Project: 

Human iPSC-derived Sensory Neurons to Interrogate the Molecular Interplay between mTORC1 and Histamine H3R in the Progression of Neuropathic Pain

Supervisors

1. Dr Mouhamed Alsaqati - Mouhamed.alsaqati@newcastle.ac.uk
2. Dr Ilona Obara -  ilona.obara@ncl.ac.uk
3. Dr Seva Telezhkin - vsevolod.telezhkin@ncl.ac.uk

Project outline

Neuropathic pain is the pain caused by a lesion or disease of the somatosensory system. This system allows for the perception of touch, pressure, pain, temperature and movement. It involves nerves that arise in the skin, muscles and joints, and include thermoreceptors, mechanoreceptors, chemoreceptors and nociceptors that send signals to the spinal cord and eventually to the brain for further processing.

Conditions associated with neuropathic pain include diabetic neuropathy and peripheral nerve injury pain. Several reports suggest the involvement of mammalian target of rapamycin complex-1 (mTORC1) in chronic neuropathic pain processing (Obara et al., 2011). In particular, research showed that inhibition of Histamine H3 receptors (H3R) caused inhibition of the Akt/GSK-3β pathways, which subsequently inhibits mTORC1 activity (Yan et al., 2014). Hence, H3R is potentially involved in the regulation of pain perception through a mechanism directly involving the modulation of the mTORC1 pathway.

Research in our lab showed that scavenging of peripheral Histamine by Votucalis produced a potent and complete anti-nociceptive effect in neuropathic animal models (Alrashdi et al., 2022). We have previously used patient iPSC-derived neurons with Tuberous sclerosis (TSC) mutation to understand the effect of knocking down TSC function (associated with mTORC1 hyperactivity) on neuronal network behaviours (Alsaqati et al., 2021). This research showed that promoting autophagy can rescue the aberrant neuronal network behaviours seen in TSC patient neurons. We have then generated a homozygous TSC stable knockout (KO) human iPSC cell line using CRISPR-Cas9 technology.

We are now planning to use those cells to generate sensory neurons to understand the abnormal pain pathology in patients with TSC mutation, determine the molecular link between mTORC1 and histamine receptors pathways, and examine the effect of several pharmacological agents targeting H3R i.e. PF-0868087 on the aberrant neural functional behaviours of these neurons. The projects promise to offer biological insight of pathogenic mechanisms and could pave the way towards personalized medicine for patients with chronic neuropathic pain.

This project will be performed in Mouhamed Alsaqati lab under the co-supervision of Ilona Obara and Seva Telezhkin.

Hypothesis: Sensory neurons derived from TSC KO cells exhibit abnormal spontaneous functional behaviours, and aberrant response to pain stimuli which could be rescued by modulating the function of H3R.

Aim: To understand the molecular interplay between mTORC1 and H3R and their involvement in the development of neuropathic pain.

Objectives

1. Identify the main deregulated pain pathways in sensory neurons derived from TSC KO human iPSC-derived sensory neurons
2. Identify the functional abnormalities of TSC KO sensory neurons
3. Understand the interaction between Histamine pathways and mTORC1 activity in pain progression
4. Identify the potential therapeutic values of H3R targets in rescuing the aberrant response to pain stimuli in TSC KO neurons

Research training: This project represents a unique opportunity to gain in-depth training in neural stem cell and peripheral nervous system. The appointed student will be trained in culturing human iPSCs and their differentiation into sensory neurons containing nociceptors, proprioceptors and mechanoreceptors.

Methodologies

• A variety of cellular, genetics, molecular and functional techniques will be combined:
• Cell biology; Imaging, Western blotting
• Genetics; PCR and RT-qPCR, cloning
• Functional Assays; calcium imaging, Patch-clamp, Multi-electrode arrays (MEAs)
• Advanced molecular biology techniques; RNA-Seq, CHIP-Seq,CRISPR-Cas9

Project:

Understanding Essential Tremor as a Miscalibrated Internal Model

Supervisors

1. Professor Stuart N Baker - stuart.baker@ncl.ac.uk
2. Dr Maria Germann - maria.germann@ncl.ac.uk

Project outline

Essential tremor (ET) is the most common reason for referral to a neurologist, with a prevalence of around 1-3%. Sufferers experience involuntary shaking of the limbs at around 5Hz; mild cases cause only social embarrassment, but more severe tremor can be disabling and limit activities of daily living. ET has been shown to result from specific pathological changes in the cerebellum, a part of the brain which is responsible for motor adaptation.

The student will carry out studies with both healthy human volunteers and people with ET. Participants will make movements with a limb inside a motorised device which can simulate different resistive forces, for example to make the limb feel heavier than it actually is, and also can constrain movements to pre-defined trajectories. By pairing these behavioural manipulations with quantitative assessment of muscle activation (measured by electromyogram) and contractile force (measured with a force transducer), the student will seek to provide evidence for the hypothesis that ET results from an inability of the cerebellum to calibrate movements for the correct physical properties of the limb (e.g. inertia, friction, viscosity).

If successful, this project will pave the way for novel therapies for ET, based on recalibrating faulty internal models within the brain. The project will be supervised by Prof. Stuart Baker and Dr Maria Germann, providing multi-disciplinary training within the successful and lively environment of Newcastle University’s Movement Laboratory.

Applicants should have strong quantitative skills and be comfortable applying mathematical and computational concepts to real world problems, both for off-line data analysis and for real time feedback and control while a movement is being performed. A familiarity with the neuroscience background, especially aspects relevant to motor control, is desirable but not essential.

Project: 

Exploring the cross-domain function of the medial temporal lobe with virtual reality and eye-tracking

Supervisors

1. Dr Andrej Bicanski - andrej.bicanski@ncl.ac.uk
2. Dr Quoc Vuong - quoc.vuong@newcastle.ac.uk

Project outline

Background: The hippocampal formation in the medial temporal lobe have been the target of intense research regarding the neural underpinnings of long-term memory. The areas are key players in episodic and spatial memory. Single neuron-recordings in behaving animals have also revealed neurons that code for specific spatial variables such as location (through place cells and grid cells), headings, and the presence of boundaries or objects in space. These cells comprise a sophisticated spatial mapping system. Moreover, direct recordings from human epilepsy patients confirm that these cells exist in humans. However, the hippocampal formation also plays a key role in visual memory for complex stimuli, as well as in other domains of cognition. Intriguingly, recordings from Monkey entorhinal cortex suggest grid cells may also map the visual field.

