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48 of the UK's leading medical researchers have been recognised for excellence in medical science with their election to the Academy Fellowship.
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.
Evaluating functional brain organization in individuals and identifying contributions to network overlap
Abstract 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.
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/).
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.).
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.
Automated quality control of T1-weighted brain MRI scans for clinical research datasets: methods comparison and design of a quality prediction classifier
Abstract 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.
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.
Using arterial spin labelling to investigate spontaneous and evoked ongoing musculoskeletal pain
Clinical pain is difficult to study using standard Blood Oxy-genation Level Dependent (BOLD) magnetic resonance imaging because it is often ongoing and, if evoked, it is associated with stimulus-correlated motion. Arterial spin labelling (ASL) offers an attractive alternative. This study used arm repositioning to evoke clinically-relevant musculoskeletal pain in patients with shoulder impingement syndrome. Fifty-five patients were scanned using a multi post-labelling delay pseudo-continuous ASL (pCASL) sequence, first with both arms along the body and then with the affected arm raised into a painful position. Twenty healthy volunteers were scanned as a control group. Arm repositioning resulted in increased perfusion in brain regions involved in sensory processing and movement integration, such as the contralateral primary motor and primary somatosensory cortex, mid- and posterior cingulate cortex, and, bilaterally, in the insular cortex/operculum, putamen, thalamus, midbrain and cerebellum. Perfusion in the thalamus, midbrain and cerebellum was larger in the patient group. Results of a post hoc analysis suggested that the observed perfusion changes were related to pain rather than arm repositioning. This study showed that ASL can be useful in research on clinical ongoing musculoskeletal pain but the technique is not sensitive enough to detect small differences in perfusion.
The GLM-spectrum: A multilevel framework for spectrum analysis with covariate and confound modelling
AbstractThe frequency spectrum is a central method for representing the dynamics within electrophysiological data. Some widely used spectrum estimators make use of averaging across time segments to reduce noise in the final spectrum. The core of this approach has not changed substantially since the 1960s, though many advances in the field of regression modelling and statistics have been made during this time. Here, we propose a new approach, the General Linear Model (GLM) Spectrum, which reframes time averaged spectral estimation as multiple regression. This brings several benefits, including the ability to do confound modelling, hierarchical modelling, and significance testing via non-parametric statistics. We apply the approach to a dataset of EEG recordings of participants who alternate between eyes-open and eyes-closed resting state. The GLM-Spectrum can model both conditions, quantify their differences, and perform denoising through confound regression in a single step. This application is scaled up from a single channel to a whole head recording and, finally, applied to quantify age differences across a large group-level dataset. We show that the GLM-Spectrum lends itself to rigorous modelling of within- and between-subject contrasts as well as their interactions, and that the use of model-projected spectra provides an intuitive visualisation. The GLM-Spectrum is a flexible framework for robust multilevel analysis of power spectra, with adaptive covariate and confound modelling.
Human motor cortical gamma activity relates to GABAergic intracortical inhibition and motor learning
Abstract 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.
Cerebrovascular variability interactions after acute ischemic stroke: insights from directionality analysis based on transfer entropy.
Dynamic cerebral autoregulation (CA) limits fluctuations of mean cerebral blood flow, approximated as mean cerebral blood velocity (MCBv) measured via transcranial Doppler ultrasound, in the presence of variations of mean arterial pressure (MAP). This mechanism is impaired after acute ischemic stroke (AIS). CA impairment is usually assessed by hypothesizing that MAP variations are completely responsible for MCBv changes, while disregarding the MCBv contributions to MAP variability. We exploited transfer entropy (TE) and conditional TE (CTE) to assess the strength of the directional interactions from MAP to MCBv and vice versa accounting for partial pressure of end-tidal carbon dioxide. Traditional markers were computed for comparison. We analyzed recordings from 34 control individuals (CTRL, age: 66 ± 7 yrs) and 48 AIS patients (age: 66 ± 13 yrs) acquired within 48 hours of stroke symptom onset. MCBv was recorded in both hemispheres including affected and unaffected hemispheres in AIS patients. AIS patients exhibited hypertension and hypocapnia. After AIS MCBv diminished, especially in the affected hemisphere. TE and CTE decreased along the pressure-to-flow pathway as well. Both directional markers tended to increase along the flow-to-pressure arm irrespective of the hemisphere. Traditional indexes could not detect any difference. Our analysis suggests that the CA impairment was characterized by an imbalance of information transfer within the MCBv-MAP closed loop with a reduced importance of the pressure-to-flow and increased relevance of the flow-to-pressure arm. The study stresses the relevance of assessing MCBv-MAP relationship in closed loop especially when variability of MAP and MCBv are considered.
