Brain最新文献

{"title":"Combinatorial approaches increasing neuronal activity accelerate recovery after spinal cord injury.","authors":"Bing Chen, Siddharth Gaikwad, Robert H Powell, Hang Jin Jo, Allison Kessler, David Chen, C J Heckman, Linda Jones, James Guest, Jonathan Wolpaw, Martin Oudega, Andrew R Blight, Monica A Perez","doi":"10.1093/brain/awaf099","DOIUrl":"https://doi.org/10.1093/brain/awaf099","url":null,"abstract":"<p><p>Combinatorial approaches targeting multiple aspects of spinal cord injury (SCI) pathophysiology are needed to maximize functional recovery. We hypothesized that strengthening corticospinal synapses via Hebbian stimulation and increasing neuronal transmission with 4-aminopyridine (4-AP, a potassium blocker) could accelerate locomotor recovery in individuals with chronic SCI. Participants were randomly assigned to receive 10 mg of 4-AP or placebo, where both groups followed with 60-min of Hebbian stimulation targeting corticospinal-motoneuronal synapses supplying leg muscles involved in locomotion and 60-min of standard exercise rehabilitation for 40 sessions over 8-14 weeks. During Hebbian stimulation, 720 paired pulses were delivered to elicit corticospinal action potentials via electrical stimulation of the thoracic spine, ensuring volleys reached the spinal cord 1-2 milliseconds before motoneurons were retrogradely activated through bilateral electrical stimulation of the femoral, common peroneal, and posterior tibial nerves (targeting the quadriceps femoris, tibialis anterior, and soleus muscles, respectively). Results showed that participants who received 4-AP exhibited significantly greater improvements in walking speed and endurance, corticospinal transmission, and light touch sensation compared to those who received the placebo. The minimal clinically important difference in walking speed and endurance was achieved after 20 sessions in the 4-AP group, but was not consistently reached in the placebo group. Although walking continued to improve in both groups over the course of 40 sessions, the 4-AP group demonstrated significantly greater progress. Improvement in the 4-AP group was still present twelve months later. These findings suggest that 4-AP represents a strategy to potentiate and accelerate Hebbian stimulation effects on motor recovery in individuals with chronic SCI.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699584","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":"Inferring the 'functions' of tracts: a cautionary note.","authors":"Emiel van den Hoven, Cornelius Weiller, Marco Reisert, Michel Rijntjes","doi":"10.1093/brain/awaf114","DOIUrl":"https://doi.org/10.1093/brain/awaf114","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699588","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 relationship between kidney health and neurodegenerative diseases","authors":"Melody Zuo, Le Chang, Nikita Neale, Lyza Maameri, Sadaf Gawhary, Frida Lona-Durazo, Sarah A Gagliano Taliun","doi":"10.1093/brain/awaf113","DOIUrl":"https://doi.org/10.1093/brain/awaf113","url":null,"abstract":"Neurodegenerative diseases are multi-faceted disorders influenced by and affecting more than just the brain and nervous system. Here, we provide a review of the potential links, including mechanistic and genetic, between kidney health and neurodegeneration, mainly dementia and the two most prevalent late-onset neurodegenerative disorders, Alzheimer’s disease and Parkinson’s disease. We also discuss lines of evidence from various study designs and methodologies that either support or do not support an association between kidney health and neurodegeneration. We conclude with a summary of current gaps and provide possible ways forward to overcome them in future research. The goal of this review is to encourage further exploration of the relationship between these two biological systems to better elucidate potential actionable options to improve brain health.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"183 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675201","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":"ADAT3 variants disrupt the activity of the ADAT tRNA deaminase complex and impair neuronal migration","authors":"Jordi Del-Pozo-Rodriguez, Peggy Tilly, Romain Lecat, Hugo Rolando Vaca, Laureline Mosser, Elena Brivio, Till Balla, Marina Vitoria Gomes, Elizabeth Ramos-Morales, Noémie Schwaller, Thalia Salinas-Giegé, Grace VanNoy, Eleina M England, Alysia Kern Lovgren, Melanie O’Leary, Maya Chopra, Naomi Meave Ojeda, Mehran Beiraghi Toosi, Atieh Eslahi, Masoome Alerasool, Majid Mojarrad, Lynn S Pais, Rebecca C Yeh, Dustin L Gable, Mais O Hashem, Firdous Abdulwahab, Muath Rakiz Alqurashi, Loai Z Sbeih, Omar Abu Adas Blanco, Renad Abu Khater, Gabriela Oprea, Aboulfazl Rad, Hamad Alzaidan, Hesham Aldhalaan, Ehab Tous, Afaf Alsagheir, Mohammed Alowain, Abdullah Tamim, Khowlah Alfayez, Amal Alhashem, Aisha Alnuzha, Mona Kamel, Bashayer S Al-Awam, Walaa Elnaggar, Nihal Almenabawy, Anne O'Donnell-Luria, Jennifer E Neil, Joseph G Gleeson, Christopher A Walsh, Fowzan S Alkuraya, Lama AlAbdi, Nour Elkhateeb, Laila