Question and hypothesis: The fact that the same brain area (the hippocampal formation) is involved across different domains of cognition begs the question: are there a common neural representations underlying related tasks across different cognitive domains? The implication is that the same neurons perform similar computations across domains. This is the key hypothesis of this PhD project, the candidate neural representation being that of grid cells, which codes for a 2-dimensional metric.

Methods:  The PhD candidate will develop combined visual+spatial cognitive tasks in a fully immersive virtual-reality environment to tease apart effects on human spatial and visual memory as emergent from common coding principles. For reference: prototypical tasks that are thought to engage grid cells are spatial homing and visual relational memory. During the homing task participants follow a guided outbound path and must return to the start location once visual cues are removed. During a visual relational memory task, participants must demonstrate memory for the relative arrangement of objects on a screen or within object features. The candidate will track people’s position in space (in virtual reality) and their eye-movements to measure their attention to objects in the environment. The project will then test for fMRI signatures of grid cells to link observed behaviours to brain functions.

Impact: Direct evidence for shared neural representations and mechanisms in spatial and visual memory would constitute a major advance in our understanding of long-term memory. It would also increase our understanding of cognitive deficits due to Alzheimer’s Disease, as the entorhinal cortex (where grid cells reside) is among the earliest affected areas. It would allow us to understand cognitive deficits across different cognitive domains (spatial and visual) as task-specific manifestations of impairments to a single coding scheme. Understanding the shared neural mechanisms in spatial and visual memory will also pave the way to future mechanistic models of grid cells.

The supervisory Team:
Dr Andrej Bicanski is an expert in models of spatial cognition (Bicanski and Burgess, 2018;2019;2020). He has developed the first model of visual grid cells and is currently developing spatial memory VR experiments as well a relational memory eye-tracking study (separately). Dr Quoc Vuong investigates how people use information from their senses to recognise and interact with people and objects in the environment. He has expertise in eye tracking and brain imaging.

Project:

Abnormalities in proteins and lipids in Lewy body dementia 

Supervisors

1. Dr Daniel Erskine – Daniel.erskine@newcastle.ac.uk
2. Dr Fiona E N LeBeau – fiona.lebeau@ncl.ac.uk
3. Dr Lee J Higham – lee.higham@newcastle.ac.uk

Project outline

Lewy body dementia (LBD) is the second most common form of age-associated dementia disorder. The cause of LBD is not known, but the brains of individuals with LBD have accumulations of the protein alpha-synuclein and damaged mitochondria, which has led many researchers to suggest alpha-synuclein accumulation may cause mitochondrial dysfunction that underlies LBD. As a result, preventing or alleviating alpha-synuclein accumulation is a major goal of current therapies being developed for LBD.

We have recently reported accumulated alpha-synuclein with similarities to LBD in the brains of infants deceased from Krabbe disease, a rare lipid metabolic disease that affects young children. Alpha-synuclein accumulation has previously only been found in the brains of elderly people with LBD and, therefore, observing it in the brains of babies was remarkable and these findings received some media coverage.

Our hypothesis is that the lipid metabolic dysfunction that underlies Krabbe disease may contribute to the LBD disease process and thus offer a new target for therapeutic development in LBD. To address this question, the student will receive a unique training experience in cutting-edge methods for studying human brain tissue, combining neuropathological analysis of post-mortem tissues with culture of living human brain sections from neurosurgical patients, a method in which Newcastle is one of few centres in the world to have expertise. Combining these leading methods with novel mouse models and neuronal cell culture systems, the student will gain experience in immunofluorescence, molecular methods such as western blot, protein aggregation assays and electrophysiology. The appointee will also have the opportunity to work with the Chemistry department to design and characterise probes to study important aspects of biological systems, including mitochondrial function.

This project has great potential to impact LBD research as most current candidate therapies for LBD aim to remove alpha-synuclein once it accumulates, or repair mitochondria, with few examining the interaction between these pathophysiological changes. The aim of this study is to determine whether lipid metabolic dysfunction could underlie both alpha-synuclein aggregation and mitochondrial dysfunction in LBD, thus presenting a novel target for therapeutics that would treat all aspects of LBD and, we hope, be genuinely disease-modifying.

The supervisory team are multi-disciplinary, ranging from expertise in neuropathology and alpha-synuclein aggregation (Erskine), to using rodent models to study neurodegenerative diseases (LeBeau), and the development of probes to answer biological questions (Higham). Overall, this is a novel and exciting project that will provide the opportunity for the student to answer critically important questions in trying to understand dementia, whilst receiving training in world-leading methods. At Newcastle University the student will be part of a vibrant research environment and, as Newcastle is an international centre for excellence in LBD research, there will be considerable opportunity to meet other LBD researchers and clinicians.  The student will also be able to engage with a wide range of courses and seminars and will be encouraged to become involved with public engagement events. 

Project:

Do somatic mutations in bone marrow influence neurodegenerative disorders?  

Supervisors

1. Dr Michael J Keogh - michael.keogh@newcastle.ac.uk
2. Professor Matthew Collin – matthew.collin@newcastle.ac.uk

Project outline:

Background

Age remains the primary risk factor for neurodegenerative disorders such as Alzheimer’s disease (AD) and Lewy body diseases (LBD). They affect over 50 million people world-wide and no disease modifying treatments exist.

A universal feature of aging is the development of somatic mutations in DNA. When these age-related mutations arise within bone marrow they (and their subsequently differentiated blood cells) are termed clonal haematopoietic mutations of indeterminate potential or ‘CHIP’ mutations.  CHIP mutations are present in almost 30% of individuals aged over 80 years and are major drivers of multiple age-related disorders such as cardiovascular disease.

