Department of Neuroscience projects

Intercalated BSc Medical Sciences Research available projects

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Projects: 

Head injury and Motor Neuron disease - neuropathology

Main Supervisor

Dr Robin Highley (robin.highley@sheffield.ac.uk)

Second Supervisor

Dr Jonathan Cooper-Knock (j.cooper-knock@sheffield.ac.uk)

Aim and Objectives

We will assess:

  1. What is the burden of chronic traumatic encephalopathy CTE pathology in the brain
  2. What is the best method to assess the burden of TDP43 pathology in the brain
  3. In what way do CTE and TDP43 pathology correlate with clinical indices of MND, from review of patient notes.

Research Methodology

Immunohistochemistry and image analysis on post mortem brain and spinal cord tissue will be used to assess which pathological brain changes relate most closely with clinical phenotype of motor neuron disease. We aim to study brain changes related to chronic traumatic encephalopathy, as well as TDP43 proteinopathy and gliosis.

Expected Outcome

We will assess:

  1. What is the burden of chronic traumatic encephalopathy CTE pathology in the brain
  2. What is the best method to assess the burden of TDP43 pathology in the brain
  3. In what way do CTE and TDP43 pathology correlate with clinical indices of MND, from review of patient notes.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

Critical appraisal of scientific literature.

Laboratory histology, including immunohistochemistry.

Digital pathology.

Case control cohort study to understanding the disease progression and molecular mechanisms associated with hereditary spastic paraparesis and spastic ataxia due to genetic mutations

Main Supervisor

Dr Channa Hewamadduma (chewamadduma1@sheffield.ac.uk)

Second Supervisor

Professor Nigel Hoggard (n.hoggard@sheffield.ac.uk)

Aim and Objectives

1. To systematically assess the MRI/DTI of a cohort of genetic spastic ataxia patients for gene specific changes in DTI with disease progression
2. To accurately determine disease progression using neurological examination, clinical severity scores and instrumented gait assessments and detailed neurocognitive assessments using recognised scales
3. To analyse correlation between MRI/DTI findings and clinical assessments to identify radiological markers that can predict early potential clinical deterioration

Research Methodology

Sheffield has the larges UK cohort of spastic ataxia patients due to SPG7 gene mutation. Consecutive patients who carry genetic diagnosis of genetic spastic ataxia will be approached if they meet the inclusion and exclusion criteria for the study
and consented to take part in the study. Our study is a descriptive cohort study which will compare DTI/MRI imaging and clinical correlations with an age and gender matched historical control group. Patients will have their gait assessed together with clinical assessments. Student will be trained to carry out all the assessments.

This is a funded project and ethics is already in place.

Expected Outcome

1. obtain longitudinal data on clinical progression
2. Able to correlated MRI findings and clinical progression
3. Assess data from cognitive function, clinical progression and identify neuro-imaging / MRI biomarker/s
4. Publish the findings in a reputable journal
5. Present the findings at national and international conferences

Type of Project

Clinical project - based in the clinical environment with patients/including service evaluation

Additional Training

Student will be fully trained to conduct a detailed neurological examination.
Student will attend regular consultant clinics and will be exposed to patient assessments
Student will have his/her own cohort of patients that they will liaise with directly for clinical assessments and MRI scanning
Student will receive guidance on analysis of clinical and radiological data by experts

Electrical impedance spectroscopy of muscle for neurological disorders

Main Supervisor

Dr James Alix (j.alix@sheffield.ac.uk)

Second Supervisor

Dr Jamie Healey (jamie.healey@nhs.net)

Aim and Objectives

The aim is to assess the utility of novel impedance spectroscopy as a biomarker of neurological disease.

The objectives are to assess the intra- and inter-observer reliability of the novel impedance system, to assess the ability of the novel impedance system to detect disease in different neurological disorders and to assess the correlation between impedance data and patient symptoms.

Research Methodology

Identifying and monitoring neurological diseases can be difficult. We have developed a novel impedance system which uses a tiny, imperceptible electrical current to assess the health of muscle.

In this project we will be testing the new system on patients with neurological disorders. The main areas of interest are motor neurone disease and spasiticity in stroke.

In this project the student will learn how to undertake clinical research. They will learn how to undertake the muscle impedance recordings from patients, perform muscle ultrasound and assess disease burden using established disease scales. Over the duration of the project the student will become increasingly independent in performing all measurements and lead the data collection.

