theme 2 neurosciences, psychiatry and mental [email protected] projects listed in this...

Theme 2

Neurosciences, Psychiatry and

Mental Health

2

1.2 Course of ADHD from childhood to adulthood and physical health outcomes: a multi cohort

epidemiological study…………………………………………………………………………………………………………... 6

2.2 Mental Health Consequences of AIR pollution ........................................................................................ 7

3.2 Epigenetic regulation of learning and memory ......................................................................................... 8

4.2 Investigating the role of mTOR signalling in epilepsy and intellectual disability .................................... 9

5.2 Mechanisms of chronic migraine ............................................................................................................. 10

6.2 Cannabidiol for psychosis in neurodegenerative disorders ..................................................................... 11

7.2 Whole body movements in the aging human brain in real-world environments .................................... 12

8.2 A neuroimaging assessment of brain metastability changes in Epilepsy ................................................. 13

9.2 Can combining neurocognitive and behavioural markers improve our ability to predict trajectories and

outcomes in infants at familial risk of ASD and ADHD? .............................................................................. 14

10.2 Systems Analysis of Food-Sensing Neuroendocrine Circuits that Regulate Ageing ........................... 15

11.2 The early consequence, pathophysiology and pathology in Alzheimer’s disease; Synapse function and

structure ......................................................................................................................................................... 16

12.2 Mapping the pharmacology of Autism using multi-modal brain imaging data from drug shiftability

studies. ........................................................................................................................................................... 17

13.2 The genetic architecture of reported childhood trauma ........................................................................ 18

14.2 Urbanicity and psychosis- are cities bad for mental health? A large-scale data linkage study using

electronic health records ................................................................................................................................ 19

15.2 Harnessing wearable devices with transdermal alcohol sensor for clinical and public health use. ...... 20

16.2 What makes some people at risk of developing an Eating Disorder? ................................................... 21

17.2 Stratification of people at risk of psychosis via frequent online assessments of decision-making ....... 22

18.2 A structural bioinformatics approach to the study of how genetic variations can cause

neurodegeneration ......................................................................................................................................... 23

19.2 The role of interoceptive accuracy in physiological coordination and social interactions in self-

regulation disorders ....................................................................................................................................... 24

20.2 Using artificial intelligence to facilitate early identification and treatment of depressive symptoms in

primary care ................................................................................................................................................... 25

21.2 The nature and natural history of overdoses, drug-related mortality, and treatment-seeking in people

attending hospitals for drug-related health conditions ................................................................................. 26

22.2. The effect of Social Media on children and Adolescents: A Randomised controlled Trial (eSMART).

........................................................................................................................................................................ 27

23.2 Discovering disease modifying therapies for Parkinson’s disease using a drug repurposing approach 28

24.2 Anxiety, somatic symptoms, and service use: Using genetics to understand links between emotional

and physical health ........................................................................................................................................ 29

25.2 Neuroinflammation and neuron-glia signalling through extracellular vesicles excreted during neuronal

cell death in neurodegeneration. .................................................................................................................... 30

26.2 Electrophysiological assessment of synaptic potentiation in human visual cortex as a biomarker for

prodromal dementia. ...................................................................................................................................... 31

27.2 Mechanisms of cannabis-based medicines in treating tumour-associated seizures .............................. 32

3

28.2 Preventing cancer chemotherapy-induced neuropathy ........................................................................ 33

29.2 Living Evidence on First-EpiSode of psychosis Treatments and Outcomes (EFESTO): a living

individual participant data network meta-analysis and learning healthcare system. ................................... 34

30.2 Precision medicine and mechanism: How and for whom do psychological treatments work? ............ 35

31.2 Adult neurogenesis in the olfactory bulb: unlocking the secrets of newborn neuron function............. 36

32.2 Investigating the role of TRP channels in the pathogenesis of multiple sclerosis ............................... 37

33.2 Role of autism-linked gene mutations in aggression ............................................................................. 38

34.2 Targeting alpha-synuclein mediated synaptopathy .............................................................................. 39

35.2 The impact of tobacco control and vaping policies on smoking in people with mental health and

substance use problems .................................................................................................................................. 40

36.2 Exploring whether bone disease is a driver and/or marker of dementia .............................................. 41

37.2 Understanding RNA/splicing factor transport dynamics in live developing and degenerating neurons

in culture and whole animals. ........................................................................................................................ 42

38.2 The effects of stressful life events on the brain and subsequent development of psychosis: A

longitudinal MRI study.................................................................................................................................. 43

39.2 The role of tau in ß-amyloid synaptotoxicity ....................................................................................... 44

40.2 ADHD and preterm birth: applying remote measurement technology to identify persisting

impairments and targets for intervention ...................................................................................................... 45

41.2 Transdiagnostic mechanisms in cognitive behavioural interventions for patients with Persistent

Physical Symptoms: How do transdiagnostic psychological therapies work? ............................................. 46

42.2 Imagine a brighter future: Understanding treatment predictors and mechanisms of a school-based

positive imagery intervention to target anhedonia in adolescents. ............................................................... 47

43.2 Understanding neuronal migration disorders using human tissue models. ........................................... 48

44.2 What impact do pharmacological treatments have on self-harm and suicide in psychosis? A

pharmaco-epidemiological study ................................................................................................................... 49

45.2 Role of alternative splicing in diversity of mammalian neurons ........................................................... 50

46.2 Emerging brain networks in babies vulnerable to neurodevelopmental conditions (Autism Spectrum

Disorder and ADHD): An MRI study of fetal and neonatal brain. .............................................................. 51

47.2 Investigating hippocampal dysfunction in people at clinical high-risk for psychosis with implications

for novel drug discovery………………………………………………………………………………………………… .... .. 52

48.2 Wearable technology to improve the management of Psychogenic Non-Epileptic Seizures ............... 53

49.2 Developing a new cognitive model and targeted psychological intervention to reduce worry and

distress in informal carers .............................................................................................................................. 54

50.2 Cellular models to identify causal molecular mechanisms of early life stress (els)-induced

comorbidity ................................................................................................................................................... 55

51.2 Enhancing patient benefits from IAPT psychological therapy services through machine learning

informed decision-making tools and personality measurement .................................................................... 56

52.2 Does cognitive behaviour therapy for psychosis alter psychophysiological mechanisms associated

with distressing psychotic symptoms?........................................................................................................... 57

53.2 Stress Vulnerability in Sexual Minorities: Genetic and Environmental Influences………….…………… 58

54.2 Investigation of the cell biological basis for polypharmacy and their risks and benefits for Alzheimer’s

disease……………………………………………………………………………………………………………………………... 59

55.2Developing a microfluidic model of headache “pain”…………………………………………………………….60

4

56.2 Molecular basis of visual learning…………………………………………………………………………………….. 61

57.2 Nonconformity to gender-related expectations and ideals: Investigation of interpersonal difficulties

and mental health……………………………………………………………………………………………………………….. 62

58.2 The impact of diet on early adversity, brain maturation and mental health in young adolescents…… 63

59.2 Healthy ageing and cognitive decline: How important is remembering through our own eyes?.......... 64

60.2 Investigating pain mechanisms in wound healing and pathological keloid scars…………………………..65

61.2 Using virtual reality to investigate sense of body ownership and agency in patients with functional

neurological disorder…………………………………………………………………………………………………………… 66

62.2 Adolescent psychopathology and disrupted decision making about the future: An investigation of

behavioural and neural processes…………………………………………………………………………………………… 67

63.2 Regulation of neural stem cell quiescence by non-coding RNA………………………………………………. 68

64.2 Illuminating the darkness: Developing neuroimaging biomarkers for bipolar depression……………… 69

65.2 Imaging glutamate with GluCEST: investigating the mechanistic action of ketamine in depression...

70

66.2 Aggression and Irritability in Neurodevelopmental Disorders: A Translational Approach……………. 71

67.2 Autism Spectrum Disorders and eating disorders: exploration of the benefits and costs of a tailored

clinical pathway…………………………………………………………………………………………………………………. 72

68.2 Using smartphone-based personal sensing to understand and predict risk of psychotic relapse at the

individual level…………………………………………………………………………………………………………………...

