Sheffield Institute for
Translational Neuroscience

NIHR Sheffield Biomedical Research Centre training positions

Projects available in Translational Neuroscience for Chronic Neurological disorders 

The NIHR Sheffield Biomedical Research Centre is currently offering 4 training positions in Translational Neuroscience for either immediate or flexible 2018 starts:

  • Two PhD positions (stipends at current RCUK rates plus Home/EU fees for 3-year projects)
  • Two Clinical Research Fellowships (full-time for 1 year)

The NIHR Sheffield Biomedical Research Centre is focused on the pull-through of developments in Neurodegeneration, Neuroinflammation and Cerebrovascular disease into early phase clinical trials. Research in these areas is supported by cross-cutting themes of Advanced Medical Imaging, Genomic Medicine and Bioinformatics, and in silico medicine. The Sheffield BRC brings together outstanding scientists from the University of Sheffield Departments of Neuroscience and Engineering in multidisciplinary research institutes SITraN and INSIGNEO to improve the treatment and care of people living with chronic neurological disorders.

Clinical Research projects will take place in conjunction with the Academic Neurology department at the Royal Hallamshire Hospital and will be supported by the NIHR Sheffield Clinical Research Facility. Sheffield Teaching Hospitals NHS Foundation Trust recruited over 8000 patients onto Clinical trials in 2016.

Applications for the PhD should be made using this form after making contact with the project supervisor:

For applications for the Clinical Research Fellow positions, please contact Laura Evans regarding the application procedure. 

Project proposals for full-time 3-year PhD studentships with the Sheffield BRC are outlined below, and for 1-year Clinical Research placements below that.

The closing date for applications is 7 December. 

PhD project title:  Understanding the transcriptional response to low-dose interleukin-2 in the blood of amyotrophic lateral sclerosis patients

Supervisor: Janine Kirby

Project details:

The PhD project is associated with the Horizon 2020 funded project MIROCALS, a clinical trial of low dose interleukin-2 (IL2) in patients with amyotrophic lateral sclerosis. As part of the trial, long longitudinal biosamples are being collected to analyse the response of the patients to the drug.

In Sheffield, we are leading the Transcriptomics workpackage, of which the main objective is to establish the changes in transcriptomic profiles in response to both riluzole and IL-2 treatment. In addition, we also want to establish the gene expression profiles associated with high and low levels of phosphorylated neurofilament heavy protein (pNFH), a proposed biomarker of ALS, and those profiles associated with responders and non-responders to IL2. Measurements to quantify the levels of pNFH and establish with patients are responders are being completed by our collaborators in other workpackages and will feed into our analyses.

Blood samples are being taken throughout the treatment period and patients will be followed up for 18 months. Patients are already being recruited to the study and the blood and CSF samples from across trial sites France and the UK will be sent to Sheffield for processing and transcriptional analysis. A total of 216 patients will be recruited to the double-blind, randomized and placebo-controlled study.

Following blood collection, samples are being processed to collect the white blood cells on LeukoLock filters and preserve the RNA in RNAlater. RNA will be extracted using the LeukoLock Total RNA Isolation System, the quantity and quality of the RNA assayed, before the RNA is biotinylated and applied to the Clariom D arrays (Affymetrix). These arrays will allow us to distinguish not only differential expression of genes but also detect alternatively spliced exons, using the Transcriptome Analysis Console (TAC) (Affymetrix). Weighted gene co-expression network analysis will be used to identify genes behaving similarly following treatment and DAVID and Webgestalt online software will be used to identify significantly enriched biological pathways. Gene and splicing changes will be validated through reverse transcriptase PCR (RT-PCR) and quantitative PCR (q-PCR) on a sub group of patients.

Initial work will also focus on analyzing data generated from the MIROCALS pilot study, which comprises of gene expression profiles from 24 patients at two time points (baseline and 3 months), in whom 12 who received IL2 and 12 who received the placebo.

Funding: Open to Home/EU and will be fully funded through the Sheffield NIHR BRC for 3 years.

Entry Requirements: Candidates must have a first or upper second class honors degree or significant research experience.A background in neuroscience or immunology would be desirable, but not essential

Enquiries: Interested candidates should in the first instance contact Dr Janine Kirby via email:

How to apply: Please complete a University Postgraduate Research Application form available here:

PhD project title: Using resting state QEEG parameters as early diagnostic indicators of Alzheimer's Disease and biomarkers of cognitive decline in ageing.

