Neuroscience & Biobehavioral Reviews

Background: Altered gamma-aminobutyric acid (GABA) neurotransmission is a proposed mechanism underlying autism spectrum disorder (ASD), prompting evaluation of several GABA-modulating pharmacotherapies. However, it remains unclear whether these interventions improve ASD broadly or preferentially affect specific symptom domains. Methods: We conducted a systematic review and random-effects meta-analysis of randomized controlled trials evaluating GABA-modulating pharmacotherapies in individuals with ASD. PubMed/MEDLINE, Embase, Scopus, and CENTRAL were searched from inception to April 1, 2026. Outcomes were prespecified as global autism severity, social communication, functional communication, restricted and repetitive behaviours (RRBs), adaptive behaviour, and irritability. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool, and certainty of evidence was evaluated using GRADE. Results: Thirteen randomized controlled trials evaluating three GABA-modulating interventions (bumetanide, arbaclofen, and valproate) were included. GABA-modulating therapies were associated with statistically significant improvements in global autism severity (Hedges' g = -0.25, 95% CI -0.46 to -0.03; p = 0.028) and adaptive behaviour (Hedges' g = -0.09, 95% CI -0.15 to -0.02; p = 0.023). No significant pooled effects were observed for social communication (Hedges' g = -0.26, p = 0.077), functional communication (Hedges' g = -0.01, p = 0.869), RRBs (Hedges' g = -0.21, p = 0.126), or irritability (Hedges' g = -0.07, p = 0.543). After Holm-Bonferroni step down procedure, neither global autism severity nor adaptive behaviour remained statistically significant (Holm-adjusted p = .140 and .138, respectively). Adverse events were predominantly gastrointestinal, neurological, metabolic, and appetite-related. Overall risk of bias was variable, and the certainty of evidence ranged from very low to moderate. Conclusions: GABA-modulating pharmacotherapies did not demonstrate a robust, multiplicity-corrected benefit in any of the six prespecified ASD symptom domains. Nominal, unadjusted improvements in global autism severity and adaptive behaviour did not withstand correction for multiple comparisons and should be regarded as hypothesis-generating rather than confirmatory. Larger, adequately powered randomized trials using standardized domain-specific outcome measures are needed to determine whether individual GABA-modulating agents provide clinically meaningful benefit.

Objectives To evaluate the positive and adverse effects of parent-mediated interventions (PMIs) versus care as usual for children with autism. Setting Systematic review and meta-analysis and Trial Sequential Analyses (TSA), following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Methods We searched for randomised clinical trials of PMIs for children with autism in the databases CENTRAL, EMBASE, LILACS, PsycINFO, MEDLINE, and SCI-EXPANDED (up to 13 August, 2025), complemented with manual searches. 12,359 articles were screened. Data were synthesised using meta-analyses and Trial Sequential Analyses (TSA), and risks of bias and certainty of the evidence were evaluated. Primary and secondary outcome measures The primary outcome was autism characteristics. Secondary outcomes were adverse effects, child adaptive functioning, child language, child and parent quality of life, and parental stress. Ten exploratory outcomes were included. Results 32 trials (N=1,625) comparing PMIs to usual care, waiting list, or no intervention were included. All trials had a high risk of bias. The multiplicity-adjusted threshold for statistical significance was p = 0.013 due to the number of outcomes. Meta-analyses and TSAs showed it could be rejected that PMIs reduced autism characteristics (MD = -0.88; 95% confidence interval -2.92 to 1.15; p = 0.05, 4 trials, N=353, low certainty), child adaptive functioning (7 trials, N=408), child language (4 trials, N=308), or parental stress (7 trials, N=385). Due to insufficient data, the remaining secondary meta-analyses could not be conducted. Meta-analyses of exploratory outcomes showed beneficial effects concerning child behaviour problems and parent sensitivity/synchronicity. Conclusions This meta-analysis found no benefits of PMIs on child autism characteristics, child adaptive functioning, child language, or parental stress. Benefits were found in reduction of child behaviour problems and improved parent sensitivity/synchronicity. The evidence remains uncertain, and more trials including outcomes of adverse effects and quality of life are needed.

