Multidisciplinary research priorities for the COVID-19 pandemic: a call for action for mental health science.

The coronavirus disease 2019 (COVID-19) pandemic is having a profound effect on all aspects of society, including mental health and physical health. We explore the psychological, social, and neuroscientific effects of COVID-19 and set out the immediate priorities and longer-term strategies for mental health science research. These priorities were informed by surveys of the public and an expert panel convened by the UK Academy of Medical Sciences and the mental health research charity, MQ: Transforming Mental Health, in the first weeks of the pandemic in the UK in March, 2020. We urge UK research funding agencies to work with researchers, people with lived experience, and others to establish a high level coordination group to ensure that these research priorities are addressed, and to allow new ones to be identified over time. The need to maintain high-quality research standards is imperative. International collaboration and a global perspective will be beneficial. An immediate priority is collecting high-quality data on the mental health effects of the COVID-19 pandemic across the whole population and vulnerable groups, and on brain function, cognition, and mental health of patients with COVID-19. There is an urgent need for research to address how mental health consequences for vulnerable groups can be mitigated under pandemic conditions, and on the impact of repeated media consumption and health messaging around COVID-19. Discovery, evaluation, and refinement of mechanistically driven interventions to address the psychological, social, and neuroscientific aspects of the pandemic are required. Rising to this challenge will require integration across disciplines and sectors, and should be done together with people with lived experience. New funding will be required to meet these priorities, and it can be efficiently leveraged by the UK's world-leading infrastructure. This Position Paper provides a strategy that may be both adapted for, and integrated with, research efforts in other countries

Multidisciplinary research priorities for the COVID-19 pandemic: a call for action for mental health science

The coronavirus disease 2019 (COVID-19) pandemic is having a profound effect on all aspects of society, including mental health and physical health. We explore the psychological, social, and neuroscientific effects of COVID-19 and set out the immediate priorities and longer-term strategies for mental health science research. These priorities were informed by surveys of the public and an expert panel convened by the UK Academy of Medical Sciences and the mental health research charity, MQ: Transforming Mental Health, in the first weeks of the pandemic in the UK in March, 2020. We urge UK research funding agencies to work with researchers, people with lived experience, and others to establish a high level coordination group to ensure that these research priorities are addressed, and to allow new ones to be identified over time. The need to maintain high-quality research standards is imperative. International collaboration and a global perspective will be beneficial. An immediate priority is collecting high-quality data on the mental health effects of the COVID-19 pandemic across the whole population and vulnerable groups, and on brain function, cognition, and mental health of patients with COVID-19. There is an urgent need for research to address how mental health consequences for vulnerable groups can be mitigated under pandemic conditions, and on the impact of repeated media consumption and health messaging around COVID-19. Discovery, evaluation, and refinement of mechanistically driven interventions to address the psychological, social, and neuroscientific aspects of the pandemic are required. Rising to this challenge will require integration across disciplines and sectors, and should be done together with people with lived experience. New funding will be required to meet these priorities, and it can be efficiently leveraged by the UK's world-leading infrastructure. This Position Paper provides a strategy that may be both adapted for, and integrated with, research efforts in other countries.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.The stakeholder survey was funded by MQ: Transforming Mental Health. Activity costs for this work, including the Ipsos MORI survey, were partly supported by a core grant the Academy of Medical Sciences receives annually from the Government Department for Business, Energy & Industrial Strategy for policy, communications and public engagement.published version, accepted version (12 month embargo

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Previously we observed differential activation in individual columns of the periaqueductal grey (PAG) during breathlessness and its conditioned anticipation (Faull et al., 2016). Here, we have extended this work by determining how the individual columns of the PAG interact with higher cortical centres, both at rest and in the context of breathlessness threat. Activation was observed in ventrolateral PAG (vlPAG) and lateral PAG (lPAG), where activity scaled with breathlessness intensity ratings, revealing a potential interface between sensation and cognition during breathlessness. At rest the lPAG was functionally correlated with cortical sensorimotor areas, conducive to facilitating fight/flight responses, and demonstrated increased synchronicity with the amygdala during breathlessness. The vlPAG showed fronto-limbic correlations at rest, whereas during breathlessness anticipation, reduced functional synchronicity was seen to both lPAG and motor structures, conducive to freezing behaviours. These results move us towards understanding how the PAG might be intricately involved in human responses to threat

The Role of the Brain in Complex Regional Pain Syndrome (CRPS) Pain and Motor Dysfunction

