Supervisors

• Dr Gabriele Jordan - Gabriele.jordan@ncl.ac.uk
  
• Dr Laura Young - laura.k.young@ncl.ac.uk 
• Dr Quoc Vuong - https://www.staff.ncl.ac.uk/q.c.vuong/

Project outline

Background

Colour vision is critical for many everyday tasks such as finding objects (your pink tie), identifying material properties (fresh or old banana), or recognising objects (a poppy in a field).  In recent decades colour is used increasingly in education, instrument codes, and digital signalling. Unsurprisingly, deficits in colour vision may negatively affect aspects of behaviour and are perceived to cause issues in more than 100 professions worldwide, excluding 8% of congenitally colour-vision deficient (CVD) men (2.64 million men in the UK) from employment (e.g. police or transport).

However, there are two important reasons to reconsider this practice. First, due to the underlying genetic mechanisms, human red-green colour vision is very variable. Thus, for most affected men (6% of men are classified with an anomaly rather than loss of red-green colour vision), the behaviour on colour tests can vary from almost indistinguishable from normal to very severe and safety critical. There are currently no population statistics available for these severity-subtypes of anomalous individuals and those with a milder condition may be seriously disadvantaged in their career choice.  Second, most employers are currently excluding individuals based on a yes/no test unsuitable for a fine-grained diagnosis of severity, and no predictions can be made as to the performance on occupational tasks.

Objective

To investigate the relationship between low-level, retinal variations across individuals with CVD and behaviours based on higher-level, cortical processing. Hypotheses will test whether (1) cortical processing of retinal signals differ between individuals with the same retinal photoreceptor types; (2) cortical processes may compensate for reduced, low-level chromatic discrimination; and (3) the compensatory mechanisms may be learned through perceptual learning.

Methods

Methodologies include physiological optics and visual psychophysics using Maxwellian view to characterise cone spectral sensitivities and ratios; measurements of amplitude and latency of visual evoked potentials (VEP) to chromatic vs achromatic images to assess contributions from distinct stages of the retino-cortical pathway; psychophysical measurements using custom-made, computer-based tests to measure chromatic discrimination, colour naming, memory and recognition before and after targeted perceptual learning.

Timeliness and impact

The impact of this project may be substantial, with implications for both colour-vision policies in occupations (e.g. police, military, medicine), and interventions to improve perceptual abilities in CVD.

Supervisory team

Very few research groups investigate individual differences in colour vision. The proposed supervisory team has the expertise and specialised laboratory set-ups to tackle questions of lower-level mechanisms (Jordan and Young), and higher-level processing (Vuong).

Supervisors

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

Project outline

Background

Monocytes are white blood cells that can differentiate into macrophages and dendritic cells in tissues. Their activity is associated with the progression of multiple neurodegenerative disorders, but whether or how they contribute to disease remains unclear.

Monocytes are largely prevented from entering the central nervous system (CNS) by the blood-brain barrier, and studies in mice suggest they do not cross into brain to contribute to the microglial pool (the resident immune cells of the CNS). Recent observations in humans however have shown that monocytes carrying some somatic mutations may cross into brain and differentiate into microglia. This raises the possibility that peripheral monocytes may directly infiltrate and contribute to the microglial pool modifying the immune response that can drive neurodegenerative diseases.

Secondly, skull bone marrow is a rich source of monocytes and other immune cells that surround the brain called the meningeal immune system. This system is highly dynamic and can modify the process of neurodegeneration in animal models, but the molecular changes that arise in human skull marrow in aging and neurodegeneration, and how this controls this immune response remains unknown.

Question

Using carefully collected human post-mortem brain tissue from patients with somatic mutations in blood identified in our previous studies, you will determine the degree and extent of monocyte incorporation into microglia across the brain. Secondly, using intraoperative and post-mortem human bone marrow you will determine whether or how skull marrow responds differently to other marrow regions in the presence of stimuli seen in neurodegeneration.

Methods

You will use flow cytometry and amplicon DNA sequencing on post-mortem and intraoperative brain tissue to characterise the mutational profile of bone marrow, monocytes and microglia throughout the brain. Secondly, you will perform cloning, cell culture, and immunohistochemistry to understand the development of immune cells from bone marrow and their response to disease stimuli.

Impact

This project aims to understand the degree of microglial replacement by monocytes challenging our understanding of how monocytes may contribute to neurodegeneration. Secondly determining if and how skull marrow shapes the meningeal immune-response in neurodegeneration could place skull marrow as a therapeutic target for neurodegeneration.

