Search results
Found 62204 matches for
A Phase 3 Trial of Inebilizumab in Generalized Myasthenia Gravis.
BACKGROUND: Autoimmune generalized myasthenia gravis is a disease that manifests with fluctuating muscle weakness. Inebilizumab is a monoclonal antibody that depletes CD19+ B cells, which are central to disease pathogenesis. METHODS: In this phase 3, double-blind, randomized, placebo-controlled trial, we enrolled participants with myasthenia gravis who had anti-acetylcholine receptor antibodies or anti-muscle-specific kinase antibodies. Participants were randomly assigned, in a 1:1 ratio, to receive intravenous inebilizumab (300 mg administered on days 1 and 15 for all, and additionally on day 183 for participants who were acetylcholine receptor antibody-positive) or matching placebo for 52 weeks (in participants who were acetylcholine receptor antibody-positive) or 26 weeks (in those who were muscle-specific kinase antibody-positive). Glucocorticoid therapy was tapered, starting at week 4, to a target of 5 mg per day by week 24. The primary end point was the change from baseline in the score on the Myasthenia Gravis Activities of Daily Living scale (MG-ADL; scores range from 0 to 24, with higher scores indicating greater disease activity) at week 26 in the combined acetylcholine receptor antibody-positive and muscle-specific kinase antibody-positive trial populations. A key secondary end point was the change from baseline in the score on the Quantitative Myasthenia Gravis scale (QMG; scores range from 0 to 39, with higher scores indicating greater disease activity) at week 26 in the combined population. Safety was assessed. RESULTS: A total of 238 participants underwent randomization (119 per group). Participants who received inebilizumab had a greater reduction in the MG-ADL score than those who received placebo (least-squares mean change, -4.2 vs. -2.2; adjusted difference, -1.9; 95% confidence interval [CI], -2.9 to -1.0; P<0.001) at week 26. Participants who received inebilizumab had a greater reduction in the QMG score than those who received placebo (least-squares mean change, -4.8 vs. -2.3; adjusted difference, -2.5; 95% CI, -3.8 to -1.2; P<0.001). The most common adverse events with inebilizumab were headache, cough, nasopharyngitis, infusion-related reactions, and urinary tract infections. Inebilizumab was not associated with a higher incidence of serious adverse events. CONCLUSIONS: In participants with acetylcholine receptor antibody-positive or muscle-specific kinase antibody-positive generalized myasthenia gravis, inebilizumab improved function and reduced disease severity. (Funded by Amgen; MINT ClinicalTrial.gov number, NCT04524273.).
Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment: consensus guidelines from a global Delphi panel.
Despite its superior effectiveness for treatment-resistant schizophrenia, clozapine has a high burden of adverse drug reactions (ADRs), which require monitoring and treatment. This global Delphi study has established consensus guidelines for absolute neutrophil count (ANC) thresholds for consideration of clozapine cessation and provided monitoring protocols for ADR management. Recommendations include lowering ANC cessation thresholds to 1·0 × 109 cells per L (0·5 × 109 cells per L for Duffy antigen receptor for chemokines-null individuals) and discontinuing routine ANC monitoring after 2 years. Comprehensive ADR monitoring every 3 months should address the metabolic syndrome, constipation, gastro-oesophageal reflux, sialorrhea, nocturnal enuresis, tachycardia, sleep apnoea, sedation, and other ADRs. Consumer representatives underscored the need for shared decision-making, streamlined monitoring, and accessible patient education. Although barriers persist, these findings support updating global policies to reduce burden on patients, enhance adherence, and optimise clinical outcomes. Incorporating evidence-based guidelines into practice could transform clozapine care, balancing safety with practicality to improve the lives of those with treatment-resistant schizophrenia.
An atlas of trait associations with resting-state and task-evoked human brain functional organizations in the UK Biobank.