Supervisor/s: Daniel Blackburn or Ptolemy Sarrigiannis

Project details: An accurate and early diagnosis of Alzheimer’s disease is crucial in order to provide support for people with dementia and their carers. Changes in brain connectivity (correlations between pairs of signals [electrodes] in relevant frequency bands) may be a useful early marker of dementia. We have resting-state (i.e. no specified task) EEG data, along with detailed neuropsychology and structural and functional MRI from patients with mild cognitive impairment, Alzheimer’s disease and age- and gender-matched healthy volunteers.

The student will gain proficiency in

  1. Quantitative EEG utilising novel software developed in the University of Sheffield the Error Reduction Ratio Causality test.
  2. Using other software packages MATLAB and SPIKE
  3. Neuropsychological tests to diagnose AD and predict conversion of MCI to AD
  4. Neuroradiological techniques of structural and functional MRI.

The studentship will map onto the Biomedical Research Centre’s aims of focusing on dementia research and biomarker development. The proposed research has the potential to be translational in a relatively short time as the timely diagnosis of dementia is a UK policy priority and there are urgent public health needs to improve its accurate early diagnosis and produce biomarkers to measure disease progression.

Funding:  The post will be fully funded through the Sheffield NIHR BRC for 3 years

Entry Requirements: Candidates must have a first or upper second class honors degree or significant research experience. The studentship would be particularly suitable for someone from a biomedical background with competence in mathematical / computational / statistical analysis and who would therefore be able to develop linear and non-linear analysis algorithms to characterise snapshot and longitudinally evolving brain states. The project would also be suitable for someone with a background in clinical neurophysiology wishing to pursue an academic career.

Enquiries: Interested candidates should in the first instance contact Dr Daniel Blackburn ( or Dr Ptolemaios Sarrigiannis (

How to apply: Please complete a University Postgraduate Research Application form available here:

PhD project Title:  TG6 autoimmunity in the development of Gluten Ataxia and other neurological manifestations of gluten sensitivity.

Supervisors: Professors Marios Hadjivassiliou, Daniel Aeschlimann, Nicola Woodroofe and David S Sanders.

Summary of project: The term Gluten Related Disorders (GRD) refers to a spectrum of diverse manifestations triggered by the ingestion of gluten (found in wheat, barley and rye) in genetically susceptible individuals. One of the commonest extraintestinal manifestations is gluten ataxia (GA). The identification of transglutaminase 2 (TG2) as the autoantigen in gluten sensitive enteropathy (coeliac disease-CD) was a major breakthrough in understanding the pathophysiology of CD. Previous work by the supervisors led to the identification of TG6 as an autoantigen in GA. Patients with GA have circulating antibodies against TG6. IgA deposits against TG6 can be found in cerebellar tissue in disease, and passive transfer of autoantibodies into the brain precipitates ataxia in animal model. Furthermore mutations in the gene encoding TG6 have been shown to result in ataxia (SCA35). Finally patients with GA show clinical and radiological improvement (NAA/Cr ratio within the vermis of the cerebellum) following the introduction of strict gluten free diet.

The proposed work aims to investigate the mechanism by which TG6 autoimmunity develops and results in cerebellar dysfunction. The work will determine the presence of TG6 specific B cell/plasma cells in duodenal biopsies and if the immunoglobulin produced by these cells is specific to TG6 or cross-reactive with TG2. It will also examine the presence of gluten related antibodies in the cerebrospinal fluid of patients with gluten ataxia. This work will not only contribute to our understanding of the pathophysiology of GA but will also allow for a more sensitive and specific means of diagnosing gluten related neurological dysfunction.