Background: Placebo responding involves the reduction of symptoms in response to contextual features of an intervention (e.g., verbal suggestions), yet it is characterized by pronounced heterogeneity. Although verbal suggestions are widely recognised as a hallmark method for inducing placebo responses, an open question is whether variability in placebo responding can be partly attributed to individual differences in trait responsiveness to verbal suggestions (REVS). We conducted a pre-registered meta-analysis (PROSPERO registration number CRD420250654692) to quantitatively synthesize available research on the association between trait REVS and placebo responding. Methods: PsycInfo, PubMed, MEDLINE, and Embase were searched up to June 2026 for original clinical or experimental studies involving both the assessment of REVS and symptom measures (self-report, behavioural, and/or physiological) in response to an inactive intervention (placebo). Results: Of 1,512 search results, 24 articles presenting 66 correlations between REVS and placebo responding were analysed (N = 1,137). A multi-level meta-analysis revealed a significant, albeit weak, positive correlation between REVS and placebo responses, r = 0.18 [95% CI: 0.13, 0.24], such that individuals with higher REVS reported greater symptom relief in response to the placebo. Meta-regression analyses did not identify any significant moderators of the correlation between REVS and placebo responding and sensitivity analyses based on Bayesian subgroup estimates indicated that the aggregate correlation was stable across methodological quality indicators and study features. Conclusion: These findings suggest that individual differences in REVS may partly explain variability in symptom reduction in response to placebos, with implications for the sources of variance in placebo effects in experimental and applied contexts.

Individuals with schizophrenia show well-documented impairment in metaphor comprehension, often exhibiting a bias toward concrete, literal interpretations. While this tendency has traditionally been linked to psychopathological and cognitive factors, the contribution of perceptual processes remains underexplored. Here, we tested the hypothesis that figurative language impairment reflects altered perceptual processing, whereby the visual representations evoked by metaphors remain abnormally active and hinder abstraction. A sample of 143 individuals with schizophrenia and healthy controls was administered a novel paradigm where metaphors (e.g., Wisdom is a flashlight) served as primes for target words related to the metaphor vehicle based on visual (e.g., microphone), action (e.g., remote), or semantic features (e.g., lamp). While in healthy participants metaphors activated semantically associated words, individuals with schizophrenia showed sustained visual priming, emerging 1000 ms after metaphor presentation and persisting up to 1400 ms, with both groups showing reverse priming for action targets. Critically, greater visual priming predicted lower metaphor comprehension in patients, whereas greater semantic priming was correlated with better metaphor skills in controls. These results suggest that visual-perceptual representations are not only overactivated in patients compared to controls during metaphor processing but may also interfere with figurative comprehension. We argue that concretism arises from an imbalance between bottom-up sensory signals and top-down contextual priors, leading to the persistence of the visual representations and impaired abstraction. More broadly, these results support multimodal and predictive accounts of metaphor processing and point to altered perceptual dynamics as a previously unappreciated mechanism contributing to pragmatic impairment in schizophrenia.

Background: Neuropathic pain (NP) remains a therapeutic challenge, with conventional repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) yielding a response rate of approximately 40%. Personalised targeting based on dysfunctional neurocircuitry offers a promising strategy to enhance efficacy, yet its application in NP is unexplored. This open-label trial investigated a novel targeting approach guided by the recently described cingulo-opercular and somato-cognitive action (CON-SCAN) network, a circuit integrating cognitive and affective dimensions of pain. Methods: Twenty patients with NP received 10 sessions of M1-rTMS over two weeks, with the stimulation site individually localised based on maximal functional connectivity to a CON template. Results: Increased CON-SCAN connectivity from baseline to post-treatment was associated with reduction in pain interference, anxiety and depression scores. The response rate was 50% post-treatment, which was maintained at the 1-month follow-up. Improvements were also observed in neuropathic pain symptoms, negative affect, and overall health. Conclusions: As the first connectivity-guided rTMS trial for NP, this study provides preliminary evidence that personalised targeting of the CON-SCAN network is feasible and associated with the analgesic effects of M1-rTMS, supporting further investigation in randomised controlled trials. Trial registration: Chinese Clinical Trial Registry, ChiCTR2500104679. Registered 20 June 2025, http://www.chictr.org.cn. Chinese Clinical Trial Registry, ChiCTR2400094568. Registered 24 December 2024, http://www.chictr.org.cn. Keywords: Personalised TMS; Pain; M1; CON; SCAN