Recent data suggest that CHIP mutations in blood also influence the risk and progression of AD. We have identified a significant excess of CHIP mutations in tissue samples from the brain of AD and LBD patients, but it is not clear (a) how these mutations arose within the brain or (b) whether or how they modify the development or progression of neurodegenerative diseases.

Question

We hypothesise that white blood cells with CHIP mutations cross into the brain and differentiate into resident cells such as microglia and alter the development of neurodegenerative processes. In this programme you will be the first to determine (a) which cells these mutations reside in within the brain, (b) how cells these cells may cross into the brain and (c) how CHIP-mutant cells in the brain may modify the risk and progression of AD and PD. Together this will transform our understanding of how the aging brain may incorporate mutations with age and potentially identify a new disease modifying mechanism of neurodegeneration.

Methods

To achieve these aims you will utilise cutting edge flow-cytometric techniques in human post-mortem brain tissue, high-depth DNA-sequencing techniques and novel co-culture cell models with CRISPR-induced CHIP mutations to simulate the genetic architecture you will define within the brain. This will offer candidates the opportunity to learn innovative and advanced laboratory and computational skills in an exciting new domain of clinical neuroscience with transformative potential to understand how ageing blood cells may act as ‘Trojan horses’ inserting new mutations into the brain throughout life.

Impact 

We believe that by understanding how naturally arising somatic mutations in blood influence neurodegeneration we can develop genetically modified myeloid (blood) cells to treat neurological disorders. This would have huge translational potential for a multitude of disorders and we anticipate that this PhD programme will directly prime such research.

Supervisory team

Dr Keogh is an academic neurologist who was the first to identify CHIP mutations and several other somatic mutations in the brain. Prof Collin is a world-leading haematologist whose laboratory aims to understand the evolution of CHIP and other mutations in blood/myeloid cells. Collaborative opportunities with a world-leading brain organoid laboratory in continental Europe may also be possible within the PhD.

Taken together this PhD position offers a superb opportunity for those who wish to pursue a career in academic neuroscience, haematology or immunology and those who may wish to work in industry - particularly advanced or genetic therapies.

Project:

To assess the engraftment of human pluripotent stem cell-derived photoreceptors in early and advanced stages of Retinitis Pigmentosa

Supervisors

1. Professor Majlinda Lako – Majlinda.lako@ncl.ac.uk
2. Professor Evelyne Sernagor – Evelyne.sernagor@ncl.ac.uk

Project outline

Background: The retina, transmits information from our visual world to the brain via the optic nerve. One of the important roles of the retina is to convert light into electrical signals, through phototransduction. The cells responsible for phototransduction are the photoreceptors, the rods (responsible for vision in dim light conditions) and the cones (responsible for colour and high acuity vision in bright light conditions. One of the main causes of blindness is rod/cone malfunction. This is often due to genetic mutations, leading to gradual rod and/or cone degeneration, and eventual partial or total and irreversible blindness. There are currently no available preventative treatments or new therapeutic interventions to cure patients suffering from these devastating conditions. Retinitis pigmentosa (RP) is a common form of hereditary photoreceptor dystrophy associated with progressive rod degeneration, leading to night blindness and loss of visual acuity. At later stages of the disease, cones degenerate as well, resulting in complete blindness. Therefore, there is a pressing need to develop novel approaches either for photoreceptor replacement or for reactivation of dysfunctional surviving photoreceptor by gene therapy (if performed at early disease stages).

Methods and hypothesis: We develop artificial retinas (organoids) from human pluripotent stem cells (hPSCs). We isolate photoreceptors from these organoids and inject them in mouse retinas with photoreceptor dystrophies, with the goal to achieve integration of these healthy photoreceptors into the host retina, eventually restoring visual function. We have successfully achieved these goals using a cone-enriched population of photoreceptor precursors in a mouse model of RP, resulting in partial restoration of visual function assessed by behavioural and electrophysiological testing (Zerti et al. 2021). However, given the prevalence of rod degeneration in RP, our hypothesis is that transplantation of hPSCs-derived rods at early stages may lead to improved rod integration and function, while also protecting cones from degenerating at later stages. Moreover, we suggest that a combination of rod and cone transplantation may achieve optimal results at advanced degeneration.

Plan of work: Here we propose to test this hypothesis in a mouse model of RP. The student will generate a novel hPSC reporter line, which will enable enrichment of cone and rod precursors, each one carrying a genetically encoded fluorescent marker of a different colour for easier identification once engrafted in the host retina. In one set of experiments, we will inject rods alone at early degeneration stages, with the goal of improving their integration into the host retina and protecting cones from later degeneration. In another set of experiments, we will inject a mixed population of rod and cone precursors at later stages of degeneration to see whether this approach improves photoreceptor integration at the advanced stages of RP.

Impact: Using all the tools we have developed to generate homogenous populations of cone and rod precursors from hPSCs, perform successful cell transplantation and assess vision restoration using behavioural and electrophysiological approaches, this project will provide fundamental knowledge to establish the optimal conditions necessary for successful engraftment of stem cell-derived healthy photoreceptors to restore sight in devastating photoreceptor dystrophies.

Project:

Fighting the zombie apocolypse: developing new compounds to counteract senescence in the brain through type-I interferon signalling reduction

Supervisors

1. Dr Kate S Madden – kate.madden@newcastle.ac.uk
2. Dr Satomi Miwa – satoi.miwa@ncl.ac.uk
3. Professor Ian C Wood -  i.c.wood@leeds.ac.uk

Project outline

Treatment of neurodegenerative disease desperately needs a breakthrough as drugs for current targets, e.g. amyloid in Alzheimer’s Disease, are failing to translate to patients. This lack of translation requires a new approach, with neuroinflammation, particularly its link to cellular senescence, being one of the most promising areas. Senescent cells, where the cell undergoes a number of phenotypic changes and stops dividing, but does not die, are linked to ageing and observed at an increased level in neurodegenerative disease. Unravelling the complex biology around neuroinflammation, cellular senescence and neurodegeneration to design a successful drug discovery programme requires excellent chemical probes, which we currently don’t have. We are developing a range of new type-I interferon (IFN-I) signalling inhibitors within the Madden group at Newcastle, particularly focusing on compounds with novel mechanisms of action compared to widely available competitive Janus kinase (JAK) inhibitors, which struggle due to a lack of selectivity. JAK inhibitors have been shown to reduce cellular senescence, leading us to hypothesise that IFN-I signalling plays a role in cellular senescence as well as neuroinflammation.