Aims:  Preliminary data by our group have revealed that gluten ataxia patients positive for TG6 antibodies have B cells/plasma cells in duodenal biopsies that can be identified by incubation with labeled TG6 antigen suggesting that the respective immune response involves the gut. Therefore, our aim is to characterize the nature of these cells and respective antibodies by:

  1. determining whether these B cells/plasma cells are lamina propria resident fully differentiated IgA secreting plasma cells or belong to an immature B cell population.
  1. determining whether the immunoglobulin produced by these cells is specific to TG6 or cross-reactive with TG2.
  1. determining if such plasma cells and corresponding antibodies against TG6 are present in the cerebrospinal fluid in patients with gluten ataxia

Anti-TG2 IgA deposits in the intestine have been identified as a highly specific marker of developing Coeliac Disease (CD), and this precedes villous atrophy (enteropathy) and sero-conversion (ie the presence of anti-TG2 antibodies in the serum). Therefore, detection of autoantigen-specific differentiated effector plasma cells may be a highly specific diagnostic tool, particularly in patients with gluten ataxia who often have ambiguous duodenal biopsy findings as a result of which they are often deprived of a potential treatment. Detection of cells producing TG6-specific autoantibodies on biopsy could therefore facilitate accurate early diagnosis in a Neurology setting as well as identify risk for future neurological problems in patients presenting with gastrointestinal manifestations.

The Royal Hallamshire Hospital cares for over 1700 patients with ataxias, over 900 patients with neurological dysfunction related to gluten sensitivity and over 2000 patients with CD at dedicated ataxia, gluten sensitivity and Coeliac Disease clinics. We have a detailed plan of investigation to select and recruit patients from these clinics and investigate the mechanism of neurological dysfunction in gluten sensitivity. This will be done by looking at cells isolated from small bowel biopsies, CSF examination in patients with Gluten Ataxia and serological assessment of gluten related antibodies. We will investigate the presence of IgA deposits and TG2 and TG6 specific plasma cells in biopsies from ataxia patients  to understand whether all neurology patients with gluten sensitivity have underlying TG6-directed autoimmunity at gut level even when serologically negative.  One of our overall long term aims would be to identify new biomarkers o0f the neurological spectrum of gluten sensitivity to add to the existing rather limited diagnostic markers Such markers can then be applied to screen neurology patients for evidence of gluten related neurological dysfunction e.g. ataxia patients screened from the Sheffield Ataxia Centre, patients with axonal neuropathy and sensory ganglionopathy (from the neuromuscular clinics) and patients with non-specific “vascular” small vessel disease on MR imaging either as an incidental finding or in the context of vascular dementia. Ataxia, neuropathy and white matter abnormalities on MR imaging are the 3 commonest neurological manifestations of gluten sensitivity. 

Relevance of to the health of patients and the public:

Coeliac disease affects 1% of the UK population. It is estimated that only 24% of patients with CD are currently diagnosed. This means that half a million people in the UK are living with coeliac disease undiagnosed. If one also considers the group of patients with gluten sensitivity without enteropathy then the number of undiagnosed patients is likely to be significantly higher. The mean age of diagnosis of classic CD (ie those patients presenting to the gastroenterologists) is 43 and the mean age of diagnosis of CD in those patients presenting to neurologists with established neurological deficits is 53. This difference suggests that those patients with neurological manifestations are less likely to be diagnosed in a timely manner as clinicians fail to consider CD as the likely cause of their neurological deficit. Unfortunately such neurological deficits (eg ataxia) may be permanent if diagnosis and treatment are delayed. Furthermore, even if clinicians consider the possibility of CD in such neurology patients, they are likely to use the serological tests that are readily available locally (ie TG2 and endomysium antibodies) both of which will be negative in 50% of patients presenting with neurological dysfunction.

In addition to clarifying how autoimmunity to TG6 develops and leads to neurological dysfunction, this project will help in optimising diagnosis of gluten related neurological dysfunction by identifying specific biomarkers. This would potentially benefit a very large number of patients with neurological disease that is currently progressive but potentially treatable. Early diagnosis will result in stabilisation and prevention of permanent disability.

Funding:  The post will be fully funded through the Sheffield NIHR BRC for 3 years

Entry Requirements: Candidates must have a first or upper second class honors degree or significant research experience.

Enquiries: Interested candidates should in the first instance contact Professor Marios Hadjivassiliou on

How to apply: Please complete a University Postgraduate Research Application form available here:

PhD Project title: Remote Ischaemic Conditioning after Stroke

Supervisor/s: Prof Arshad Majid, Dr A Ali, Dr J Redgrave

Project details:

Remote ischaemic conditioning (RIC) is where a tourniquet (tight band) is applied to an arm or leg and inflated to a pressure that blocks the flow of blood. This is continued for a short period of time (5 minutes) that does not cause harm to the tissues or cells, but stimulates the release of chemicals in the blood that can improve the way blood is supplied to areas of the body and improve the way the body uses oxygen.