Supervisory team

Dr Keogh is an academic neurologist who studies somatic mutations in neurodegeneration. Prof Collin is a world-leading haematologist who’s laboratory aim to understand the ontogeny and role of immune cells in disease. Collaborative opportunities with a world-leading genetics laboratory may also be possible depending on funding.

Supervisors

• Dr Yuki Kikuchi - yukiko.kikuchi@ncl.ac.uk
• Dr Marc Woodbury-Smith - marc.woodbury-smith@newcastle.ac.uk

Project outline

Background

Atypical theta synchrony between the amygdala and the medial prefrontal cortex (mPFC) is a hallmark of social cognitive disorders such as anxiety and autism spectrum disorder (ASD). The mPFC-amygdala circuit is extensively connected with auditory regions that are responsive to natural vocalisations characterised by theta rhythms. These vocalisations entrain theta oscillations in the auditory cortex, facilitating sound processing in both humans and nonhuman primates. Thus, auditory stimulation offers a promising non-invasive approach to modulate theta oscillations within the amygdala-mPFC circuitry. This project aims to develop a novel marmoset model with closed-loop acoustic stimulation designed to influence prefrontal-amygdala theta oscillations and social cognitive behaviours.

The project will involve 3 phases:

1. Crete a wireless electrophysiology system for auditory stimulation in free-moving marmosets.
2. Implement closed-loop auditory stimulation using phase-shifted local field potentials to manipulate theta oscillations in the amygdala and the mPFC.
3. Evaluate the stimulation’s effect on marmoset social cognition using tests derived from those for autistic children.

Hypothesis

Timed closed-loop auditory stimulation, synchronised with theta oscillations in the mPFC-amygdala circuit, modulates these oscillations and thereby regulate social cognitive functions.

Methods

Employing the auditory stimulation closed-loop system with human EEG, the student will tailor this technology to control theta oscillations in marmoset amygdala and prefrontal cortex circuitry. The student will examine the impact of auditory stimulation on marmoset natural social behaviours at their home cages using AI-based motion detection systems. Marmosets are well-suited for this proposal due to their highly developed vocal communication abilities, intricate social structures, and a well-developed frontal cortex.

Potential impact

Successful outcomes may establish the basis for novel closed-loop therapies using acoustic stimulation enhancing social cognition, significantly advancing mental health treatments.

Supervisory team

The student will join a multidisciplinary team at Newcastle University and undergo comprehensive training in bioengineering, neurotechnology, primate electrophysiology and behavioural testing closely aligned with clinical research to enhance the study’s translational potential. Dr Yuki Kikuchi has extensive experience in primate auditory neuroscience and her laboratory is well-equipped for developing closed-loop electrophysiology system on behaving nonhuman primates through her strong collaboration with the neural engineering team that provides the development of wireless recording and closed-loop neurostimulation algorithms. Dr Marc Woodbury-Smith, a clinical academic specialising in ASD, will facilitate the translation of primate research findings to therapies for autistic children, boosting the study's clinical application potential.

Supervisors

• Dr Fiona LeBeau - Fiona.lebeau@ncl.ac.uk
• Professor Mark R Baker - mark.baker@ncl.ac.uk
• Dr Gavin Clowry - gavin.clowry@ncl.ac.uk

Project outline

This PhD studentship offers an exciting opportunity to work on a project investigating the cellular and cortical network changes occurring in early-stage neurodegenerative disease. Phospho-tau (pTau) in the brain is a key pathological hallmark of many neurodegenerative diseases, particularly Alzheimer’s disease, while phosphorylation of TAR DNA binding protein 43 (pTDP-43) is central to the development of motor neurone disease and frontotemporal dementia. Neurodegenerative diseases are progressive, and to-date there are no effective treatments. Furthermore, it is still unclear how phosphorylation of these proteins leads to cell death and disease progression.

We are in a unique position to study disease-related changes in the brain using both mouse but also, importantly, live adult human cortical brain slice cultures. This project will extend our existing models of adult mouse and human organotypic cultures to gain important new insights into the early pathophysiological changes associated with pTau and pTDP-43. Using viral transduction methods, or application of human aggregated fibrils, we can increase the levels of pTau and pTDP-43 in neurons and/or glial cells.

We hypothesise that pTau and pTDP-43 pathology will lead to early cellular changes, particularly, neuroinflammation, synapse loss and network hyperexcitability. Studies will include detailed immunohistochemistry to quantify pTau and pTDP-43 along with changes in markers of oxidative stress, mitochondrial function, senescence and neuroinflammation. We will also use electrophysiological approaches, including whole cell patch-clamp and multichannel recordings to elucidate how pTau and pTDP-43 alter neuronal properties. Our goal is to develop an organotypic model platform that will improve our understanding of the early changes associated with neurodegenerative disease. In addition, working with our industrial collaborators at Nevrargenics, we will test novel compounds that target retinoic acid receptors as a new approach aimed at delaying or preventing pathophysiological changes. The data from this project will advance our understanding of disease mechanisms and help identify potential novel targets that could lead to improved treatments for neurodegenerative diseases in the future.

