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The 2019 MSD Teaching Excellence Awards were celebrated in a ceremony at Merton College on Wednesday 23 October.
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Image credit: Rema Ramakrishnan
Yawning as Therapy? The Potential of the Conditioned Yawn Reflex as a Novel Treatment for Insomnia Disorder.
In 1986, Provine, the pioneer of yawning research wrote that 'Yawning may have the dubious distinction of being the least understood, common human behaviour' (p. 120); and so yawning remains some 40 years later, as something of a biological and social curiosity. However, this article examines contemporary scientific understanding of this age-old conundrum, proposing not only that yawning is a universal component of sleep's normal stimulus control paradigm, but that the conditioned yawn reflex might be harnessed to treat insomnia disorder. The core features of yawning as a ubiquitous, involuntary, periodic and conditionable behaviour; its associated actions on arousal, biofeedback and selective attention, as well as thermoregulation and airway patency; and its potential to signal and promote sleep engagement, lead to the proposition that the conditioned yawn reflex as therapy (CYRaT) is a feasible and potentially effective novel therapeutic for sleep-onset and sleep-maintenance insomnia disorder. Much research is required to test this hypothesis, but the article describes preliminary protocols for the administration and testing of CYRaT that might be utilised for this purpose.
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.
Cryoneurolysis: A Novel Treatment for Management of Spasticity. Presentation of a Case Series
Background: Spasticity is a motor phenomenon occurring in disorders of the central nervous system that impacts on active and passive function, and quality of life. Pharmacological, physical and surgical management options are available, each of which have limitations. Cryoneurolysis is a technique developed for the treatment of pain which involves the controlled freezing and thawing of peripheral nerves. Recent case reports and series have suggested it may offer a novel treatment approach for pain associated with spasticity. Objectives: To report on the evaluation of cryoneurolysis in the first cohort of patients treated in a UK spasticity clinic. Methods: Eight patients with a variety of neurological conditions (aged 25-75 years) underwent cryoneurolysis. Each had been receiving regular botulinum toxin injections and had ongoing treatment goals. All patients first underwent diagnostic nerve blocks with local anaesthetic to determine their appropriateness for the treatment. Cryoneurolysis was then performed with ultrasound and nerve stimulator guidance. Assessments included goal attainment, Modified Ashworth Scale (MAS), ArmA, LegA and the patient reported impact of spasticity scale (PRISM), alongside patient satisfaction and side effect questionnaires. Assessments were at baseline and at regular intervals over 9 to 12 months. Results: All patients attained at least one of their goals, with sustained effect for more than 6 months. MAS demonstrated mixed or modest improvements. Functional outcome measures (ArmA/LegA) showed several meaningful improvements, particularly in passive function. There was an indication of an improvement in PRISM across domains, which plateaued at 6 months. Post-procedure pain was the most common side effect but subsided in all affected patients by 3 months. Patient satisfaction was positive. Conclusions: Our findings contribute to a growing base of case reports and series suggesting that cryoneurolysis could be a potentially useful treatment modality for spasticity. Future controlled studies should aim to evaluate cost-effectiveness and compare with existing treatments.
Registered reports in neuropsychology: Insights from the burning houses study
We recently completed our first registered report project within a neuropsychological population (Moore et al., 2025). In this project, we set out to evaluate the replicability of the seminal case study by Marshall & Halligan (1988) on pre-attentive semantic processing in neglect, and replicated this effect under stringent experimental conditions. Our undertaking of this registered report study spanned over five years. In this viewpoint, we aim to share our personal reflections on this project in the hope that our experiences (and setbacks) can prove helpful for future studies aiming to conduct registered reports in neuropsychological populations. More broadly, our experience with this project provides a salient example of the challenges faced by registered report studies which may help account for the low uptake of this format in neuropsychology. Ultimately, we believe that encouraging adherence to fundamental open science practices including openly pre-registering plans and open reporting of data/code should be prioritised in neuropsychology and call for targeted discussions surrounding registered report formats specific to neuropsychological studies.
The rising incidence of stroke in the young: epidemiology, causes and global impact.