Background: Complex regional pain syndrome (CRPS) is the most painful disorder known to man and presents with altered sensory perceptions and motor dysfunction. Past neuroimaging studies demonstrate that CRPS is associated with brain changes. The overall aim of this thesis was to investigate the role of the brain in CRPS pain and motor dysfunction. The sensorimotor cortex is important in pain and motor function. Sensorimotor cortical reorganisation and disinhibition have been identified in CRPS and many have postulated that such changes involve altered gamma-aminobutyric acid (GABA) mechanisms. These sensorimotor changes are thought to be so significant that treatments of CRPS aim to restore sensorimotor cortical reorganisation and disinhibition. And yet despite the postulated GABAergic mechanisms for sensorimotor disinhibition, sensorimotor cortex concentrations of inhibitory and excitatory neurotransmitters have never been evaluated in CRPS. In addition to the sensorimotor cortex, the basal ganglia also regulates pain. The basal ganglia has separate functional loops involved in motor and non-motor functions. In CRPS, it has been shown that there are changes to basal nuclei such as the putamen and caudate nucleus and such changes have been linked to CRPS pain and motor dysfunction. Further, neuroinflammation by infiltration of activated astrocytes has been found in the basal ganglia of CRPS patients. However, the basal ganglia functional loops have not been systematically evaluated in CRPS. Finally, the transmission and modulation of pain involves multiple brainstem nuclei such as the periaqueductal gray (PAG), locus coeruleus (LC), and rostral ventromedial medulla (RVM). In other chronic pain conditions, the PAG, LC, and RVM have been found to facilitate pain. Interestingly, many CRPS studies have postulated that pain processing is altered at the brainstem, yet the brainstem has not yet been directly investigated in CRPS. Methods: A series of three experiments were conducted comparing upper limb CRPS patients with pain-free controls to investigate various brain regions important in pain and motor function. i) In Chapter 2, magnetic resonance spectroscopy (MRS) was used to determine GABA and glutamate concentrations in the sensorimotor cortex of 14 CRPS and 30 pain-free controls. The relationship between GABA and glutamate concentrations and tactile acuity in CRPS was determined using Pearson’s correlation. ii) In Chapter 3, resting-state functional magnetic resonance imaging (fMRI) was used to determine infraslow oscillations (ISO) and functional connectivity of the motor and non-motor basal ganglia loops in 15 CRPS and 45 age- and sex-matched pain-free controls. Pearson’s correlation was used to determine the relationship between basal ganglia ISO and pain and motor function in CRPS. iii) Finally, in Chapter 4 resting-state fMRI was used to determine the functional connectivity between the PAG, LC, and RVM, and the functional connectivity of the PAG and LC to higher brain areas in 15 CRPS and 30 age and sex-matched pain-free controls. Using Pearson’s correlations, the relationship between CRPS functional connectivity changes of brainstem nuclei and pain intensity was determined. Results: Contrary to our original hypothesis, sensorimotor cortex GABA and glutamate concentrations did not differ between CRPS and controls or between CRPS brain hemispheres and neither concentration was correlated to tactile acuity in CRPS. Investigations of the basal ganglia circuitry revealed the motor putamen of CRPS patients had increased ISO power and both the putamen and caudate body had increased functional connectivity to the basal ganglia cortical input areas such as the primary motor cortex (M1), cingulate motor area, and orbitofrontal cortex. Increased ISO and functional connectivity of the putamen were correlated to increased perceived pain and motor dysfunction in CRPS. Additionally, functional connectivity between the PAG, LC, and RVM was not different between CRPS and controls. However, compared to controls, the PAG and LC had altered functional connectivity to higher brain areas in CRPS, with decreased PAG to S1 and posterior parietal cortex connectivity and increased LC to the caudate nucleus, anterior cingulate cortex, and hippocampus connectivity. Decreased PAG to S1 functional connectivity correlated to decreased pain in CRPS. Conclusions: Overall these findings demonstrate that CRPS involves changes to the basal ganglia motor and non-motor loops and brainstem pathways to the higher brain areas but does not involve changes to sensorimotor cortex GABA or glutamate concentration. Increased ISOs in the motor putamen may indicate neuroinflammation via astrogliosis and increased astrocytic calcium wave propagation in CRPS. It is postulated that noradrenaline released by the LC may induce the basal ganglia ISO increases of CRPS by activation of astrocytic α1 receptors. This in turn can potentially decrease GABAA receptor activity which may explain CRPS sensorimotor reorganisation and disinhibition. Additionally, altered functional connectivity of the PAG and LC to higher brain areas but not the RVM suggests that there are altered ascending brainstem pain pathways but not descending pain modulatory pathways in CRPS. Together with the correlations of brain changes to pain and motor dysfunction, this thesis suggests that basal ganglia and ascending brainstem pain pathways may underpin pain and motor dysfunction in CRPS. Future CRPS studies could aim to investigate the role of GABAA and α1 receptors

Functional subdivision of the human periaqueductal grey in respiratory control using 7 tesla fMRI.

