Human mechanosensation: From 1st-order neurone to somatosensory cortex

Information about the external and internal world is conveyed to the brain by an extensive system of sensory nerves. The skin contains multiple types of sensory receptors/nerves which inform the brain about events occurring on the body surface. There are many very basic questions about the neuroscience underlying human tactile processing that remain unanswered. We aim to use recent advances in the neuroimaging techniques of ultra-high field functional magnetic resonance imaging (UHF-fMRI) and magnetoencephalography (MEG), coupled in conjunction with nerve recording (microneurography) and stimulating techniques (intraneural microstimulation (INMS)), to provide novel insight into the brain mechanisms involved in operating the sense of touch in humans.

Using fMRI, we can measure changes in the local blood flow that occur with increased neural activity. These changes cause an increase in the signal intensity in the MR image in the part of brain that is active. This means that we can measure, for example, which parts of the brain are more active while subjects feel an object touch their finger. One of the problems we face when studying the mechanism underlying our sense of touch is that the changes in signal intensity that occur are relatively small. We have overcome this problem by using a very high field magnetic resonance scanner which allows us to measure robust neural responses to touch, non-invasively, with much higher spatial resolution than has previously been possible, and we can now obtain robust activation maps of individual participants brains. This makes UHF- fMRI a very attractive tool for clinical applications. MEG is another non-invasive neuroimaging technique that offers a way to probe the temporal aspects of somatosensory processing.
The technique of microneurography allows unprecedented access to the earliest stages of information transfer to the brain, it involves inserting a very fine needle through the skin into an underlying nerve, so you can hear and see (the nerve recording) sending messages to the brain. A step further is to electrically stimulate a single nerve fibre with a very small current, using the technique of INMS, so that a person can feel touch when there is no actual skin stimulus. Combining INMS with neuroimaging UHF-fMRI and MEG, will allow us to reveal the representation of single sensory nerves in the brain.
In this project, we will use these cutting-edge techniques and take a multidisciplinary approach, combining expertise in MRI, neuroscience, neurophysiology and neurology, to improve our understanding of sensory pathways. Specifically, we will use UHF-fMRI to map carefully the detailed anatomy and function of the somatosensory cortex, and will use MEG to characterize the temporal dynamics of brain responses to tactile stimulation of the skin. We will develop a new MR- and MEG-compatible device to perform INMS in the UHF-fMRIscanner and MEG scanner. The use of fMRI during INMS will allow us to map the brain's response to single sensory afferents (in contrast to vibration, which stimulates multiple sensory receptors of various types). We will also apply these methods to measure alterations in the somatosensory pathways in patient groups with neuropathologies. Specifically we will study Focal Hand Dystonia and Carpal Tunnel Syndrome, and assess how somatosensory processing is altered by therapeutic interventions.

Overall, this research will considerably advance our understanding of human somatosensation and perception and will be relevant to a wide range of clinical disorders related to neurotraumatic injury, neurology, neurodevelopment, neurodegeneration, neuropathology, pharmaceutical interventions and pain.

Our research addresses tactile sensation and perception in healthy and neurologically compromised patients. We will build on established experimental designs and analyses to map the representation of the fingers in the human somatosensory cortex in individual subjects. We will measure the cortical mapping of the fingers at very high spatial resolution using ultra-high field functional magnetic resonance imaging (UHF-fMRI) at 7T. By using 1mm isotropic voxels in our fMRI experiments, we have already been able to reveal the fine-grained topographic map of the digit representation in somatosensory cortex much better than in any previous studies. We will extend this mapping to other aspects of the organization of somatosensory cortex that occur at the sub-millimetre length scale. In particular, we will characterize digit organization patterns across inter-areal boundaries in primary somatosensory cortex (SI), between SI and SII (secondary) somatosensory cortex, and measure cortical layer specific activity to determine the microcircuitry underlying inter-hemispheric inhibition in healthy individuals. We will combine functional measures with high resolution structural MRI measures of cortical thickness, myelin content and fibre connections, and will assess spatial and spectro-temporal mapping and synchrony between SI/II using MEG.
We will also combine neuroimaging (UHF-fMRI and MEG) with single-unit intraneural microstimulation (INMS) of peripheral nerve afferents to explore the relationships between bespoke patterns of stimulation in 1st-order neurons, their perceptual consequences, and cortical/areal correlates in primary somatosensory cortex.
Using these methodologies, we will reveal the mechanisms underlying maladaptive plasticity associated with abnormal sensory input and assess the effect of therapeutic interventions in two clinical conditions - carpal tunnel syndrome (CTS) and focal hand dystonia (FHD).

The research outlined in this proposal will benefit multiple stakeholders outside the immediate basic neuroscience academic research arena, generating cutting-edge fundamental scientific information that will produce a step-change in knowledge relating to the somatosensory system, and cortical function generally. This grant is strongly driven by a clinical need for improved knowledge of the somatosensory system, with important impacts within the health sector and the wider public.
The key intended impacts of this grant are:

Scientific: The proposed project will take advantage of the full potential of 7T to develop and optimize acquisition and image analysis techniques for ultra-high resolution fMRI to assess somatosensory processing and study neuroplasticity at the individual subject level. We will measure the cortical reorganization and changes in temporal dynamics of neuronal activity that are induced by somatosensory disability. This will provide in the longer term, wider clinical, industrial and economic benefits. The clinical applications within this grant have been designed to validate the improved methodology through assessment of functional and structural neuroplasticity in CTS and FHD patients, therefore providing particular insights into the genesis of maladaptive cortical plasticity mechanisms.

Health and Quality of Life: This grant will provide the methodology to assess the effectiveness of therapeutic interventions on cortical reorganization, providing an improved understanding of the neurobiological mechanisms underlying sensory dysfunction to potentially allow more effective rehabilitation/treatment techniques. There are inherent translational opportunities in other clinical fields in neurology in a wide range of peripheral neuropathy conditions, including diabetic neuropathy and complex regional pain syndrome (CRPS), as well as disorders of the central nervous system (CNS) including neurotraumatic injury, neurodegenerative disorders and pain. This research will also help lay the groundwork for feedback in the field of neural prosthetics. Future neural prosthetics will not only need to decode and process the neural code, but also to deliver into the CNS the specific somatosensory and proprioceptive feedback that limbs naturally produce. This project will add scientific weight to the increasing use of touch in paediatrics, geriatrics, palliative care, intensive care and psychiatry.

Industrial: A major barrier to investment in the developments of pharmacological agents to treat maladaptive plasticity induced disabilities, such as FHD, is the lack of a reversible marker for neuroplasticity. This project will assess the effectiveness of Botilum Toxin treatment and nerve decompression on cortical reorganization in FHD and CTS respectively. If functional cortical sensory maps can be shown to display treatment sensitive reversible abnormalities in response to therapeutic intervention, this could represent a significant advance in the evaluation of other treatments including physical and pharmacological therapies. The success of this project would hence attract R&D investment from pharmaceutical and neuromodulation companies in the developments of therapeutics and other sensory disabilities such as CRPS.

Social-economical: Neurological disorders are the most common cause of disability in the UK, with disturbances of somatic sensation being a major contributor to this disability. With an ageing UK population, the incidence of age-related neurological disease and associated costs is increasing. The proposed research is a step towards confronting the economic and social challenges posed by management of brain diseases.

Educational: New windows into brain function will fuel the public's interest in neuroscience and somatosensory perception, creating educational impact across all age and societal groups.