Abstract Background Transcranial direct current stimulation (tDCS) is increasingly used as an adjunct to rehabilitation for young people with cerebral palsy (CP), yet considerable variability exists in clinical response. Individualised electric field modelling provides an opportunity to estimate the distribution of electrical fields generated by the stimulation delivered to the brain and explore potential relationships with functional outcomes. Methods Structural MRI scans from nineteen participants (10-16 years) from a previously published randomised controlled trial ( ISRCTN74235136 ) investigating the effects of tDCS combined with motor training, underwent participant-specific finite element modelling using SimNIBS. Electric field strength was quantified within anatomically defined motor regions of interest, including the primary motor cortex (M1), dorsal premotor cortex (PMd), supplementary motor area (SMA), and a combined motor network. Global grey matter electric field metrics and stimulation focality were also extracted. Results Estimated electric field strength differed significantly across motor regions (p<0.001), with PMd receiving significantly greater stimulation than both M1 and SMA. Electric field strength within a control region (primary visual cortex) was significantly lower than within M1 (p<0.001). Despite inter-individual variability in regional and global electric field metrics, no significant associations were observed between estimated electric field strength or focality and changes in function following intervention. Conclusion Individualised electric field modelling demonstrated that an M1-targeted tDCS montage preferentially stimulated PMd rather than M1 in young people with CP. These findings highlight the importance of subject-specific modelling when characterising current distribution and suggest that variability in electric field strength alone does not explain variability in behavioural response. Highlights Individualised modelling characterised tDCS electric fields in paediatric CP. M1-targeted tDCS produced greater electric field strength in PMd than M1. Motor regions received greater electric field strength than control visual cortex. Electric field strength did not predict upper- or lower-limb functional change.

In medicine and public health, the randomised controlled trial (RCT) is generally considered the key generator of ‘gold standard’ evidence. However, basic and clinical research and trials are often unrepresentative of real-world populations. Recruiting insufficiently diverse cohorts of participants in trials (e.g. in terms of socioeconomic status, racial and ethnic background, or sex and gender) may not only overstate the general effectiveness of a technology; it may also actively increase health inequalities. We highlight some general issues in this domain, before discussing several specific illustrative examples in the context of medical devices. High quality evidence on factors that would improve trial recruitment is extremely limited. There is a clear need for research on candidate strategies for improving recruitment of under-represented groups in RCTs. These could include, for example, offering various forms of financial incentives; non-monetary incentives, such as preferential access to the technologies that are being tested if they are found to be effective; and various types of informational messages and nudges; as well as involvement of community partners and champions in the recruitment process. Ideally, recruitment practices should ultimately be based on evidence generated from RCTs. Studies Within a Trial (SWAT), where randomised experiments are built into the actual recruitment processes in RCTs, are an ideal way to gain this evidence. SWAT studies are seeing an increase in traction, as indicated by funding streams in bodies such as the UK-based NIHR. Making greater funding available for studies of this kind is needed to improve the evidence base on how best to improve diversity in trial recruitment.

Sleep disturbance is common but often overlooked after stroke. Regular sleep is increasingly recognised as important for overall health, yet little is known about how sleep regularity changes after stroke. This study examined differences in the Sleep Regularity Index (SRI) between stroke survivors and healthy controls using actigraphy data from an existing dataset (~ 1 week per participant). Data were analysed for 162 stroke survivors (mean age 61 ± 14 years, 5 ± 5 years post-stroke, 89 males) and 60 controls (mean age 57 ± 17 years, 32 males). Stroke survivors had significantly lower SRI scores than controls (p = 0.001), indicating less regular sleep. In the stroke group, higher SRI correlated with longer total sleep time (p = 0.003) and better self-reported sleep quality (p = 0.001) but not with other sleep metrics. Lower SRI was associated with worse depressive symptoms (p = 0.006) and lower quality of life (p = 0.001) but not with disability (p = 0.886) or time since stroke (p = 0.646). These findings suggest that sleep regularity is disrupted post-stroke and may influence well-being. Future research should explore interventions to improve sleep regularity and related health outcomes in stroke survivors.

