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niimath and fslmaths: replication as a method to enhance popular neuroimaging tools
Neuroimaging involves the acquisition of extensive 3D images and 4D time series data to gain insights into brain structure and function. The analysis of such data necessitates both spatial and temporal processing. In this context, “fslmaths” has established itself as a foundational software tool within our field, facilitating domain-specific image processing. Here, we introduce “niimath,” a clone of fslmaths. While the term “clone” often carries negative connotations, we illustrate the merits of replicating widely-used tools, touching on aspects of licensing, performance optimization, and portability. For instance, our work enables the popular functions of fslmaths to be disseminated in various forms, such as a high-performance compiled R package known as “imbibe”, a Windows executable, and a WebAssembly plugin compatible with JavaScript. This versatility is demonstrated through our NiiVue live demo web page. This application allows ‘edge computing’ where image processing can be done with a zero-footprint tool that runs on any web device without requiring private data to be shared to the cloud. Furthermore, our efforts have contributed back to FSL, which has integrated the optimizations that we’ve developed. This synergy has enhanced the overall transparency, utility and efficiency of tools widely relied upon in the neuroimaging community.
MMORF—FSL’s MultiMOdal Registration Framework
Abstract We present MMORF—FSL’s MultiMOdal Registration Framework—a newly released nonlinear image registration tool designed primarily for application to magnetic resonance imaging (MRI) images of the brain. MMORF is capable of simultaneously optimising both displacement and rotational transformations within a single registration framework by leveraging rich information from multiple scalar and tensor modalities. The regularisation employed in MMORF promotes local rigidity in the deformation, and we have previously demonstrated how this effectively controls both shape and size distortion, leading to more biologically plausible warps. The performance of MMORF is benchmarked against three established nonlinear registration methods—FNIRT, ANTs, and DR-TAMAS—across four domains: FreeSurfer label overlap, diffusion tensor imaging (DTI) similarity, task-fMRI cluster mass, and distortion. The evaluation is based on 100 unrelated subjects from the Human Connectome Project (HCP) dataset registered to the Oxford-MultiModal-1 (OMM-1) multimodal template via either the T1w contrast alone or in combination with a DTI/DTI-derived contrast. Results show that MMORF is the most consistently high-performing method across all domains—both in terms of accuracy and levels of distortion. MMORF is available as part of FSL, and its inputs and outputs are fully compatible with existing workflows. We believe that MMORF will be a valuable tool for the neuroimaging community, regardless of the domain of any downstream analysis, providing state-of-the-art registration performance that integrates into the rich and widely adopted suite of analysis tools in FSL.
Improving the measurement properties of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R): deriving a valid measurement total for the calculation of change.
BACKGROUND: The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score is a widely used measure of functional status in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS), but recent evidence has raised doubts about its validity. The objective was to examine the measurement properties of the ALSFRS-R, aiming to produce valid measurement from all 12 scale items. METHOD: Longitudinal ALSFRS-R data were collected between 2013-2020 from 1120 people with ALS recruited from 35 centers, together with other scales in the Trajectories of Outcomes in Neurological Conditions-ALS (TONiC-ALS) study. The ALSFRS-R was analyzed by confirmatory factor analysis (CFA), Rasch Analysis (RA) and Mokken scaling. RESULTS: No definite factor structure of the ALSFRS-R was confirmed by CFA. RA revealed the raw score total to be invalid even at the ordinal level because of multidimensionality; valid interval level subscale measures could be found for the Bulbar, Fine-Motor and Gross-Motor domains but the Respiratory domain was only valid at an ordinal level. All four domains resolved into a single valid, interval level measure by using a bifactor RA. The smallest detectable difference was 10.4% of the range of the interval scale. CONCLUSION: A total ALSFRS-R ordinal raw score can lead to inferential bias in clinical trial results due to its non-linear nature. On the interval level transformation, more than 5 points difference is required before a statistically significant detectable difference can be observed. Transformation to interval level data should be mandatory in clinical trials.
Stroke in the Time of Circadian Medicine
Time-of-day significantly influences the severity and incidence of stroke. Evidence has emerged not only for circadian governance over stroke risk factors, but also for important determinants of clinical outcome. In this review, we provide a comprehensive overview of the interplay between chronobiology and cerebrovascular disease. We discuss circadian regulation of pathophysiological mechanisms underlying stroke onset or tolerance as well as in vascular dementia. This includes cell death mechanisms, metabolism, mitochondrial function, and inflammation/immunity. Furthermore, we present clinical evidence supporting the link between disrupted circadian rhythms and increased susceptibility to stroke and dementia. We propose that circadian regulation of biochemical and physiological pathways in the brain increase susceptibility to damage after stroke in sleep and attenuate treatment effectiveness during the active phase. This review underscores the importance of considering circadian biology for understanding the pathology and treatment choice for stroke and vascular dementia and speculates that considering a patient’s chronotype may be an important factor in developing precision treatment following stroke.