The effects of RIC were first described nearly 30 years ago and have been studied mainly in patients with cardiac disease, where it has been shown to reduce the amount of cardiac damage after a heart attack. More recently studies in athletes have shown that performing RIC before training sessions enhances physical performance in swimmers, cyclists, and runners. Research to date suggests that the effect of RIC may occur due to beneficial changes in perfusion to tissues and their metabolic efficiency.

Stroke is the leading cause of adult disability worldwide and affects 150,000 new patients in the UK each year, costing ~£9 billion to the NHS. Stroke patients commonly experience fatigue (extreme tiredness) that can be debilitating in up to 50%. This often limits the amount of therapy and physical activity that stroke patients can undertake. We aim to establish whether RIC in stroke patients undergoing rehabilitation can reduce fatigue and improve physical performance so that greater levels of rehabilitation and independence can be achieved.

In addition to this, RIC is being investigated extensively in the hyperacute treatment of stroke. However, very little is known about how quickly the effects of RIC occur.

To this effect, this research project will aim to investigate the following:

1)     The acute effects of RIC on cerebral perfusion and cerebral metabolic function in-vivo as measured by MRI perfusion and Spectroscopy. This will involve an exploratory study of 6 healthy volunteers who will have baseline MRI perfusion and spectroscopy of the brain followed by a protocol of 4 cycles of RIC. MRI scans will then be repeated acutely to evaluate any interval changes.

2)     The effect of RIC on fatigue after stroke. To do this we will recruit 40 patients who have had a stroke within Sheffield. Information about these participants will be recorded and tests to evaluate motor function, balance, cognition, fatigue, metabolic demand and healthcare utilisation. Half (20 participants) will then be randomly assigned to a plan where RIC is applied daily for 6 weeks, while the other half will receive a sham (‘dummy’) tourniquet. At the end of this period, the tests of function, cognition, fatigue, and physical performance will be repeated to see if RIC results in improvements in scores of fatigue and levels of physical performance. The effects of chronic RIC on cerebral perfusion and metabolic function will also be investigated in 8 of these participants (4 RIC and 4 sham) using MRI parameters previously described.

3)     The mechanism by which RIC exerts its effects. This will involve taking blood samples from participants in the above study at baseline and at the end of 6 weeks. These will be analysed for a number of blood markers including pro and anti-inflammatory mediators and gene expression.

Sheffield will be the first centre in the world to test chronic RIC in stroke patients for fatigue. Ultimately, if RIC can improve levels of fatigue and physical activity in stroke survivors, it may help patients achieve greater levels of recovery, independence and quality of life.

In addition to this it is hoped that a PhD candidate could also progress a pilot RCT of transcutaneous vagal nerve stimulation (tVNS) for upper limb rehabilitation after stroke. Exploratory work has also started in small cohort of patients led by our research group that has found the technique to be feasible and acceptable to undertake. The PhD candidate would aim to:

1)     Recruit patients to an RCT of tVNS vs sham stimulation alongside routine NHS upper limb rehabilitation in tandem with the RIC study.

2)     Facilitate mechanistic evaluation of tVNS – including collaboration with technicians using transcranial Doppler studies and studies of cerebral perfusion.

This project aligns to the strategic aims of the BRC:

1-     Translational Neuroscience Theme:

This project will be the first pilot trial to evaluate the effect of chronic RIC on an important clinical problem – fatigue. The results from this pilot RCT will help progress work towards a funding application for a large multi-centre RCT that is powered for effectiveness. The project will involve sub-studies to help understand the mechanisms by which RIC exerts its effect. This will involve an analysis of serum biomarkers at baseline and post intervention for both active and sham arms, such as inflammatory mediators, heat-shock protein, GLP-1 and micro-RNA analysis of gene expression. Further, we will be working closely with Prof Ian Wilkinson and the Academic department of radiology to be the first to undertake exploratory investigation of both the acute and chronic effects of RIC on cerebral perfusion and cerebral metabolism and energy metabolism. This will be undertaken using cerebral MR perfusion and MR spectroscopic techniques.