Intelligence or general cognitive ability (GCA) is fundamental to human behavior and cognition. It impacts important life outcomes like educational success and even health and longevity have been related to differences in GCA. Understanding the biological basis of such individual variations presents a crucial goal of neuroscience. The mismatch negativity (MMN) is an event-related brain potential that can be measured when--within a series of frequent standard stimuli, rare deviants are presented--and is suggested to reflect conscious (active) or unconscious (passive) detection processes of the brain. Importantly, variations in MMN amplitude and latency have been linked to differences in GCA. Yet findings vary considerably. This preregistered meta-analysis provides a comprehensive and structured overview of the current state of research. Following the study selection process in accordance with the PRISMA guidelines, and the rating of study design quality with the Study Design and Implementation Assessment Device for Individual Difference Research (DIAD-ID), the association between GCA and MMN amplitude and latency was examined in 695 healthy adults across 13 included studies. The estimated across-sample associations between MMN and GCA were small, but significant (MMN amplitude-GCA: r = -0.08, MMN latency-GCA: r = -0.13; p < 0.05) and moderators were identified. Between-sample heterogeneity was moderate, with no evidence of publication bias. Our findings suggest that higher cognitive ability is associated with slightly stronger and faster MMN responses. However, the low estimated across-sample effect sizes and the small number of included studies also highlight the need for more research.

Source and reality monitoring enable individuals to distinguish the origins of remembered information, including whether information was self- or other-generated and whether it was perceived or imagined. Although the dorsolateral prefrontal cortex (dlPFC) and temporoparietal junction (TPJ) have been implicated in these processes, their independent causal contributions remain unclear. We investigated whether focal transcranial direct current stimulation (f-tDCS) of the left dlPFC and left TPJ differentially modulates source and reality monitoring. One hundred participants were randomly assigned to receive anodal or sham stimulation of the left dlPFC or TPJ before completing an episodic memory task manipulating agent (self, experimenter), context (spoken, imagined), and emotional valence (positive, negative). Discrimination sensitivity (d') and response criterion (c) were examined separately. For source monitoring, stimulation interacted with context and cortical region: anodal dlPFC stimulation was associated with a greater spoken-imagined difference in self-experimenter discrimination than sham stimulation, whereas no equivalent context-dependent effect emerged following TPJ stimulation. For reality monitoring, stimulation effects also differed by cortical target, with reduced spoken-imagined discrimination following anodal relative to sham TPJ stimulation and no significant effect of dlPFC stimulation. These effects were not accompanied by corresponding stimulation effects on response criterion. Independent of stimulation, source discrimination was substantially greater for spoken than imagined information, while reality-monitoring sensitivity was enhanced for self-generated relative to experimenter-generated negative information. Together, these findings provide evidence that the dlPFC and TPJ make dissociable contributions to source and reality monitoring, while highlighting the importance of contextual and affective features in determining how the origins of memories are evaluated.