This project aims to evaluate and develop these new IFN-I signalling inhibitors as agents which change the function of senescent cells, known as senomorphic agents, to study how they affect brain immune and nerve cell phenotypes.  Based at Newcastle University, you will work with other molecular neuroscientists in the group of Dr Kate Madden, collaborating with senescence expert Dr Satomi Miwa. You will also collaborate with Professor Ian Wood at Leeds University, where you will have the opportunity to learn the latest techniques for studying brain immune cell activation and senescence. You will perform chemical synthesis of new IFN-I signalling inhibitors, then test them in a range of cellular assays studying immune activation and cellular senescence. Assay technologies such as high content imaging, cell metabolism studies, flow cytometry and automated liquid handling will be used to profile these chemical tools, supported by excellent facilities within Newcastle.

By the end of this project, you will have developed a broad range of interdisciplinary skills in chemical neuroscience and developed a range of well-defined chemical tools that will be used to interrogate the role of IFN-I signalling in senescence. This will enable us to find new targets for drug discovery aimed at reducing cellular senescence, neuroinflammation and neurodegeneration, taking us a step closer to finding drugs for millions of people worldwide suffering from neurodegenerative disease.

Supervisor

1. Dr Bas MJ Olthof bas.olthof@ncl.ac.uk
2. Dr Sasha E Gartside sasha.gartside@ncl.ac.uk

Project outline

The brain has a remarkable ability to respond to experience, whether that be adapting to environmental stimuli or learning skills or knowledge. The mechanism underlying this phenomenon is known as neuronal plasticity. Plasticity is a crucial process for the healthy brain however, aberrant plasticity may result in neuropsychiatric disorders such as epilepsy, schizophrenia, depression, PTSD, and tinnitus.

Both functional and structural changes contribute to neuronal plasticity. One of the key initiators of neuronal plasticity is NMDA receptor activation. This, triggers multiple intracellular signalling cascades, ultimately strengthening the activated synapses. Recently, we showed that NMDA receptors form a complex with nNOS, the enzyme which produces nitric oxide (NO). Thus, NO signalling is at the centre of the neuronal plasticity process.

This project will address the role of NMDA receptor mediated NO signalling in neuronal plasticity in health and disease. We will examine mechanisms underpinning structural and functional plastic changes in cortical and subcortical brain regions (including those involved in memory, fear/anxiety, and sensory processing). We will also examine how these mechanisms are altered in rodent models of neuropsychiatric disorders.

The student will use techniques including immunohistochemistry, multiplexed imaging, multi-electrode electrophysiology, and optogenetics, in both established and novel rodent models of plasticity. This project will increase our understanding of normal as well as pathological brain function and may lead to the identification of novel treatment targets for neuropsychiatric disorders.

The project, supervised by Dr Bas Olthof and Dr Sasha Gartside, will take place within the vibrant neuroscience community of Newcastle University.

Project:

Using multiomic approaches to understand how mitochondrial DNA mutations cause severe neurological disease

Supervisors

1. Dr Sarah J Pickett – sarah.pickett@ncl.ac.uk
2. Dr Gavin Hudson – gavin.hudson@ncl.ac.uk
3. Professor Heather J Cordell – heather.cordell@newcastle.ac.uk

Project outline:

Background

Mitochondria convert food energy into cellular energy, relying on genetic information from both nuclear DNA and their own mitochondrial DNA (mtDNA) to function. Mutations in either genome can cause incurable mitochondrial disease which can affect any organ, at any age and with any degree of severity. Although 1 in 200 people carry a pathogenic mtDNA mutation, only a small proportion develop disease; why this is the case is poorly understood and so offering patients accurate advice regarding their likely disease progression is almost impossible. This project focuses on the most common mtDNA mutation, m.3243A>G, which can cause devastating and life-limiting stroke-like episodes in 10-15% patients. Understanding what drives severe neurological disease in these patients is one of the biggest challenges for mitochondrial disease research.

Question

What are the nuclear genetic factors that drive severe neurological outcomes in disease caused by mutations in mitochondrial DNA and how do they disrupt cellular processes?

Work in our group has identified regions of the nuclear genome that contain variation that are likely to contribute to severe neurological outcomes of the m.3243A>G variant. This current project aims to identify and characterise the casual variation within these regions through multiomic analyses in a well-characterised and unique patient cohort.

Methods

This project applies techniques that are widely used to understand common, complex disease to a rare mitochondrial disease using a unique clinical cohort of over 400 patients. This has the potential to transform the way we understand disease caused by mtDNA mutations.

The student will use annotated whole genome sequence data from individuals who carry m.3243A>G, comparing those who have these severe phenotypes to those with milder, non-neurological disease. Variant effect predictors will be used to narrow down the likely causative variants, and gene burden testing and pathway analysis will allow modelling of genetic diversity. Further prioritisation and characterisation will be undertaken through multiomic analysis of patient skeletal muscle biopsies, including analysis of RNA sequencing, metabolomic and proteomic datasets. These data will be integrated using cutting-edge computational tools to determine causal relationships and determine disease mechanism.

Potential Impact

This project has the potential to answer one of the biggest questions in the field of mitochondrial disease research, recently highlighted by patients, their families and clinicians: “Why are people with the same genetic mutation affected so differently in mitochondrial disease?” Identifying nuclear genetic factors that influence disease outcome will allow clinicians to offer more informed prognostic advice to patients and could lead to the identification of new therapeutic targets.