Dynamics of Critical Closing Pressure Explain Cerebral Autoregulation Impairment in Acute Cerebrovascular Disease.
INTRODUCTION: Cerebral autoregulation (CA) is impaired in acute ischemic stroke (AIS) and is associated with worse patient outcomes, but the underlying physiological cause is unclear. This study tests whether depressed CA in AIS can be linked to the dynamic responses of critical closing pressure (CrCP) and resistance area product (RAP). METHODS: Continuous recordings of middle cerebral blood velocity (MCAv, transcranial Doppler), arterial blood pressure (BP), end-tidal CO2 and electrocardiography allowed dynamic analysis of the instantaneous MCAv-BP relationship to obtain estimates of CrCP and RAP. The dynamic response of CrCP and RAP to a sudden change in mean BP was obtained by transfer function analysis. Comparisons were made between younger controls (≤50 years), older controls (>50 years), and AIS patients. RESULTS: Data from 24 younger controls (36.4 ± 10.9 years, 9 male), 38 older controls (64.7 ± 8.2 years, 20 male), and 20 AIS patients (63.4 ± 13.8 years, 9 male) were included. Dynamic CA was impaired in AIS, with lower autoregulation index (affected hemisphere: 4.0 ± 2.3, unaffected: 4.5 ± 1.8) compared to younger (right: 5.8 ± 1.4, left: 5.8 ± 1.4) and older (right: 4.9 ± 1.6, left: 5.1 ± 1.5) controls. AIS patients also demonstrated an early (0-3 s) peak in CrCP dynamic response that was not influenced by age. CONCLUSION: These early transient differences in the CrCP dynamic response are a novel finding in stroke and occur too early to reflect underlying regulatory mechanisms. Instead, these may be caused by structural changes to cerebral vasculature.
Baseline serum ferritin predicts myocardial iron uptake following intravenous iron therapy - a hypothesis-generating study.
AIMS: Many patients with heart failure (HF) are iron-deficient. Intravenous (IV) iron therapy improves symptoms and reduces hospitalizations for HF. Several mechanisms have been proposed, including myocardial iron repletion. However, it is unknown if serum iron markers predict the extent of this repletion. To address this question, data from two clinical studies that evaluated changes in myocardial iron using cardiac magnetic resonance (CMR) were harnessed. METHODS AND RESULTS: The Myocardial-IRON trial measured change in myocardial iron, denoted by a decrease in CMR T1 and T2*, at 7 and 30 days after IV ferric carboxymaltose (FCM) in patients with iron deficiency (ID) and HF (n = 53). The STUDY trial measured myocardial and spleen iron at multiple timepoints after FCM in patients with ID without HF (n = 12). In this post-hoc analysis, we examined the association between baseline serum iron markers (transferrin saturation and ferritin) and change in myocardial iron in the weeks after FCM therapy. Changes in spleen iron were also examined, due its role as an intermediary in the redistribution of iron from iron-carbohydrate complexes such as FCM. In patients with or without HF, higher serum ferritin at baseline predicted lower rise in myocardial iron in the weeks after therapy with FCM. In contrast, higher serum ferritin at baseline predicted a greater rise in spleen iron. CONCLUSIONS: These data point towards the hypothesis that functional ID, which is characterized by elevated ferritin, could limit myocardial iron repletion after IV iron therapy, by favouring iron trapping in the spleen.
Implementing Acute Stroke Services in Sub-Saharan Africa: Steps, Progress, and Perspectives from the Tanzania Stroke Project.