73

69.2 Investigating markers of neuroprogression in Anorexia Nervosa…………………………………………….. 74

70.2 The effect of mitochondrial transport and function on synaptic integrity during ageing……………….. 75

5

Neurosciences, Psychiatry and Mental Health Priorities in this theme are linking developmental, molecular, cellular & systems neuroscience to clinical research; sensory disorders (including pain); neurodevelopmental disorders; neurodegeneration; experimental medicine in psychiatry; and the social sciences interface. Lead: Prof Francesca Happé and Dr Sandrine Thuret

When choosing a project from this catalogue in the funding section of the online application form please enter MRCDTP2020_Theme2 Deadline for application: Sunday 1st December, 23:59pm Shortlisted candidates will be contacted in mid-January. Interviews: Wednesday 29th & Thursday 30th January The 2020/21 studentships will commence in September 2020. For further Information or queries relating to the application process please contact [email protected]

Projects listed in this catalogue are subject to amendments, candidates invited to interview will have the opportunity to discuss projects in further detail.

mailto:[email protected]

6

1.2 Course of ADHD from childhood to adulthood and physical health outcomes: a

multi cohort epidemiological study

Co-Supervisor 1A: Louise Arseneault

School/Division & CAG: SGDP Centre/PaSS

KCL/KHP E-mail: [email protected]

KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/louise.arseneault.html

Co-Supervisor 1B: Jessica Agnew-Blais

School/Division & CAG: SGDP Centre/PaSS

KCL/KHP Email: [email protected]

KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/jessica.agnew-blais.html

Project Description:

ADHD is associated with poor mental and physical outcomes (Agnew-Blais et al., 2019; Agnew-Blais, 2018;

Chen et al., 2018). However, much of the current research in this area is limited to cross-sectional studies and

often relies on clinical populations. We propose to investigate, across several population-based cohorts, the

longitudinal association between ADHD and physical outcomes, including obesity, asthma and inflammation.

Four separate but related studies focus on: (1) the epidemiology of the longitudinal association between

ADHD and obesity; (2) the developmental association between ADHD with inflammation and asthma from

childhood to mid-life (possibly mediated by cigarette smoking); (3) the genetic link between ADHD and

obesity using ADHD polygenic risk scores (PRS), possibly modified by gender; and (4) the role of

inflammation in the link between ADHD and poor health. We aim to replicate findings and harmonise

measures across cohorts.

This project will capitalise on existing data collected as part of international longitudinal cohort studies

including the UK National Child Development Study (NCDS), the Environmental Risk Longitudinal Twin

Study in the UK, Generation R in the Netherlands, 1993 Pelotas cohort in Brazil, and ELEDEQ from Canada.

The student will gain statistical skills on longitudinal and genetically sensitive analyses (e.g., PRS, twin design)

and experience disseminating findings.

Timeline

Objectives

Year 1: Get familiarised with literature on ADHD and physical health; consolidate statistical knowledge and

skills

Year 2: Appreciate the value of cross cohort approaches and learn scientific writing

Year 3: Practice communication skills and learn genetic analyses

Year 4: Grants(wo)manship and public engagement

Two representative publications from supervisors:

Agnew-Blais, J.C., Polanczyk, G.V., Danese, A., Wertz, J., Moffitt, T.E., Arseneault, L. (2018). Young adult

mental health and functional outcomes among individuals with remitted, persistent and late-onset ADHD.

British Journal of Psychiatry, 213, 526-534. (doi: 10.1192/bjp.2018.97.)

Chen, Q., Hartman, C.A., Haavik, J., Harro, J., Klungsøyr, K., Hegvik, T.A., Wanders, R., Ottosen, C.,

Dalsgaard, S., Faraone, S,V., Larsson, H. (2018). Common psychiatric and metabolic comorbidity of adult

attention-deficit/hyperactivity disorder: A population-based cross-sectional study. PLoS One, 13,

(doi.org/10.1371/journal.pone.0204516).

7

2.2 Mental Health Consequences of AIR pollution

Co-Supervisor 1A: Ioannis Bakolis

School/Division & CAG: Department of Biostatistics and Health Informatics, Centre for Implementation

Science, Health Services Research, IoPPN


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/ioannis.bakolis.html

Co-Supervisor 1B: Dr Ian S Mudway

School/Division & CAG: MRC-PHE Centre for Environment and Health, School of Population Health &

Environmental Sciences; National Institute for Health Research, Health Protection Research Unit on Health

Effects of Environmental Hazards


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/en/persons/ian-mudway(3b1c16af-3c30-47fd-b210-

cbc6ad24c0d8).html


The World Health Organization (WHO) recently estimated that ambient air pollution causes 482,000 premature

deaths within the WHO European Region with an estimated economic cost of 1.575 trillion US$ including

morbidity costs. However, the significant potential health and societal costs of poor mental health in relation to

air quality are not represented in the WHO report due to limited evidence and gaps and uncertainties in our

knowledge of the underlying pathophysiologic mechanisms that drive the reported associations. Benefiting from

collaborations within King’s College London, University of Leicester and University College London in

providing access to data on air pollution (e.g. KCLUrban) and mental health (e.g. Clinical Record Interactive

Search (CRIS) , 1946 birth cohort, Urban Mind (https://www.urbanmind.info/)), this project aims to

systematically explore associations between air pollution and mental function using a range of advanced

Geographical Information Systems (GIS) and state of the art statistical techniques. Throughout the project, the

PhD candidate will gain a deep understanding of how air pollution stressors could affect mental function (under

main supervision of ISM) and learn and apply a range of epidemiological designs and modelling techniques

(under main supervision of IB).

Yr1: A systematic review of the associations between air pollution and a range of psychiatric and neurological

outcomes

Yr2: Augment the linkages of existing air pollution databases with Urban Mind, CRIS, and 1946 birth cohort.

Yr3: Conduct epidemiological analysis

Yr4: Synthesise findings and draft a list of recommendations for tackling air pollution levels and identifying

populations at risk.


Bakolis I, Hammoud R, Smythe M, Gibbons J, Davidson N, Tognin S, Mechelli A. Urban Mind: Using

Smartphone Technologies to Investigate the impact of Nature on Mental Wellbeing in Real Time. BioScience

2018 68 (2), 134-145

Mudway IS, Dundas I, Wood HE, et al. Impact of London’s low emission zone on air quality and children’s

respiratory health: a sequential annual cross-sectional study. Lancet Public Health 2019; 4: e28–e40.

8

3.2 Epigenetic regulation of learning and memory

Co-Supervisor 1A: Prof. M. Albert Basson

School/Division & CAG: Centre for Craniofacial and Regenerative Biology, FoDOCs


KCL/KHP Website: https://www.kcl.ac.uk/people/albert-basson

Co-Supervisor 1B: Prof. K. Peter Giese

School/Division & CAG: Basic and Clinical Neuroscience, IoPPN


KCL/KHP Website: https://www.kcl.ac.uk/ioppn/depts/bcn/Our-research/Cells-behaviour/giese-memory-

mechanisms


The ability to learn and remember is essential for survival of all animal species. Fundamental questions remain

about how memories are encoded and stored in the brain. The formation of long-term memories (memory

consolidation), requires new gene transcription. As long-term memory is established or modified through gene

expression changes, epigenetic mechanisms that regulate gene transcription are likely to have key roles in

memory consolidation. Indeed, mutation of genes encoding chromatin remodelling factors have been linked to

intellectual disability and specific learning deficits in the human population. Deficits in memory consolidation

are thought to be the primary cause of age-related learning deficits. Thus, manipulating the epigenome may help

prevent or even treat memory deficits in old age. Understanding the epigenetic basis of memory consolidation

and how we might improve this process, is of significant importance in maintaining lifelong cognitive health.

In this project, the student will investigate the epigenetic basis whereby mutations in chromatin remodelling

factors affect memory and learning in mouse models. Mouse genetics, targeted delivery of substances in the brain,

and quantitative (PCR, Western blot), semi-quantitative (immunostaining) and genome-wide next-generation

sequencing methods (RNA-seq, ChIP-seq, ATAC-seq) will be employed.

Specific aims:

1) To identify transcriptomic changes that characterise specific memory phenotypes in mutant mice during

learning (Year 1),

2) To identify alterations in chromatin structure and dynamics that underlie these transcriptional changes (Year

2),

3) To validate functionally relevant chromatin and gene expression changes in vivo (Year 3-4).

