, blocked THC’s effects in males. In females, THC-induced reconsolidation blockade was cycle-dependent, occurring at estrus and diestrus but not at proestrus, and was mediated exclusively through CB1 activation. These findings identified sex-specific neuroimmune pathways mediating THC’s reconsolidation impairment, offering a mechanistic basis for novel sex-tailored therapeutic opportunities.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"2163-2174"},"PeriodicalIF":7.6,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02434-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147864867","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":"Examining fronto-limbic brain and sleep mechanisms of antidepressant effects in cognitive-behavioral therapy for insomnia","authors":"Adam J. Krause, Raquel Osorno, Natalie L. Solomon, Maryam Ahmadi, Pandora Lam, Olivia Magana, Emilija Blozyte-Sakenis, Leah N. Harris, Madeline C. Babros, Sarah S. Izabel, Rebecca A. Bernert, Leanne M. Williams, James J. Gross, Jun Ma, Laura C. Lazzeroni, Jerome A. Yesavage, Rachel Manber, Jared M. Saletin, Andrea N. Goldstein-Piekarski","doi":"10.1038/s41386-026-02431-0","DOIUrl":"10.1038/s41386-026-02431-0","url":null,"abstract":"Treating insomnia with Cognitive-Behavioral Therapy for Insomnia (CBT-I) improves depression symptoms, but the underlying mechanisms remain unknown. This single-arm mechanistic trial (ClinicalTrials.gov, NCT04424407) examined fronto-limbic and sleep mechanisms of CBT-I’s antidepressant response in 48 participants (64% female; age 25–60) with insomnia and depression symptoms. Participants completed functional magnetic resonance imaging (fMRI), polysomnography (PSG), and symptom assessments before and after 6 CBT-I sessions. CBT-I resulted in reduced amygdala reactivity to fearful faces (d = 0.55, p = 0.008). Depression and sleep (objective and self-reported insomnia symptoms also improved. However, fMRI-assessed fronto-limbic changes were not associated with a reduction of depressive symptom severity. Instead, reduced depressive symptoms correlated with reduced self-reported insomnia symptoms (p = 0.001, η2p = 0.19) and increased objective sleep efficiency (p = 0.04, η2p = 0.10). Notably, pre-treatment PSG-assessed sleep efficiency, but not fronto-limbic function nor insomnia symptoms, predicted reduced depressive symptoms (p = 0.007, η2p = 0.16), suggesting that lower objective sleep efficiency prior to treatment may be associated with greater antidepressant benefit from CBT-I.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 9","pages":"1657-1668"},"PeriodicalIF":7.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02431-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147849179","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":"Computational phenotyping of effort-based decision-making in type-2 diabetes on and off semaglutide","authors":"Sara Z. Mehrhof, Hugo Fleming, Camilla L. Nord","doi":"10.1038/s41386-026-02433-y","DOIUrl":"10.1038/s41386-026-02433-y","url":null,"abstract":"Motivation plays a fundamental role in human behaviour. Dopaminergic pathways have long been implicated in individual differences in motivation. Emerging evidence suggests such neural mechanisms interact with metabolic processes to coordinate energy expenditure with energy resources, thereby linking motivation with metabolic health. We ask whether a cognitive-computational index of motivation—reliably linked to neuropsychiatric symptoms—is altered in the context of type-2 diabetes and treatment with a GLP-1 agonist (semaglutide). In a pre-registered experiment, we quantified computational effort-based decision-making parameters in participants with diabetes on (N = 58) or off (N = 54) semaglutide treatment, compared to two groups of matched controls without diabetes (N = 58 each). Subjects with type-2 diabetes showed a blunted acceptance bias, a computational parameter describing the bias to accept effort for reward. This effect was not driven by neuropsychiatric comorbidity or antidepressant use. Across all participants, we found that increasing diabetes risk linearly predicted reduced acceptance bias. Participants with diabetes treated with semaglutide did not show restored motivation. Metabolic ill-health is associated with reduced acceptance bias during motivational decision-making. This blunting mirrors—but is largely independent of—neuropsychiatric motivational deficits. This suggests metabolic ill-health is accompanied by a cognitive shift towards energy conservation, potentially contributing to comorbidity between metabolic ill-health and mental illness.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"1924-1931"},"PeriodicalIF":7.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02433-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147849201","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}