Functional magnetic resonance imaging (fMRI) has been widely used to identify brain regions linked to critical functions, such as language and vision, and to detect tumors, strokes, brain injuries, and diseases. It is now known that large sample sizes are necessary for fMRI studies to detect small effect sizes and produce reproducible results. Here we report a systematic association analysis of 647 traits with imaging features extracted from resting-state and task-evoked fMRI data of more than 40,000 UK Biobank participants. We used a parcellation-based approach to generate 64,620 functional connectivity measures to reveal fine-grained details about cerebral cortex functional organizations. The difference between functional organizations at rest and during task was examined, and we have prioritized important brain regions and networks associated with a variety of human traits and clinical outcomes. For example, depression was most strongly associated with decreased connectivity in the somatomotor network. We have made our results publicly available and developed a browser framework to facilitate the exploration of brain function-trait association results (http://fmriatlas.org/).
Evaluating functional brain organization in individuals and identifying contributions to network overlap.
Individual differences in the spatial organization of resting-state networks have received increased attention in recent years. Measures of individual-specific spatial organization of brain networks and overlapping network organization have been linked to important behavioral and clinical traits and are therefore potential biomarker targets for personalized psychiatry approaches. To better understand individual-specific spatial brain organization, this paper addressed three key goals. First, we determined whether it is possible to reliably estimate weighted (non-binarized) resting-state network maps using data from only a single individual, while also maintaining maximum spatial correspondence across individuals. Second, we determined the degree of spatial overlap between distinct networks, using test-retest and twin data. Third, we systematically tested multiple hypotheses (spatial mixing, temporal switching, and coupling) as candidate explanations for why networks overlap spatially. To estimate weighted network organization, we adopt the Probabilistic Functional Modes (PROFUMO) algorithm, which implements a Bayesian framework with hemodynamic and connectivity priors to supplement optimization for spatial sparsity/independence. Our findings showed that replicable individual-specific estimates of weighted resting-state networks can be derived using high-quality fMRI data within individual subjects. Network organization estimates using only data from each individual subject closely resembled group-informed network estimates (which was not explicitly modeled in our individual-specific analyses), suggesting that cross-subject correspondence was largely maintained. Furthermore, our results confirmed the presence of spatial overlap in network organization, which was replicable across sessions within individuals and in monozygotic twin pairs. Intriguingly, our findings provide evidence that overlap between 2-network pairs is indicative of coupling. These results suggest that regions of network overlap concurrently process information from both contributing networks, potentially pointing to the role of overlapping network organization in the integration of information across multiple brain systems.
Corrigendum to “Relating TMS measures of GABAergic and Cholinergic signalling to attention” [Brain Stimul 18 (1) (2025) 507–508, (S1935861X24010489), (10.1016/j.brs.2024.12.853)]
The authors regret that some of the authors are omitted in the original publication. The correct list of authors is as presented above. The authors also regret the errors in the abstract text. The corresponding corrections are provided below: The first line of paragraph 3 of the abstract should read: Here we investigated the role of GABA and ACh in healthy vision (n = 35). The last two paragraphs of the abstract should read as follows: We found that higher GABAergic Cholinergic inhibition in the motor cortex relates to better orienting attention allocation, as indicated by a significant correlation between the alerting orienting index of the ANT and SICI-1msSAI (r = −0.5942, p = 0.004). Despite the proposed role of Cholinergic signalling024). Our results are in line with evidence suggesting cholinergic mechanisms are responsible for successful orienting of attention, we did not find a significant correlation between SAI and any of the attentional indices (alerting, orienting, executive) of the ANT. Our findings suggest that GABAergic Cholinergic inhibition plays an important role in success fulorienting attention allocation and have guided the design of our ongoing pharmaco-TMS study investigating the effects of Zolpidem (GABA agonist) and Donepezil (cholinesterase antagonist) on behavioural and neurophysiological indices of attention. The authors would like to apologise for any inconvenience caused.