The subgenual anterior cingulate cortex (sgACC) is a key node in treatment-resistant depression (TRD), but precise non-invasive neuromodulation of this target is challenging. Preclinical studies of non-ablative stereotactic radiosurgery (SRS) have shown neuromodulatory ("radiomodulation") effects. In this single-center, double-masked, randomized, dose-seeking pilot trial, nine adults with TRD were randomly assigned to bilateral sgACC radiomodulation at a dose of either 15, 20, or 25 Gy per hemispheric target. Primary endpoints were safety and feasibility; the efficacy endpoint was week-4 change in the Montgomery-Asberg Depression Rating Scale (MADRS). Both primary endpoints were met: the only treatment-related adverse event was transient grade 1 dizziness, with no structural MRI abnormality through week 12. Mean MADRS fell from 33.0 to 17.0 (48.5% reduction); 67% responded and 44% remitted, with benefit sustained to week 12. Resting-state fMRI revealed regional connectivity changes correlating with clinical improvement, with tractography showing streamline counts differing by response status. These first-in-human findings support a larger randomized controlled trial of sgACC radiomodulation for TRD. ClinicalTrial.gov registration: NCT07274917.

Although a substantial body of evidence has demonstrated that emotional interference affects cognitive performance, relatively little is known about its temporal evolution and the respective brain regions underlying its regulation. The present study investigated the temporal dynamics of emotional interference and the contribution of prefrontal regions involved in its regulation. Forty-eight participants completed a 2-back task and a Set-switching task under neutral and negative emotional conditions while receiving sham, dorsolateral prefrontal cortex (dlPFC), or ventromedial prefrontal cortex (vmPFC) stimulation. Stimulation was administered either online during task performance or after a 5 min pre-task period. Consistent with previous findings, negative emotions impaired executive performance, particularly during high-demand updating conditions. Critically, time-resolved analyses revealed that emotional interference evolved dynamically throughout task performance and was differentially modulated by prefrontal stimulation. The most consistent stimulation effects emerged after approximately 10 minutes of cumulative stimulation exposure and varied as a function of the stimulation site, executive-control demands, and stimulation timing. Notably, online stimulation produced more consistent modulation than pre-task stimulation. Together, these findings indicate that both emotional interference and its neuromodulation are dynamic processes. More broadly, they suggest that the contribution of prefrontal control systems to emotion-cognition interactions may be better understood through their temporal evolution rather than through static measures of performance alone.

Background: Pain relief is the principal patient-centered goal of surgery for symptomatic lumbar synovial facet cysts, yet comparative reviews have often emphasized cyst recurrence. Whether adding fusion improves postoperative pain or reduces later surgery remains uncertain. Objective: To compare decompression alone with decompression plus fusion, with postoperative back- and leg-pain outcomes as the primary domain. Methods: PubMed, Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception to 2 June 2026. Comparative cohorts and case series with at least five patients were eligible. Twenty-two studies were re-extracted for VAS/NRS scores, change scores, and persistent or recurrent pain. Random-effects restricted maximum likelihood models with Hartung-Knapp inference were used; clinically distinct pain outcomes were analyzed separately. Results: Twenty-two studies (16 cohorts, 6 case series; 51,899 participants) were included. Two studies provided compatible final VAS data. Fusion did not improve postoperative back pain (MD -0.04, 95% CI -0.17 to 0.10; I2=0%) or leg pain (MD -0.03, 95% CI -0.28 to 0.21; I2=0%). Postoperative back pain (RR 0.58, 95% CI 0.14-2.30) and leg/radicular symptoms (RR 0.75, 95% CI 0.42-1.32) were also not significantly reduced. Fusion decreased confirmed cyst recurrence (RR 0.29, 95% CI 0.15-0.57) but not reoperation or subsequent lumbar surgery (RR 0.80, 95% CI 0.42-1.50). Conclusion: Current comparative evidence does not demonstrate superior postoperative pain control with routine fusion. Fusion reduces cyst recurrence without clearly reducing reoperation, supporting selective use when instability is present or anticipated.