Sleep is often disrupted after stroke. However, little is known about how stroke lesion extent or location influences sleep, particularly at the chronic stage of recovery. In this pragmatic study, we aimed to explore whether lesion characteristics could explain sleep variability in chronic stroke survivors. We analysed previously collected structural brain images (Magnetic Resonance Imaging) from 38 stroke participants (11 female, mean (SD) age 64 (12), mean (SD) time since stroke 95 (66) months) and sleep data (questionnaires (N=38, actigraphy (N=37), and electrophysiology (N=18)) which were collected in their home environment. Neither lesion volume nor lesion overlap with regions of interest (brainstem, basal ganglia, amygdala, hippocampus, thalamus) significantly predicted interindividual variability in subjective or objective sleep measures. However, a data-driven approach revealed clusters of voxels disconnected by the stroke lesions were linked to lower spindle density and amplitude (threshold free cluster enhancement p < 0.050). Overall, these results provide preliminary insights that lesion induced brain disconnection, rather than the extent and overlap of the lesion with grey matter regions, may be more informative when explaining sleep variability. However, larger prospective studies are needed to fully understand the effect of stroke lesions on sleep. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work is supported by the Wellcome Trust and the NIHR Oxford Health Biomedical Research Centre (NIHR203316). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. MKF is Funded by Guarantors of Brain and HJB is funded by the Wellcome Trust (222446/Z/21/Z). CJS holds a Senior Research Fellowship, funded by the Wellcome Trust (224430/Z/21/Z). The Wellcome Centre for Integrative Neuroimaging is supported by core funding from the Wellcome Trust (203139/Z/16/Z and 203139/A/16/Z). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Central University Research Ethics Committee, University of Oxford (reference R85306) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data derivatives and analysis scripts will be made available here: https://osf.io/vbu7c/. Raw data are available upon reasonable request from the corresponding author.

PURPOSE:Cerebral Palsy (CP) is the commonest cause of childhood motor disability. Transcranial direct current stimulation (tDCS) is a promising adjuvant therapy, but research targeting upper and lower limbs simultaneously is needed. We aimed to pilot tDCS with upper/lower limb motor training, estimate the potential effect on motor function, and investigate brain imaging correlates of function. MATERIALS AND METHODS:Participants (10-16 years) with CP affecting upper and/or lower limbs were randomised (online software) to 10 sessions of active (n = 14) or sham (n = 13) tDCS combined with motor training. The primary outcomes were upper and lower limb function assessed at 1-week post-intervention using the Jebson Taylor hand function (JTT) and Timed Up and Go (TUG) tests. Secondary, imaging outcomes included baseline tractography, grey matter volume, and resting state connectivity. RESULTS:Adherence was good: 74% completed all intervention sessions, 100% completed the primary outcome assessment. There were no between-group differences (1-week post-intervention, intention-to-treat; group-by-time JTT: F(1,25)=1.189,p = 0.286, partial-eta-squared = 0.05; TUG: F(1,25)=1.605,p = 0.217, partial-eta-squared = 0.06). Imaging showed subtle associations between better JTT at baseline and higher grey matter volume (caudate nucleus) and stronger sensorimotor resting state connectivity. CONCLUSIONS:The trial was well tolerated, but effect sizes were small. Larger studies are needed to further explore tDCS for CP.

Memory reactivation during sleep is known to have an impact upon the gradual consolidation of memory traces, but the nature of plastic changes induced by such reactivation remains unclear. Here, we use diffusion-weighted imaging to track the location and timescale of microstructural changes associated with behavioural effects of Targeted Memory Reactivation (TMR) 20 days post-manipulation, when the behavioural effect first became significant. Because we used a serial reaction time task that is known to draw on the sensorimotor system as well as both medial temporal and striatal memory systems, we included all these areas as regions of interest. We also included precuneus, a structure known for plasticity relating to the neural engram. Our analysis was based on correlations between behavioural benefit of TMR and microstructural plasticity over early (first 24 h) and late (24 h to 10 days) consolidation periods. This showed significant TMR-related microstructural plasticity in the striatum over the early period. Over the late period, we observed TMR-related microstructural changes in both sensorimotor cortex and precuneus. Taken together, these findings demonstrate that TMR-related microstructural changes correlate with subsequent memory benefits across multiple brain regions.