Human motor cortical gamma activity relates to GABAergic intracortical inhibition and motor learning
Gamma activity (γ, >30 Hz) is universally demonstrated across brain regions and species. However, the physiological basis and functional role of γ sub-bands (slow-γ, mid-γ, fast-γ) have been predominantly studied in rodent hippocampus; γ activity in the human neocortex is much less well understood. We use electrophysiology, non-invasive brain stimulation, and several motor tasks to examine the properties of sensorimotor γ activity sub-bands and their relationship with both local GABAergic activity and motor learning. Data from three experimental studies are presented. Experiment 1 (N = 33) comprises magnetoencephalography (MEG), transcranial magnetic stimulation (TMS), and a motor learning paradigm; experiment 2 (N = 19) uses MEG and motor learning; and experiment 3 (N = 18) uses EEG and TMS. We characterised two distinct γ sub-bands (slow-γ, mid-γ) which show a movement-related increase in activity during unilateral index finger movements and are characterised by distinct temporal–spectral–spatial profiles. Bayesian correlation analysis revealed strong evidence for a positive relationship between slow-γ (~30–60 Hz) peak frequency and GABAergic intracortical inhibition (as assessed using the TMS-metric short interval intracortical inhibition). There was also moderate evidence for a relationship between the power of the movement-related mid-γ activity (60–90 Hz) and motor learning. These relationships were neurochemical and frequency specific. These data provide new insights into the neurophysiological basis and functional roles of γ activity in human M1 and allow the development of a new theoretical framework for γ activity in the human neocortex.
Automated quality control of T1-weighted brain MRI scans for clinical research datasets: methods comparison and design of a quality prediction classifier
T1-weighted (T1w) MRI is widely used in clinical neuroimaging for studying brain structure and its changes, including those related to neurodegenerative diseases, and as anatomical reference for analysing other modalities. Ensuring high-quality T1w scans is vital as image quality affects reliability of outcome measures. However, visual inspection can be subjective and time consuming, especially with large datasets. The effectiveness of automated quality control (QC) tools for clinical cohorts remains uncertain. In this study, we used T1w scans from elderly participants within ageing and clinical populations to test the accuracy of existing QC tools with respect to visual QC and to establish a new quality prediction framework for clinical research use. Four datasets acquired from multiple scanners and sites were used (N = 2438, 11 sites, 39 scanner manufacturer models, 3 field strengths—1.5T, 3T, 2.9T, patients and controls, average age 71 ± 8 years). All structural T1w scans were processed with two standard automated QC pipelines (MRIQC and CAT12). The agreement of the accept–reject ratings was compared between the automated pipelines and with visual QC. We then designed a quality prediction framework that combines the QC measures from the existing automated tools and is trained on clinical research datasets. We tested the classifier performance using cross-validation on data from all sites together, also examining the performance across diagnostic groups. We then tested the generalisability of our approach when leaving one site out and explored how well our approach generalises to data from a different scanner manufacturer and/or field strength from those used for training, as well as on an unseen new dataset of healthy young participants with movement-related artefacts. Our results show significant agreement between automated QC tools and visual QC (Kappa = 0.30 with MRIQC predictions; Kappa = 0.28 with CAT12’s rating) when considering the entire dataset, but the agreement was highly variable across datasets. Our proposed robust undersampling boost (RUS) classifier achieved 87.7% balanced accuracy on the test data combined from different sites (with 86.6% and 88.3% balanced accuracy on scans from patients and controls, respectively). This classifier was also found to be generalisable on different combinations of training and test datasets (average balanced accuracy of leave-one-site-out = 78.2%; exploratory models on field strengths and manufacturers = 77.7%; movement-related artefact dataset when including 1% scans in the training = 88.5%). While existing QC tools may not be robustly applicable to datasets comprising older adults, they produce quality metrics that can be leveraged to train more robust quality control classifiers for ageing and clinical cohorts.
Brain and muscle chemistry in myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and long COVID: a 7T magnetic resonance spectroscopy study.
Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a common debilitating medical condition, whose main symptoms - fatigue, post-exertional malaise and cognitive dysfunction - are also present in many cases of long COVID. Magnetic resonance spectroscopy (MRS) allows the insight into their pathophysiology through exploration of a range of biochemicals putatively relevant to aetiological processes, in particular mitochondrial dysfunction and energy metabolism. 24 patients with ME/CFS, 25 patients with long COVID and 24 healthy controls (HC) underwent brain (pregenual and dorsal anterior cingulate cortex, respectively, pgACC and dACC) and calf muscle MRS scanning at 7 Tesla, followed by a computerised cognitive assessment. Compared to HC, ME/CFS patients had elevated levels of lactate in both pgACC and dACC, while long COVID patients had lowered levels of total choline in dACC. By contrast, skeletal muscle metabolites at rest did not significantly differ between the groups. The changes in lactate in ME/CFS are consistent with the presence of energetic stress and mitochondrial dysfunction. A reduction in total choline in long COVID is of interest in the context of the recently reported association between blood clots and 'brain fog', and earlier animal studies showing that choline might prevent intravascular coagulation. Importantly, differences in findings between ME/CFS and long COVID suggest that the underlying neurobiological mechanisms, while leading to similar clinical presentations, may differ. An important implication is that patients with ME/CFS and those with fatigue in the course of long COVID should not be studied as a single group, at least until the mechanisms are better understood.
Negative bias in encoding and recall memory in depressed patients with inadequate response to antidepressant medication.
RATIONALE: Cognitive theories propose that negative biases in emotional processing contribute to the maintenance of depressive states. Previous studies reported that acute antidepressant treatment in depressed patients reversed negative emotional biases. However, studies addressing the differences in emotional processing between healthy volunteers and clinically depressed patients with inadequate response to standard antidepressant treatments are limited. OBJECTIVES: To investigate the differences in emotional processing domains between depressed patients with inadequate response to current antidepressant treatment and healthy controls. METHODS: Fifty-four medicated patients with major depression and 45 age- and sex-equated healthy volunteers were tested using the Oxford Emotional Testing Battery. RESULTS: There was no difference between the two groups in the accuracy of recognising emotional facial expressions. However, there was a significant difference in the pattern of response times in an emotional categorisation task (F1,97 = 6.44, p = 0.013, partial η2 = 0.017) where healthy controls had faster responses towards positive than negative self-referent words (95%CI: -0.291 - -0.054, p = 0.005). In contrast, patients had no significant differences in reaction time for categorizing positive and negative self-referent descriptors. There was also a significant group interaction in an emotional memory task (F1,91 = 7.90, p = 0.006, partial η2 = 0.080) where healthy volunteers recalled significantly more positively valenced words than depressed patients (95%CI: -2.104 - -0.168, p = 0.022). CONCLUSIONS: Depressed patients with inadequate responses toward antidepressants had negative biases in emotional categorisation and emotional memory. These psychological abnormalities may represent targets for treatment in patients with difficult-to-treat depression.
The molecular circadian clock: From fundamental mechanisms to therapeutic promise in neurological disorders.
Circadian rhythms are intrinsic biological processes in all forms of life, governed by a molecular clock, organising physiological and behavioural cycles to align with a 24-hour light-dark cycle. The disruption of these rhythms has been linked to a plethora of neurological conditions and impacting cognitive and metabolic functions. This review offers a clear overview of the genetic and molecular mechanisms that govern the circadian clock. It focuses on the core clock feedback loops, the pathways involved and how these mechanisms are regulated. We explore how clocks in peripheral tissues are synchronised to the suprachiasmatic nucleus and how this is achieved through neuronal and humoral pathways. Additionally, we discuss how dysregulation in circadian rhythms contribute to neurological conditions and potential therapeutic treatments targeting circadian mechanisms. Understanding the mechanisms of circadian dysregulation provides insight into disease pathology and potential therapies. Interventions targeting circadian mechanisms, such as gene and drug delivery systems, show promise to restore rhythms and mitigate neurological symptoms. This review collates current knowledge on circadian biology and its applications addressing neurological dysfunctions, providing a foundation for potential chronotherapeutic interventions.
Transdiagnostic early warning score for psychiatric hospitalisation: development and evaluation of a prediction model.
