Background:Somatic, cognitive and mental health issues have been identified in three-quarters of people 5 months after hospitalisation for severe acute SARS-CoV-2 (COVID-19) infection. The underlying neuroanatomical basis of these symptoms remains unclear, but recent studies suggest a role for altered brainstem physiology. We aimed to test the hypothesis that brainstem neurochemical profiles differ in patients who had been hospitalised for COVID-19 compared to matched controls using 7T magnetic resonance spectroscopy (MRS). Methods:This prospective case-control study recruited 34 individuals who were hospitalised for COVID-19 and 15 healthy controls with no history of COVID-19 infection from two major UK hospitals before vaccines became available. The participants underwent 7T semi-adiabatic localization by adiabatic selective refocusing (sLASER) 1H-MRS at the ponto-medullary junction. Water-referenced metabolite concentrations were compared between the patients and controls and correlated with infection severity, as measured by maximum C-reactive protein (CRPmax) assay during inpatient admission. Linear mixed modelling was used with a 0.05 significance level. Results:Spectral quality was high/acceptable in 44/49 participants according to the MRS Consensus criteria. The magnitude of inflammation during patient admission (i.e., CRPmax) correlated positively with myo-inositol concentration (β = 0.005, p = 0.035), as did patient-reported symptoms (β = -0.564, p = 0.023). However, metabolite concentrations were not significantly different between the patients and controls. Conclusion:We show the feasibility of assessing brainstem neurochemical profiles using 7T 1H-MRS in a multi-centre study. Technical limitations at one site's 7T MRI led to variable repetition times, which limited our statistical power and should be avoided in future studies. Our findings highlight the need for further investigation into the role of neuroinflammation in post-acute COVID-19.

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.

Post-mortem studies have shown that patients dying from severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection frequently have pathological changes in their CNS, particularly in the brainstem. Many of these changes are proposed to result from para-infectious and/or post-infection immune responses. Clinical symptoms such as fatigue, breathlessness, and chest pain are frequently reported in post-hospitalized coronavirus disease 2019 (COVID-19) patients. We propose that these symptoms are in part due to damage to key neuromodulatory brainstem nuclei. While brainstem involvement has been demonstrated in the acute phase of the illness, the evidence of long-term brainstem change on MRI is inconclusive. We therefore used ultra-high field (7 T) quantitative susceptibility mapping (QSM) to test the hypothesis that brainstem abnormalities persist in post-COVID patients and that these are associated with persistence of key symptoms. We used 7 T QSM data from 30 patients, scanned 93-548 days after hospital admission for COVID-19 and compared them to 51 age-matched controls without prior history of COVID-19 infection. We correlated the patients' QSM signals with disease severity (duration of hospital admission and COVID-19 severity scale), inflammatory response during the acute illness (C-reactive protein, D-dimer and platelet levels), functional recovery (modified Rankin scale), depression (Patient Health Questionnaire-9) and anxiety (Generalized Anxiety Disorder-7). In COVID-19 survivors, the MR susceptibility increased in the medulla, pons and midbrain regions of the brainstem. Specifically, there was increased susceptibility in the inferior medullary reticular formation and the raphe pallidus and obscurus. In these regions, patients with higher tissue susceptibility had worse acute disease severity, higher acute inflammatory markers, and significantly worse functional recovery. This study contributes to understanding the long-term effects of COVID-19 and recovery. Using non-invasive ultra-high field 7 T MRI, we show evidence of brainstem pathophysiological changes associated with inflammatory processes in post-hospitalized COVID-19 survivors.

Introduction Sciatica is a common condition and is associated with higher levels of pain, disability, poorer quality of life, and increased use of health resources compared with low back pain alone. Although many patients recover, a third develop persistent sciatica symptoms. It remains unclear, why some patients develop persistent sciatica as none of the traditionally considered clinical parameters (eg, symptom severity, routine MRI) are consistent prognostic factors.The FORECAST study (factors predicting the transition from acute to persistent pain in people with 'sciatica') will take a different approach by exploring mechanism-based subgroups in patients with sciatica and investigate whether a mechanism-based approach can identify factors that predict pain persistence in patients with sciatica. Methods and analysis We will perform a prospective longitudinal cohort study including 180 people with acute/subacute sciatica. N=168 healthy participants will provide normative data. A detailed set of variables will be assessed within 3 months after sciatica onset. This will include self-reported sensory and psychosocial profiles, quantitative sensory testing, blood inflammatory markers and advanced neuroimaging. We will determine outcome with the Sciatica Bothersomeness Index and a Numerical Pain Rating Scale for leg pain severity at 3 and 12 months.We will use principal component analysis followed by clustering methods to identify subgroups. Univariate associations and machine learning methods optimised for high dimensional small data sets will be used to identify the most powerful predictors and model selection/accuracy.The results will provide crucial information about the pathophysiological drivers of sciatica symptoms and may identify prognostic factors of pain persistence. Ethics and dissemination The FORECAST study has received ethical approval (South Central Oxford C, 18/SC/0263). The dissemination strategy will be guided by our patient and public engagement activities and will include peer-reviewed publications, conference presentations, social media and podcasts. Trial registration number ISRCTN18170726; Pre-results.