Together, this work will reveal how altered chromatin dynamics impact learning.


Suetterlin, P., Hurley, S., Mohan, C., Riegman, K.L.H., Pagani, M., Caruso, A., Ellegood, J., Galbusera, A.,

Crespo-Enriquez, I., Michetti, C., Yee, Y., Ellingford, R., Brock, O., Delogu, A., Francis-West, P., Lerch,

J.P., Scattoni, M.L., Fernandes, C. & Basson, M.A. (2018). Altered neocortical gene expression, brain

overgrowth and functional over-connectivity in Chd8 haploinsufficient mice. Cereb. Cortex. 28:2192-2206.

https://doi.org/10.1093/cercor/bhy058

Mizuno K, Dempster E, Mill J, Giese KP (2012). Long-lasting regulation of hippocampal Bdnf gene

transcription after contextual fear conditioning. Genes Brain Behav. 11, 651-659. doi: 10.1111/j.1601-

183X.2012.00805.x

9

4.2 Investigating the role of mTOR signalling in epilepsy and intellectual disability

Co-Supervisor 1A: Joseph Bateman

School/Division & CAG: IOPPN/Neuroscience


KCL/KHP https://www.kcl.ac.uk/ioppn/depts/bcn/our-research/neurodegeneration/bateman/index.aspx

Co-Supervisor 1B: Cathy Fernandes

School/Division & CAG: IOPPN/Psychology & Systems Sciences


KCL/KHP Website: https://www.kcl.ac.uk/people/cathy-fernandes


Defects in neurogenesis lead to epilepsy, intellectual disability and other common neurological disorders.

Mechanistic target of rapamycin (mTOR) signalling is a key molecular pathway that regulates neurogenesis

(Tee et al., 2016, PMID 26849906). Activation of mTOR signalling causes neurological diseases associated

with epilepsy, autism and intellectual disability. However, the mechanism by which mTOR regulates

neurogenesis is very poorly understood. We previously identified a novel component of the mTOR pathway,

called Unkempt, in Drosophila (Avet-Rochex et al., 2014, PMID 25210733). We have recently determined

the molecular mechanism by which mTOR regulates Unkempt in mammals and shown that Unkempt

knockout mice have altered neurogenesis, learning and memory (Vinsland et al, 2019, in revision). In this

project the PhD student will use a powerful combination of protein biochemistry and mouse

behavioural/imaging techniques to dissect the role of Unkempt and mTOR signalling in epilepsy and

intellectual disability.

Objectives:

Year 1 (or rotation project): Biochemical analyses of mTOR-dependent Unkempt phosphorylation;

immunohistochemical analysis of adult neurogenesis in Unkempt knockout mice.

Year 2: Phenotypic analysis of Unkempt/Tsc1 double mutant mice. Use of in utero electroporation to test the

function of Unkempt phosphorylation in vivo.

Year 3: Behavioural (including learning and memory) analyses of Unkempt/Tsc1 double mutant mice.

Year 4: Completion of behavioural experiments, writing papers and thesis.

The student will be trained in and use: Cell culture, mutagenesis, biochemical analysis of protein

phosphorylation, mouse genetics, in utero electroporation, mouse behaviour.


Vinsland et al. The mTOR substrate Unkempt regulates hippocampal neurogenesis and cognitive flexibility. In

revision.

Egeland et al. (2017) Depletion of adult neurogenesis using the chemotherapy drug temozolomide in mice

induces behavioural and biological changes relevant to depression. Transl Psychiatry 7:e1101. doi:

10.1038/tp.2017.68.

10

5.2 Mechanisms of chronic migraine

Co-Supervisor 1A: Stuart Bevan

School/Division & CAG: IoPPN, Wolfson CARD


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/stuart.bevan.html

Co-Supervisor 1B: Anna Andreou

School/Division & CAG: IoPPN, Wolfson CARD & Clinical Neurosciences Clinical Academic Group


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/anna.andreou.html

Name of Collaborating Clinician: Dr Giorgio Lambru, MD, PhD

School/Division & CAG: Headache Centre, GSST/Neuroscience

Email: [email protected]

Website: https://www.guysandstthomas.nhs.uk/our-services/pain/headache-centre/overview.aspx


Chronic migraine (CM) is a debilitating painful disorder characterized by patients experiencing 15 or more

headache days per month. The mechanisms responsible for CM are unknown but involve sensitization and

activation of sensory neurons innervating the meningeal blood vessels.

Many CM patients also suffer from pain and hypersensitivity in other regions of the body and about 20-30% are

diagnosed as having fibromyalgia (FM), which is characterized by chronic widespread pain, fatigue, and

emotional distress. Our recent studies have made the breakthrough discovery that FM is an autoimmune disorder

in which antibodies sensitize peripheral neurons. As CM and FM are frequently co-morbid these two conditions

are likely to share common mechanisms. This studentship will examine the mechanisms responsible for CM pain

by transferring serum from CM patients to mice and elucidate the factors that lead to neuronal sensitization.

Year 1: Study the behavioural effects of transferring serum and immunoglobulins from CM patients (with and

without FM) and healthy subjects to mice. The transfer of symptoms from patients to mice will be validated by

measuring pain sensitivities.

Years 2-3: Determine the effects of CM/FM serum and other factors on the properties of pain-sensing nerve

fibres in the intact dura mater and on isolated neurons using ‘calcium imaging’ and electrophysiology. Identify

mechanisms underlying neuronal hypersensitivity in CM using biochemical and immunological approaches.

Year 4 (0.5 year): Write manuscripts, thesis and fellowship applications. The student will be encouraged to

present their findings at national and international meetings throughout their project.


Quallo T, Vastani N, Horridge E, Gentry C, Parra A, Moss S, Viana F, Belmonte C, Andersson DA, Bevan S

(2015) TRPM8 is a neuronal osmosensor that regulates eye blinking in mice. Nat Commun 6:7150.

(Discovery of TRPM8 is an exquisitely sensitive sensor of osmolality that controls the rate of eye blinking.)

Jones MG, Andreou AP, McMahon SB, Spanswick D. (2016) Pharmacology of reflex blinks

in the rat: a novel model for headache research. J Headache Pain. 7:96.

(Characterization of a model for evaluating headache pain.)

11

6.2 Cannabidiol for psychosis in neurodegenerative disorders

Co-Supervisor 1A: Prof Sagnik Bhattacharyya

School/Division & CAG: IoPPN/ Psychosis Studies


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/sagnik.2.bhattacharyya.html

Co-Supervisor 1B: Dr Latha Velayudhan

School/Division & CAG: IoPPN/ Academic Division & Old Age Psychiatry


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/latha.velayudhan.html


Symptoms of psychosis in Alzheimer’s disease (ADP) or Parkinson’s disease (PDP) can be very distressing, cause

considerable suffering to patients and caregivers and there are currently no approved treatments available. While

cannabidiol is a promising candidate treatment, it’s unclear if it will work for ADP or PDP. The next stage of

clinical development for cannabidiol as a treatment for ADP or PDP involves the conduct of fully powered

pivotal clinical trials. Such studies are expensive. Therefore, go/no-go decisions regarding further clinical

development need to be informed by supportive mechanistic evidence in these patient groups to complement

preliminary efficacy signals. However, no such evidence exists at this point of time. The proposed PhD will be

nested within Randomized Controls Trials (RCT) using cannabidiol (CBD) in ADP and PDP. The proposed

PhD project will generate such mechanistic evidence if it can demonstrate an effect of cannabidiol on some of

the brain substrates implicated in psychosis in neurodegenerative disorders.

Planned research methods and training provided:

· Acquisition & analysis of neuroimaging and cognitive data.

· Evaluation of novel treatments; clinical research in neurodegenerative disorders; industrial collaboration

Year 1: Liaison with RCT team; subject enrolment; cognitive data acquisition, neuroimaging data (verbal

learning and resting state fMRI) will be acquired on a 3T MRI scanner using established protocols.

Year 2: Data collection; Industrial secondment with the supplier of study drug.