BACKGROUND: The lack of an early warning score for psychiatric hospitalisation means that the decision to initiate preventative interventions is based solely on clinical judgement, which is prone to bias. OBJECTIVE: The objective is to develop and externally validate a transdiagnostic score that predicts psychiatric hospitalisation. METHODS: In this retrospective cohort study using deidentified electronic health records from 20 healthcare organisations in the NeuroBlu Data, we identified all patients with any of seven major psychiatric disorders with at least five Clinical Global Impressions of Severity and five Global Assessment of Functioning measured over a period of 6 consecutive months before any hospitalisation. From these measurements, metrics of clinical severity and instability and functional severity and instability were derived and incorporated into a score predicting the 6-month risk of incident psychiatric hospitalisation. Discrimination and calibration of this score were validated in an external sample. The transdiagnostic validity of the score was evaluated and its performance was compared between white and non-white people. FINDINGS: Altogether, 37 049 individuals (531 incident hospitalisations) were included. The predictive model showed good discrimination in the training (optimism-adjusted c-index: 0.74, 95% CI 0.72 to 0.76) and external validation (c-index: 0.80, 95% CI 0.78 to 0.82) samples, with adequate calibration. Discrimination improved with adjustment for organisation-level hospitalisation rates (c-index: 0.80, 95% CI 0.78 to 0.82 and 0.84, 95% CI 0.82 to 0.86 in the derivation and validation samples). Good discrimination was also achieved for each diagnostic category (c-index: 0.71-0.82 and 0.64-0.75 with/without adjustment for organisation-level hospitalisation rates, respectively). There was no significant difference in model performance between white and non-white people. DISCUSSION: A transdiagnostic early warning system based on simple longitudinal measurements can reliably and robustly predict psychiatric hospitalisation. It will help target preventative interventions to individuals most at risk.
Neurodegenerative disease in C9orf72 repeat expansion carriers: population risk and effect of UNC13A.
The C9orf72 hexanucleotide repeat expansion (HRE) is the most common monogenetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neurodegenerative disease incidence in C9orf72 HRE carriers has been studied using cohorts from disease-affected families or by extrapolating from population disease incidence, potentially introducing bias. Age-specific cumulative incidence of ALS and dementia was estimated using Kaplan-Meier and competing risk models in C9orf72 HRE carriers compared to matched controls in UK Biobank. Risk modification by UNC13A genotype was examined. Of 490,331 individuals with valid genetic data, 701 had >100 repeats in C9orf72 (median age 55 [IQR 48-62], follow-up 13.4 years [12.3-14.1]). The cumulative incidence of ALS or dementia was 66% [95% CI 57-73%] by age 80 in C9orf72 HRE carriers versus 5.8% [4.5-7.0%] in controls, or 58% [50-64%] versus 5.1% [4.1-6.4%] accounting for the competing risk of other-cause mortality. Forty-one percent of dementia incidence accrued between age 75-80. C-allele homozygosity at rs12608932 in UNC13A increased ALS or dementia risk in C9orf72 HRE carriers (hazard ratio 1.81 [1.18 - 2.78]). C9orf72 HRE disease was incompletely penetrant in this population-based cohort, with risk modified by UNC13A genotype. This has implications for counselling at-risk individuals and modelling expected phenoconversion for prevention trials.
Crossmodal semantics in memory: Scoping review and meta-analyses of multisensory effects in short-term and episodic memory systems.
The human brain represents objects and events in the environment by binding together their defining semantic attributes across the senses (e.g., vision, hearing, touch). Semantic relationships between these attributes in different senses, or crossmodal semantic relationships, are fundamental to carving out meaningful categories and to encode and store experiences in the form of memories for later retrieval. Unsurprisingly, the subject of crossmodal semantic interactions in human memory has been on the agenda of researchers interested in multisensory processes for several decades now and there appears to be a renewed wave of interest in the field currently. By and large, the central question has been whether or not memories for events with crossmodally congruent semantic attributes are better remembered. Nevertheless, this research area has been characterized by mixed methodological approaches, inconsistent outcomes, and alternative theoretical interpretations, with few attempts at synthesis. Here, we examine the past 30 years of research on the topic, covering short-term as well as episodic memory systems. First, we garner existing evidence in a systematic scoping review of studies, complemented by meta-analyses. Then, we provide a synthesis highlighting outstanding empirical questions and potential contradictions between competing theoretical interpretations. With some exceptions, there is abundant support for the hypothesis that crossmodally congruent events are better remembered than single-modality or crossmodal but incongruent events. Nevertheless, the mechanisms underlying this multisensory benefit and its theoretical interpretation are still the subject of substantial debates. We propose avenues to resolve these issues and advance current knowledge in this burgeoning research area. (PsycInfo Database Record (c) 2025 APA, all rights reserved).