The supervisory team are multidisciplinary, and includes both basic neuroscientists (Dr. Fiona LeBeau, Dr. Gavin Clowry), a clinician scientist (Professor Mark Baker), in collaboration with industry (Professor Andy Whiting, Nevrargenics). The student will join an active neuroscience community in Newcastle, including the Centre of Research Excellence in Transformative Neuroscience, and will work in well-equipped laboratories. There is a regular programme of lab meetings and departmental seminars and a vibrant post-graduate student community.

Supervisors

• Dr Sarah J Pickett – sarah.pickett@newcastle.ac.uk
• Professor Gavin Hudson – gavin.hudson@newcastle.ac.uk

Project outline

Background

Mitochondria convert food energy into cellular energy, relying on genetic information from both nuclear DNA and mitochondrial (mt)DNA to function. Mutations in either can cause incurable mitochondrial disease. 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 15-20% 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 are likely to contribute to severe neurological outcomes of m.3243A>G-disease. This 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 widely used to understand common, complex disease to rare mtDNA disease. The student will perform genome-wide association, gene burden testing and polygenic risk score analyses in a unique clinical cohort of over 400 m.3243A>G patients (increasing to ~800 during the project) to identify genetic factors that influence the risk of developing severe, neurological disease. 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 to determine causal relationships and disease mechanisms will be investigated using patient cell-lines.

Timeliness and impact

This project has the potential to answer one of the biggest questions in the field, recently highlighted by patients, their families and clinicians: “Why are people with the same genetic mutation affected so differently in mitochondrial disease?” Identifying molecular signatures of neurological disease will allow clinicians to offer more informed prognostic advice to patients and identify potential therapeutic targets.

Supervisory team

The student will join the world leading Newcastle 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 and multiomics to investigate diseases of mitochondrial dysfunction.

Supervisors

• Dr Mouhamed M Alsaqati - Mouhamed.alsaqati@newcastle.ac.uk
• Dr Ilona I Obara - ilona.obara@ncl.ac.uk
• Dr Ruoxiao, R, Xie - ruoxiao.xie@liverpool.ac.uk

Project outline

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by bradykinesia, rigidity, and resting tremor. It is generally thought that the loss of dopaminergic neurons in the substantia nigra underlies the PD symptoms. The dysfunction of dopaminergic neurons results in an imbalance between excitatory and inhibitory neurons within the pathways of the basal ganglia, ultimately leading to the suppression of motor representations in the motor cortex. According to this model, the inhibition of dopamine in PD is expected to result in elevated GABA signalling in the thalamus and a diminished facilitation of the motor cortex. However, a recent study measured the level of GABA using magnetic resonance spectroscopy, in PD patients’ brain found that GABA levels were unaltered in the brain. In contrast, they found that motor cortex GABA was inversely correlated with disease severity, particularly rigidity, which suggests that GABA signalling might have beneficial effects rather than detrimental impacts. Therefore, the interlink between GABA and dopamine depletion in PD pathology is still poorly understood. The aim of this PhD project is to understand the dopaminergic-GABAergic interactions in PD pathology using human induced Pluripotent Stem Cells (iPSC)-derived neurons to mimic the complexity of the neuronal circuits at the basal ganglia. Existing in-vitro models fall short of enabling comprehensive functional assessments of the interaction between the neuronal models, hindering a thorough understanding of relevant cellular interactions. To address these problems, we will design a microfluidic device, with 3D printed micropatterning to enhance interactions between iPSCs-derived GABAergic and dopaminergic neurons to establish advanced PD models in vitro. This model enables the seamless integration with various existing functional neuronal assessment tools like patch clamp, multi-electrode arrays and immunocytochemistry. By patterning the neuron circuits in the micropatterned microfluidic device, we will be able to control and assess their functions and interactions. We will employ two models for Parkinson's; PD patient iPSCs obtained from the brain bank at Newcastle University, PINK1 stable knockout hiPSCs which will be created using CRISPR interference (CRISPRi), and isogenic healthy controls for each model. By investigating the intricate interactions between GABAergic and dopaminergic neurons in this setup, our project holds the potential to unveil novel insights into PD pathogenesis, provide an advanced platform for drug testing and may open new avenues for therapeutic interventions. This project will be performed in Dr Mouhamed Alsaqati lab under the co-supervision of Dr Ilona Obara and Dr Ruoxiao Xie from the University of Liverpool.