<p>Description of additional methods and procedures used in the study. Also includes Supplementary References.</p>

The goals of this study were to implement a MEGA-sLASER sequence with prospective field drift correction on a preclinical scanner, develop the processing tools and validate them on a group of wild type mice.

Neuroimaging in the human brainstem presents multiple challenges. With its small size, deep location, and distance from radiofrequency coils used for signal transmission and reception, the brainstem suffers from reduced signal-to-noise compared to cortical structures. While the increased signal provided by ultra-high field (UHF) MRI can be leveraged to improve image resolution and aid localization of small brainstem nuclei, scanning protocols require careful optimization to make the best use of these advantages. Additionally, major challenges remain regarding signal dropout and distortion, as well as the strong influence of physiological noise of cardiac and respiratory origin. Therefore, while UHF allows for more detailed investigation of the human brainstem in vivo, consideration must be given to the unique (or sometimes exacerbated) obstacles that may be encountered when moving to higher fields.

Legends for Supplementary Figures S1-S5.

Phantom experiments and density-matrix simulations of the timing of the semi-LASER sequence were performed at TE = 36 (TE1 =11 ms, TE2 = 15 ms and TE3 = 10 ms) and 110 ms (TE1 =11 ms, TE2 = 65 ms and TE3 = 34 ms).

Post mortem studies have shown that patients dying from severe SARS-CoV-2 infection frequently have pathological changes in their central nervous system, particularly in the brainstem. Many of these changes are proposed to result from para-infectious and/or post-infection immune responses. Clinical symptoms such as fatigue, breathlessness, and chest pain are frequently reported in post-hospitalized COVID-19 patients. We propose that these symptoms are in part due to damage to key neuromodulatory brainstem nuclei. While brainstem involvement has been demonstrated in the acute phase of the illness, the evidence of long-term brainstem change on magnetic resonance imaging (MRI) is inconclusive. We therefore used ultra-high field (7T) quantitative susceptibility mapping (QSM) to test the hypothesis that brainstem abnormalities persist in post-COVID patients and that these are associated with persistence of key symptoms. We used 7T QSM data from 30 patients, scanned 93-548 days after hospital admission for COVID-19 and compared them to 51 age-matched controls without prior history of COVID-19 infection. We correlated the patients' QSM signals with disease severity (duration of hospital admission and COVID-19 severity scale), inflammatory response during the acute illness (C-reactive protein, D-Dimer and platelet levels), functional recovery (modified Rankin scale; mRS), depression (PHQ-9) and anxiety (GAD-7). In COVID-19 survivors the MR susceptibility increased in the medulla, pons and midbrain regions of the brainstem. Specifically, there was increased susceptibility in the inferior medullary reticular formation and the raphe pallidus and obscurus. In these regions, patients with higher tissue susceptibility had worse acute disease severity, higher acute inflammatory markers, and significantly worse functional recovery. Using non-invasive ultra-high field 7T MRI, we show evidence of brainstem pathophysiological changes associated with inflammatory processes in post-hospitalized COVID-19 survivors. This study contributes to understanding the mechanisms of long-term effects of COVID-19 and recovery. ### Competing Interest Statement Dr. Pattinson is named as co-inventor on a provisional U.K. patent application titled "Use of cerebral nitric oxide donors in the assessment of the extent of brain dysfunction following injury". Dr Pattinson is named as co-inventors on a provisional U.K. patent titled "Discordant sensory stimulus in VR based exercise" UK Patent office application: 2204698.1 filing date 31/3/2022. ### Funding Statement This work was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. JBR was supported by the Wellcome Trust (103838; 220258) and Medical Research Council (M C\_UU\_00030/14). VFJN was supported by an Academy of Medical Sciences / The Health Foundation Clinician Scientist Fellowship. ETB was supported by an NIHR Senior Investigator award. BR, MC, SN are supported by NIHR Oxford BRC and BHF Oxford CRE. WTC was supported by funding from Wellcome Trust [225924/Z/22/Z]. CTR was supported by funding from Wellcome Trust [098436/Z/12/B]. For the purpose of open access, the authors have 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 study was approved by the following ethics committees: Cambridgeshire Research Ethics Committee HBREC.2016.13.am3, East of England Research Ethics Committee 17/EE/0025 , Norfolk Research Ethics Committee EE/0395, and North West Preston Research Ethics Committee 20/NW/0235. All participants provided informed consent in accordance with the Declaration of Helsinki. 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 We can provide average QSM χ extracted values from the brainstem and subregions upon reasonable request.