In addition, progressing work in relation to using tVNS for upper limb rehabilitation after stroke was highlighted as a specific short term aim within the translational neuroscience theme.

Funding:  The post will be fully funded through the Sheffield NIHR BRC for 3 years

Entry Requirements: Candidates must have a relevant first or upper second class honors degree or significant research experience.

Enquiries: Interested candidates should in the first instance contact Prof Arshad Majid (

How to apply: Please complete a University Postgraduate Research Application form available here:

PhD Project title: MNDMove: movement-based biomarkers of Motor Neuron Disease

Supervisor/s: Thomas Jenkins, Claudia Mazzà, Chris Mc Dermott

Project details:

An objective biomarker is an important area of need in MND in order to facilitate future clinical trials over short time-scales. No such biomarker currently exists, mainly due to the phenotypic heterogeneity of MND presentation and course and there is a recognised need for more sensitive outcome measures of function in MND patients.

Loss of muscle strength is a core feature of MND and it is now well established that quantitative strength measures are sensitive to change and that they demonstrate a remarkably linear, predictable loss of power within each patient. There is nonetheless still a need to develop simple protocols to assess muscle strength and function using technology that can be easily embedded within the clinic.Another established core feature of MND is muscle denervation. Preliminary findings from a longitudinal study of whole-body magnetic resonance imaging (MRI) in MND have demonstrated denervation, associations between higher T2 muscle MR signal and greater weakness and loss of motor units, and longitudinal increases in anterolateral leg compartment muscles over time.  Despite the above progress in establishing objective quantitative biomarkers, very little is known about if and how loss of muscle strength, muscle denervation, atrophy and spasticity in different regions translate into the abnormal movements of patients with MND. To fill this gap, there is a need to validate simple protocols to assess muscle strength against more sophisticated measures to properly understand the aspects of pathophysiology we are measuring.

This PhD project will aim to develop a new simple clinic-based outcome measure to inform disease progression, and replace current burdensome functional muscle outcome measures in MND clinical studies.

Simple and objective biomarkers of MND progression will be obtained by analysing data collected from both the upper and the lower extremities during the execution of a series of functional upper and lower limb movements. We will focus on clinical viability of the proposed solution by: 1) choosing low cost and easy to use devices; 2) limiting the length of the protocol to reduce burden to patients, and 3) defining a limited number of easy to understand parameters to describe the motion, which we will use as biomarkers to objectively quantify disease progression. In order to interpret the clinical meaningfulness of changes observed in the movement data, we will investigate how these changes are associated with changes in muscle volume and denervation as measured using MR and electrophysiology from the same patients, and validated against existing quantitative clinical power assessment techniques using a state-of-the-art dynamometer in a number of muscles.


  • Andres PL, Allred MP, Stephens HE, et al., Fixed dynamometry is more sensitive than vital capacity or ALS rating scale.
  • Cudkowicz ME, Zhang H, Qureshi M, Schoenfeld DA. Maximum voluntary isometric contraction (MVIC). Amyotroph Lateral Scler Other Motor Neuron Disord 2004;5(Suppl 1):84–85.
  • Moeller LM, Pierry IA, Alix JJP, Rao DG, Hoggard N, Bigley J, McDermott CJ, Shaw PJ, Wilkinson ID, Jenkins TM (2016). Imaging muscle denervation in motor neuron disease using whole-body MRI.
  • Pancani S, Tindale W, Shaw PJ, McDermott CJ, Mazzà C (2017), An objective functional characterisation of head movement impairment in individuals with neck muscle weakness due to
  • Amyotrophic Lateral Sclerosis’, PLoS One. 2017; 12(1): e0169019.

Funding:  The post will be fully funded through the Sheffield NIHR BRC for 3 years

Entry Requirements: Candidates must have a relevant first or upper second class honors degree or significant research experience.

Enquiries: Interested candidates should in the first instance contact Dr Tom Jenkins (

How to apply: Please complete a University Postgraduate Research Application form available here:

Clinical Research Fellowship Project title: Does mitochondrial dysfunction in peripheral tissue of patients with Parkinson’s disease mirror mitochondrial dysfunction in their brain tissue and correlate with disease progression?