Selim, Siddharth Srivastava, Danny D Nedialkova, Laurence Drouard, Christophe Romier, Efil Bayam, Juliette D Godin","doi":"10.1093/brain/awaf109","DOIUrl":"https://doi.org/10.1093/brain/awaf109","url":null,"abstract":"The ADAT2/ADAT3 (ADAT) complex catalyzes the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3, the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders. Yet, the physiological function of ADAT2/ADAT3 complex during brain development remains totally unknown. Here, we investigated the role of the ADAT2/ADAT3 complex in cortical development. First, we reported 21 neurodevelopmental disorders patients carrying biallelic variants in ADAT3. Second, we used structural, biochemical, and enzymatic assays to deeply characterize the impact of those variants on ADAT2/ADAT3 structure, biochemical properties, enzymatic activity and tRNAs editing and abundance. Finally, in vivo complementation assays were performed to correlate functional deficits with neuronal migration defects in the developing mouse cortex. Our results showed that maintaining a proper level of ADAT2/ADAT3 catalytic activity is essential for radial migration of projection neurons in the developing mouse cortex. We demonstrated that the identified ADAT3 variants significantly impaired the abundance and, for some, the activity of the complex, leading to a substantial decrease in I34 levels with direct consequence on their steady-state. We correlated the severity of the migration phenotype with the degree of the loss of function caused by the variants. Altogether, our results highlight the critical role of ADAT2/ADAT3 during cortical development and provide cellular and molecular insights into the pathogenic mechanisms underlying ADAT3-related neurodevelopmental disorders.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"26 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675206","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":"CXCR3-mediated natural killer cell infiltration exacerbates white matter injury after intracerebral haemorrhage.","authors":"Anson C K Ng, Cuiting Zhang, Tsz Lung Lam, Karrie M Kiang, Vaness N C Ng, Zhiyuan Zhu, Jiaxin Liu, Wenwei Tu, Wanjun Tang, Katrina C W Chau, Kwan Man, Gilberto K K Leung","doi":"10.1093/brain/awaf108","DOIUrl":"https://doi.org/10.1093/brain/awaf108","url":null,"abstract":"<p><p>Intracerebral haemorrhage (ICH), a subtype of stroke, carries a grim prognosis. Inflammatory response during the early phase of ICH is a major perpetuator of neurological damage. Recent clinical studies suggest the possible participation of the CXC chemokine receptor 3 (CXCR3)-chemokine system in mediating neuroimmune crosstalk, which exacerbates neurological dysfunction and may serve as a potential therapeutic target in the management of ICH. CXCR3 is expressed by natural killer (NK) cells, which are known to be pathogenic in ICH. However, whether and how CXCR3 promotes NK cell infiltration and functioning in ICH, and whether the attenuation of CXCR3 may affect neurological outcome, have not been delineated. The present preclinical study has demonstrated, for the first time, the role of CXCR3 in facilitating the ingress of NK cells from the systemic compartment into the haemorrhagic brain and in causing ICH-related neurological injury. CXCR3 expression was found to be upregulated in the peri-haematomal region including the white matter tracts, with CXCR3+ leukocytes being the main contributor. When compared with wild-type (WT) mice, CXCR3 knock-out (KO) mice showed splenic pooling of NK cells, suggestive of impaired systemic recruitment. Adoptive intravenous transfer of NK cells obtained from wild-type mice resulted in significantly greater cerebral homing of NK cells than after the transfer of NK cells obtained from CXCR3 knock-out mice, thus confirming the pivotal role of CXCR3. Global CXCR3 deficiency was associated with reduced recruitment of NK cells expressing interferon-gamma (IFN-γ), the prototypic cytokine responsible for NK cell-induced inflammatory responses, as well as better corticospinal tract integrity in the cervical spinal cord and improved neurological outcomes in terms of gross and fine motor functions. Systemic administration of AMG487, a CXCR3 antagonist, likewise achieved the same effects. In conclusion, CXCR3, NK cells, and IFN-γ operate in concert in ICH pathogenesis, and the attenuation of CXCR3 has important translational potential. Our findings present a new research direction in identifying novel strategies for mitigating the detrimental neuroinflammatory responses found in ICH, and possibly in other neurological conditions.