Neighbourhood deprivation is one of the few potential policy-modifiable risk factors for psychiatric and neurological disorders, but the neurobiological pathways underlying these associations remain unclear. We investigated these relationships across three cohorts spanning the life span: the Healthy Brain and Child Development (HBCD) Study (n = 84, aged 0 to 4 weeks postnatal), the Adolescent Brain Cognitive Development (ABCD) Study (n = 4,792, aged 9 to 10 years), and the UK Biobank (UKB; approximately 500,000 adults, aged 44 to 87 years). Neighbourhood deprivation was associated with elevated disease risk, and individual lifestyle factors accounted for only a small fraction of this burden, indicating that the much larger residual effect reflects broader contextual characteristics of deprived environments rather than individual behaviours alone. Across all cohorts, greater deprivation consistently predicted lower cortical and subcortical brain volume, with effects detectable in early development and substantially stronger in adulthood. Across disorders, regional brain volume emerged as a consistent neuroanatomical mediator linking neighbourhood deprivation to neuropsychiatric disease. We further showed that deprivation preferentially affects brain regions intrinsically vulnerable to neuropsychiatric disorders. Spatial decoding analyses implicated dopaminergic and serotonergic neurotransmitter systems together with specific excitatory and inhibitory neuronal classes. Importantly, both the deprivation effects and their neuroanatomical mediation patterns were replicated across independent populations. Our study delivers a translational framework linking neighbourhood deprivation to brain health, which could inform public health policies and preventive interventions.

Background: In Denmark, perioperative high-dose glucocorticoid treatment were step-wisely implemented for total hip arthroplasty (THA), total knee arthroplasty (TKA), and unicompartmental knee arthroplasty (UKA). We aimed to estimate the effect of a single high dose of glucocorticoids on opioid consumption following primary THA, TKA, and UKA. Methods: This was a prespecified analysis of a multicenter natural experiment using electronic health record data. We included elective THA, TKA, or UKA surgeries performed in Eastern Denmark from 2017-2025. At each center, surgeries before implementation of high-dose glucocorticoids served as controls, whereas surgeries after implementation comprised the intervention group. The primary outcome was the between-group difference in cumulative 0-24h opioid consumption, which included preemptive end-of-surgery doses. The predefined minimal important difference was set at 5 mg IV morphine equivalents. Secondary outcomes were maximum 0-10 numerical rating scale (NRS) pain score and incidence of opioid-related adverse events within 24 hours, hospital length of stay, and days alive and out of hospital at 30 days. Results: A total of 47,317 surgeries performed at nine centers were analyzed: 13,010 controls and 34,307 in the intervention group. During the study period, five centers implemented high-dose glucocorticoids for THA patients, two for TKA/UKA patients. High-dose glucocorticoids were administered to 6% of patients before implementation versus 92% after. High-dose glucocorticoids resulted in a mean reduction of 3.8 mg intravenous (IV) morphine equivalents (95% CI 3.3;4.3). The intervention also reduced the maximum 0-24h NRS pain score by 0.8 points (99% CI 0.7;0.9), but there was no difference in adverse events, length of stay, or days alive and out of hospital. Conclusions: Implementation of high-dose glucocorticoids reduced 0-24-hour opioid consumption by 3.8 mg IV morphine equivalents after elective hip and knee arthroplasty. This difference was below the prespecified minimal important difference threshold. Online registration: https://doi.org/10.1101/2025.11.11.25339982

Background: Substance use disorders (SUDs) remain common worldwide and inadequately treated. Neuromodulation targets neural circuits involved in reward, craving, and cognitive control. However, the primary research literature has not been systematically mapped regarding the relative contributions of clinical and preclinical studies. Methods: We conducted a multi-database bibliometric analysis of primary studies on neuromodulation for SUD. Web of Science, Scopus, and PubMed were searched covering 2000-2025. After scope classification and exclusion of secondary literature, 810 primary research documents remained. Performance analysis and science mapping were performed with bibliometrix and VOSviewer. Results: Scientific output grew at a compound annual growth rate of 14.16% (2001-2025), accelerating after 2015. Of 810 studies, 82.8% were clinical, 12.5% preclinical, and 4.7% mixed/translational. Alcohol (31.5%) and nicotine/tobacco (25.7%) dominated the literature and were overwhelmingly clinical (>92%), whereas cocaine and opioids retained larger preclinical shares (24-27%). Repetitive transcranial magnetic stimulation (rTMS) was the leading modality (31.6%), followed by deep brain stimulation (24.9%) and transcranial direct current stimulation (24.2%). Keyword co-occurrence revealed three clusters: a clinical neuromodulation core, a nicotine/tobacco axis, and a preclinical reward-circuitry module. The United States and China led in output. Conclusions: Neuromodulation research for SUD is expanding rapidly and is heavily skewed toward clinical investigations. A persistent clinical-preclinical asymmetry and limited explicitly translational work constitute structural features of the field. Greater integration between mechanistic and clinical research is needed to advance definitive trials.