Supervisory Team

The student will join the world leading Wellcome Centre for Mitochondrial Research, which offers an excellent training environment and a vibrant ‘young scientists’ network. Dr Sarah Pickett and Dr Gavin Hudson have a track record in using genomics to investigate diseases of mitochondrial dysfunction and Professor Heather Cordell is an expert in statistical genetics and the integration of multiomic data. All supervisors will provide excellent supervision, mentorship and training.

Project:

Take the next left: The impact of GPS technology on the development of spatial cognition

Supervisors

1. Dr Hannah E Roome – Hannah.roome@newcastle.ac.uk
2. Dr Tom Smulders – tom.smulders@newcastle.ac.uk

Project outline

This proposal will examine the long-term impact of GPS navigational systems on spatial memory in adults and children. Mammals have evolved specialized neural systems that support efficient navigation and optimize species’ success in survival and reproduction. Key to this is active interaction, and exploration of environments. With experience, we build spatial knowledge, actively engaging with our surroundings, and refine learned relationships between streets, landmarks and locations. However, as technology has advanced, external GPS systems have become second nature and automated how humans navigate. We will investigate whether navigational technology has, despite providing humans with a greater capacity to explore the world, made us worse navigators.

This will be studied in children and adults using state of the art virtual reality paradigms and neuroimaging techniques. The developmental work will explore how growing up in a world of external technology impacts the development of spatial memory. A longitudinal study will test whether children with greater experience of GPS, and the use of technology will follow a different spatial memory trajectory to those that have not been exposed to the same degree. The adult work will aim to support current literature that shows habitual GPS use negatively impacts spatial memory in adults. The neural component will investigate the relationship between the maturation of the developing human brain and spatial memory. London taxi drivers, who undergo extensive training, show a correlation between greater navigational experience and hippocampal volume.  If you were to compare Uber drivers that rely on navigational technology, would they show the same brain-behaviour link? Following this notion, the PhD will investigate whether adult and children’s exposure to technology mediates the relationships between brain regions known to support the prolonged development of spatial memory. This multi-component approach will provide a rich, impactful understanding of how human interaction with technology is affecting fundamental human behaviours that are key to our success as a species.

This project will be supervised by Dr. Hannah Roome, a lecturer in the School of Psychology, and affiliate of the Institute of Biosciences. This PhD proposal has three key components:

1. The analysis of pre-existing data to establish a link between children’s sense of direction, technological experience, spatial memory and the structural maturation of the hippocampal formation. This will be in collaboration with The Center for Learning and Memory, University of Texas at Austin, and will teach statistical analyses and structural neuroimaging techniques.
2. A longitudinal behavioral study to track the development of spatial memory in children with varying experience with technology and GPS devices, using virtual and real-world environments. This will provide experience in 1) longitudinal experimental design; 2) data collection with children, adolescents and adults; 3) data management and analysis of large datasets.
3. A neurodevelopmental perspective analyzing the structural maturation of the hippocampus, and whether its link with spatial memory is mediated by technological experience. This will involve collecting neuroimaging data, and applying skills learned from Aim 1.

All three components share the aim of disseminating high-quality research to impactful journals

Project:

Neuropharmacology of decision-making: causal brain network modelling across species

Supervisors

1. Professor Alexander Thiele – alex.thiele@ncl.ac.uk
2. Professor Andy Jackson – Andrew.jackson@ncl.ac.uk

Project outline

Decision-making deficits are a prominent feature of a number of clinical disorders, including attention deficit hyperactivity disorder (ADHD), schizophrenia, depression  and Parkinson’s disease (PD). Although decision neuroscience has made great strides in identifying neural metrics of decision-making that are comparable across species and time scales, critical knowledge gaps remain. These gaps include an incomplete understanding of: (i) how different brain regions communicate with one another to support decision-making processes and (ii) how neurochemicals modulate these decision-making communications. In this collaborative project you will investigate the neurochemical modulation of decision-making in both humans and macaques, whereby your focus will be on using the non-human primate model. Colleagues at Monash University (Prof. M. Bellgrove and collaborators) will perform the human aspects of the project, and colleagues at Universitat Pompeu Fabre, Barcelona (Prof. G. Deco and collaborators), will perform the relevant modelling aspects. You will have opportunities to closely interact with all of these and thereby extend your knowledge base. 

Your focus will be to investigate the neurobiology of decision-making across 3 spatiotemporal scales: the micro-scale (single units); the meso-scale (LFPs; EEG); and the macro-scale (fMRI). Jointly with collaborators, you will use computational approaches to understand causal (directed) interactions between brain regions central to decision making across these scales. To understand the underlying neuropharmacology, you will perturb the system using drugs that are effective in treating aspects of the above mentioned disorders, namely: methylphenidate, atomoxetine and ketamine. You will study their impact on neural metrics of decision-making.

Project:

Designing a wearable epilepsy medication monitor

Supervisors

1. Dr Rhys H Thomas – rhys.thomas@ncl.ac.uk
2. Dr Marloes Peeters – marloes.peeters@ncl.ac.uk

Project outline:

Background

Over 2,500 women with epilepsy get pregnant each year in the UK, most taking one of two medications throughout pregnancy to control their seizures. The levels of one of these tablets drops significantly (60-90% in some women) and unpredictably during pregnancy, and measuring blood levels is the only way to gauge this. In clinical practice it can take two weeks to get a result back and by then the woman may have had seizures damaging her health and that of her unborn child. Although 1% of pregnancies are to women with epilepsy, epilepsy is a cause or complication of 7% of all deaths in pregnancy. However, there are legitimate concerns about the safety of epilepsy medication in pregnancy, as the neurodevelopmental impact of these drugs on the unborn child are dose related and using the lowest possible dose is critical.

We propose a wearable device, integrated with digital health technology, to monitor epilepsy drug levels in the community. The Peeters lab has a track record of studying biomarkers including endogenous (such as troponin) and exogenous (such as levodopa), and designing real-time drug monitoring devices.

Hypothesis

It is possible to measure anti-seizure medications with a wearable device that can non-invasively monitor biomarkers in interstitial fluid (ISF).