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676657","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":"Structural network-specific effect of extreme capsule stimulation for drug-resistant focal epilepsy.","authors":"Yueyang Cheng, Di Wang, Xiaohua Zhang, Guangyuan Jin, Di Wu, Qiao Wang, Jialin Du, Lei Qi, Cuiping Xu, Zichen Qiao, Xiaopeng Wang, Junliang Ge, Siyi Wang, Hao Yan, Xueyuan Wang, Huaqiang Zhang, Tao Yu, Yuping Wang, Fang-Cheng Yeh, Guoguang Zhao, Liankun Ren","doi":"10.1093/brain/awaf097","DOIUrl":"https://doi.org/10.1093/brain/awaf097","url":null,"abstract":"<p><p>Treatment for drug-resistant epilepsy in poor candidates for resection surgeries remains challenging. The prevailing deep brain stimulation of subcortical nuclei is effective but exhibits heterogeneous efficacy and unpredictable side effects. Therefore, the investigation of novel DBS targets holds paramount importance. Here, we focused on the unique structure known as the extreme capsule (EC), being \"butterfly\"-like structure passing through the uncinate fasciculus, the inferior fronto-occipital fasciculus and the convergence of the short association fibers connecting to insula. We investigated the modulation effect of extreme capsule stimulation in 11 drug-resistant epilepsy patients (mean age:28 years; male: female = 8:3) who underwent stereoelectroencephalography as part of presurgical evaluation. One electrode was extended to EC ipsilateral to the presumed seizure onset zone. Structural connectivity to the EC derived from structural human connectome data (n=1065) were estimated to compare with the effective connectivity to the EC using single-pulse stimulation at 1 Hz during the resting state. To assess the modulation effect of EC stimulation, we employed stepwise incremental stimulation ranging from 5 Hz to 145 Hz in a cyclical pattern. We evaluated how neural activity across distributed cortical areas synchronized with EC stimulation frequencies, and the changes in interictal epileptiform discharges and ripples during the stimulation period compared to the baseline. Moreover, 1 Hz burst stimulation mode was applied to further refine the stimulation protocol. We showed the EC effective connectivity aligned well with the EC structural network. We further observed that the synchronized and desynchronized modulation effect of EC stimulation is frequency specific across all the patients. Most importantly, we found that the modulation effect of EC stimulation is constrained by its structural connectivity. Specifically, high-frequency stimulation of EC significantly suppressed the epileptic discharges in the ipsilateral orbitofrontal lobe, occipital gyrus, inferior frontal gyrus, insula and temporal pole, which were inside the EC structural network rather than outside it (P<0.001). Of note, EC 1 Hz burst stimulation demonstrated a comparable inhibitory efficacy to conventional high-frequency stimulation (ANOVA, F=5.331, P<0.001). This proof-of-concept study demonstrates that the EC is a promising deep brain stimulation target for treating substantial focal epilepsy with seizure originating from EC structurally connected cortex. It further demonstrates the feasibility of transforming knowledge of white matter node stimulation for seizures originating from its physically connected cortex and offers a promising therapeutic approach using alternative stimulation methods.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673314","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":"Effects of focal brain damage on political behaviour across different political ideologies.","authors":"Shan H Siddiqi, Stephanie Balters, Giovanna Zamboni, Shira Cohen-Zimerman, Jordan H Grafman","doi":"10.1093/brain/awaf101","DOIUrl":"https://doi.org/10.1093/brain/awaf101","url":null,"abstract":"<p><p>Intense political behavior is associated with brain regions involved in emotional and cognitive processing. However, it remains unclear if this neuroanatomy is causal, compensatory, or otherwise correlated. We employed lesion network mapping in a cross-sectional study of 124 male military Veterans with penetrating head trauma. 40-45 years after the injury, participants reported current political behavior and recollection of political behavior pre-injury. Using a normative connectome database (n = 1000), we mapped the circuitry functionally connected to lesions associated with changes in intensity of political involvement, ideological polarity, and party affiliation. No significant neuroanatomical circuit was associated with political ideology or party affiliation, but a distinct circuit was associated with intensity of political involvement. Political involvement was more intense after lesions connected to the left dorsolateral prefrontal cortex and posterior precuneus, in the full sample and in conservative-leaning participants. Political involvement was less intense after lesions connected to the amygdala and anterior temporal lobe, in the full sample and in liberal-leaning participants. These effects survived cross-validation in the full sample (p=0.01) and in both conservative-leaning and liberal-leaning participants. These findings may inform cognitive mechanisms of political behavior as well as clinical assessment after brain lesions.