Antiestrogenic therapy is widely used in the treatment of hormone receptor positive breast cancer and alters estrogen signaling through different mechanisms, which may affect brain regions sensitive to estrogenic modulation. However, its early effects on brain architecture remain poorly understood. In this study, we examined whether the initiation of antiestrogenic therapy (tamoxifen or letrozole) is associated with short-term changes in brain structure and psychological symptoms, and whether these changes differ between the two treatment types. For now, data from twenty women with breast cancer and twenty healthy controls undergoing MRI scanning and psychological assessments at baseline (t1) and again approximately 2 to 3 weeks later (t2) were used. Patients started antiestrogen therapy immediately after the first assessment. Structural analyses included whole-brain cortical thickness and gyrification, as well as region of interest measures of hippocampal and amygdala volume. Changes in psychological parameters were also assessed, and hormone levels were measured but are not reported here. No robust time-by-group effects were observed for total brain volume, cortical thickness, gyrification, or hippocampal and amygdala volume after correction for multiple comparisons. An exploratory within-patient analysis identified a localized increase in cortical thickness in the right anterior insula/inferior frontal operculum; however, the corresponding time-by-group interaction was not significant. Somatic depressive symptom scores showed a significant time by group interaction, with scores increasing in the breast cancer group but remaining stable in healthy controls. Across time points, women with breast cancer also reported higher overall depressive symptoms and state anxiety and lower positive affect than healthy controls. Exploratory associations between changes in brain structure and psychological symptoms were observed at uncorrected thresholds but did not survive correction for multiple comparisons. In this interim sample, no robust group-level macrostructural brain changes were detected over the first 2 to 3 weeks following initiation of antiestrogen therapy. However, this does not exclude the possibility of early structural effects, which may be subtle or heterogeneous and therefore difficult to detect in the current sample. Somatic depressive symptoms increased in the BC group relative to healthy controls during this early treatment period, while exploratory neural findings suggested potential localized changes and individual difference associations that warrant cautious interpretation and require confirmation in larger samples. Recruitment is ongoing toward the prospectively defined final sample.

The Component Process Model of Emotion conceptualizes any emotional episode (e.g., the discrete emotions of sadness, anger, fear, or interest) as being driven by the multiple appraisal components. However, both the specificity of the neural mechanisms underlying appraisal processes and the way these appraisal networks relate to the neural circuits underlying discrete emotions remain unclear. Here we investigated the neural correlates of appraisal processes and compared them with those of discrete emotions. Participants (n = 97) were scanned with functional magnetic resonance imaging (fMRI) while watching short movie clips with varying emotional contents. Intensity for 12 appraisals and 12 basic and epistemic emotions evoked by the movie clips were rated by independent participants (n = 444). The neural responses were modelled with convolved ratings of appraisals and discrete emotions. The results indicated that appraisals and discrete emotions are supported by a shared set of distributed brain regions that extend beyond typically reported emotion-related areas, encompassing perceptual, action-related, and higher-order cognitive systems. Activations were more consistent for and better explained by appraisals versus discrete emotions. Within this network, epistemic emotions elicited less consistent activations than basic emotions, particularly in limbic regions. Our results highlight the functional organization of appraisals and discrete emotions under dynamic and complex conditions and indicate that appraisal theories better explain neural responses than discrete emotion models.