Methods

In this research study, students will be involved in developing an electrochemical sensor for anti-seizure medication. The receptors used for selective detection of the analyte of interest (e.g. antibodies, polymers) will contain an electrochemical probe molecule. When binding occurs at the receptor, there will be a change in electrochemical signal that can be correlated to the concentration of the drug compound.

The Peeters lab has been successfully collaborating with an industrial partner who have a platform for non-invasive (e.g. without pain or marking the skin) extraction of ISF. ISF is the fluid just below the skin and is rich in biomarkers that are <100 kDa, which includes drug molecules. This platform is currently being trialled for measuring of glucose and lactate in ISF and can be easily adapted to measure anti-seizure medication.

Potential Impact

If successful this device would have the potential to be the new standard of care, with the potential to be lifesaving for women with epilepsy. This study would facilitate a major clinical trial of this device in pregnancy.

Long term monitoring of epilepsy medication may bring many benefits including measuring drug clearance in pregnancy and monitoring adherence. 

Supervisory Team

Dr Marloes Peeters is a Senior Lecturer and Deputy Director of Chemical Engineering at Newcastle University. She runs the Peeters Research Group focusing on drug delivery, in vivo sensing, and continuous monitoring. Her background is in the development of polymer-based sensing platforms were used for the electrochemical and thermal detection of neurotransmitters.

Dr Rhys Thomas is a Clinical Senior Lecturer and Honorary Neurologist, looking after adults with epilepsy. He works closely with SUDEP Action, the UK’s primary resource for epilepsy related death support, advocacy and research. He is helping to lead a wearable diagnostic technology study in epilepsy (NIHR funded).

Project:

Understanding the heterogeneity of pathology in dementia with Lewy bodies to aid the interpretation of biomarkers

Supervisors

1. Dr Lauren Walker – lauren.walker1@ncl.ac.uk
2. Professor Johannes Attems – Johannes.attems@ncl.ac.uk
3. Dr Chris Morris – c.m.morris@ncl.ac.uk

Project outline:

Background

The primary pathology of dementia with Lewy bodies (DLB) is alpha-synuclein, however multiple studies have demonstrated that Alzheimer’s disease (AD) related pathologies (tau and beta amyloid) play an important role in disease progression driving spread of pathology and accelerating cognitive decline. Clinically, it is difficult to diagnose patients with both AD and DLB pathologies and therefore finding biomarkers for assessing cognitive impairment in individuals with high levels of all 3 pathologies would be extremely beneficial. Tau biomarkers in plasma, particularly, are proven as an accurate biomarker for AD, providing a cost effective and minimally invasive alternative to cerebrospinal fluid and positron emission tomography biomarkers. Plasma tau levels in patients with a clinical diagnosis of probable DLB are higher than in healthy control cases, but lower than AD.  There is though, considerable heterogeneity across the DLB spectrum, particularly regarding the burden of AD related neuropathology, and studies have confirmed that multiple pathologies can alter the typical pattern of clinical progression. Work from our lab and Mayo clinic has suggested that tau pathology is atypical, potentially sparing the hippocampus in Lewy body disease individuals. Tau exists in many conformational states and can be post translationally modified, and data on the topographical distribution of tau species in DLB cases with considerable AD related pathology is lacking. Data from this study will provide pathological groundwork to aid the assessment of candidate plasma biomarkers.

Question/hypothesis

We will investigate an extremely well neuropathologically and clinically characterised cohort of DLB cases and assess the burden and spread of different tau species and compare this to AD cases and healthy controls. We hypothesise the burden and spread of tau species will differ across DLB cases with differing tau burdens and between AD and DLB cases, which may need to be considered when assessing plasma biomarker data.

Methods

Using quantitative neuropathological and biochemical techniques we will fully characterise a DLB cohort to assess pathology burden and topographical distribution of tau species using our novel tissue microarray platform incorporating 15 distinct brain regions, and analyse how this relates to other markers of neurodegeneration including amyloid beta, alpha-synuclein, activated astrocytes and microglia, and clinical scores collected from patients during life.   

Potential impact

To fully understand and accurately interpret biomarker data from patients with DLB we need to understand the underlying pathological burden and clinical correlates. Data from this study will also shed light on other markers of neurodegeneration that may be useful in parallel with plasma tau species to increase the accuracy of clinical diagnosis of DLB.

Supervisory team

Dr Lauren Walker holds an excellent track record for neuropathological studies of neurodegenerative diseases in particular assessing multiple pathologies in DLB, and has routinely supervised multiple master’s and undergraduate students to successful completion of their projects in the lab. With the support of Professor Johannes Attems and Dr Chris Morris who both have extensive experience in the field of neurodegeneration and have supervised many PhD students, we have both the enthusiasm and experience necessary to deliver this successful PhD project.

Project:

Understanding the lived experience of Parkinson’s Disease across 7 African countries

Supervisors

1. Professor Richard W Walker – richard.walker@newcastle.ac.uk
2. Dr Matthew Breckons – matthew.breckons@newcastle.ac.uk
3. Dr Natasha Fothergill-Misbah – tash.fothergill-misbah@newcastle.ac.uk

Project outline:

Background

A growth in people aged over 60 in low- and middle-income countries means that, in addition to infectious disease, there is a large rise in age-related diseases in sub-Saharan Africa such as Parkinson’s disease. While effective drug treatment to manage symptoms exists, access to diagnosis and medication is limited. Gaining an understanding of Parkinson’s Disease (PD) from the perspective of those living with the disease in Africa is vital to understanding the challenges faced, implications of care pathways and how improvements in the management of the disease can be implemented.

Hypothesis

Experience of PD may be impacted by multiple factors including; culture, interpretations of symptoms, stigma and the availability and organisation of health services, all of which vary between African countries.