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673297","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":"Novel modelling approaches to elucidate the genetic architecture of resilience to Alzheimer's disease.","authors":"Jared M Phillips, Logan C Dumitrescu, Derek B Archer, Alexandra N Regelson, Shubhabrata Mukherjee, Michael L Lee, Seo-Eun Choi, Phoebe Scollard, Emily H Trittschuh, Walter A Kukull, Sarah Biber, Jesse Mez, Emily R Mahoney, Michelle Clifton, Julia B Libby, Skylar Walters, William S Bush, Corinne D Engelman, Qiongshi Lu, David W Fardo, Keith F Widaman, Rachel F Buckley, Elizabeth C Mormino, R Elizabeth Sanders, Lindsay R Clark, Katherine A Gifford, Badri Vardarajan, Michael L Cuccaro, Margaret A Pericak-Vance, Lindsay A Farrer, Li-San Wang, Gerard D Schellenberg, Jonathan L Haines, Angela L Jefferson, Sterling C Johnson, Marilyn S Albert, C Dirk Keene, Andrew J Saykin, Shannon L Risacher, Eric B Larson, Reisa A Sperling, Richard Mayeux, Alison M Goate, Alan E Renton, Edoardo Marcora, Brian Fulton-Howard, Tulsi Patel, David A Bennett, Julie A Schneider, Lisa L Barnes, Carlos Cruchaga, Jason Hassenstab, Michael E Belloy, Shea J Andrews, Susan M Resnick, Murat Bilgel, Yang An, Lori L Beason-Held, Keenan A Walker, Michael R Duggan, Brandon S Klinedinst, Paul K Crane, Timothy J Hohman","doi":"10.1093/brain/awaf106","DOIUrl":"https://doi.org/10.1093/brain/awaf106","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Up to 30% of older adults meet pathological criteria for a diagnosis of Alzheimer's disease at autopsy yet never show signs of cognitive impairment. Recent work has highlighted genetic drivers of this resilience, or better-than-expected cognitive performance given a level of neuropathology, that allow the aged brain to protect itself from the downstream consequences of amyloid and tau deposition. However, models of resilience have been constrained by reliance on measures of neuropathology, substantially limiting the number of participants available for analysis. We sought to determine if novel approaches using APOE allele status, age, and other demographic variables as a proxy for neuropathology could still effectively quantify resilience and uncover novel genetic drivers associated with better-than-expected cognitive performance while vastly expanding sample size and statistical power. Leveraging 20,513 participants from eight well-characterized cohort studies of aging, we determined the effects of genetic variants on resilience metrics using mixed-effects regressions. The outcome of interest was residual cognitive resilience, quantified from residuals in three cognitive domains (memory, executive function, and language) and built within two frameworks: \"silver\" models, which obviate the requirement for neuropathological data (n=17,241), and \"gold\" models, which include post-mortem neuropathological assessments (n=3,272). We then performed cross-ancestry genome wide association studies (European ancestry n=18,269, African ancestry n=2,244), gene and pathway-based tests, and genetic correlation analyses. All analyses were conducted across all participants and repeated when restricted to those with unimpaired cognition at baseline. Despite different modeling approaches, the silver and gold phenotypes were highly correlated (R=0.77-0.88) and displayed comparable performance in quantifying better-than or worse-than-expected cognition, enabling silver-gold meta-analyses. Genetic correlation analyses highlighted associations of resilience with multiple neuropsychiatric and cardiovascular traits (PFDR values &lt; 5.0x10-2). In pathway-level tests, we observed three significant associations with resilience: metabolism of amino acids and derivatives (PFDR=4.1x10-2), negative regulation of transforming growth factor beta production (PFDR=1.9x10-2), and severe acute respiratory syndrome (PFDR=3.9x10-4). Finally, in single-variant analyses, we identified a locus on chromosome 17 approaching genome-wide significance among cognitively unimpaired participants (index single nucleotide polymorphism: rs757022, minor allele frequency = 0.18, β=0.08, P=1.1x10-7). The top variant at this locus (rs757022) was significantly associated with expression of numerous ATP-binding cassette genes in brain. Overall, through validating a novel modeling approach, we demonstrate the utility of silver models of resilience to increase statistical power and participant diversity.","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668674","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":"Impaired reward sensitivity in Parkinson's depression is unresponsive to dopamine treatment.","authors":"Harry Costello, Yumeya Yamamori, Karel Kieslich, Mackenzie Murphy, Kamilla Bobyreva, Anette-Eleonore Schrag, Robert Howard, Jonathan P Roiser","doi":"10.1093/brain/awaf098","DOIUrl":"https://doi.org/10.1093/brain/awaf098","url":null,"abstract":"<p><p>Willingness to exert effort for a given goal is dependent on the magnitude of the potential rewards and effort costs of an action. Such effort-based decision making is an essential component of motivation, in which the dopaminergic system plays a key role. Depression in Parkinson's disease (PD) is common, disabling and has poor outcomes. Motivational symptoms such as apathy and anhedonia, are prominent in PD depression and related to dopaminergic loss. We hypothesised that dopamine-dependent disruption in effort-based decision-making contributes to