Depression and treatment-resistant depression (TRD) are significant public health issues, but the associated network-level neurobiological mechanisms remain poorly understood. This study used magnetoencephalography (MEG) to identify altered resting-state connectivity within the default mode (DMN), executive control (ECN), salience (SN), dorsal attention (DAN), motor (MN), and visual (VN) networks as potential biomarkers of depression and treatment resistance. The study recruited 168 participants (80 healthy volunteers (HVs) and 88 currently experiencing a major depressive episode (74 with TRD and 14 without TRD (noTRD))). Data Integration Analysis for Biomarker Discovery using Latent Variable Approaches for Omics Studies (DIABLO) was used to differentiate the depression, TRD, and HV subgroups and identify neural markers of depression and treatment resistance. For differentiating the depression and HV groups, the triple network model (area under the receiver operating curve (AUROC): 0.759-0.787) - which includes the DMN, ECN, and SN - outperformed the six-network model (AUROC: 0.747-0.762) across different bandwidths. For differentiating the TRD and HV groups, the triple network model demonstrated reasonable prediction across different bandwidths (AUROC: 0.737-0.807); potential within-network connectivity differences distinguished those with TRD from HVs, especially DMN within-network connectivity between the inferior parietal lobule and precuneus in the beta band (FDR-corrected p<.05). Hyperconnectivity within the SN (superior parietal lobule and frontal operculum in the alpha band) and DMN (inferior parietal lobule and lateral prefrontal cortex in the beta band) was associated with number of treatment failures (ps<.05). These findings highlight key brain regions and connectivity patterns, advancing our understanding of neural mechanisms underlying depression and treatment resistance.

Chronic pain in later life may be accompanied by alterations in brain structure and cognition, but whether pain extent and central sensitization symptoms identify distinct brain-behavior patterns remains unclear. We examined associations of pain extent and central sensitization symptoms, assessed using the 9-item Central Sensitization Inventory (CSI-9), with regional gray matter volume and cognitive function in community-dwelling older adults. This cross-sectional study included 272 participants with chronic pain from the Bunkyo Health Study. Participants were classified as having single-site or multisite pain and by CSI-9 score as having lower or higher scores, with 12 or higher defining the higher group. Regional gray matter volume was quantified using 0.3-Tesla magnetic resonance imaging, and cognition was assessed using the Trail Making Test Part B (TMT-B), processing speed, and global and domain-specific measures. Pain extent and CSI-9 group interacted for TMT-B performance, with the longest completion time in participants with single-site pain and a higher CSI-9 score. No other cognitive outcome remained significant after correction for multiple testing. In categorical analyses, the higher CSI-9 group had smaller volumes in the right middle frontal gyrus, bilateral anterior cingulate cortex, right insula, right hippocampus, and bilateral amygdala, whereas pain extent and the interaction were not associated with regional volume. In a contextual comparison, only the single-site/higher CSI-9 group showed slower TMT-B performance than participants with no current pain. Pain extent and central sensitization symptoms may represent partly distinct dimensions of chronic pain, although the small single-site/higher CSI-9 group and attenuation in several sensitivity analyses warrant caution. Significance StatementChronic pain is often described by where it hurts, but location alone may miss important differences between patients. In older adults, pain extent and symptoms measured by the 9-item Central Sensitization Inventory captured partly different aspects of chronic pain. Participants with pain at one site and a higher CSI-9 score performed most slowly on a task requiring attention and mental flexibility, whereas differences in regional brain structure were related mainly to CSI-9 score rather than pain extent. These findings support a multidimensional approach to chronic pain and may inform future research on cognitive vulnerability and brain health across pain conditions. Graphical Abstract Text O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/742487v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@17eacb7org.highwire.dtl.DTLVardef@17d535borg.highwire.dtl.DTLVardef@ebb79forg.highwire.dtl.DTLVardef@16464b7_HPS_FORMAT_FIGEXP M_FIG C_FIG Among older adults with chronic pain, pain extent and CSI-9 score captured different aspects of vulnerability. Slower performance on a task requiring attention and cognitive flexibility was concentrated in those with single-site pain and higher CSI-9 scores, whereas regional brain-volume differences tracked CSI-9 category more broadly.