Methods

Qualitative work will take a phenomenological approach; focussing on the lived experience of PD in SSA. A purposive sample of people with PD and their families will be recruited from clinical and community settings in seven African countries (Egypt, Ethiopia, Ghana, Kenya, Nigeria, South Africa and Tanzania) involved in a recently commenced grant relating to PD in Africa (TraPCAf) for which Professor Richard Walker is chief investigator and Dr Matthew Breckons is a co-applicant. A maximum variation sample will be sought in order to recruit people with different severities and duration of disease, socioeconomic backgrounds, sex, age and access to healthcare. Qualitative interviews will be conducted in settings of participants’ choosing and flexible topic guides will be used to explore experience, and impact of symptoms, knowledge and understanding of PD, use of health services and self-management practices. Data will be analysed using principles of Thematic Analysis and a reflexive approach will be taken. Data will be examined within and between countries in order to understand differences and commonalities that exist between countries and if (and  how) these are influenced by contextual factors such as health systems and culture.  The PhD student will work with other researchers in each of the countries, as well as with the London based charity “Parkinson’s Africa”, who are collaborators on the grant, and helping to lead on the community engagement and involvement work package. 

Potential Impact

Gaining an understanding of the experience of PD in the context of available health services is vital to informing improvements in diagnosis, management and drug treatment of PD in Africa. In conjunction with the other components of the TraPCAf grant this research has the potential to transform Parkinson’s research, and care, in Africa.   

Supervisory team

Professor Richard Walker has been conducting research in Africa relating to non-communicable diseases for over 30 years.  Dr Matthew Breckons has also been involved with qualitative research in Tanzania, including supervision of PhD and MRes students. Dr Natasha Fothergill-Misbah conducted her qualitative PhD research on this topic in Kenya, has supervised 7 MSc student dissertations to completion over the past year, and is a Research Associate on the TraPCAf project. 

Project:

Longitudinal brain imaging and modelling to infer ageing and disease processes

Supervisors

1. Dr Yujiang Wang – yujiang.wang@ncl.ac.uk
2. Professor John-Paul Taylor – john-paul.taylor@ncl.ac.uk 

Project outline

Introduction:

The structure and shape of the brain changes through development, ageing, and in disease. It has been used as a biomarker to identify diseased or at-risk patients, and regional abnormalities can help localise tissue that is causing the disorder, for example in focal epilepsies. However, with some rare exceptions, it is less clear if brain structure and shape derived from neuroimaging can also reliably track (disease) processes and progression in individual human subjects.

On a cohort-level, cross-sectionally, changes in cortical shape and structural connectivity between brain regions have been correlated with age, and markers of disease severity or progression. These changes include local or global shape alterations, increased or reduced connectivity between specific regions, or a widespread network reorganisation. However, the relationship and causality of the processes and the morphological and connectivity changes are generally not established. Thus, longitudinal tracking of individual subjects alongside with ageing/disease outcome variables are crucial in developing individualised neuroimaging markers of ageing, degenerative processes, progressive diseases, and restoration. 

Proposed research:

We propose to use large-scale open-access longitudinal structural neuroimaging datasets to establish the relationship between morphological and connectivity changes across different processes, and relate them to outcome measures of the process. We will use healthy ageing as an initial process, given the previous work on brain-age prediction; and outcome measures will include age and other neuropsychological measures. Having established a baseline with healthy ageing, we propose to then turn to dementia and epilepsy as application domains, given the strength and expertise in the supervisory team in those areas.

Another key expertise in Newcastle is the development of computational biomarkers based on mechanistic understanding of the processes driving brain shape (see references below). Thus, this project is a unique opportunity to combine computational and machine learning/AI methods with huge neuroimaging datasets to gain a mechanistic understanding of how and why brain structure and shape change in a range of processes.

Potential impact:

This project will improve our understanding of how ageing and brain disorders progress and how reorganisation occurs. The study of longitudinal data will inform on the potential causality of the neuroimaging structural changes. This will enable us to predict disease progression on an individual basis based on the interaction of outcome measure, morphological and connectivity measures, which can be translated into computational tools to aid prognosis and inform medical decisions.

Environment:

This project is interdisciplinary and will be supported by a rich research environment as part the Computational Neuroscience, Neurology, and Psychiatry (CNNP) lab and the Lewy Body Lab. We expect the student to work and collaborate with neuroscientists, computer scientists, mathematicians, and clinicians; thus being exposed to different styles of working and different ways of scientific thinking. This will ensure that we train the next generation of interdisciplinary researchers with crucial transferable skills. We will run weekly group meetings, often with external speakers, which help to create a vibrant and stimulating research environment.

Project:

Understanding the role of the reward system in the pathophysiology and treatment of mood disorders

Supervisors

1. Dr Stuart Watson – stuart.watson@newcastle.ac.uk
2. Dr Peter Gallagher – peter.gallagher@newcastle.ac.uk

Project outline

Reward sensitivity (the value attributed to rewarding outcomes by an individual) is attenuated in people with mood disorders and is known to be mediated by dopaminergic signalling. Reward sensitivity can be estimated using computer-based learning tasks and analysed using computational modelling (Huys and Browning). We hypothesise that reduced reward sensitivity is causally related to the lack of motivation (i.e. anhedonia) experienced in depressive episodes, that it may be improved by enhancing dopaminergic function and that it is therefore a potentially useful treatment target.

Aripiprazole acts as an augmenting agent in the treatment of difficult to treat major depressive disorder. It enhances dopamine function and facilitates reward activation. Quetiapine has demonstrated efficacy in the treatment bipolar depression but does not have a pro-dopamine effect.

ASCEnD is an NIHR-HTA funded RCT of aripiprazole vs quetiapine (n=270) in bipolar depression (led by Watson). It focuses on clinical effectiveness, but not on mechanisms. This studentship would provide a unique opportunity to utilise this substantial clinical-research framework to apply computational psychiatry approaches to study reward and anhedonia. The studentship will begin with a systematic literature review to inform an amendment to the ASCEnD study protocol, specifically the inclusion of a probabilistic decision-making task to determine whether reward sensitivity is differentially impacted by aripiprazole vs quetiapine, whether reward sensitivity predicts response to pharmacological intervention in bipolar depression, whether this effect is specific to pro-dopamine drug treatment and whether changes in reward sensitivity mediate the change in depressive symptoms.