Supervisors

• Professor Evelyne Sernagor - evelyne.sernagor@newcastle.ac.uk
• Dr Faye McLeod - faye.mcleod@newcastle.ac.uk

Project outline

How does the developing brain wire itself up? Early spontaneous electrical activity (long before the onset of sensory experience) in neurones helps them make the right connections. But since this requires excellent blood supply to deliver metabolic energy in the form of oxygen and nutrients, we believe that early neural activity may also guide the formation of blood vessels. The concept of a potential angiogenic role for early neural activity is not new, but surprisingly little work had been done to test such fundamental questions in developmental neuroscience because it is very challenging to access and visualise neural and vascular networks in the 3-dimensional living central nervous system (CNS).

We recently discovered evidence in the neonatal mouse retina that spontaneous waves of neural activity are mostly generated in not-yet vascularized peripheral areas, strongly correlating with the growing superficial blood vasculature. We hypothesise that this early activity originates from specialised immature transient neurones, perhaps via purinergic signalling through pannexin 1 hemichannels (somehow similar to gap junction channels) or chemical synapses. This early activity triggers angiogenesis, resulting in blood vessels growth towards these strong activity hotspots to bring local oxygen supply.

In this project, we propose to investigate whether these early observations are relevant to other areas of the developing CNS, focusing on cortical networks. For this purpose, we will use a combination of sophisticated approaches to record spontaneous activity from the embryonic mouse cortex and foetal human cortical brain slices while visualising the growing vasculature and performing pharmacological manipulations. The embryonic cortex will be flattened as a sheet for large-scale visualization recordings using calcium imaging or large-scale, high-density multielectrode array recordings. Confocal microscopy and immunohistochemistry will be implemented post hoc to evaluate cortical anatomy in more detail. We will also use sophisticated closed-loop electrical stimulation protocols to localise activity hotspots.

Using cutting-edge electrophysiological and imaging techniques, this project offers exciting and unique opportunities to study highly novel fundamental mechanisms in developmental neuroscience, linking early neural activity to the formation of blood vessels in the immature CNS.

Supervisors

• Dr Tom V Smulders - tom.smulders@ncl.ac.uk
• Dr Timothy Boswell - timothy.boswell@ncl.ac.uk

Project outline

Bird brains diverged from mammalian brains over 300 million years ago. Over that time, the hypothalamic and brainstem mechanisms of the stress response have been remarkably conserved. The forebrain, however, evolved in very different ways in the two lineages. In this project, you will explore how the avian forebrain regulates the stress response, and how this regulation is affected by treatments aimed at increasing stress coping ability in poultry. The PhD consists of two main experiments:

• Experiment 1: using immediate-early-gene expression, state-of-the-art whole-brain clearing, and light-sheet microscopy, you will map the brain areas that change their activity in response to an acute stressor. In parallel, you will also investigate whether a commercial remedy aimed at increasing stress resilience changes these activity patterns and stress-related behaviours.
• Experiment 2: chronic stress is known to decrease the number of doublecortin-positive (DCX+) neurons in the chicken hippocampus. In this study, you will induce chronic stress in one group of chickens and investigate whether the stress-resilience-inducing treatment can stop the reduction in DCX+ neurons. Using double-labelling immunocytochemistry you will also investigate whether hippocampal DCX+ neurons are involved in the acute stress response, as they are believed to be in mammals. Using the results from Experiment 1, you will also investigate the effect of chronic stress on the response to acute stress in other brain areas. Finally, you will investigate the effect of chronic stress (and its potential remediation) on neurotransmitters like serotonin and dopamine.

This project helps us understand similarities and differences between avian and mammalian brains when it comes to the regulation of the stress response. You will increase our fundamental understanding of the brain areas, neurotransmitters and cell types involved in avian stress response regulation. Increasing stress resilience is crucial to improving the welfare of commercially-housed poultry. You will investigate whether stress resilience can be increased using a commercially available treatment, and if so, what the brain mechanisms are associated with increased stress resilience. This will have implications beyond birds, as stress resilience is a big topic both in animal welfare and human mental health.

The project is a collaboration between the supervisory team at Newcastle University, who specialize in the effects of stress on the avian brain, the Max Planck Institute for Neurobiology of Behaviour (Bonn, Germany), who are experts in the whole-brain clearing method and light-sheet microscopy, and ProBioTech International Inc., a feed supplement producer.