Research priorities in regional anaesthesia: an international Delphi study.
BACKGROUND: Regional anaesthesia use is growing worldwide, and there is an increasing emphasis on research in regional anaesthesia to improve patient outcomes. However, priorities for future study remain unclear. We therefore conducted an international research prioritisation exercise, setting the agenda for future investigators and funding bodies. METHODS: We invited members of specialist regional anaesthesia societies from six continents to propose research questions that they felt were unanswered. These were consolidated into representative indicative questions, and a literature review was undertaken to determine if any indicative questions were already answered by published work. Unanswered indicative questions entered a three-round modified Delphi process, whereby 29 experts in regional anaesthesia (representing all participating specialist societies) rated each indicative question for inclusion on a final high priority shortlist. If ≥75% of participants rated an indicative question as 'definitely' include in any round, it was accepted. Indicative questions rated as 'definitely' or 'probably' by <50% of participants in any round were excluded. Retained indicative questions were further ranked based on the rating score in the final Delphi round. The final research priorities were ratified by the Delphi expert group. RESULTS: There were 1318 responses from 516 people in the initial survey, from which 71 indicative questions were formed, of which 68 entered the modified Delphi process. Eleven 'highest priority' research questions were short listed, covering themes of pain management; training and assessment; clinical practice and efficacy; technology and equipment. CONCLUSIONS: We prioritised unanswered research questions in regional anaesthesia. These will inform a coordinated global research strategy for regional anaesthesia and direct investigators to address high-priority areas.
Gender-specific brain regional variation of neurons, endogenous estrogen, neuroinflammation and glial cells during rotenone-induced mouse model of Parkinson's disease
Rotenone (RT) produces reactive oxygen species (ROS) by inhibiting the mitochondrial electron transport chain; causing dopaminergic (DA) cell death in the substantia nigra (SN) and simulates other models of induced Parkinson's disease (PD). There is a sincere dearth of knowledge regarding the status of glial cells, neuroprotective estrogen and the status of neuroinflammatory TNF-α in the different brain regions in either sex during healthy, as well as during PD conditions. In the present study of RT-induced mouse model of PD, we have selected the frontal cortex (FC), hippocampus (HC) and SN from either sex of Swiss albino mice as these are the major regions involved during PD pathogenesis.During non pathogenic conditions, the ROS-scavenging enzyme activity varied among the brain regions and also in between genders. The number of DOPA decarboxylase-positive cells, astrocytes and microglia was similar in the respective regions of the brain in both the sexes. The level of proinflammatory cytokine TNF-α was same in the respective FC and HC in either sex except that of SN. The expression level of estrogen and its receptors varied among the three brain regions. During RT treatment, ROS-scavenging enzyme activities increased, DOPA decarboxylase-positive neurons and fibers in DA as well as in norepinephrinergic (NE) systems become degenerated, number of astrocytes decreased and microglial cells increased in those specific brain regions in either of the sexes except in the SN region of males where astrocyte number remained unaltered and microglial cell percentage decreased. TNF-α increased in the FC and SN but remained unaltered in the HC of both sexes. Estradiol level decreased in the HC and SN but the level unevenly varied in the FC. Similarly, the estrogen bound and nuclear-cytosolic receptor α and β also varied differentially among the brain regions of the two sexes.Therefore our present study depicts that there exists a clear variation of neuronal and astroglial cell population, estrogen and its receptor levels in different brain regions of both the sexes during control and RT-treated pathogenic condition and these variations have major implication in PD pathogenesis and progression.
Oxford Video Informed Consent Tool (OxVIC): a pilot study of informed video consent in spinal surgery and preoperative patient satisfaction
ObjectivesThe British Association of Spinal Surgeons recently called for updates in consenting practice. This study investigates the utility and acceptability of a personalised video consent tool to enhance patient satisfaction in the preoperative consent giving process.DesignA single-centre, prospective pilot study using questionnaires to assess acceptability of video consent and its impacts on preoperative patient satisfaction.SettingA single National Health Service centre with individuals undergoing surgery at a regional spinal centre in the UK.Outcome measureAs part of preoperative planning, study participants completed a self-administered questionnaire (CSQ-8), which measured their satisfaction with the use of a video consent tool as an adjunct to traditional consenting methods.Participants20 participants with a mean age of 56 years (SD=16.26) undergoing spinal surgery.ResultsMean patient satisfaction (CSQ-8) score was 30.2/32. Median number of video views were 2–3 times. Eighty-five per cent of patients watched the video with family and friends. Eighty per cent of participants reported that the video consent tool helped to their address preoperative concerns. All participants stated they would use the video consent service again. All would recommend the service to others requiring surgery. Implementing the video consent tool did not endure any significant time or costs.ConclusionsIntroduction of a video consent tool was found to be a positive adjunct to traditional consenting methods. Patient–clinician consent dialogue can now be documented. A randomised controlled study to further evaluate the effects of video consent on patients’ retention of information, preoperative and postoperative anxiety, patient reported outcome measures as well as length of stay may be beneficial.