Project:

Investigating fatigue in motor neuron disease using single motor unit imaging

Supervisors

1. Professor Roger G Whittaker – r.whittaker@ncl.ac.uk
2. Professor Andrew M Blamire – Andrew.blamire@newcastle.ac.uk

Project outline

Motor neuron disease (MND) affects 5,000 people in the UK at any one time. The disease is characterised by progressive loss of motor nerves, leading to muscle weakness and eventual paralysis. Surviving motor units attempt to compensate by becoming larger and more complex. A fundamental question is how this change in motor unit structure affects its function. For example, how does increased complexity influence resistance to fatigue, and do muscle fibres fatigue equally within a given motor unit?

Our group recently patented a novel imaging technique called motor unit MRI (MUMRI) which for these first time allows these questions to be addressed. This combines diffusion-weighted MRI with in-scanner electrical nerve stimulation to reveal the 3D structure and twitch dynamics of individual motor units. We are the only group in the world currently undertaking these studies. Our recent study in healthy human subjects showed human motor units to have a complex 3D structure, with discrete regions of muscle fibres dividing and coalescing along the length of the muscle.

This project aims to study 3D motor unit structure and function in patients with MND. We hypothesise that motor units in patients with MND will have an even more complex 3D structure, and that increased size and complexity will correlate with increased fatigue. We aim to image the contraction of single motor units at different points in the contraction cycle, both before, during and after a fatiguing electrical stimulus.

The project will involve 4 phases;

1. Optimise a 3D MUMRI protocol for upper limb muscles. To date we have only applied 3D MUMRI in the leg. You will develop an upper-limb paradigm by comparing coil configuration (flex coils vs body coil), acquisition methodologies and subject positioning (head first vs feet first) during in-scanner median, ulnar, and musculocutaneous nerve stimulation.
2. Increase the yield of detected motor units. We currently use manual identification of motor unit alternation in response to liminal nerve stimulation, allowing up to 6 motor units to be detected per subject. You will develop an automated image analysis pipeline using time-series correlation of simultaneously activated voxels within and between adjacent image slices to increase speed and yield.
3. Optimise motor unit fatigue. We currently use a force transducer and voluntary muscle activation to induce fatigue throughout the muscle. You will induce fatigue in single motor units using high frequency liminal nerve stimulation.
4. Perform a proof-of-concept study comparing motor unit complexity and fatigue in upper and lower limb muscles of ALS patients and healthy controls. This will include state-of-the-art neurophysiological motor unit counting and size estimates, to understand complexity in the context of motor unit number.

You will join a vibrant cross-disciplinary team including MR physicists, neuroscientists, clinical neurophysiologists and neuroradiologists with a strong track record in developing novel diagnostic techniques and translating these to patients. Our ultimate aim is to develop more effective therapies for fatigue in MND based on a better understanding of the underlying pathophysiology. The project is particularly suited to students with a background in imaging and/or computational neuroscience.

Please submit your documents in the following formats only:

Submit .pdf documents where possible for your application form, CV, cover letter, transcripts and certificates. Do not submit photos of certificates.

Your Application Form should be a Word document – not a pdf.

Each document type listed above should be submitted as a separate document. It should be named as follows: [candidate surname candidate name document]. For example: Jones Anna CV; Jones Anna cover letter; Jones Anna BSc transcript.

Do NOT combine all the documents into one pdf.

Please zip together the separate documents into a zip file. Name the zip file: surname_name_[project number]

Applications not meeting these criteria may be rejected.

Acknowledgement: you will receive confirmation by email that your application has been received. If we require any further information from you about your application, we will be in touch.

You will need two referees, one of which must be an academic reference. This could be:

• an undergraduate or master’s project/dissertation supervisor
• personal tutor
• a module director/organiser
• someone you have worked for in an academic context from your university

If you are applying for a position with your current (or past) supervisors, it is not advisable to use them as a referee. Supervisors are also competing for funding, so there is a conflict of interest. In such cases your chosen supervisor can provide guidance on the most suitable referee to include.

We will fund up to three PhDs studentships provided suitably qualified candidates apply.

You will not be judged for having been out of academia, whether it is for work, caring duties, illness or anything else. Like everyone else, you will need a degree – however, there is no time limit on when this was awarded. We appreciate that experiences outside of academia can be a rich source of key skills that you would need for a PhD. Be sure to think about skills this experience has given you and make sure you tell us about them. It is likely that the supervisor or interview panel might want to know what drew you back to academia. Use this time to show how passionate you are about research.

You will not be penalised for not having a master’s degree. PhD studentships are highly competitive, and most successful applicants will have a master’s qualification. This is because of the experience a master’s degree provides rather than the certificate. However, experience can equally come from many other sources, such as work, both academic and non-academic.

If you are offered an interview, a standard email will be sent from the Centre team to your referees requesting a reference before your interview. We would advise that you contact your referees to tell them that they may receive a reference request.

A regular CV should be approximately 1-2 pages depending on how much experience you have (but please make sure to note all your experience).

The cover letter should explain your interest in your chosen projects and should include any additional information you feel is important to your application. You may wish to add why you are choosing Newcastle University. There are no formal word limits for your CV or cover letter, but we recommend you keep them concise.

Each student has a different set of strengths and weaknesses. That said, a passion for the project is an essential part of being a successful PhD student. It is a basic requirement that any supervisor will look for in selecting a student. Do remember that there may be some (but not endless) flexibility in what you actually do within the PhD project.

This will be dependent on the project supervisor. Our funding does not dictate any work schedule. It does ask that any difference from standard working patterns be agreed with your supervisor. It would be sensible to discuss this with them before you apply. Most supervisors will support a student's requirements (for example, to accommodate caring responsibilities), but the project may have specific requirements. E.g., where a particular type of lab work is necessary to complete the project.

Students may take on teaching or demonstration work, where this is compatible with their training in addition to a full-time studentship. This needs to be approved by their supervisors, in addition to a full-time studentship. Other paid work would need the consent of the supervisor and should not delay or interfere with your research training. You may ask primary supervisors about flexibility of the PhD; this varies depending on the PhD project. Part time study is usually available; we advise that you discuss this further with the project supervisor.