depression in PD. In the present study, an effort-based decision-making task was administered to 62 patients with PD, with and without depression, ON and OFF their dopaminergic medication across two sessions, as well as to 34 patients with depression and 29 matched controls on a single occasion. During the task, on each trial, participants decided whether to accept or reject offers of different levels of monetary reward in return for exerting varying levels of physical effort via grip force, measured using individually calibrated dynamometers. The primary outcome variable was choice (accept/decline offer), analysed using both logistic mixed-effects modelling and a computational model which dissected the individual contributions of reward and effort on depression and dopamine state in PD. We found PD depression was characterised by lower acceptance of offers, driven by markedly lower incentivisation by reward (reward sensitivity), compared to all other groups. Within-subjects analysis of the effect of dopamine medication revealed that, although dopamine treatment improves reward sensitivity in non-depressed PD patients, this therapeutic effect is not present in PD patients with depression. These findings suggest that disrupted effort-based decision-making, unresponsive to dopamine, contributes to PD depression. This highlights reward sensitivity as a key mechanism and treatment target for PD depression that potentially requires non-dopaminergic therapies.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655808","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":"Reward circuit local field potential modulations precede risk taking","authors":"Natasha C Hughes, Helen Qian, Derek J Doss, Ghassan S Makhoul, Michael Zargari, Zixiang Zhao, Balbir Singh, Zhengyang Wang, Jenna N Fulton, Graham W Johnson, Rui Li, Benoit M Dawant, Dario J Englot, Christos Constantinidis, Shawniqua Williams Roberson, Sarah K Bick","doi":"10.1093/brain/awaf107","DOIUrl":"https://doi.org/10.1093/brain/awaf107","url":null,"abstract":"Risk-taking behaviour is a symptom of multiple neuropsychiatric disorders and often lacks effective treatments. Reward circuitry regions including the amygdala, orbitofrontal cortex, insula, and anterior cingulate have been implicated in risk-taking, but electrophysiological activity predictive of risk taking in these regions is not well understood in humans. Identifying local field potential frequency signatures of risk-taking may provide therapeutic insight into disorders associated with risk-taking. Eleven patients with medically refractory epilepsy who underwent stereotactic electroencephalography with electrodes in the amygdala, orbitofrontal cortex, insula, and/or anterior cingulate participated in this experiment. Patients completed a gambling task where they wagered on a visible playing card being higher than a hidden card, betting $5 or $20 on this outcome, while local field potentials were recorded from implanted electrodes. We used linear regression models and cluster-based permutation testing to identify oscillatory power modulations associated with reward prediction error signal. We also computed a risk-taking value for each trial using card number and bet choice and similarly used linear regression and cluster-based permutation testing to identify power changes associated with risk-taking value. We then used two-way ANOVA with bet and risk level to identify power clusters predictive of risky decisions. We used linear mixed effects models to evaluate the relationship between reward prediction error and risky decision signals across trials. Time-frequency clusters associated with reward prediction error were identified in the amygdala (2 clusters: all p&amp;lt;0.001) and orbitofrontal cortex (4 clusters: all p&amp;lt;0.001). Risky decisions were predicted by increased oscillatory power in theta-to-beta frequency range during card presentation in the orbitofrontal cortex (p=0.00053; η2bet=0.15, η2risk=0.27, η2bet*risk=0.017), and by high beta power in the insula (p=0.0003; η2bet=0.15, η2risk=0.20, η2bet*risk=0.0018). Subsequent analysis localized these signals to lateral orbitofrontal cortex and posterior insula respectively. The power within an insula cluster associated with risky decisions was associated with a theta-alpha reward prediction error signal in the orbitofrontal cortex (p=0.023). In addition, an amygdala reward prediction error signal was associated with overall percentage of high bets (p=0.0015) and a lateral OFC risky decision signal was associated with high bets in risky scenarios (p=0.028). Our findings identify and help characterize reward circuitry activity predictive of risk-taking in humans. These findings identify oscillatory power signatures within these regions preceding risky decisions, which may serve as potential biomarkers to inform the development of novel treatment strategies such as closed loop neuromodulation for disorders of risk taking.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"6 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653471","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}