Statistical analyses will then be undertaken.

Expected Outcome

The project will contribute results on the reliability of the new impedance device and its ability to detect disease.

The data will be used to generated publications and opportunities to present the results at conferences will be explored (many conferences have been cancelled during covid which may limit the latter opportunity).

Type of Project

Clinical project - based in the clinical environment with patients/including service evaluation

Additional Training

Training in the following will be provided: impedance recordings, muscle ultrasound, quantitative muscle strength testing and disease severity assessments.

Data analysis will be performed using the skills gained in the statistics course.

Developing and testing clinical digital tools to assess and manage emotional distress in patients with motor neurone disease and their carers

Main Supervisor

Dr Esther Hobson (e.hobson@sheffield.ac.uk)

Second Supervisor

Dr Emily Mayberry (emily.mayberry@sheffield.ac.uk)

Other supervisors

Professor Chris McDermott

Aim and Objectives

  1. Evaluate current tools used to assess emotional distress, anxiety and depression with particular relevance to patients and carers of people with motor neuron disease
  2. Identify the components of emotional distress and how they are experienced and communicated by those living with MND
  3. Develop and evaluate a clinical tool that can be used remotely to assess emotional distress
  4. Implement the tool and assess levels of emotional distress in the MND clinic in Sheffield

Research Methodology

The student will work within the internationally recognised clinical MND research team who are developing an innovative telehealth system (TiM) which has enabled clinical care to continue remotely during COVID-19.

This is now being used within MND centres in Europe. At present the tools to detect emotional distress are limited and may not be acceptable in MND. The student will:

  1. Conduct a literature review to a) identify questionnaires that measure emotional symptoms and evaluate them using COSMIN approved checklists and use qualitative methods to assess their acceptability, validity and reliability in patients and carers and b) describe the incidence and nature of of emotional distress in MND
  2. Conduct qualitative interviews with patients, carers and healthcare professionals and do secondary analysis of existing data to look at how patients and carers experience emotional distress, depression and anxiety and explore their language, relationships with their physical and mental health and their attitudes and experiences of emotional/psychological care
  3. Develop a tool and do initial testing with patients, carers and healthcare professionals using interviews/questionnaires and applying user-centred design techniques
  4. The questionnaire will then be placed into TiM and used with patients and carers and we will conduct analysis of these results in combination with other clinical measures that are also collected (depression, anxiety scores, cognitive assessments etc.)

Expected Outcome

The ultimate aim is to develop a tool(s) that can monitor patient and carers' emotional distress which will be integrated into our telehealth system used in multiple MND centres to support MND care as well as measure the success of new psychological interventions that we are developing. The students will work in the large, dynamic clinical research group working on the clinical care of MND which includes doctors, psychologists, nurses and therapists. They will develop a wide range of research skills and typically students working on these projects publish 1-2 papers in high impact journals and present their work at international conferences. Previous students have also continued to be involved in the research which have led to successful research grants and publications and the implementation of an assessment tool in the clinic.

Type of Project

Clinical project - based in the clinical environment with patients/including service evaluation

Additional Training

Literature review skills, qualitative research methods (interviewing), structured patient reported outcome measure development, training in NVivo

Investigating the link between infection and cognitive decline in patients with dementia

Main Supervisor

Dr Julie Simpson (julie.simpson@sheffield.ac.uk)

Second Supervisor

Professor Steve Wharton

Other supervisors

Dr Vikki Ridger

Aim and Objectives

Background. Many carers of people with dementia often notice that symptoms get worse following an infection. This suggests that systemic inflammation has direct effects on brain function and accelerates dementia. Systemic inflammation is associated with a large increase in the number of circulating neutrophils, which are the most abundant white blood cell. Neutrophils produce large numbers of small pouch-like vesicles which impact the function of blood vessels in the body. Endothelial cells lining blood vessels in the brain are normally very tightly linked together but in Alzheimer’s disease they become leaky, allowing the movement of damaging substances into the brain. Our research has shown that the vesicles produced by neutrophils enter human brain endothelial cells, affecting their leakiness, and that they contain small molecules called miRNAs which are able to control gene expression. We hypothesise that the miRNA content of neutrophil vesicles from dementia patients makes blood vessels in the brain more leaky, contributing to cognitive decline during an infection. This study aims to identify a potential mechanism linking infection and accelerated cognitive decline in dementia patients. Specifically, we aim to i. compare the miRNA profile these vesicles from dementia patients to age and gender matched healthy controls. ii. investigate if the candidate miRNAs are present in the vessels of dementia patient post-mortem human brain samples