Year 3: Investigate the effect of CBD treatment on the fMRI BOLD signal and analysis of neuroimaging data

using established software; Dissemination; Submission of PhD


Bhattacharyya S, Wilson R, Appiah-Kusi E, et al. Effect of Cannabidiol on Medial Temporal, Midbrain, and

Striatal Dysfunction in People at Clinical High Risk of Psychosis: A Randomized Clinical Trial. JAMA

Psychiatry. 2018;75(11):1107-1117.

Velayudhan L, Van Diepen E, Marudkar M, Hands O, Suribhatla S, Prettyman R,Murray J, Baillon S,

Bhattacharyya S. Therapeutic Potential of Cannabinoids in Neurodegenerative Disorders: A Selective Review.

Curr Pharm Des. 2014;20(13):2218-30.

12

7.2 Whole body movements in the aging human brain in real-world environments

Co-Supervisor 1A: Dr Jorge Cardoso, Senior Lecturer

School/Division & CAG: School of Biomedical Engineering & Imaging Sciences, Faculty of Life Sciences


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/m.jorge.cardoso.html

Co-Supervisor 1B: Dr James Teo, Visiting Clinical Senior Lecturer, Consultant Neurologist & Director of Data

Science (KCH)

School/Division & CAG: Neuroscience, Institute of Psychiatry, Psychology and Neuroscience

KCL/KHP Email: [email protected] or [email protected]

KCL/KHP Website: https://www.kch.nhs.uk/profiles/49096/james-teo


Human gait is a high-dimensional vector optimised for accuracy, stability, speed or energy efficiency

in healthy young adults. As the brain ages through chronic cerebral ischaemia, properties of whole

body motion changes; eventually gait and balance are compromised. Previous studies have

limitations – small number of gaits studied, recordings in non-ecological gait laboratory

environments, excess dimensional minimisation due to computational limits. KCL biomedical

engineering has developed a low-cost portable motion capture system with on-board computing

enabling real-world data capture and computation of human motion using modern machine learning

approaches.

The PhD candidate will learn to use the above technologies to catalogue and characterise whole body motion

of patients with cerebral small vessel disease recruited from clinical environments (neurology and stroke units

of KHP hospitals).

Departmental support:

1) Departmental support and training from KCL Biomedical Engineering

2) Pre-processing of quantitative neuroimaging data from projects of the Wellcome Trust

UCL/KCL Flagship Programme in High Dimensional Neurology (co-supervisor is Co-I)

3) Co-develop AI projects in the London Medical Imaging AI Centre for Value-based Healthcare

(co-supervisor is Co-I)

Skills to acquire:

- Data Science (dimensionality reduction techniques, e.g. PCA, Manifold Learning)

- Machine Learning (e.g. Convolutional and Graph Neural Networks)

- Motion kinematics (e.g. body modelling fitting, spatial-temporal analysis)

Year 1 Objective: Ethics and study setup; Data Science training (learn coding skills)

Year 2 Objective: Conduct a Clinical Research Study (recruitment and motion data collection);

Year 3 Objective: Translate body parametrisation neural network to clinical environment; Develop

spatial-temporal graph neural network model for analysing motion


NiftyNet: a deep-learning platform for medical imaging; E Gibson, W Li; MJ Cardoso; T Vercauteren (2018)

Computer Methods and Programs in Biomedicine 158, 113-122

Non-invasive brain stimulation for the lower limb after stroke: what do we know so far and what

should we be doing next? MK Fleming, M Pavlou, DJ Newham, L Sztriha, JT Teo (2017) Disability and

rehabilitation 39 (7), 714-720

13

8.2 A neuroimaging assessment of brain metastability changes in Epilepsy

Co-Supervisor 1A: David Carmichael

School/Division & CAG: FoLSM/School of Biomedical Engineering


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/david.carmichael.html

Co-Supervisor 1B: Robert Leech

School/Division & CAG: IoPPN/Neuroscience & Neuroscience CAG


KCL/KHP Website: www.epilepsy-london.org

Name of Collaborating Clinician (if not one of the two co-supervisors) Mark Richardson

School/Division & CAG: IoPPN/Neuroscience & Neuroscience CAG


Website: https://kclpure.kcl.ac.uk/portal/mark.richardson.html


We have been engaged in understanding epilepsy as disease where the brain is considered a complex network

with a resulting repertoire of dynamics. Neuroimaging methods such as EEG and fMRI both measured

individually and simultaneously can provide a window onto these dynamics. We have a hypothesis that epilepsy

has an effect on the brain where its dynamics become more stable, and the brain becomes ‘stuck’ in certain states

where brain networks are in synchrony. This has important implications because the brain being in a metastable

(switching between stable states) regime is thought to be a desirable property that underpins attentional changes,

cognitive flexibility and consciousness.

In this project, we will use EEG and fMRI to characterise focal and generalised epilepsy patients in terms of their

brains synchrony and metastability both during and in the absence of ongoing epileptic activity and alterations

related to treatment effects.

YR1: Training in neuroimaging and associated analysis methods

YR2: Characterise brain metastability and synchrony at the whole brain and network level for focal and

generalised epilepsy patients using fMRI data. Measure differences associated with epileptic discharges.

YR3: Relate metastability and synchrony to treatment effects including drug effects comparing drug naïve to

treated cohorts and focal epilepsy syndromes.

YR4: The main objective will be to complete and write up scientific papers and thesis.

This project will give a strong training in neuroimaging analysis methodology and its application to brain

dynamics. It will provide strong computational abilities and an introduction to a range of mathematical concepts

as applied to neuroscience.


Dynamic brain network states in human generalized spike-wave discharges.

Tangwiriyasakul C, Perani S, Centeno M, Yaakub SN, Abela E, Carmichael DW, Richardson MP.

Brain. 2018 Aug 28.

Combined electroencephalography-functional magnetic resonance imaging and electrical source imaging

improves localization of pediatric focal epilepsy.

Centeno M, Tierney TM, Perani S, Shamshiri EA, St Pier K, Wilkinson C, Konn D, Vulliemoz S, Grouiller F,

Lemieux L, Pressler RM, Clark CA, Cross JH, Carmichael DW.

Ann Neurol. 2017 Aug;82(2):278-287.

14

9.2 Can combining neurocognitive and behavioural markers improve our ability to

predict trajectories and outcomes in infants at familial risk of ASD and ADHD?

Co-Supervisor 1A: Prof. Tony Charman

Research Division or CAG: PASS, Psychology Department

E-mail: [email protected]

Website: https://kclpure.kcl.ac.uk/portal/tony.charman.html

Co-Supervisor 1B: Prof. Andrew Pickles

Research Division or CAG: PASS, Biostatistics and Health Informatics Department


Website: https://kclpure.kcl.ac.uk/portal/andrew.pickles.html


Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are neurodevelopmental

disorders with high heritability and high rates of co-occurrence. This allows prospective study of infants at

familial risk for ASD and ADHD due to having a first degree relative with a diagnosis. By studying

neurocognitive and behavioural profiles of infants in the two risk groups (and low-risk controls with no family

history) it will be possible to identify common and distinct mechanisms that lead to the two clinical disorders.

However, to date most work has focused on single antecedent markers. Variability in both aetiology and

presentation of these disorders suggests that different neurodevelopment risk factors will act in combination, and

further that these combinations will differ between individuals. As part of the MRC-funded BASIS network

(http://www.basisnetwork.org/) we study infants at familial risk of ASD and ADHD using multiple methods

(EEG, eye-tracking, electrophysiology, behavioural experiments, clinical measures) at multiple timepoints from

6 months of age to 7 years.

The PhD student will develop expertise in statistical modeling approaches (e.g. SEM, LCA, MIMIC) to test

whether combinations of risk markers better predict developmental trajectories and clinical outcomes than single

markers alone. Identifying mechanisms of atypical development will inform translational approaches to early

intervention.

Skills: Complex statistical modelling. Clinical assessments of infants and toddlers. Training in EEG, eye-tracking

and electrophysiological data collection and analysis.

Year 1: Training on assessments. Year 2: Training in statistical modelling Year 3: Analysis and paper writing.

Year 4: Completion of thesis.