The periaqueductal grey (PAG) is a nucleus within the midbrain, and evidence from animal models has identified its role in many homeostatic systems including respiration. Animal models have also demonstrated a columnar structure that subdivides the PAG into four columns on each side, and these subdivisions have different functions with regard to respiration. In this study we used ultra-high field functional MRI (7 T) to image the brainstem and superior cortical areas at high resolution (1mm(3)voxels), aiming to identify activation within the columns of the PAG associated with respiratory control. Our results showed deactivation in the lateral and dorsomedial columns of the PAG corresponding with short (~10s) breath holds, along with cortical activations consistent with previous respiratory imaging studies. These results demonstrate the involvement of the lateral and dorsomedial PAG in the network of conscious respiratory control for the first time in humans. This study also reveals the opportunities of 7 T functional MRI for non-invasively investigating human brainstem nuclei at high-resolutions

Neural Representations of Visual Motion Processing in the Human Brain Using Laminar Imaging at 9.4 Tesla

During natural behavior, much of the motion signal falling into our eyes is due to our own movements. Therefore, in order to correctly perceive motion in our environment, it is important to parse visual motion signals into those caused by self-motion such as eye- or head-movements and those caused by external motion. Neural mechanisms underlying this task, which are also required to allow for a stable perception of the world during pursuit eye movements, are not fully understood. Both, perceptual stability as well as perception of real-world (i.e. objective) motion are the product of integration between motion signals on the retina and efference copies of eye movements. The central aim of this thesis is to examine whether different levels of cortical depth or distinct columnar structures of visual motion regions are differentially involved in disentangling signals related to self-motion, objective, or object motion. Based on previous studies reporting segregated populations of voxels in high level visual areas such as V3A, V6, and MST responding predominantly to either retinal or extra- retinal (‘real’) motion, we speculated such voxels to reside within laminar or columnar functional units. We used ultra-high field (9.4T) fMRI along with an experimental paradigm that independently manipulated retinal and extra-retinal motion signals (smooth pursuit) while controlling for effects of eye-movements, to investigate whether processing of real world motion in human V5/MT, putative MST (pMST), and V1 is associated to differential laminar signal intensities. We also examined motion integration across cortical depths in human motion areas V3A and V6 that have strong objective motion responses. We found a unique, condition specific laminar profile in human area V6, showing reduced mid-layer responses for retinal motion only, suggestive of an inhibitory retinal contribution to motion integration in mid layers or alternatively an excitatory contribution in deep and superficial layers. We also found evidence indicating that in V5/MT and pMST, processing related to retinal, objective, and pursuit motion are either integrated or colocalized at the scale of our resolution. In contrast, in V1, independent functional processes seem to be driving the response to retinal and objective motion on the one hand, and to pursuit signals on the other. The lack of differential signals across depth in these regions suggests either that a columnar rather than laminar segregation governs these functions in these areas, or that the methods used were unable to detect differential neural laminar processing. Furthermore, the thesis provides a thorough analysis of the relevant technical modalities used for data acquisition and data analysis at ultra-high field in the context of laminar fMRI. Relying on our technical implementations we were able to conduct two high-resolution fMRI experiments that helped us to further investigate the laminar organization of self-induced and externally induced motion cues in human high-level visual areas and to form speculations about the site and the mechanisms of their integration

MICROSTRUCTURE AND CONNECTIVITY OF THE CEREBELLUM WITH ADVANCED DIFFUSION MRI IN HEALTH AND PATHOLOGY

The cerebellum contains most of the central nervous system neurons and it is classically known to be a key region for sensorimotor coordination and learning. However, its role in higher cognitive functions has been increasingly recognised, thus raising the interest of neuroscience and neuroimaging communities. Despite this, knowledge of cerebellar structure and function is still incomplete and the interpretation of experimental results is often problematic. For these and also technical reasons the cerebellum is still frequently disregarded in magnetic resonance imaging (MRI) studies. Therefore, the principal aim of this work was to use MRI to investigate cerebellar microstructure and macrostructural connectivity in health and pathology, focusing also on technical aspects of image acquisition. The starting point of each project described in the present thesis were techniques, models and pipelines currently accepted in clinical practice. The meeting of inadequacies or problems of such techniques raised questions that pushed research to a more fundamental level. This thesis has three main contributions. The first part presents a clinical study of cerebellar involvement in processing speed deficits in multiple sclerosis, where combined tractography and network science highlighted the importance of the cerebellum in patients\u2019 cognitive performance. Then a deeper investigation conducted on high-quality diffusion MRI data with advanced diffusion signal models showed that subregions of the cerebellar cortex are characterised by different microstructural features: this represents one of the very first attempts to use diffusion MRI to face the widespread idea of cerebellar cortex uniformity, which has been recently challenged by findings from other research fields, thus providing new perspectives for the study of cerebellar information processing in health and pathology. Finally, the emerging technical problems that hamper the study of small structures within the cerebellum were tackled by developing dedicated acquisition protocols that exploit reduced field-of-view techniques for 3T and 7T MRI scanners