While humans are known to have several premotor cortical areas, secondary motor cortex (M2) is often considered to be the only higher-order motor area of the mouse brain and is thought to combine properties of various human premotor cortices. Here, we show that axonal tracer, functional connectivity, myelin mapping, gene expression, and optogenetics data contradict this notion. Our analyses reveal three premotor areas in the mouse, anterior-lateral motor cortex (ALM), anterior-lateral M2 (aM2), and posterior-medial M2 (pM2), with distinct structural, functional, and behavioral properties. By using the same techniques across mice and humans, we show that ALM has strikingly similar functional and microstructural properties to human anterior ventral premotor areas and that aM2 and pM2 amalgamate properties of human pre-SMA and cingulate cortex. These results provide evidence for the existence of multiple premotor areas in the mouse and chart a comparative map between the motor systems of humans and mice.

Introduction The number of people living with dementia worldwide is growing. Devising and implementing preventive strategies that are globally applicable is of paramount importance. However, previous studies have largely been limited to cohorts that are geographically and culturally homogenous. It is not known whether the associations between demographics, vascular risk factors (VRFs), and cognitive changes are consistent across cohorts with cultural and geographical variations. Methods Data were analysed retrospectively from 6 community-dwelling cohorts (> 60 years old) with cultural and geographical variations (British = 536; Hong Kong Chinese = 494; Australian = 302; Singaporean Chinese = 108; German = 102; Swedish = 94). Clinical demographics, VRFs, longitudinal cognitive changes, and MRI data (including T1, FLAIR, and diffusion images) were analysed from all 6 cohorts. First, across all cohorts, a grand canonical correlation analysis (n=1636) was used to establish common modes of covariation between demographics and VRFs on one side, and cognitive changes on the other side. Second, separately for each cohort, mediation analysis was used to investigate the mediating role of normalised total grey matter volume, microstructural integrity, white matter hyperintensity, and hippocampal structural network in the association mentioned above. Then the mediation outputs will be used in the meta- analysis to assess the indirect effect estimates and variance of each significant brain mediator. Results We identified three modes of covariation between dementia risk and cognition across all cohorts (p< 0.01). The strongest mode linked younger age and higher levels of education with better cognition at baseline and follow-up (Figure 1). Meta-analysis showed that, across cohorts, normalised total grey matter volume (Indirect effect = 0.02, Z = 3.13, p < 0.001, I² = 0%) was a significant mediator between demographics, VRFs, and cognitive decline after Bonferroni correction (Figure 2). The hippocampal structural network did not survive Bonferroni correlation while other brain mediators were not significant in the meta-analyses. Discussion This study investigated the complex relationship between demographics, VRFs, brain health, and cognition. Cohorts with cultural and demographic variations shared a common relationship between age, education, and cognition. However, individual cohort differences are detected in the contribution of different neuroimaging metrics.

[This corrects the article DOI: 10.3389/fnins.2023.1187790.].

Oligodendrocytes continue to differentiate from their precursor cells even in adulthood, a process that can be modulated by neuronal activity and experience. Previous work has indicated that conditional ablation of oligodendrogenesis in adult mice leads to learning and memory deficits in a range of behavioral tasks. The current study replicated and re-evaluated evidence for a role of oligodendrogenesis in motor learning, using a complex running wheel task. Further, we found that ablating oligodendrogenesis alters brain microstructure (ex vivo MRI) and brain activity (in vivo EEG) independent of experience with the task. This suggests a role for adult oligodendrocyte formation in the maintenance of brain function and indicates that task-independent changes due to oligodendrogenesis ablation need to be considered when interpreting learning and memory deficits in this model.

Memory reactivation during Non-Rapid Eye Movement (NREM) sleep is important for memory consolidation but it remains unclear exactly how such activity promotes the development of a stable memory representation. We used Targeted Memory Reactivation (TMR) in combination with longitudinal structural and functional MRI to track the impact of reactivating memories in one night of sleep over the next 20 days. Our exploratory analysis showed that such cued reactivation leads to increased precuneus activation 24 h post-TMR. Furthermore, the behavioural impact of cueing, which only emerged 20 days later, was predicted by both functional and structural TMR related changes in the sensorimotor cortex. These preliminary findings demonstrate that TMR leads to neuroplasticity, starting as early as 24 h after the manipulation, and evolving over the next few weeks.