Research Methodology

We have developed a robust protocol to sequence the miRNA contents of vesicles isolated from dementia patients and healthy controls. To address Aim (i) we will perform a detailed analysis of this data and determine which miRNAs are contained within the vesicles and if the content differs in dementia patients. To address Aim (ii) we will use RNAscope to detect and visualise miRNA in post-mortem human brain samples from patients with dementia, enabling us to determine if our candidate miRNAs are associated with leaky blood vessels in the brain of patients with Alzheimer’s disease.

Expected Outcome

The proposed research will advance our understanding of neutrophil derived microvesicles in AD, potentially providing a
mechanistic explanation for the relationship between systemic inflammation, neuroinflammation and cognitive decline.
Understanding how systemic inflammation contributes to dementia is essential to identify new therapeutic treatments.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

The student will be trained in a range of specific lab techniques, including bioinformatic analysis, immunohistochemistry,
RNAscope, microscopy and image analysis. During their project the student will attend the weekly neuropathology meetings and have the opportunity to develop their communication skills by presenting their research at one of the weekly SITraN seminars, the Department of Neuroscience research day and/or the annual Medical School research meeting.

Role of Remote Ischaemic Preconditioning (RIPC) on Activity, Fatigue and Gait in people with Multiple Sclerosis.

Main Supervisor

Dr Krishnan Padmakumari Sivaraman Nair (siva.nair@nhs.net)

Second Supervisor

Professor Claudia Mazza (c.mazza@sheffield.ac.uk)

Aim and Objectives

Primary Aims
1) To assess whether RIPC can increase activity in people with MS
2) To assess whether RIPC can reduce fatigue in people with MS
3) To assess whether RIPC can improve gait in people with MS

Secondary Aims
1) To assess whether RIPC can reduce the impact of MS on people’s life.
2) To assess whether RIPC can improve the quality of life in people with MS.

Research Methodology

Participants will be randomised to receive either RIPC or a sham intervention (sham). They will not be told which group they are in.
Participants and their carer will be taught how to perform the relevant intervention and be asked to do so at home every day for six weeks.

Physical activity, gait and fatigue will be compared before and after the intervention period. Participants will be asked to wear an activity monitor at home for 1 week before and after the intervention to measure levels of activity. To assess gait, participants will complete the 6 minute walk test wearing inertial sensors which measure gait and distance walked. The modified fatigue impact scale will be completed before and after the intervention and levels of exertion recorded after each 6 minute walk test.

Expected Outcome

Primary analysis will focus on the comparison of the outcome measures at baseline and after the 6 week home intervention period. As a secondary analysis, the outcome measures will be compared before and after the intervention within the visit.

Type of Project

Clinical project - based in the clinical environment with patients/including service evaluation

Additional Training

Progress in new technologies has given rise to devices and techniques which allow more objective evaluation of activity, gait and fatigue. This reduces the error margin caused by subjective techniques [4] and potentially shortens the time needed to detect changes resulting from an intervention. Among these technologies, the currently most adopted are wearable sensors and pressure insoles, dynamometry (DYN), and surface electromyography (sEMG). The INSIGNEO biomechanics laboratory, recently established as part of the NIHR Sheffield Biomedical Research Centre (BRC), is now equipped with all the state of the art sensors needed to perform the above type of assessments.

Wearable sensor systems (e.g. pressure and bend sensors, accelerometers and gyroscopes, heart rate monitors) allow for recording and characterisation of walking “out of the laboratory”, for example, in patient’s homes, at clinic visits, and during the course of their everyday lives. Their most common application is in the analysis of a patient’s motor performance, as recorded while the patient is performing traditionally established tests such as the six-minute walk, 10-minute walk, or timed up and go (the participant is asked to rise from a chair, walk seven metres, turn around, walk back to the chair, and sit down). In addition, wearable sensors can be used to monitor a patient’s gait and physical activity patterns for prolonged periods of time, such as while at home or at work. Wearable sensors allow the recording of several parameters, such as step and stride duration and frequency, gait speed, balance, symmetry and joint angles.