Computationally designed haemagglutinin with nanocage plug-and-display elicits pan-H5 influenza vaccine responses.
The increasing spread of highly pathogenic avian influenza (HPAI) A/H5 viruses poses a pandemic threat. Circulating clade 2.3.4.4b viruses have demonstrated rapid transcontinental dissemination, extensive reassortment, epizootic spread and potential sustained mammal-to-mammal transmission, signifying a heightened risk of becoming a human pathogen of high consequence. A broadly protective, future-proof vaccine against multiple clades of H5 influenza is urgently needed for pandemic preparedness. Here, we combine two novel vaccine technologies to generate a Digitally Immune Optimised and Selected H5 antigen (DIOSvax-H5inter) displayed multivalently on the mi3 nanocage using the SpyTag003/SpyCatcher003 conjugation system. Mice immunized with DIOSvax-H5inter Homotypic Nanocages at low doses demonstrate potent, cross-clade neutralizing antibody and T cell responses against diverse H5 strains. DIOSvax-H5inter Homotypic Nanocages provide a scalable vaccine candidate with the potential for pan-H5 protection against drifted or newly emergent H5 strains. This World Health Organization preferred characteristic is essential for prospective strategic stockpiling in the pre-pandemic phase.
The SpyBLI cell-free pipeline for the rapid quantification of binding kinetics from crude samples.
Accurate measurements of binding kinetics, encompassing equilibrium dissociation constant (K D), association rate (k on), and dissociation rate (k off), are critical for the development and optimisation of high-affinity binding proteins. However, such measurements require highly purified material and precise ligand immobilisation, limiting the number of binders that can be characterised within a reasonable timescale and budget. Here, we present the SpyBLI method, a rapid and cost-effective biolayer interferometry (BLI) pipeline that leverages the SpyCatcher003-SpyTag003 covalent association, eliminating the need for both binder purification and concentration determination. This approach allows for accurate binding-kinetic measurements to be performed directly from crude mammalian-cell supernatants or cell-free expression blends. We also introduce a linear gene fragment design that enables reliable expression in cell-free systems without any PCR or cloning steps, allowing binding kinetics data to be collected in under 24 hours from receiving inexpensive DNA fragments, with minimal hands-on time. We demonstrate the method's broad applicability using a range of nanobodies and single-chain antibody variable fragments (scFvs), with affinity values spanning six orders of magnitude. By minimising sample preparation and employing highly controlled, ordered sensor immobilisation, our workflow delivers reliable kinetic measurements from crude mixtures without sacrificing precision. We expect that the opportunity to carry out rapid and accurate binding measurements in good throughput should prove especially valuable for binder engineering, the screening of next-generation sequencing-derived libraries, and computational protein design, where large numbers of potential binders for the same target must be rapidly and accurately characterised to enable iterative refinement and candidate selection.
Origin and evolution of bacterial periplasmic force transducers.