Oligodendrocyte dynamics dictate cognitive performance outcomes of working memory training in mice.
Previous work has shown that motor skill learning stimulates and requires generation of myelinating oligodendrocytes (OLs) from their precursor cells (OLPs) in the brains of adult mice. In the present study we ask whether OL production is also required for non-motor learning and cognition, using T-maze and radial-arm-maze tasks that tax spatial working memory. We find that maze training stimulates OLP proliferation and OL production in the medial prefrontal cortex (mPFC), anterior corpus callosum (genu), dorsal thalamus and hippocampal formation of adult male mice; myelin sheath formation is also stimulated in the genu. Genetic blockade of OL differentiation and neo-myelination in Myrf conditional-knockout mice strongly impairs training-induced improvements in maze performance. We find a strong positive correlation between the performance of individual wild type mice and the scale of OLP proliferation and OL generation during training, but not with the number or intensity of c-Fos+ neurons in their mPFC, underscoring the important role played by OL lineage cells in cognitive processing.
Sleep and motor learning in stroke (SMiLES): a longitudinal study investigating sleep-dependent consolidation of motor sequence learning in the context of recovery after stroke
IntroductionThere is growing evidence that sleep is disrupted after stroke, with worse sleep relating to poorer motor outcomes. It is also widely acknowledged that consolidation of motor learning, a critical component of poststroke recovery, is sleep-dependent. However, whether the relationship between disrupted sleep and poor outcomes after stroke is related to direct interference of sleep-dependent motor consolidation processes, is currently unknown. Therefore, the aim of the present study is to understand whether measures of motor consolidation mediate the relationship between sleep and clinical motor outcomes post stroke.Methods and analysisWe will conduct a longitudinal observational study of up to 150 participants diagnosed with stroke affecting the upper limb. Participants will be recruited and assessed within 7 days of their stroke and followed up at approximately 1 and 6 months. The primary objective of the study is to determine whether sleep in the subacute phase of recovery explains the variability in upper limb motor outcomes after stroke (over and above predicted recovery potential from the Predict Recovery Potential algorithm) and whether this relationship is dependent on consolidation of motor learning. We will also test whether motor consolidation mediates the relationship between sleep and whole-body clinical motor outcomes, whether motor consolidation is associated with specific electrophysiological sleep signals and sleep alterations during subacute recovery.Ethics and disseminationThis trial has received both Health Research Authority, Health and Care Research Wales and National Research Ethics Service approval (IRAS: 304135; REC: 22/LO/0353). The results of this trial will help to enhance our understanding of the role of sleep in recovery of motor function after stroke and will be disseminated via presentations at scientific conferences, peer-reviewed publication, public engagement events, stakeholder organisations and other forms of media where appropriate.Trial registration numberClinicalTrials.gov:NCT05746260, registered on 27 February 2023.
A group-based exercise and behavioural maintenance intervention for adults over 65 years with mobility limitations: the REACT RCT
BackgroundMobility limitation in older age reduces quality of life, generates substantial health- and social-care costs, and increases mortality.ObjectiveThe REtirement in ACTion (REACT) trial aimed to establish whether or not a community-based active ageing intervention could prevent decline in physical functioning in older adults already at increased risk of mobility limitation.DesignA multicentre, pragmatic, two-arm, parallel-group randomised controlled trial with parallel process and health economic evaluations.SettingUrban and semi-rural locations across three sites in England.ParticipantsPhysically frail or pre-frail older adults (aged ≥ 65 years; Short Physical Performance Battery score of 4–9). Recruitment was primarily via 35 primary care practices.InterventionsParticipants were randomly assigned to receive brief advice (three healthy ageing education sessions) or a 12-month, group-based, multimodal exercise and behavioural maintenance programme delivered in fitness and community centres. Randomisation was stratified by site and used a minimisation algorithm to balance age, sex and Short Physical Performance Battery score. Data collection and analyses were blinded.Main outcome measuresThe primary outcome was change in lower limb physical function (Short Physical Performance Battery score) at 24 months, analysed using an intention-to-treat analysis. The economic evaluation adopted the NHS and Personal Social Services perspective.ResultsBetween June 2016 and October 2017, 777 participants (mean age 77.6 years, standard deviation 6.8 years; 66% female; mean Short Physical Performance Battery score 7.37, standard deviation 1.56) were randomised to the intervention arm (n = 410) or the control arm (n = 367). Data collection was completed in October 2019. Primary outcome data at 24 months were provided by 628 (80.8%) participants. At the 24-month follow-up, the Short Physical