INTRODUCTION: Stroke is a leading cause of morbidity and mortality globally, with Africa bearing a disproportionately high burden of poor outcomes. In sub-Saharan Africa, acute stroke care remains inconsistent, with organized stroke units being either absent or rarely available, contributing to the high stroke mortality rates in the region. To address this issue, the Tanzania Stroke Project (TSP) was launched, aimed at establishing acute stroke services at two of the largest tertiary care centers in collaboration with the Tanzanian Ministry of Health, the World Stroke Organization, and Hospital Directorates. METHODS: TSP utilized a three-tier implementation approach to establish a more organized stroke care system in two large academic hospitals. Here, we detail the process of this initiative, which took place between August 2023 and August 2024. The three-tier approach included (1) the establishment of stroke registries; (2) the training of healthcare workers (HCWs); and (3) the development of acute stroke protocols and establishment of stroke units at Muhimbili National Hospital-Mloganzila and Bugando Medical Center in Tanzania. RESULTS: In tier one (stroke registry), two comprehensive stroke registries were established, including 460 adults (mean age 60 ± 15 years). Hemorrhagic stroke was the most common subtype, accounting for 59% of cases (n = 269). Premorbid hypertension was the most prevalent risk factor, affecting 81% (n = 373) of the patients. More than half of patients (58%, n = 171) arrived at the hospital after 24 h from stroke symptoms. Only 11% (n = 50/452) had documented swallowing screenings, and among patients with intracerebral hemorrhage, 11% (n = 28/251) achieved the target for blood pressure control, while 47% (n = 99/213) met blood glucose control targets. The in-hospital mortality rate was 27% (n = 93/340). In tier two (training of HCWs), extensive evidence-based mentorship training was provided with higher participation rates among HCWs at Bugando Medical Center compared to Muhimbili National Hospital-Mloganzila (57% [29/51] vs. 23% [7/31], p = 0.002). In tier three (stroke unit protocols), stroke protocols were developed based on the training and current evidence, leading to the establishment of dedicated stroke units at each facility, with a minimum of 8 beds per unit. The full impact of these implementations has yet to be fully assessed. CONCLUSION: This was the first initiative to implement stroke services at two large tertiary healthcare centers in Tanzania. Our findings highlight the importance of multilevel stakeholder engagement through a 3-tier approach in countries starting to establish stroke services and the need for ongoing quality-of-care monitoring and continuous efforts to sensitize both HCWs and the broader community.
The spatiotemporal distribution of human pathogens in ancient Eurasia
Abstract Infectious diseases have had devastating effects on human populations throughout history, but important questions about their origins and past dynamics remain1. To create an archaeogenetic-based spatiotemporal map of human pathogens, we screened shotgun-sequencing data from 1,313 ancient humans covering 37,000 years of Eurasian history. We demonstrate the widespread presence of ancient bacterial, viral and parasite DNA, identifying 5,486 individual hits against 492 species from 136 genera. Among those hits, 3,384 involve known human pathogens2, many of which had not previously been identified in ancient human remains. Grouping the ancient microbial species according to their likely reservoir and type of transmission, we find that most groups are identified throughout the entire sampling period. Zoonotic pathogens are only detected from around 6,500 years ago, peaking roughly 5,000 years ago, coinciding with the widespread domestication of livestock3. Our findings provide direct evidence that this lifestyle change resulted in an increased infectious disease burden. They also indicate that the spread of these pathogens increased substantially during subsequent millennia, coinciding with the pastoralist migrations from the Eurasian Steppe4,5.
A Validated Model to Predict Severe Weight Loss in Amyotrophic Lateral Sclerosis
ABSTRACTSevere weight loss in amyotrophic lateral sclerosis (ALS) is common, multifactorial, and associated with shortened survival. Using longitudinal weight data from over 6000 patients with ALS across three cohorts, we built an accelerated failure time model to predict the risk of future severe (≥ 10%) weight loss using five single‐timepoint clinical predictors: symptom duration, revised ALS Functional Rating Scale, site of onset, forced vital capacity, and age. Model performance and generalisability were evaluated using internal–external cross‐validation and random‐effects meta‐analysis. The overall concordance statistic was 0.71 (95% CI 0.63–0.79), and the calibration slope and intercept were 0.91 (0.69–1.13) and 0.05 (−0.11–0.21). This study highlights clinical factors most associated with severe weight loss in ALS and provides the basis for a stratification tool.