Introduction Consolidation of motor skill learning, a key component of rehabilitation post-stroke, is known to be sleep dependent. However, disrupted sleep is highly prevalent after stroke and is often associated with poor motor recovery and quality of life. Previous research has shown that digital cognitive behavioural therapy (dCBT) for insomnia can be effective at improving sleep quality after stroke. Therefore, the aim of this trial is to evaluate the potential for sleep improvement using a dCBT programme, to improve rehabilitation outcomes after stroke. Methods and analysis We will conduct a parallel-arm randomised controlled trial of dCBT (Sleepio) versus treatment as usual among individuals following stroke affecting the upper limb. Up to 100 participants will be randomly allocated (2:1) into either the intervention (6–8 week dCBT) or control (continued treatment as usual) group. The primary outcome of the study will be change in insomnia symptoms pre to post intervention compared with treatment as usual. Secondary outcomes include improvement in overnight motor memory consolidation and sleep measures between intervention groups, correlations between changes in sleep behaviour and overnight motor memory consolidation in the dCBT group and changes in symptoms of depression and fatigue between the dCBT and control groups. Analysis of covariance models and correlations will be used to analyse data from the primary and secondary outcomes. Ethics and dissemination The study has received approval from the National Research Ethics Service (22/EM/0080), Health Research Authority (HRA) and Health and Care Research Wales (HCRW), IRAS ID: 306 291. The results of this trial 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 number NCT05511285 .

Introduction There 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 analysis We 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 dissemination This 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 number ClinicalTrials.gov: NCT05746260, registered on 27 February 2023.

With the rise in numbers of people living with dementia and new disease modifying therapies entering the market, there is increasing need for brain magnetic resonance imaging (MRI) for diagnosis and safety monitoring. The number of scans that need reporting is expected to rapidly grow. Clinical radiology reports are currently largely qualitative and variable in structure and content. By contrast, research software typically uses automated methods to extract quantitative metrics from brain scans. To better understand the unmet clinical need for brain reporting software for dementia we conducted a barrier to adoption study using the Lean Assessment Process (LAP)methodology. We first assessed the role of brain imaging in the diagnostic pathway for people with suspected dementia in the NHS in England. We then explored the views of (neuro)radiologists, neurologists and psychiatrists on the potential benefits and level of acceptance of software to support brain MRI analysis, using the FMRIB software library (FSL) as a technology exemplar. The main perceived utilities of the proposed software were: increased diagnostic confidence; support for delivery of disease modifying therapies; and the possibility to compare individual results with population norms. In addition to assessment of global atrophy, hippocampal atrophy and white matter hyperintensities, additional user requirements included assessment of microbleeds, segmentation of multiple brain structures, clear information about the control population used for reference, and possibility to compare multiple scans. The main barriers to adoption related to the limited availability of 3T MRI scanners in the UK, integration into the clinical workflow, and the need to demonstrate cost-effectiveness. These findings will guide future technical development, clinical validation, and health economic evaluation. ### Competing Interest Statement SS and LG receive royalties from licensing of FSL to non-academic, commercial parties. SS is part-owner of a neuroimaging analysis company SBGneuro. The remaining authors report no potential conflicts of interest. ### Funding Statement This project was supported by the Wellcome Centre for Integrative Neuroimaging (203139/Z/16/Z, 203139/A/16/Z and 215573/Z/19/Z) and by the NIHR Oxford Health Biomedical Research Centre (NIHR203316). LG was also supported by an Alzheimer's Association Grant (AARF-21-846366). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The project was conducted by Health Innovation Oxford and Thames Valley, hosted by Oxford University Hospitals NHS Foundation Trust. This work does not require approval from an NHS Research Ethics Committee, according to the following criteria: participants in the study were not randomised to different groups, the study does not demand changing treatment/patient care from accepted standards, and the findings are not going to be generalisable. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymised data produced in the present study are available upon reasonable request to the authors for non-commercial purposes.