Shephard, E., Bedford, R., Milosavljevic, B., Gliga, T., Jones, E. J. H., Pickles, A., Johnson, M. H., Charman,

T., & The BASIS Team. (2019). Early developmental pathways to childhood symptoms of attention-deficit

hyperactivity disorder (ADHD), anxiety, and autism spectrum disorder (ASD). Journal of Child Psychology &

Psychiatry, 60, 963-974.

Pickles, A., Harris, V., Green, J., Aldred, C., McConachie, H., Slonims, V., Le Couteur, A., Hudry, K.,

Charman, T. & The PACT Consortium. (2015). Treatment mechanism in the MRC Pre-school Autism

Communication Trial: Implications for study design and parent-focused therapy for children. Journal of Child

Psychology and Psychiatry, 56, 162-170.

15

10.2 Systems Analysis of Food-Sensing Neuroendocrine Circuits that Regulate

Ageing

Co-Supervisor 1A: QueeLim Ch’ng

School/Division & CAG: Developmental Neurobiology, IoPPN


KCL/KHP Website: https://devneuro.org/cdn/group-overview.php?groupID=73

Co-Supervisor 1B: Attila Csikász-Nagy

School/Division & CAG: BMBS/Randall


KCL/KHP Website: http://csikasznagylab.org


Age is the major risk factor for many diseases, including diabetes, heart attacks, and cancer. Ageing

populations are also a major challenge for developed countries globally. Genetic and environmental factors

converge on hormonal pathways in the brain to affect the ageing process. These pathways are highly

conserved, enabling studies in the experimentally tractable roundworm C. elegans to provide new insights into

the neural regulation of ageing. Our project combines experimental and computational approaches to delineate

the neuroendocrine circuitry involving TGF-beta, serotonin, and catecholamines that are conserved from

roundworms to humans.

Year 1: Investigate the effects of food-gene interactions on lifespan by testing mutants in neuroendocrine

pathways under different food levels. Construct transcriptional reporters for the corresponding genes.

Year 2: Perform high-throughput microscopy to quantify single-cell expression of neuroendocrine reporter

genes using a unique microfluidics system to automate experiments.

Year 3: Model communication in these hormonal circuits to predict food-gene interaction and validate

prediction with experiments.

During this work, the student will discover how hormonal activity in the nervous system can modulate the

effects of food on lifespan. These results will help explain why different individuals show different lifespans

despite eating the same amount of food.

The student will work closely with both supervisors to design experiments and interpret results. Dr Ch’ng will

train the student in molecular genetics, automated microscopy, and lifespan measurements. Dr Csikasz-Nagy

will train the student in data handling, data analysis, and modelling. This project provides a unique opportunity

to learn systems biology to as a new approach in biomedicine.


Entchev E. V., Patel D. S., Zhan M., Steele A, Lu H. and Ch’ng Q. (2015) A Gene-Expression-Based Neural

Code for Food Abundance that Mediates Dietary Effects on Lifespan. eLife 4:e06259

Bajpai, A., Feoktistova, A., Chen, J.S., McCollum, D., Sato, M., Carazo-Salas, R.E., Gould, K.L. and Csikász-

Nagy, A., (2013) Dynamics of SIN asymmetry establishment. PLoS Computational Biology, 9(7), p.e1003147.

16

11.2 The early consequence, pathophysiology and pathology in Alzheimer’s

disease; Synapse function and structure

Co-Supervisor 1A: Professor Kei Cho

School/Division & CAG: Basic and Clinical Neuroscience


KCL/KHP Website: https://www.kcl.ac.uk/ioppn/depts/bcn/DRI/Lab-Groups/Index

Co-Supervisor 1B: Professor Juan Burrone

School/Division & CAG: Developmental Neurobiology


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/juan.burrone.html


The pathophysiology of Alzheimer’s disease (AD) involves the weakening of synaptic connections and

ultimately their elimination, which is thought to correlate with disease severity. Synapse weakening is an early

and pivotal point in AD pathogenesis and an important therapeutic target. Evidence suggests that synaptic

dysfunction and aberrant decomposition of dendritic spines occurs prior to Aβ/Tau plaque and tangle formation.

The focus of this programme is to explore the consequence of pathogens in synaptic dysfunction and its

contribution to neural circuit in the hippocampus. Using multi-photon imaging, electrophysiology and advanced

gene-manipulation in hippocampal slice model, we will investigate three key questions:

Aim1 – The role of pTau in dendritic spine function and structure in the hippocampal neurons (Year1). We will

test whether pTau regulates dendritic spine activity, synapse structure and excitatory input in conjunction with

basal & apical dendrites in CA1 and CA3 hippocampal neurons.

Aim 2 – Pathophysiological consequences of AD/pTau in relation to the proximal and distal segmentation of

dendritic spines and inhibitory and excitatory circuit (Year 2). We will examine at proximal and distal locations

to determine potential factors that confer vulnerability and ultimately lead to spine loss (e.g. are some spines

more vulnerable that others).

Aim 3 – Determine the consequences of aberrant pTau upon DNA methylation: synapse weakening associated

DNA methylation targets (Year 3). The cytosol will be collected from various groups of neurons (eg., control,

pathogen exposed, shRNAs). The sample will be processed to induce bisulfite conversion, amplification, PCR

to target the specific targets and deep sequencing analysis.


Cho: Jo J. et al. (2011) Aβ1-42 inhibition of LTP is prevented by manipulation of a signalling pathway involving

caspase-3, Akt and GSK-3β. Nat Neurosci 14, 545-.

Burrone: Grillo et al., (2018) A distance-dependent distribution of presynaptic boutons tunes frequency-

dependent dendritic integration. Neuron 99, 275- .

17

12.2 Mapping the pharmacology of Autism using multi-modal brain imaging data

from drug shiftability studies.

Co-Supervisor 1A: Dr Eileen Daly

School/Division & CAG: IoPPN/Behavioural and Development


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/eileen.daly.html

Co-Supervisor 1B: Professor Declan Murphy



KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/declan.murphy.html

Name of Collaborating Clinician (if not one of the two co-supervisors) Professor Grainne McAlonan



Website: https://kclpure.kcl.ac.uk/portal/grainne.mcalonan.html


At present, there are no medications for the treatment of Autism core or co-occurring symptoms. There is

evidence that the neurobiological underpinnings of ASD include aberrations in brain growth, neuronal patterning

and cortical connectivity. Altered molecular pathways implicated include serotonin system and

excitation/inhibition neurotransmitter systems. The PhD will investigate if modulation of these abnormalities from

multiple perspectives (brain function, structure and pharmaco-challenge) can lead to a medication stratification

biomarker for translation to clinical trials. Our laboratory has been performing randomised, double blind, placebo-

controlled biomarker shiftability studies comparing brain functional resonse in adults with and without.

Specifically, we have tested the impact of acute doses of several medications, using multimodal imaging

techniques, on resting and active brain functional connectivity, structure and chemistry.While each brain imaging

modality reveals different aspect of the brain, this PhD will develop multivariate methods which use higher order

statistics to combine diverse information to identify correspondence among data types. The PhD candidate will

utilise our completed and ongoing multimodal pharmoco-challenge datasets to investigate this mapping.

Pharmacological Agents

GABA & glutamate – Arbaclofen, Riluzole & AZD7325

Serotonin – Citralopram & Tianeptine

Cannabanoid – Cannabadiol & Cannabidvarin

Imaging

Anatomical Magnetic Resonance Imaging (MRI), Diffusion Tensor Imaging (DTI), Resting state functional

Magnetic Resonance Imaging (rsfMRI), Task based functional Magnetic Resonance Imaging (fMRI)

Magnetic Resonance Sprectroscopy (MRS), Electroenchephalogram (EEG)

Year-1: Training in all neuroimaging paradigms and analysis. Participate in data collection of ongoing studies

Year-2: Neuroimaging data Analysis. Training in Multimodal Data analysis.

Year-3: Data analysis. Thesis write-up.


Pretzsch, Freyberg, Voinescu, Lythgoe, Horder, Mendez, Wichers, Ajram, Ivin, Heasman, Edden, Williams,

Murphy DGM, McAlonan, Daly, E (2019). Effects of cannabidiol on brain excitation and inhibition systems; a

randomised placebo-controlled single dose trial during magnetic resonance spectroscopy in adults with and without

autism spectrum disorder. Neuropsychopharmacology, 2019 (44:8).