Supervisors

• Professor Richard W Walker - Richard.walker@newcastle.ac.uk
• Doctor Matthew D Breckons - Matthew.Breckons@newcastle.ac.uk
• Doctor Natasha K Fothergill-Misbah - tash.fothergill-misbah@newcastle.ac.uk

Project outline

Background

A growth in people aged over 60 in sub-Saharan Africa (SSA) means that there is a large rise in age-related diseases, 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 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, which vary between African countries.

Methods

Qualitative work will focus 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 TraPCAf. A maximum variation sample will be sought to recruit people with different severities and duration of disease, socioeconomic backgrounds, sex, age and access to healthcare. Qualitative interviews will be conducted utilising 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 to understand differences and commonalities and the influence of contextual factors. The PhD student will work with other researchers in selected countries, and the charity “Parkinson’s Africa”, who are helping to lead on the community engagement and involvement work package.

Timeliness

This work is timely, given the adoption of the World Health Organization ‘Intersectoral global action plan on epilepsy and other neurological disorders’ (2022-2031) by all Member States.

Potential Impact

Gaining an understanding of the experience of PD in Africa is vital to informing improvements in diagnosis, management, and drug treatment. 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 30 years. Dr Matthew Breckons has 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.

Supervisors

• Dr Peter N Taylor - peter.taylor@newcastle.ac.uk
• Professor Christopher Petkov - chris.petkov@ncl.ac.uk

Project outline

Background

Epilepsy is a common neurological disorder in which patients have spontaneous seizures which can be severely debilitating. One treatment for epilepsy is brain surgery, where the part of the brain thought to be causing seizures is removed or ablated. Accurate identification of the correct ‘epileptogenic’ part of the brain is crucial. Unfortunately, around half of patients still experience post-operative seizures suggesting possible incorrect identification and removal of ‘epileptogenic’ sites in those patients. Research is urgently needed integrating multi-modal MRI, capable of identifying brain areas within the epileptogenic network, and intracranial EEG (iEEG) recordings, using cutting-edge big data analytics to generate better predictive models of candidate brain sites for treatment.

This PhD student will develop a novel combination of MRI based markers of epileptogenic brain tissue, to predict epilepsy treatment outcomes.

Data & Methods

Through collaborations with multiple hospitals worldwide, we have access to large datasets from >1,000 individuals with epilepsy. These data include multimodal neuroimaging such as T1 weighted MRI, and diffusion weighted MRI capable of identifying the unique connectivity fingerprints in each patient, together with intracranial recordings in which epileptiform activity can be detected from specific brain areas. Most previous studies investigate MRI or iEEG data in isolation. In this study we will leverage the complementary information across multiple types of MRI scans and iEEG to make predictions of candidate surgical resection sites, comparing these predictions to actual outcomes following neurosurgical treatment in the patients. We will use advanced statistical techniques and machine learning in our analysis by comparing MRI scans to healthy controls, together with iEEG data identifying sites with abnormal neurophysiological activity.

The PhD student will validate the predictions in two ways. First, they will perform a retrospective analysis, comparing predictions of seizure-freedom to actual patient outcomes. Second, they will prospectively show our predictions in clinical meetings and record if decisions around where to resect are reconsidered or consistent with planned neurosurgical treatment.

This research is timely with recent growth in data availability and more advanced machine learning methods for brain MRI and iEEG analysis.

Environment

The candidate will join the CNNP lab, in the school of computing with access to offices at the recently built Newcastle Helix site. The lab currently has around 20 members from a variety of backgrounds including computing, statistics, and neuroscience. We are inclusive and diverse team with support for flexible working and a pro-active approach to training and development.

Supervisors

• Dr Polina L Yarova - Polina.Yarova@newcastle.ac.uk
• Dr Vsevolod S Telezhkin - vsevolod.telezhkin@ncl.ac.uk

Project outline

Sepsis is the leading cause of admission to intensive care unit (ICU), and the major cause of ICU mortality. Severe septic inflammation also causes a short- and long-term neurological dysfunction. It is estimated that encephalopathy is present in over 70% of septic patients and is associated with poor ICU survival. Growing body of evidence suggests that septic encephalopathy can also lead to permanent neurocognitive impairments and promote development of neurodegenerative diseases including dementia. Lack of precise understanding of pathophysiological mechanisms of septic neuronal damage underlies the absence of effective therapy.

Sepsis leads to brain hypoxia, disrupts the blood-brain barrier, and promotes severe neuroinflammation. Human brain expresses a cation sensor, CaSR, which responds to various positively charged molecules concentration of which increase in hypoxia and inflammation. Notably, CaSR expression also rise in brains of patients with neuroinflammatory and neurodegenerative conditions, such as Alzheimer’s disease, with CaSR negative allosteric modulators (calcilytics) showing promising results in relevant animal models. Thus, CaSR represents an emerging target for treatment of various pro-inflammatory conditions, including neurodegeneration.