In double-membraned bacteria, non-equilibrium processes that occur at the outer membrane (OM) are typically coupled to the chemiosmotically-energised inner membrane (IM). TolA and TonB are homologous proteins which energetically couple IM motor proteins to the essential processes of OM-stabilisation and substrate import, respectively. The evolutionary trajectories of these proteins have been difficult to elucidate due to low sequence conservation, yet they are thought to transduce force similarly. Here, this problem was addressed using structural prediction approaches to identify and annotate force transduction operons to trace their distribution and evolutionary origins. In the process, we identify a novel OM-tethering system and a previously unknown family of monomeric force transducers. This approach revealed putative tolA genes, and thus the core organisational principles of the tol-pal operon throughout diverse bacterial taxa. We discovered that the α-helical structure of the periplasm-spanning domain II of TolA previously thought its hallmark, is anomalous amongst most Tol-Pal systems. This structure is mainly prevalent in γ-proteobacteria, likely in adaptation to their lifestyle. Comparison of Tol-Pal and Ton system distribution suggests that TolA emerged from a TonB paralogue and co-emerged with Pal, the OM-tethering lipoprotein that functionalises the Tol-Pal system. We also determined that TolB, the Pal-mobilising protein, likely emerged from a family of outer membrane proteins (OMPs); and CpoB, a periplasmic factor that coordinates peptidoglycan remodelling with cell division, was originally a lipoprotein present in the ancestral Tol-Pal system. The extensive conservation of the Tol-Pal system throughout Gracilicutes highlights its significance in bacterial cell biology.
Differential Associations of Dopamine and Serotonin With Reward and Punishment Processes in Humans: A Systematic Review and Meta-Analysis.
IMPORTANCE: Mechanistic biomarkers for guiding treatment selection require selective sensitivity to specific pharmacological interventions. Reinforcement learning processes show potential, but there have been conflicting and sometimes inconsistent reports on how dopamine and serotonin-2 key targets in treating common mental illnesses-affect reinforcement learning in humans. OBJECTIVE: To perform a meta-analysis of pharmacological manipulations of dopamine and serotonin and examine whether they show distinct associations with reinforcement learning components in humans. DATA SOURCES: Ovid MEDLINE/PubMed, Embase, and PsycInfo databases were searched for studies published between January 1, 1946, and January 19, 2023 (repeated April 9, 2024, and October 15, 2024), investigating dopaminergic or serotonergic effects on reward and punishment processes in humans according to PRISMA guidelines. STUDY SELECTION: Studies reporting randomized, placebo-controlled, dopaminergic or serotonergic manipulations on a behavioral outcome from a reward or punishment processing task in healthy humans were included. DATA EXTRACTION AND SYNTHESIS: Standardized mean difference (SMD) scores were calculated for the comparison between each drug (dopamine or serotonin) and placebo on a behavioral reward or punishment outcome and quantified in random-effects models for overall reward or punishment processes and 4 main subcategories. Study quality (Cochrane Collaboration tool), moderators, heterogeneity, and publication bias were also assessed. MAIN OUTCOMES AND MEASURES: Performance on reward or punishment processing tasks. RESULTS: In total, 102 studies conducted among healthy volunteers were included (2291 participants receiving dopamine vs 2284 receiving placebo and 1491 receiving serotonin vs 1523 receiving placebo). Dopamine was associated with an increase in overall reward (SMD, 0.18; 95% CI, 0.09 to 0.28) but not punishment function (SMD, -0.06; 95% CI, -0.26 to 0.13). Serotonin was not meaningfully associated with overall punishment (SMD, 0.22; 95% CI, -0.04 to 0.49) or reward (SMD, 0.02; 95% CI, -0.33 to 0.36). Dopaminergic and serotonergic manipulations had distinct associations with subcomponents. Dopamine was associated with reward learning or sensitivity (SMD, 0.26; 95% CI, 0.11 to 0.40), reward discounting (SMD, -0.08; 95% CI, -0.14 to -0.01), and reward vigor (SMD, 0.32; 95% CI, 0.11 to 0.54). By contrast, serotonin was associated with punishment learning or sensitivity (SMD, 0.32; 95% CI, 0.05 to 0.59), reward discounting (SMD, -0.35; 95% CI, -0.67 to -0.02), and aversive pavlovian processes (within-participant studies only; SMD, 0.36; 95% CI, 0.20 to 0.53). CONCLUSIONS AND RELEVANCE: In this study, pharmacological manipulations of both dopamine and serotonin had measurable associations with reinforcement learning in humans. The selective associations with different components suggest that reinforcement learning tasks could form the basis of selective, mechanistically interpretable biomarkers to support treatment assignment.