We aim to utilise the above technologies to assess whether RIPC can improve activity, gait and fatigue in people with Multiple Sclerosis. Using validated patient reported outcome measures we will also assess whether RIPC can reduce the impact of MS on people’s life and improve the quality of life in people with MS.

What are the views of people with genetic disease on reproductive medicine options?

Main Supervisor

Dr Alisdari McNeill (a.mcneill@sheffield.ac.uk)

Second Supervisor

Dr Megan Freeth (m.freeth@sheffield.ac.uk)

Aim and Objectives

There are several reproductive medicine options which can be used to make sure that someone with a genetic disease has a healthy child. Amniocentesis can be used to test a pregnancy, with termination of affected pregnancies. In preimplatantation genetic diagnosis the embryo is tested for the genetic disease and only unaffected embryos implanted. Despite the tremendous technical advances in this field relatively little is known about patients' views on the acceptability of these techniques and how they wish to receive information on them. In this project we will study the views of people with a given genetic disease (to be chosen after discussion with the student) on reproductive medicine options.

Research Methodology

The student will undertake qualitative interviews on people affected by a defined genetic disease (n=10). This will involve a 30-45 minute interview based upon a written interview guide. The interviews are audio recorded and transcribed. The transcripts will be analysed using software called NVivo12. The transcripts are read to identify codes within the text (e.g. negative views on genetic testing, worry about having an affected child), these codes are then grouped under over arching "themes". This method enables us to ascertain the participants' views without the bias found when asking closed questions. The genetic disease could be selected to interest the student, but we would plan to focus on genetic eye disease or neurofibromatosis type 1.

Expected Outcome

1. An understanding of the views of people with a given genetic disease on the acceptability of techniques such as preimplantation genetic diagnosis.
2. A peer reviewed research paper with the student as an author.
3. The student will receive training in qualitative interviewing and an understanding of reproductive medicine options for genetic disease

Type of Project

Qualitative Project/non-lab based - primarily using qualitative methods

Additional Training

Introduction to qualitative research methods and full training and support in the performance of interviews and the thematic analysis.

Investigation of the role of ER-mitochondria interactions Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal dementia

Main Supervisor

Dr Kurt De Vos (k.de_vos@sheffield.ac.uk)

Second Supervisor

Andrew Grierson

Aim and Objectives

The aims of this project are to characterise a novel pathway that regulates ER–mitochondria interaction and to determine its involvement in ALS and PD.

Research Methodology

Neurodegenerative disorders such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are devastating diseases with huge unmet medical need. The socio-economic burden associated with neurodegenerative disorders is enormous and is set to increase as the population ages. Our overall goal is to identify and develop new targets that can be the basis for the development of novel classes of neuroprotective drug candidates and treatments for neurodegeneration and will motivate subsequent clinical studies.
Perturbations to the communication between the endoplasmic reticulum (ER) and mitochondria at close contact sites between the organelles have been widely implicated in the aetiology of many adult-onset neurodegenerative diseases including ALS/FTD and PD. The precise causes of ER–mitochondria contact site disruption in disease and its contribution to neurodegeneration are poorly understood. However, human mutations in genes that regulate ER–mitochondria contact sites have been shown to cause genetic forms of neurodegeneration, demonstrating the importance of ER–mitochondria crosstalk for neuronal function and survival and suggesting that targeting the underlying causes of disruption may be of therapeutic benefit.
We have uncovered a novel kinase pathway that regulates ER–mitochondria contacts, and have data that suggest that upregulation of this pathway may be the underlying cause of ER–mitochondria contact disruption in SOD1-related ALS and α-synuclein-related PD.

The aim of this project is to investigate this novel pathway and its involvement in ALS and PD.

We will use a number of cell biological and biochemical techniques in our investigations. These will include among others cell culture and transfection, immunofluorescence microscopy, immunoblotting, PCR, and cloning.

Expected Outcome

We will discover the mechanism by which the kinase pathway regulates ER-Mitochondria communication. Specifically we will learn how the kinase pathway affects the tethers that link ER to mitochondria.
We will learn if the kinase pathway is involved in ALS and PD. Specifically we will learn if the pathway is unregulated in cellular models of SOD1, TDP-43, FUS and C9orf72-related ALS and in LRRK2, and synuclein-related PD.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

You will be taught all neccessary techniques and analysis methods.

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