Daly E, Ecker, Hallahan, Deeley, Craig, Murphy, Johnston, Spain, Gillan, Gudbrandsen, Brammer, Giampietro,

Lamar, Page, Toal, Schmitz, Cleare, Robertson, Rubia, Murphy DGM (2014). Response inhibition and serotonin

in autism: a functional MRI study using acute tryptophan depletion. Brain, 2014 (137:9).

18

13.2 The genetic architecture of reported childhood trauma

Co-Supervisor 1A: Professor Andrea Danese

School/Division & CAG: IoPPN/SGDP Centre and Department of Child & Adolescent Psychiatry


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/en/persons/andrea-danese(33edf814-3bb0-4ab4-a31c-

f74c94265a6e)/biography.html

Co-Supervisor 1B: Professor Gerome Breen

School/Division & CAG: IoPPN/SGDP Centre


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/gerome.breen.html


Both genetic and environmental risk factors are key to the development of psychiatric disorders, particularly

depression. Individuals reporting a history of childhood trauma are not only at heightened risk of incident

psychiatric disorders but also more likely to develop complex, recurrent, and treatment-resistant

psychopathology. The association between childhood trauma and psychopathology is complex and emerges

both from the overt experience of trauma and from poorly understood pre-existing vulnerabilities in traumatised

individuals. Large-scale genetic analysis of individuals reporting a history of childhood trauma has the potential

to uncover such pre-existing liability to psychopathology. This work has substantial translational value because

genetic analyses can identify novel targets for assessment and treatment of childhood trauma-related

psychopathology.

In Year 1, the student will carry out genome-wide association studies (GWAS) to define the genetic architecture

of reported childhood trauma and depression integrating GWAS and exome sequencing data in two large studies,

the UK Biobank Study and the Genetic Links to Anxiety and Depression (GLAD; www.gladstudy.org.uk)

Study. In Year 2, the student will also examine the genetic liability to psychopathology in individuals reporting

a history of childhood trauma using existing polygenic risk scores. In Year 3, the student will compare the results

based on retrospective measures with findings from prospective measures of child trauma. The joint supervisory

arrangements across Psychiatry and Epidemiology (Prof. Danese) and Genetics and Biostatistics (Prof. Breen)

will ensure that the student will receive world-class support on all technical skill required and gain a clear

understanding of the translational implications of the work.


Danese, A., Moffitt, T.E., Arseneault, L., Bleiberg, B., Dinardo, P., Gadelman, S., Houts, R., Ambler, A., Fisher,

H.L., Poulton, R., Caspi, A. The origins of cognitive deficits in victimized children: Implications for

neuroscientists and clinicians. Am J Psychiatry, 2017 174(4):349-361 doi: 10.1176/appi.ajp.2016.16030333

Coleman, J. R. I., Peyrot, W. J., Purves, K. L., Davis, K. A. S., Rayner, C., Choi, S. W., … Breen, G. (2018).

Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic

experiences in UK Biobank https://doi.org/10.1101/247353 Molecular Psychiatry (in press)

19

14.2 Urbanicity and psychosis- are cities bad for mental health? A large-scale data

linkage study using electronic health records

Co-Supervisor 1A: Dr Jayati Das-Munshi

School/Division & CAG: IOPPN/ Psychological Medicine


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/jayati.das-munshi.html

Co-Supervisor 1B: Prof Craig Morgan

School/Division & CAG: IOPPN/ Health Services & Population Research


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/craig.morgan.html


A growing body of evidence indicates that strong social risk factors, particularly related to urban built

environments, may be associated with an increased risk of psychosis. Urban areas may be ‘riskier’ as they may

represent areas of higher deprivation, a heightened risk of social isolation, reduced social support and may also

be less cohesive and socially fragmented. These social risk factors may represent environmental insults to the

brain in susceptible individuals, however to date, it is unclear which of these aspects play a role in the heightened

risk of psychosis in urban areas.

This project will use a large dataset with clinical data from South London & Maudsley Trust linked to data from

UK census 2011 (a rich source of social and demographic information) to determine social predictors in the urban

built environment (household poverty, social isolation, family support, neighbourhood social fragmentation)

with the onset of psychosis.

The project would suit a candidate with a strong quantitative background (e.g. statistics / epidemiology) wishing

to develop expertise within data sciences, focussing on the social determinants of severe mental illness. The

studentship will include analytical methods training as well as a rich programme of interdisciplinary and

transferable skills training provided through the DTP and the newly established Centre for Society and Mental

Health.

Annual objectives: Year 1- undertake systematic reviews, gain approvals, data cleaning / commence analyses,

upgrade to PhD from MPhil at 9 months; year 2: conduct analyses; training; year 3: finalise all analyses for

publication and PhD submission.


Das-Munshi J., Schofield P., Bhavsar V., Chang CK., Dewey M.E., Morgan C., Stewart R., Thornicroft G.,

Prince M.J. Ethnic density and other neighbourhood associations for mortality in severe mental illness: a

retrospective cohort study with multi-level analysis from an urbanised and ethnically diverse location in the UK.

The Lancet Psychiatry, Volume 6, Issue 6, 506 – 517

Jongsma, H.E., Gayer-Anderson, C., Lasalvia, A., Quattrone, D., Mulè, A., Szöke, A., Selten, J.-P., Turner, C.,

Arango, C., Tarricone, I., Berardi, D., Tortelli, A., Llorca, P.-M., De Haan, L., Bobes, J., Bernardo, M., Sanjuán,

J., Santos, J.L., Arrojo, M., Del-Ben, C.M., Menezes, P.R., Murray, R.M., Rutten, B.P., Jones, P.B., Van Os,

J., Morgan, C.*, Kirkbride, J.B.* (2018) Treated Incidence of Psychotic Disorders in the Multinational EU-GEI

Study. JAMA Psychiatry, 75, 36-46.

20

15.2 Harnessing wearable devices with transdermal alcohol sensor for clinical and

public health use.

Co-Supervisor 1A: Dr Paolo Deluca

School/Division & CAG: IoPPN, Addictions Department


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/paolo.deluca.html

Co-Supervisor 1B: Prof John Marsden

School/Division & CAG: IoPPN, Addictions Department


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/john.marsden.html


Novel, prototype wrist-wearable alcohol sensors are coming to market which measure alcohol consumption from

alcohol vapours in the skin. Such methods hold promise to significantly improve users’ engagement with a

monitoring app and likewise clinicians’ ability to accurately assess alcohol consumption, understand the

determinants of risky/harmful drinking, and trigger real-time interventions. As these methods of data collection

become more reliable, the ability to capture real-time information-process determinants will help build more

accurate models of change and targeted interventions, with minimal time required from users to enter their

drinking data.

However, before these sensors can be integrated with digital devices to provide intervention for alcohol-use,

they first need to be validated to reliably measure alcohol consumption.

This PhD aims to explore and harness the potential for this technology in clinical and public health settings by

validating and evaluating an alcohol transdermal sensor and its associated app in a group of harmful drinkers

through a series of interlinked multi-methods studies outline below.

Year 1, review of the literature and to conduct a validation study to determine measurement accuracy compared

to gold standard; Year 2 to explore acceptability of these devices in a clinical setting for both patients and staff

focussing on potential benefits and implementation barriers; Year 3 determine if it is viable to conduct a large

scale trial to assess efficacy of intervention and writing up.

If successful, this novel intervention would address health needs around alcohol misuse in primary-care and acute

clinical and public health settings.