Anxiety and maladaptive fear remain difficult to treat, and despite initial promising findings, evidence regarding the anxiolytic and translational potential of oxytocin (OT) remains inconsistent. In a preregistered, randomized, double-blind, placebo-controlled, parallel-group pharmaco-fMRI study in 67 healthy men, we tested whether intranasal OT reduces post-exposure subjective fear during prolonged naturalistic viewing a horror movie comprising independently defined low-, medium-, and high-fear segments. OT reduced subjective fear following naturalistic threat exposure after accounting for pre-exposure baseline ratings. Neuroimaging analyses revealed that OT attenuated recruitment of the dorsolateral prefrontal cortex particularly during higher fear, and enhanced coupling of this region with the bilateral amygdala. At the large-scale network level, OT increased communication between frontoparietal/default-mode control networks and subcortical/limbic networks during high fear indicating more integrative fear regulation. A whole-brain fear neuromarker (CAFE) further confirmed intensity-dependent OT effects. Together, these findings indicate that OT modulates post-exposure fear experience and fear-related neural dynamics in ecologically valid contexts.

Transcranial alternating current stimulation (tACS) is a promising noninvasive intervention for modulating pathological brain oscillations in Parkinson's disease (PD). To evaluate its clinical and neurophysiological efficacy, we searched five databases (Web of Science, PubMed, Scopus, Google Scholar and APA PsycInfo) up to August 31, 2025, for trials employing tACS in patients with idiopathic PD. Risk of bias was assessed using the RoB 2 and ROBINS-I tools. Random-effects meta-analyses were used to calculate standardized (SMD) and unstandardized mean differences (MD) with 95% confidence intervals (CIs). We included 10 studies (184 patients with PD, mean age: 64.9, mean disease duration: 5.2 years) in the qualitative review and seven trials (146 patients with PD, mean age: 65.6, mean disease duration: 5 years) in the meta-analysis. No statistically significant differences favoring active tACS over control were found in overall motor severity (UPDRS: SMD = 0.21, 95% CI [-0.10, 0.52], p = 0.097), tremor (SMD = -0.40, 95% CI [-1.97, 1.17], p = 0.478), or a neurophysiological marker of inhibitory response, represented by short intracortical inhibition (MD = 0.00, 95% CI [-0.40, 0.41], p = 0.971). The prediction intervals indicated substantial uncertainty, and significant between-study heterogeneity was observed, particularly for tremor outcomes (I2 = 86.1%). This variability and limitation in evidence quality is largely driven by small sample sizes, highly heterogeneous stimulation protocols, and varying outcome assessments. Systematically, tACS was generally well-tolerated, with no serious adverse events reported across the included studies; however, formal safety assessment was beyond the scope of this review. Current exploratory evidence shows a lack of consistent improvements in motor symptoms or functions in PD largely due to protocol-level heterogeneity. Future studies should consistently assess the MDS-UPDRS III post-tACS and report its specific subscores alongside neurophysiological measures to enable robust meta-analyses.

Can grammatical gender in a bilingual's first language shape gender-stereotype processing in a second language? Spanish (L1)-English (L2) bilinguals (n = 28) and English monolinguals (n = 28) completed an event-related potential (ERP) priming task in which English pronouns (SHE/HE) followed gender-stereotyped English nouns, half of which had gender-marked Spanish translation equivalents (e.g., NURSE 'enfermera/o', SURGEON 'cirujana/o'), and half unmarked translation equivalents (e.g., SINGER 'cantante', JANITOR 'conserje'). Both groups showed asymmetric stereotype priming: male pronouns elicited a larger N400 for incongruent than congruent primes, whereas female pronouns elicited a larger P300 for incongruent than congruent primes. Crucially, only bilinguals showed modulation by Spanish grammatical gender marking: the N400 effect for male pronouns was larger for primes with gender-marked than unmarked Spanish translations. These findings provide neural evidence that grammatical gender in a bilingual's first language can influence gender-stereotype processing in a second language, linking cross-linguistic activation to social cognition.