Performance Battery score was significantly greater in the intervention arm (mean 8.08, standard deviation 2.87) than in the control arm (mean 7.59, standard deviation 2.61), with an adjusted mean difference of 0.49 (95% confidence interval 0.06 to 0.92). The difference in lower limb function between intervention and control participants was clinically meaningful at both 12 and 24 months. Self-reported physical activity significantly increased in the intervention arm compared with the control arm, but this change was not observed in device-based physical activity data collected during the trial. One adverse event was related to the intervention. Attrition rates were low (19% at 24 months) and adherence was high. Engagement with the REACT intervention was associated with positive changes in exercise competence, relatedness and enjoyment and perceived physical, social and mental well-being benefits. The intervention plus usual care was cost-effective compared with care alone over the 2 years of REACT; the price year was 2019. In the base-case scenario, the intervention saved £103 per participant, with a quality-adjusted life-year gain of 0.04 (95% confidence interval 0.006 to 0.074) within the 2-year trial window. Lifetime horizon modelling estimated that further cost savings and quality-adjusted life-year gains were accrued up to 15 years post randomisation.ConclusionA relatively low-resource, 1-year multimodal exercise and behavioural maintenance intervention can help older adults to retain physical functioning over a 24-month period. The results indicate that the well-established trajectory of declining physical functioning in older age is modifiable.LimitationsParticipants were not blinded to study arm allocation. However, the primary outcome was independently assessed by blinded data collectors. The secondary outcome analyses were exploratory, with no adjustment for multiple testing, and should be interpreted accordingly.Future workFollowing refinements guided by the process evaluation findings, the REACT intervention is suitable for large-scale implementation. Further research will optimise implementation of REACT at scale.Trial registrationThis trial is registered as ISRCTN45627165.FundingThis project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 10, No. 14. See the NIHR Journals Library website for further project information.
Blunted perception of breathlessness in three cases of low grade insular-glioma.
Better understanding of breathlessness perception addresses an unmet clinical need for more effective treatments for intractable dyspnoea, a prevalent symptom of multiple medical conditions. The insular-cortex is predominantly activated in brain-imaging studies of dyspnoea, but its precise role remains unclear. We measured experimentally-induced hypercapnic air-hunger in three insular-glioma patients before and after surgical resection. Tests involved one-minute increments in inspired CO2, raising end-tidal PCO2 to 7.5 mmHg above baseline (38.5 ± 5.7 mmHg), whilst ventilation was constrained (10.7 ± 2.3 L/min). Patients rated air-hunger on a visual analogue scale (VAS). Patients had lower stimulus-response (2.8 ± 2 vs. 11 ± 4 %VAS/mmHg; p = 0.004), but similar threshold (40.5 ± 3.9 vs. 43.2 ± 5.1 mmHg), compared to healthy individuals. Volunteered comments implicated diminished affective valence. After surgical resection; sensitivity increased in one patient, decreased in another, and other was unable to tolerate the ventilatory limit before any increase in inspired CO2.We suggest that functional insular-cortex is essential to register breathlessness unpleasantness and could be targeted with neuromodulation in chronically-breathless patients. Neurological patients with insula involvement should be monitored for blunted breathlessness to inform clinical management.
Higher densities of T-lymphocytes in the subsynovial connective tissue of people with carpal tunnel syndrome
Symptoms in people with carpal tunnel syndrome (CTS) are traditionally attributed to neural tissue, but recent studies suggest that the subsynovial connective tissue (SSCT) may also play a role in CTS. The SSCT undergoes fibrotic thickening which is generally described as “non-inflammatory” based on basic histology. This study uses immunohistochemistry to determine the presence of macrophages and T-cells within SSCT and their relationship with symptoms in people with CTS. SSCT was collected from twenty people with CTS and eight controls undergoing wrist fracture surgery. Immunohistochemical quantification of CD3+ T-cells and CD68+ macrophage densities as well as CD4+/CD8+ T-cell subpopulations were compared between groups using independent t-tests. Spearman correlations were used to identify associations between immune cell densities and CTS symptom scores. The density of CD3+ T-cells was significantly higher in SSCT of people with CTS compared to controls (CTS mean 26.7 (SD 13.7); controls 6.78 (6.3), p = 0.0005) while the density of CD68+ macrophages was lower (CTS mean 9.5 (SD 6.0); controls 17.7 (8.2), p = 0.0058). Neither CD68+ nor CD3+ cell densities correlated with symptom scores. In contrast to previous assumptions, our data show that the SSCT in the carpal tunnel in both people with CTS and controls is not devoid of immune cells. Whereas the higher density of CD68+ macrophages in control participants may be associated with their early recruitment after acute fracture, CD3+ cells within the SSCT may play a role in chronic CTS.