Although reductions in stroke incidence have been reported over recent decades particularly in high-income countries, there has been a worrying trend since the start of the 21st century: stroke incidence in younger individuals (< 55 years) has not showed a similar decrease than at older ages. In high-income countries, several population-based studies have found an increase in the incidence of stroke at younger ages since 2000, reaching up to 90% in Oxfordshire, UK (2010-2018 vs 1981-1986) and 97% in Cincinnati, US (2010 vs 1993-1994). A similar picture has also been documented in low- and middle-income countries, both in population-based studies (Joinville, Brazil, 35% increase in 2012-2013 vs 2005-2006) and in the Global Burden of Diseases Study. The exact reasons for this very different picture seen in younger individuals are unknown. One possibility is that traditional modifiable risk factors are increasingly prevalent and often undertreated at younger ages. However, studies have also found increases in the incidence of young-onset cryptogenic stroke and in people with no traditional modifiable risk factors, suggesting a role for emerging risk factors. Potential culprits might include air pollution, long working hours, psychosocial stress, prior autoimmune diseases, and illicit drug use, although further research is required to determine whether these emerging risk factors are causally related to stroke at younger ages. Without further intervention, the global burden of stroke at younger ages is projected to increase further in the coming years. Therefore, there is an urgent need to better understand the drivers of these time trends in incidence, to potentially alleviate the individual and societal impacts of stroke in the young. In this narrative review, we examine the recent global changes in stroke epidemiology at younger ages, their potential drivers, and their projected consequences.
Interleukin-6, C-Reactive Protein, and Vascular Recurrence After Stroke With and Without Atherosclerosis.
BACKGROUND: Uncertainty remains whether inflammation is implicated in poststroke recurrence in patients without atherosclerosis. We evaluated the contribution of atherosclerosis status to the association between inflammatory markers and major adverse cardiovascular events (MACE) poststroke. METHODS: We performed an individual-participant data meta-analysis of 11 prospective cohorts (12 countries, 1995-2017). Studies included patients with ischemic stroke/transient ischemic attack and measured IL (interleukin)-6/hsCRP (high-sensitivity C-reactive protein) postevent. We analyzed the association between IL-6/hsCRP and recurrent stroke/MACE using multivariable Cox regression analyses (conditional logistic regression for 1 study). Analyses were stratified by the presence/absence of atherosclerosis (definition: prior history of coronary disease, peripheral artery disease, or large artery atherosclerotic stroke) and adjusted for cardiovascular risk factors/preventative medication. RESULTS: Overall 10 148 patients (3448 [34.0%] had atherosclerosis) with 21 177 years of follow-up were included (1707 MACE outcomes/1353 recurrent strokes). In patients with atherosclerosis, IL-6 was independently associated with MACE (risk ratio [RR], 1.22 [95% CI, 1.08-1.37]; per logeunit increase) and recurrent stroke (RR, 1.23 [95% CI, 1.08-1.41]). Compared with patients in the bottom quarter, those in the top quarter of IL-6 levels had double the risk of MACE (RR, 2.05 [95% CI, 1.37-3.08]) and stroke (RR, 1.97 [95% CI, 1.28-3.05]). IL-6 was also associated with MACE (RR, 1.11 [95% CI, 1.01-1.23]) but not stroke (RR, 1.08 [95% CI, 0.98-1.20]; per logeunit) in patients without atherosclerosis. However, there was no evidence of statistical interaction between IL-6 levels and atherosclerosis status for either outcome (Pinteraction=0.25 and 0.13 for MACE/recurrent stroke, respectively). hsCRP was associated with MACE in patients with (RR, 1.12 [95% CI, 1.05-1.21]; per logeunit) and without atherosclerosis (RR, 1.07 [95% CI, 1.01-1.14]; Pinteraction=0.28). No association with recurrent stroke was observed for hsCRP with (RR, 1.06 [95% CI, 0.98-1.14]) or without atherosclerosis (RR, 0.97 [95% CI, 0.91-1.04]; Pinteraction=0.18). CONCLUSIONS: IL-6/hsCRP were associated with poststroke recurrence irrespective of atherosclerosis. These data support the inclusion of patients in trials of anti-inflammatory therapies after stroke with elevated IL-6 or hsCRP, including those without prior atherosclerotic events.
Single neurons and networks in the claustrum integrate input from widespread cortical sources
Abstract The claustrum is thought to be one of the most highly interconnected forebrain structures but its organizing principles have yet to be fully explored at the level of single neurons. Here, we investigated the identity, connectivity, and activity of identified claustrum neurons to understand how the structure’s unique convergence of input and divergence of output support binding information streams. We found that neurons in the claustrum communicate with each other across efferent projection-defined modules which were differentially innervated by sensory and frontal cortical areas. Individual claustrum neurons were responsive to inputs from more than one cortical region in a cell-type and projection-specific manner, particularly between areas of frontal cortex. In vivo imaging of claustrum axons revealed responses to both unimodal and multimodal sensory stimuli. Finally, chronic claustrum silencing specifically reduced animals’ sensitivity to multimodal stimuli. These findings support the view that the claustrum is a fundamentally integrative structure, consolidating information from around the cortex and redistributing it following local computations.
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.).