Huntington's and Parkinson's disease are two movement disorders representing mainly opposite states of the basal ganglia inhibitory function. Despite being an integral part of the cortico-subcortico-cortical circuitry, the subthalamic nucleus function has been studied at the level of detail required to isolate its signal only through invasive studies in Huntington's and Parkinson's disease. Here, we tested whether the subthalamic nucleus exhibited opposite functional signatures in early Huntington's and Parkinson's disease. We included both movement disorders in the same whole-brain imaging study, and leveraged ultra-high-field 7T MRI to achieve the very fine resolution needed to investigate the smallest of the basal ganglia nuclei. Eleven of the 12 Huntington's disease carriers were recruited at a premanifest stage, while 16 of the 18 Parkinson's disease patients only exhibited unilateral motor symptoms (15 were at Stage I of Hoehn and Yahr off medication). Our group comparison interaction analyses, including 24 healthy controls, revealed a differential effect of Huntington's and Parkinson's disease on the functional connectivity at rest of the subthalamic nucleus within the sensorimotor network, i.e. an opposite effect compared with their respective age-matched healthy control groups. This differential impact in the subthalamic nucleus included an area precisely corresponding to the deep brain stimulation 'sweet spot'-the area with maximum overall efficacy-in Parkinson's disease. Importantly, the severity of deviation away from controls' resting-state values in the subthalamic nucleus was associated with the severity of motor and cognitive symptoms in both diseases, despite functional connectivity going in opposite directions in each disorder. We also observed an altered, opposite impact of Huntington's and Parkinson's disease on functional connectivity within the sensorimotor cortex, once again with relevant associations with clinical symptoms. The high resolution offered by the 7T scanner has thus made it possible to explore the complex interplay between the disease effects and their contribution on the subthalamic nucleus, and sensorimotor cortex. Taken altogether, these findings reveal for the first time non-invasively in humans a differential, clinically meaningful impact of the pathophysiological process of these two movement disorders on the overall sensorimotor functional connection of the subthalamic nucleus and sensorimotor cortex.

Whilst considerable progress has been made in using ultra-high field fMRI to study brain function at fine spatial resolution, methods are generally optimized at a single site and do not translate to studies where multiple sites are required for sufficient subject recruitment. With a recent increase in installations of human 7 T systems, there is now the opportunity to establish a framework for multi-site 7 T fMRI studies. However, an understanding of the inter-site variability of fMRI measurements is required for datasets to be combined across sites. To address this, we employ a hand digit localization task and compare across-site and within-site reproducibility of 7 T fMRI to a hand digit localization task which requires fine spatial resolution to resolve individual digit representations. As part of the UK7T Network “Travelling Heads” study, 10 participants repeated the same hand digit localization task at five sites with whole-body 7T MRI systems to provide a measure of inter-site variability. A subset of the participants (2 per site) performed repeated sessions at each site for measurement of intra-site reproducibility. Dice’s overlap coefficient was used to assess reproducibility, with hand region inter-site Dice = 0.70±0.04 significantly lower than intrasite Dice = 0.76±0.06, with similar trends for the individual digit maps. Although slightly lower than intra-site reproducibility, the inter-site reproducibility results are consistent with previous single site reproducibility measurements, providing evidence that multi-site 7 T fMRI studies are feasible. These results can be used to inform sample size calculations for future multi-site somatomotor mapping studies.

Purpose Slice-wise shimming can improve field homogeneity, but suffers from large noise propagation in the shim calculation. Here, we propose a robust shim current optimization for higher-order dynamic shim updating, based on Tikhonov regularization with a variable regularization parameter, lambda. Theory and Methods lambda was selected for each slice separately in a fully automatic procedure based on a combination of boundary constraints and an L-curve search algorithm. Shimming performance was evaluated for second order slice-wise shimming of the brain at 7T, by simulation on a database of field maps from 143 subjects, and by direct measurements in 8 subjects. Results Simulations yielded on average 36% reduction in the shim current norm for just 0.4 Hz increase in residual field SD as compared to unconstrained unregularized optimization. In vivo results yielded on average 34.0 Hz residual field SD as compared to 34.3 Hz with a constrained unregularized optimization, while simultaneously reducing the shim current norm to 2.8 A from 3.9 A. The proposed regularization also reduced the average step in the shim current between slices. Conclusion Slice-wise variable Tikhonov regularization yielded reduced current norm and current steps to a negligible cost in field inhomogeneity. The method holds promise to increase the robustness, and thereby the utility, of higher-order shim updating.