Milward, J., Drummond, C., Fincham-Campbell, S., & Deluca, P. (2018). What makes online substance-use

interventions engaging? A systematic review and narrative synthesis. Digital Health, 4.

https://doi.org/10.1177/2055207617743354

Marsden, J., Eastwood, B., Ali, R., Burkinshaw, P., Chohan, G., Copello, A., ... Day, E. (2014). Development

of the Addiction Dimensions for Assessment and Personalised Treatment (ADAPT). Drug and alcohol

dependence, 139, 121-131. https://doi.org/10.1016/j.drugalcdep.2014.03.018

21

16.2 What makes some people at risk of developing an Eating Disorder?

Co-Supervisor 1A: Sylvane Desrivières

School/Division & CAG: Social Genetic & Developmental Psychiatry


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/sylvane.desrivieres.html

Co-Supervisor 1B: Ulrike Schmidt

School/Division & CAG: Psychological Medicine and Integrated Care Clinical Academic Group


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/ulrike.schmidt.html


Eating disorders (EDs) are disabling psychiatric disorders, with a peak age of onset of 15–25 years. One in every six

or seven young women has an eating disorder that, if untreated, has lasting effects on brain, body, behaviour and life

expectancy. Furthermore, 30-40% of people with bulimia nervosa or binge eating disorder (i.e. the most common

EDs) are or will become obese, making them susceptible to obesity-related complications. Early intervention is key

in achieving full recovery. We have recently used the largest and most comprehensive longitudinal neuroimaging

genetics study in adolescents to date (the IMAGEN study; age 14 to 21) to identify early and differential

biomarkers of the vulnerability for eating disorders. These identified genetic predisposition, environmental factors

and neural mechanisms as differential predictors of disordered eating behaviours, which have significant clinical

implications for early and targeted ED prevention programs.

This project aims at refining our approach and validating the identified biomarkers in a clinical sample of current

and recovered anorexia nervosa and bulimia nervosa patients to identify biomarkers for risk, diagnosis and

prognosis. The student will:

• Year 1. (i) Familiarise themselves with the neurobiological basis of EDs (Prof. Schmidt’s area of expertise) and

the IMAGEN database (Dr. Desrivières, one of the IMAGEN PIs, will provide access and support); (ii)

conduct a systematic review (e.g. on environmental, genetic and neurobiological predictors of EDs/obesity);

(iii) be involved in recruitment or follow-up assessments of patients with a current or previous ED diagnosis

(anorexia nervosa or bulimia nervosa) and their controls and (age ~23; N = 50/group).

• Year 2. Use age 14 IMAGEN data to identify environmental, biological and psychological factors

characterizing the development of disordered eating behaviours in adolescence.

• Year 3. Validate findings in the clinical sample of emerging adults with a current or previous ED diagnosis.

Training for patients recruitment/assessment, neuroimaging and genomics data processing, and statistical analyses will

be provided.


Neural Correlates of Failed Inhibitory Control as an Early Marker of Disordered Eating in Adolescents. Bartholdy S,

O'Daly OG, Campbell IC, Banaschewski T, Barker G, Bokde ALW, Bromberg U, Büchel C, Quinlan EB, Desrivières

S, Flor H, Frouin V, Garavan H, Gowland P, Heinz A, Ittermann B, Martinot JL, Paillère Martinot ML, Nees F,

Orfanos DP, Poustka L, Hohmann S, Fröhner JH, Smolka MN, Walter H, Whelan R, Schumann G, Schmidt U;

IMAGEN Consortium. Biol Psychiatry. 2019 Jun 1;85(11):956-965.

Genetic predisposition and psychopathological mechanisms related to obesity, ADHD and neuroticism are differential

predictors for the development of disordered eating behaviors in adolescence. Robinson, L. 1*, Zhang, Z. 2*,Tianye

Jia2,3,4, Boubou, M. 2; Campbell, I.1, Irish, M. 1, Erin Burke Quinlan2, Nicole Tay, MSc2, Congying Chu2, Edward

D. Barker2,5, Tobias Banaschewski6, Gareth J. Barker7, Arun L.W. Bokde, PhD8, Herta Flor9,10, Antoine Grigis11,

Hugh Garavan12, Penny Gowland13, Andreas Heinz14, Bernd Ittermann, PhD15, Jean-Luc Martinot16, Argyris

Stringaris17, Jani Penttilâ18, Betteke van Noort19, Yvonne Grimmer6, Marie-Laure Paillère Martinot20, Corinna

Isensee21, Andreas Becker21, Frauke Nees6,9, Dimitri Papadopoulos Orfanos11, Tomáš Paus22, Luise Poustka21, Sarah

Hohmann,6, Juliane H. Fröhner23, Michael N. Smolka23, Henrik Walter14, Robert Whelan24, Gunter Schumann2,25,

Ulrike Schmidt1,26*, Sylvane Desrivières2*, and IMAGEN Consortium. (JAMA, submitted)

22

17.2 Stratification of people at risk of psychosis via frequent online assessments of

decision-making

Co-Supervisor 1A: Dr Kelly Diederen

School/Division & CAG: Department of Psychosis Studies, Institute of Psychiatry, Psychology and

Neuroscience


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/kelly.diederen.html

Co-Supervisor 1B: Dr Tom Spencer

School/Division & CAG: Department of Psychosis Studies, Institute of Psychiatry, Psychology and

Neuroscience, Psychosis Clinical Academic Group


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/tom.spencer.html


Scientific basis:

We aim to use longitudinal (8 times/2 years), large-scale (N=300), online testing in people at clinical high risk

(CHR) of psychosis to disentangle deficits in decision-making that are unique for the transition to specific

psychiatric illnesses and those that are shared across illnesses. Alterations in decision-making are central to

psychiatric illnesses and have been proposed to have greater prognostic validity than clinical assessments alone.

CHR individuals provide a distinctive opportunity to differentiate unique and shared prognostic markers of

psychiatric illness as they are at increased risk of both psychotic (schizophrenia, bipolar disorder) and affective

illnesses (depression, anxiety).

Techniques, skills and training:

The student will receive training on specific skills required to successfully carry out and complete the research

project, general academic training e.g., conference presentations, literature review and writing scientific

manuscripts and personal development goals and transferable skills. Training will be provided directly by the

supervisors, as well as through the attendance of organised courses (javascript, advanced statistical analyses

including (dynamic) structural equation modelling, R, Python, academic writing).Training will also be offered

in semi-structured interviews including the Comprehensive Assessment of At Risk Mental States by members

of the Psychosis Studies department.

Objectives:

Years 1-2:

- Recruit 300 CHR individuals and obtain baseline clinical and decision-making assessments.

- Relate baseline decision-making to baseline clinical functioning

Years 2-3:

- Carry out follow-up assessments

Identify which baseline decision-making markers, and changes in decision-making predict which CHR

individuals will (i) develop a psychotic illness or (ii) develop/retain a non-psychotic illness (depression/anxiety)


Kelly Diederen, Hisham Ziauddeen, Martin Vestergaard, Tom Spencer, Wolfram Schultz and Paul Fletcher.

Dopamine modulates adaptive prediction error coding in the human midbrain and striatum.

Journal of Neuroscience, 2017, 37 (7): 1708-1720.

Diederen KM, Spencer T, Vestergaard MD, Fletcher PC, Schultz W. Adaptive Prediction Error Coding in

the Human Midbrain and Striatum Facilitates Behavioral Adaptation and Learning Efficiency. Neuron, 2016,

90:1127-1138.

23

18.2 A structural bioinformatics approach to the study of how genetic variations can

cause neurodegeneration

Co-Supervisor 1A: Prof Richard Dobson

School/Division & CAG: Department of Biostatistics & Health Informatics (IoPPN)


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/richard.j.dobson.html

Co-Supervisor 1B: Prof Ammar Al-Chalabi

School/Division & CAG: Department of Basic and Clinical Neuroscience (IoPPN)


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/ammar.al-chalabi.html

Name of Collaborator: Dr Alfredo Iacoangeli

School/Division & CAG: Department of Biostatistics & Health Informatics (IoPPN)


Website: https://kclpure.kcl.ac.uk/portal/alfredo.iacoangeli.html


Neurodegenerative diseases, such as AD, FTD, ALS, ataxias or PD, are incurable and debilitating conditions

that result in progressive degeneration and death of nerve cells. Specific genetic variants may be causative, but

genomes carry millions of variants, most of which have no consequence on health. Being able to predict

whether a variant can cause neurodegeneration is a fundamental problem in neurodegenerative disease

research. Current computational methods have strong limitations in identifying risk variants, because most

mechanisms behind neurodegenerative diseases are unknown, and some variants result in a toxic gain-of-

function that is difficult to model.