Imaging Pain And Brain Plasticity: A Longitudinal Structural Imaging Study

Chronic musculoskeletal pain is a leading cause of disability worldwide yet the mechanisms of chronification and neural responses to effective treatment remain elusive. Non-invasive imaging techniques are useful for investigating brain alterations associated with health and disease. Thus the overall goal of this dissertation was to investigate the white (WM) and grey matter (GM) structural differences in patients with musculoskeletal pain before and after psychotherapeutic intervention: cognitive behavioral therapy (CBT). To aid in the interpretation of clinical findings, we used a novel porcine model of low back pain-like pathophysiology and developed a post-mortem, in situ, neuroimaging approach to facilitate translational investigation. The first objective of this dissertation (Chapter 2) was to identify structural brain alterations in chronic pain patients compared to healthy controls. To achieve this, we examined GM volume and diffusivity as well as WM metrics of complexity, density, and connectivity. Consistent with the literature, we observed robust differences in GM volume across a number of brain regions in chronic pain patients, however, findings of increased GM volume in several regions are in contrast to previous reports. We also identified WM changes, with pain patients exhibiting reduced WM density in tracts that project to descending pain modulatory regions as well as increased connectivity to default mode network structures, and bidirectional alterations in complexity. These findings may reflect network level dysfunction in patients with chronic pain. The second aim (Chapter 3) was to investigate reversibility or neuroplasticity of structural alterations in the chronic pain brain following CBT compared to an active control group. Longitudinal evaluation was carried out at baseline, following 11-week intervention, and a four-month follow-up. Similarly, we conducted structural brain assessments including GM morphometry and WM complexity and connectivity. We did not observe GM volumetric or WM connectivity changes, but we did discover differences in WM complexity after therapy and at follow-up visits. To facilitate mechanistic investigation of pain related brain changes, we used a novel porcine model of low back pain-like pathophysiology (Chapter 6). This model replicates hallmarks of chronic pain, such as soft tissue injury and movement alteration. We also developed a novel protocol to perform translational post-mortem, in situ, neuroimaging in our porcine model to reproduce WM and GM findings observed in humans, followed by a unique perfusion and immersion fixation protocol to enable histological assessment (Chapter 4). In conclusion, our clinical data suggest robust structural brain alterations in patients with chronic pain as compared to healthy individuals and in response to therapeutic intervention. However, the mechanism of these brain changes remains unknown. Therefore, we propose to use a porcine model of musculoskeletal pain with a novel neuroimaging protocol to promote mechanistic investigation and expand our interpretation of clinical findings

Development and application of functional MRI methods to investigate brainstem haemodynamics in the context of systemic hypertension

The selfish brain mechanism proposes that in some cases hypertension could develop as a compensatory mechanism that aims to maintain cerebral blood flow (CBF) by increasing systemic blood pressure through an increase in cardiovascular sympathetic tone. The mechanism that might trigger this hypothesised initial reduction in CBF is uncertain, but the brainstem is an important component of the central autonomic nervous system and may therefore play an important role in the development of hypertension via the selfish brain mechanism. Various techniques have been used to investigate the selfish brain mechanism in humans, including magnetic resonance imaging (MRI) methods to measure CBF and cerebrovascular reactivity (CVR). CVR quantifies the change in CBF in response to a vascular stimulus, and is related to the responsiveness, tone and functional reserve of the cerebrovascular system. This thesis aims to validate, optimise and apply a variety of MRI-based methods of quantifying human cerebrovascular function, which may then be used in future studies to further investigate the selfish brain mechanism. Firstly, methods of measuring CBF and CVR using MRI are tailored towards their application in the brainstem and the feasibility of measuring regional brainstem CBF and CVR is demonstrated. Next, existing data is explored to study the association between vertebral artery hypoplasia (VAH) and brainstem CBF in hypertensives but no statistically significant association between regional CBF, VAH and hypertension is found. Brainstem co-registration is then optimised using machine learning. The UK biobank dataset is explored to study the amplitude of low-frequency fluctuations (ALFF) in the BOLD signal, a potential surrogate index of CVR, in hypertensives. There is no statistically significant difference in the regional variation in ALFF between hypertensives and normotensives. Following this, the relationship between ALFF and CVR is investigated to validate ALFF as a surrogate marker of CVR, but no evidence to support the use of ALFF as a specific metric of CVR is demonstrated. Finally, a pilot study of functional MRI in the locus coeruleus, an important noradrenergic brainstem nucleus that is integral to the central autonomic network, is undertaken. The feasibility of mapping functional connectivity of the LC using an anatomical localiser tailored to each participant is demonstrated