It was previously demonstrated that overstimulation of neurons with excitatory agonists can cause excitotoxicity and neuronal death. Knowing that CaSR can exacerbate signalling induced by excitatory agonist, I hypothesise that:

Sepsis can induce brain neuroinflammation and neurodegeneration via promoting CaSR upregulation in neurons.

To test this hypothesis, neurons and microglia will be derived from hiPSCs according to the established protocols and subjected to sepsis-like conditions such as hypoxia and septic cytokine cocktail. Levels of CaSR expression, inflammation and degeneration in neurons and microglia will be measured using immunofluorescence, Western Blot, cell viability and apoptosis assays, function will be assessed using patch-clamp and microelectrode array, and excitotoxicity in response to glutamate will be measured using real-time fluorescence microscopy. Brain samples from patients with neurodegeneration and sepsis (Newcastle University biobank) as well as animal models of pneumonia and sepsis will also be accessed using immunohistochemistry. Effects of calcilytics on viability, function and neuroinflammation will be tested in in vitro and in vivo models.

This project will develop septic encephalopathy models, determine the roles of CaSR in septic neuroinflammation and provide an insight on calcilytics improving neurological outcomes.

The successful candidate will join a truly interdisciplinary team covering all aspects of the project from CaSR pharmacology (Dr Yarova) and neuron biophysics (Dr Telezhkin) to experts of pre-clinical calcilytic development (Prof Riccardi, collaborator) and clinical expertise in sepsis and critical illness (Prof Simpson, collaborator).

Supervisors

• Dr Karen J Suetterlin - karen.suetterlin@newcastle.ac.uk
• Dr David A Richards - david.richards@newcastle.ac.uk

Project outline

We take for granted our ability to move freely, and yet not everyone has that ability, many disorders of nerve or muscle function lead to restrictions on movement. One family of disorders of skeletal muscle are the channelopathies; rare genetic conditions characterised by episodic muscle stiffness (myotonia) or paralysis. They are caused by mutations in genes encoding the ion channels expressed in skeletal muscle, which determine the electrical properties of the muscle fibre.

It has been consistently observed that males have a more severe phenotype, and this sex difference is recapitulated in mouse models of skeletal muscle channelopathies. Understanding the basis of sex differences in clinical disease course is a major aim of modern medical science. Although sex differences in cardiac excitability were first described over 100 years ago, until now, establishing whether there are differences in skeletal muscle membrane excitability has been precluded by the limitations of existing EMG techniques.

Skeletal muscle excitability studies based on Muscle Velocity Recovery Cycles (MVRCs) explore changes in membrane excitability indirectly by recording changes in muscle fibre conduction velocity at varying interstimulus intervals following single or multiple conditioning stimuli. Changes in ion channel function in skeletal muscle channelopathy patients are reflected by changes in the MVRC profile, indicating that MVRC data can be used to indirectly assess skeletal muscle excitability and ion channel function in vivo. Changes in MVRC profile also show promise as a pharmacodynamic biomarker. We have reverse translated MVRCs so they can be used in vivo and ex vivo in mouse models. We have MVRC data demonstrating that the effect of a sodium channel mutation on skeletal muscle excitability is different in male and female mice.

This is an interdisciplinary project that will explore the molecular and genomic factors that underly the sex difference in skeletal muscle excitability and susceptibility to channelopathy phenotype. It is an exciting opportunity to apply a range of different techniques to the problem, ranging from patch-clamp electrophysiology to study ion channel behaviour directly, Muscle Velocity Recovery Cycles on isolated muscle, super resolution microscopy-based molecular analysis, mathematical modelling and bioinformatic analysis of high-depth RNA sequencing data. There is also the potential for foreign travel to develop international collaborations and teach the MVRC technique elsewhere.

Supervisors

• Dr Annette L Pantall - annette.pantall@ncl.ac.uk
• Dr Iain Spears - Iain.Spears@ncl.ac.uk
• Dr Robert Muni-Lofra - robert.muni-lofra@newcastle.ac.uk

Project outline

This multidisciplinary project is ideally suited to a student with medical as well as mathematical, computing and engineering interests. The project aims to answer a major clinical and health economics issue. This project will focus on muscle wasting, present in many pathologies including muscular dystrophy and age-related muscle wasting (sarcopenia). Sarcopenia affects 10%-20% of older adults and results in economic costs over £2.5 billion annually. Skeletal muscle is not just needed for movement but is vital for the overall health of the body through secretion of myokines which communicate with other organs. As muscle is vital for good health, it is essential we can measure the health of muscle directly, like other organs. However, there is no direct test for muscle, instead there are a barrage of indirect tests. This study aims to develop a smart band with embedded sensors and software to measure muscle health.