IntroductionWe present the reliability of ultra-high field T2* MRI at 7T, as part of the UK7T Network's “Travelling Heads” study. T2*-weighted MRI images can be processed to produce quantitative susceptibility maps (QSM) and R2* maps. These reflect iron and myelin concentrations, which are altered in many pathophysiological processes. The relaxation parameters of human brain tissue are such that R2* mapping and QSM show particularly strong gains in contrast-to-noise ratio at ultra-high field (7T) vs clinical field strengths (1.5–3T). We aimed to determine the inter-subject and inter-site reproducibility of QSM and R2* mapping at 7T, in readiness for future multi-site clinical studies.MethodsTen healthy volunteers were scanned with harmonised single- and multi-echo T2*-weighted gradient echo pulse sequences. Participants were scanned five times at each “home” site and once at each of four other sites. The five sites had 1× Philips, 2× Siemens Magnetom, and 2× Siemens Terra scanners. QSM and R2* maps were computed with the Multi-Scale Dipole Inversion (MSDI) algorithm (https://github.com/fil-physics/Publication-Code). Results were assessed in relevant subcortical and cortical regions of interest (ROIs) defined manually or by the MNI152 standard space.Results and DiscussionMean susceptibility (χ) and R2* values agreed broadly with literature values in all ROIs. The inter-site within-subject standard deviation was 0.001–0.005 ppm (χ) and 0.0005–0.001 ms−1 (R2*). For χ this is 2.1–4.8 fold better than 3T reports, and 1.1–3.4 fold better for R2*. The median ICC from within- and cross-site R2* data was 0.98 and 0.91, respectively. Multi-echo QSM had greater variability vs single-echo QSM especially in areas with large B0 inhomogeneity such as the inferior frontal cortex. Across sites, R2* values were more consistent than QSM in subcortical structures due to differences in B0-shimming. On a between-subject level, our measured χ and R2* cross-site variance is comparable to within-site variance in the literature, suggesting that it is reasonable to pool data across sites using our harmonised protocol.ConclusionThe harmonized UK7T protocol and pipeline delivers on average a 3-fold improvement in the coefficient of reproducibility for QSM and R2* at 7T compared to previous reports of multi-site reproducibility at 3T. These protocols are ready for use in multi-site clinical studies at 7T.

Neuroinflammation and microglial activation are significant processes in Alzheimer's disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer's disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer's disease and other tau-mediated neurodegenerative diseases.

Increasing numbers of 7 T (7 T) magnetic resonance imaging (MRI) scanners are in research and clinical use. 7 T MRI can increase the scanning speed, spatial resolution and contrast-to-noise-ratio of many neuroimaging protocols, but technical challenges in implementation have been addressed in a variety of ways across sites. In order to facilitate multi-centre studies and ensure consistency of findings across sites, it is desirable that 7 T MRI sites implement common high-quality neuroimaging protocols that can accommodate different scanner models and software versions. With the installation of several new 7 T MRI scanners in the United Kingdom, the UK7T Network was established with an aim to create a set of harmonized structural and functional neuroimaging sequences and protocols. The Network currently includes five sites, which use three different scanner platforms, provided by two different vendors. Here we describe the harmonization of functional and anatomical imaging protocols across the three different scanner models, detailing the necessary changes to pulse sequences and reconstruction methods. The harmonized sequences are fully described, along with implementation details. Example datasets acquired from the same subject on all Network scanners are made available. Based on these data, an evaluation of the harmonization is provided. In addition, the implementation and validation of a common system calibration process is described.

AbstractIntroductionThe goal of European Ultrahigh‐Field Imaging Network in Neurodegenerative Diseases (EUFIND) is to identify opportunities and challenges of 7 Tesla (7T) MRI for clinical and research applications in neurodegeneration. EUFIND comprises 22 European and one US site, including over 50 MRI and dementia experts as well as neuroscientists.MethodsEUFIND combined consensus workshops and data sharing for multisite analysis, focusing on 7 core topics: clinical applications/clinical research, highest resolution anatomy, functional imaging, vascular systems/vascular pathology, iron mapping and neuropathology detection, spectroscopy, and quality assurance. Across these topics, EUFIND considered standard operating procedures, safety, and multivendor harmonization.ResultsThe clinical and research opportunities and challenges of 7T MRI in each subtopic are set out as a roadmap. Specific MRI sequences for each subtopic were implemented in a pilot study presented in this report. Results show that a large multisite 7T imaging network with highly advanced and harmonized imaging sequences is feasible and may enable future multicentre ultrahigh‐field MRI studies and clinical trials.DiscussionThe EUFIND network can be a major driver for advancing clinical neuroimaging research using 7T and for identifying use‐cases for clinical applications in neurodegeneration.