Supervisors: Prof Oliver Bandmann, MD PhD FAAN (primary supervisor) and Dr Heather Mortiboys, PhD (secondary supervisor)

Project details: This project will focus on Parkinson’s disease (PD) and be at the interface of clinical medicine and state-of-the-art in vitro approaches applied to PD patient tissue. The successful candidate will learn a wide range of crucial skills including 31-P MR Spectroscopy (31-P MRS) image analysis and a range of cell culture techniques highly relevant for future Personalized Medicine strategies. The candidate will also become skilled in the critical assessment and functional validation of clinical prognostic models for Parkinson’s disease.

Purpose/aims: To determine whether mitochondrial function/ATP production in brain tissue as quantified by 31P-MRS correlates with mitochondrial function in peripheral tissue of patients with Parkinson’s disease (PD) and the likelihood of rapid clinical progression.

Background: Parkinson’s disease (PD) is the second most common neurodegenerative condition after Alzheimer's disease. Disease modifying treatment which would slow down the ongoing cell death and PD progression has repeatedly been identified as the most important issue for PD patients and their carers in surveys of the patient self-help organisation Parkinson's UK. A recent, high-profile review by leading experts in the field has identified mitochondrial dysfunction as a promising target for neuroprotective strategies in PD. Skin fibroblasts are increasingly used to study these key pathogenic mechanisms in Parkinson’s disease. We were the first group worldwide to identify mitochondrial dysfunction in both parkin- and LRRK2G2019S mutant patient tissue. Mitochondrial dysfunction can also be detected in peripheral tissue of patients with sporadic PD. We also undertook the first drug screen in PD patient tissue and identified a highly promising mitochondrial rescue drug with real potential as a putative neuroprotective compound for PD. We predict that testing of putative neuroprotective compounds in patient tissue will become an essential part of a personalized medicine approach for PD.

31-P MRS is a well-established non-invasive technique, experienced by patients in an identical manner to a conventional MRI scan, without requirement for any injection of contrast agent. Various sampling techniques exist, either focusing on a region of interest, or applying a whole-brain acquisition. 31-P MRS is ideally suited to the study of energy metabolism and mitochondrial function because measurement of adenosine triphosphate (ATP) and other phosphorylated energy substrates is possible. Previous 31-P MRS studies have confirmed that this imaging strategy can be used to detect decreased ATP levels in PD patient brains. We aim to eventually use 31-P MRS to confirm target engagement of putative mitochondrial rescue drugs.

Underlying hypothesis: Mitochondrial dysfunction in PD correlates in peripheral and brain tissue and is more marked in those newly diagnosed PD patients who are predicted to have a rapid disease progression. 

Research Plan: Patients will be recruited from the movement disorders out-patient clinics of the Royal Hallamshire Hospital. The predictive progression score will be calculated using the model by Williams-Gray and co-workers. During year 1 of this project (equivalent to the funding period of this BRC Clinical Fellowship) we propose to recruit a minimum of 20 patients (10 with predicted rapid progression and 10 with predicted slow progression) as well as a minimum of 10 control participants. Skin biopsies will be taken and fibroblast cultures established as previously described. Mitochondrial membrane potential, intracellular ATP levels and mitochondrial morphology will be assessed, using previously described methods which are in routine use at SITraN. 31-P MRS will be undertaken in all research participants, using locally established protocols.

Outlook: The proposed work will provide crucial pilot data for a future Fellowship application to the MRC, Wellcome Trust or similar. This future Fellowship application would include the transformation/differentiation of representative fibroblast lines into i-neurons with detailed functional characterization, including RNAseq-based transcriptomic analysis and pharmacological rescue experiments (“Personalized Medicine”). 

Funding: BRC Clinical Fellowship, pump priming for 1 year, with the expectation of external funding for the remaining years.

Entry Requirements: Clinical Trainees should have some experience with research and will ideally wish to build an academic career in Parkinson’s disease research and progress to a Clinical PhD Fellowship in the future.

Enquiries: Interested candidates should in the first instance contact Prof Oliver Bandmann (email:

How to apply: Please contact Laura Evans ( to be directed to the University of Sheffield application procedure.