The three parts of the project are:

1. Develop novel software to quantify muscle health directly from wearable sensor data, clinical and MRI data. A pattern classification approach will be taken to generate a muscle health index. Muscle physiological measures including fatigue and motor unit recruitment will be determined from 32 channel high density electrode arrays.
2. Investigate new sensors (e.g., electrical impedance sensors) and test properties of embedded garments in line with regulatory standards.
3. Test the new software and embedded prototype in the state-of-the-art Biomechanics laboratory at Newcastle University in older adults. The equipment used will include force platforms, motion capture system and a chair dynamometer. Additionally, the prototype will be tested on individuals with muscular dystrophy.

The supervisory team consists of Dr Annette Pantall (neuroscientist, biomedical engineer), Dr Iain Spears (biomechanist, software developer) and Dr Robert Muni Lofra (consultant physiotherapist, neuromuscular expert). The project will involve UK and European industrial partners / subcontractors.

Supervisors

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

Project outline

Everyone experiences tremor. In healthy people it is no more than a nuisance, but in movement disorders like essential tremor and Parkinson’s disease it can become disabling. Current treatments do not work in all sufferers. Tremor arises from an interaction between sensory inputs from the limb, and circuits in the central nervous system controlling movement. If these control circuits become unstable, oscillations result leading to tremor. In this project, we will add additional sensory stimuli, time-locked to tremor using closed-loop electrical stimulation. We hypothesise that this will stabilise the control systems, reducing tremor; we have shown that this can work in pilot data. The project will use non-invasive electrophysiological methods such as electromyogram recording and peripheral nerve stimulation. Closed-loop sensory feedback will use microcontroller systems and algorithms which we have already developed. These will initially be optimised on healthy volunteers performing tasks known to exacerbate tremor. We will then test the approach on patients with pathological tremor resulting from movement disorders. Finally, we will develop portable devices capable of delivering closed-loop feedback continually while a subject goes about their daily life. We will test whether long-term use of these devices can induce plasticity, giving long-lasting reduction in tremor even when the device is not being used. Success in this project will lead to a simple non-pharmacological treatment for tremor. The project will be supervised by Prof. Stuart Baker and Dr Maria Germann, who have a published track record applying wearable devices to disorders of movement. It will provide multi-disciplinary training within the successful and lively environment of Newcastle University’s Movement Laboratory. The project requires a wide range of skills, from computing and engineering to neuroscience; the successful applicant is unlikely to have all skills needed at the start, but should be willing to learn and work outside the ‘comfort zone’ of their prior training.

Supervisors

• Dr Luke Bashford – luke.bashford@newcastle.ac.uk
• Professor Tim Griffiths – tim.griffiths@newcastle.ac.uk

Project outline

Human intracortical Brain-Computer Interfaces (BCIs) use features of single unit recordings from implanted electrode arrays to decode intended behaviours of users and output this through external devices such as computers or prosthetic devices. Stimulation through the same electrode arrays can be used to evoke neural activity and behaviour. Together recording for control and stimulation for feedback can be used for a closed-loop BCI. To develop BCIs we implant humans in high level cortical areas where brain signals encode cognition and sensorimotor control. Human BCIs have been successfully used for restoring control and communication however much of the underlying neuroscience of this control and thus the potential for novel control algorithms remains to be elucidated. This is particularly important in the case of cognitive BCIs, intended to identify the neural activity underlying performance in human cognitive tasks and restore performance in clinical cases of cognitive deficit.

In this PhD project you will investigate the neural mechanisms underlying human sensorimotor and cognitive function and explore how neural signals could be decoded and modulated by closed-loop BCIs. This work will impact both basic science and clinical translation. Your research activities will be based on existing human data, and novel data collection through human clinical trials investigating intracranial and intracortical devices to restore function and quality of life in individuals with neurological injury or illness where there is a significant unmet clinical need. Data is collected and analysed through the establishment of novel trials at Newcastle University, UK, and in collaboration with ongoing trials at the University of Colorado, USA.

Supervisors

• Dr Srikanth Ramaswamy - srikanth.ramaswamy@newcastle.ac.uk
• Andrew Trevelyan - andrew.trevelyan@ncl.ac.uk
• Dr Sarah E Gartside - sasha.gartside@ncl.ac.uk

Project outline

The main aim of this project is to uncover principles of synaptic function in the human cortex by integrating experiments and computational modelling.

The human cerebral cortex is the most sophisticated biological machine we know; it is the seat of higher cognition, memory and thought. The basic architecture and the component cell types of the human neocortex appear similar to other, more widely studied mammalian brains (rodents and primates). However, little is known about synaptic function in humans. Given the critical role of synaptic function in cognition, questions about human synaptic function assume the highest importance. Studying synaptic communication in human neuronal circuits is not possible in situ but can be done using a remarkable resource: tissue that has been resected from the brains of patients having neurosurgical treatment and kept alive in artificial cerebrospinal fluid.

The student will use resected human cortical tissue to examine the structure and function of neuronal synapses, using a range of state-of-the-art imaging, electrophysiology and electron microscopy techniques. Experimental findings will be incorporated into anatomically accurate computational models, to explore how neuronal communication may flow through human cortical networks. The student will examine how neuromodulators such as acetylcholine, dopamine and serotonin, which mediate various cognitive, executive and emotional functions, may alter synaptic communication and dendritic excitability and the propensity towards epileptic discharges. The student will test the hypothesis that the peculiarly long dendrites in human pyramidal cells confer a special facility for compartmentalizing activity and achieving rapid state changes. These functional features may underlie short-term memory and attentional switching but also carry the risk of tipping into epileptic pathological discharging.

The supervisorial team combines expertise in the anatomy and physiology of mammalian neocortical microcircuits, statistical and computational modelling (Ramaswamy), cellular electrophysiology and imaging techniques and epileptic pathophysiology (Trevelyan, Gartside). Our recent work has revealed the cellular and synaptic organizational principles of cortical networks (Ramaswamy); the principles of seizure initiation and termination (Trevelyan); ionic redistribution that confer variable network functions during circadian cycles (Trevelyan and Gartside), and the anatomy, physiology and pharmacology of monoaminergic neuromodulator systems and the impact of serotonin on cortical function (Gartside).

This timely project, supervised by an internationally recognized team, is an excellent opportunity for a student to be trained in the principles and analytical techniques of experimental and computational neuroscience using resected human brain tissue.

Supervisors

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

Project outline

Background

The structure and shape of the brain changes through development, ageing, and in disease. Cross-sectionally, changes in cortical shape and structure correlate with age, cognitive function, and disease severity or progression. However, it is less clear if brain structure derived from neuroimaging can also reliably track disease progression in individuals and longitudinal research is required to establish causal relationships between brain structure and disease processes.

Question/hypothesis/aim: We aim to track brain structure of individual subjects longitudinally, alongside clinical and cognitive outcome variables to develop individualised neuroimaging markers of ageing and degenerative processes.

Methods

Using large-scale open-access structural neuroimaging datasets, structural changes across different processes will be established and related to clinical and cognitive outcome measures. We will establish a baseline with healthy ageing as an initial process, with age and neuropsychological data as primary outcome measures. We will then investigate dementia and epilepsy as application domains, given the significance of brain structural changes in these disorders, and supervisory expertise.

Timelines

This interdisciplinary project fills a crucial knowledge gap in medical neuroimaging and provides a unique opportunity to combine novel computational/AI methods with huge datasets to gain a mechanistic understanding of how and why brain structure and shape change in different processes, and how this relates to clinical and cognitive outcomes. We aim to address urgent societal needs to advance knowledge of neurodegenerative disorders.

Potential impact

Leveraging longitudinal data, the project will improve our understanding of how ageing and diseases progress and how reorganisation occurs. It will inform on potential neurobiological causes of neurodegenerative and neurological diseases. Predicting disease progression of individuals based on the interaction of outcome measures, morphological and connectivity measures offers a huge leap forward in research and, crucially, could be translated into clinical tools to aid prognosis and inform medical decisions.

Supervisory team

We offer a rich research environment in both clinical and computational labs. Dr Yujiang Wang is a UKRI Future Leaders Fellow and co-PI of the Computational Neuroscience, Neurology, and Psychiatry (CNNP) lab in the School of Computing. Key expertise: the development of computational biomarkers based on mechanistic understanding of the processes driving brain shape. Prof. John-Paul Taylor is Clinical Professor of Translational Dementia Research and PI of the Lewy Body Lab in the Faculty of Medical Sciences. Key expertise: application of neurophysiology and neuroimaging to dementia populations.

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.

The closing date for applications to both the Neuroscience Fund and the Reece Foundation Studentship Schemes is 23:59 on Monday 4 March 2024.

We aim to interview short-listed candidates in the second two weeks of March 2024.

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. 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.