The first year of this PhD will focus on training in bioinformatics methods based on statistics, physics and

machine learning, to study protein structural changes caused by variants. The second year will focus on the

modelling of the structural consequences that known neurodegenerative disease pathogenic variations cause

and identify shared patterns. Such information will be used in the third year to develop a disease-specific

classification method to interpret novel genetic variants as they are discovered in patients based on the

predicted protein structure and its predicted pathogenicity based on the computational modelling.

The project has strong translational potential, and the application of such methods to the genetic screening of

patients for diagnostic and prognostic purposes will be explored throughout the PhD. Bioinformatics, machine

learning and genetics training will be provided by the Health Informatics unit and the Basic and Clinical

Neuroscience group of the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) and our Industry

partner BenevolentAI.


Iacoangeli, Alfredo, Paolo Marcatili, and Anna Tramontano. "Exploiting homology information in nontemplate

based prediction of protein structures." Journal of chemical theory and computation 11.10 (2015): 5045-5051.

Al-Chalabi, Ammar, et al. "Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based

modelling study." The Lancet Neurology 13.11 (2014): 1108-1113

24

19.2 The role of interoceptive accuracy in physiological coordination and social

interactions in self-regulation disorders

Co-Supervisor 1A: Dr. Eleanor Dommett

School/Division & CAG: Psychology and System Science/IoPPN


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/eleanor.dommett.html

Co-Supervisor 1B: Dr. Alexandra Georgescu

School/Division & CAG: Psychology and System Science/IoPPN


KCL/KHP Website: https://orcid.org/0000-0003-1929-5673


Interoception is the perception of signals from within one’s own body, crucially contributing to self-regulatory

processes. The ability to perceive interoceptive signals is typically measured using accuracy (i.e. perceived and

actual heartbeat correspondence) and awareness (i.e. confidence and accuracy correspondence). Recent

research suggests that people synchronize their interoceptive signals and that this could be associated with

interpersonal behavioural synchrony and improved social interaction, although further investigation is needed.

Furthermore, there is no research on interoception and social interactions in clinical populations known to have

impairments in both social functioning and self-regulation. Such groups may benefit from interoceptive training.

The current project aims to:

1. Investigate the relationship between interoceptive accuracy and awareness with interpersonal

behavioural synchrony in the typical population (Rotation Projects/Year 1 PhD).

2. Establish the effectiveness of interoceptive intervention (heartbeat feedback procedure) in a typical

population (Year 2).

3. Investigate interoceptive ability in clinical populations with impaired social functioning and self-

regulation, specifically individuals with ADHD or Autism (Year 3).

4. Establish whether interoceptive interventions can improve interpersonal synchrony and social

functioning in these clinical populations and any associated impact on quality of life (Year 3/4).

Key methods/training:

• Information literacy training for literature review.

• Training given to measure interoceptive accuracy using heartbeat tracking and discrimination tasks in

relation to interpersonal synchrony which is measured by movement and physiology.

• Training in measurement of movement synchrony using objective and automated video analyses and linear

and nonlinear methods.

• Appropriate statistical training as needed throughout.


Kuschefski, M., Falter‐Wagner, C. M., Bente, G., Vogeley, K., & Georgescu, A. L. (2019). Inferring power and

dominance from dyadic nonverbal interactions in autism spectrum disorder. Autism Research, 12(3), 505-516.

Brace, L. R., Kraev, I., Rostron, C. L., Stewart, M. G., Overton, P. G., & Dommett, E. J. (2015). Altered visual

processing in a rodent model of Attention-Deficit Hyperactivity Disorder. Neuroscience, 303, 364-377.

25

20.2 Using artificial intelligence to facilitate early identification and treatment of

depressive symptoms in primary care Co-Supervisor 1A: Dr Alex Dregan

School/Division & CAG: Psychological Medicine/Academic Psychiatry


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/alexandru.dregan.html

Co-Supervisor 1B: Professor Matthew Hotopf

School/Division & CAG: Psychological Medicine/Academic Psychiatry


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/matthew.hotopf.html


Depression is a highly prevalent yet under-diagnosed chronic condition within primary care settings that can

lead to physical health problems, increased healthcare utilisation, and premature death. Patients often

experience symptoms for years before being correctly diagnosed and treated. Health IT technology, such as

electronic health records (EHR) and machine learning algorithms (MLA), have the potential to automatically

identify patients with undiagnosed depression and facilitate early interventions. The proposed project aims

evaluate the value of MLA in identifying patients with depression using primary care EHR data, document

whether learned classification models have superior predictive validity than traditional risk factors for

identification of undiagnosed depression in a prospective primary care cohort, and implement an EHR-based

screening tool to identify patients with undiagnosed depression and evaluate the diagnosis and treatment

effects. The proposed project will lead to a novel, EHR-based screening tool for identification of undiagnosed

depression that can reduce or delay depression-related morbidity and mortality through earlier and more

targeted management.

The proposed project will support the candidate to gain new skills and expand existing knowledge of deep

learning algorithms, and to evaluate the effects of an EHR-based screening tool to identify latent depression.

The supervisors have extensive knowledge of epidemiological and clinical EHR investigations, while the

Department runs several courses on MLA and EHR.

Objectives:

Year 1 - develop skills and knowledge about deep learning algorithms using EHR data;

Year 2 – design and implement and MLA algorithm in EHR to identify undiagnosed depression

Year 3 – evaluate the utility of an EHR-based screening tool to identify latent depression in primary care.


Dregan A. et al. Common mental disorders within chronic inflammatory disorders: A primary care database

prospective investigation. Annals of the Rheumatic Diseases, 2019: 78:688-695

Hotopf, M. Depression and anxiety symptom trajectory in coronary heart disease: Associations with measures

of disability and impact on 3-year health costs. J Psychosom Res, 2018;104:1-8.

26

21.2 The nature and natural history of overdoses, drug-related mortality, and

treatment-seeking in people attending hospitals for drug-related health conditions

Co-Supervisor 1A: Professor Colin Drummond

School/Division & CAG: Addictions CAG, SLAM/IOPPN BRC


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/colin.drummond.html

Co-Supervisor 1B: Professor Sir John Strang

School/Division & CAG: Addictions CAG, SLAM/IOPPN BRC


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/john.strang.html


The number of drug-related deaths is at an all-time high in England since this data was first collected. Illicit

opioids, such as heroin, account for a majority of overdose and deaths and are associated with considerable

morbidity and mortality across the lifespan. In England, a total of 2,208 drug poisoning deaths had an opioid

mentioned on the death certificate with a much higher number attending NHS hospitals for drug related harm

including acute drug overdose, abscesses and accidents while intoxicated. Little is known about the

characteristics of these people, their presenting health problems or their longer-term outcomes. This project will

access national data on patterns of health service utilization to identify a large cohort of people presenting at

NHS hospitals for drug-related problems. Linking across multiple years of HES data and to data on specialist

alcohol and drug treatment (NDTMS) and mortality (ONS) will improve understanding of longer-term

outcomes within this group and the relationship to deprivation. This project will involve ongoing training in

statistical analysis and would be ideally suited to a candidate with strong interests in quantitative methods.

Year One:

-Attend course on analysis of HES Data.

-Conduct systematic review on drug-related hospital admissions.

-Obtain permissions for access to HES data and for linkage to NDTMS and ONS data.

Year Two:

-Construct ten-year national data set of drug-related admissions among NHS hospital attenders.

-Write paper identifying sociodemographic characteristics and morbidity among this group.

-Construct in silico 10-year cohort of people initially admitted to hospital for a drug- related condition.

Year Three:

-Write paper identifying 10-year patterns of health care utilization over a 10-year period.

-Conduct analyses describing specialist drug treatment utilisation and mortality over 10 years.

-Finalise and submit Thesis based on papers described above.


Donoghue K., et al. (2017) Alcohol consumption, early-onset drinking, and health-related consequences in

adolescents presenting at emergency departments in England. Journal of Adolescent Health 60: 438-446.

Kimber J, Hickman M, Strang J, Thomas K, Hutchinson S. (2019) Rising opioid-related deaths in England and

Scotland must be recognised as a public health crisis. Lancet Psychiatry, 6(8):639-640. doi: 10.1016/S2215-

0366(19)30209-3. Epub 2019 Jun 11.

27

22.2 The effect of Social Media on children and Adolescents: A Randomised

controlled Trial (eSMART).

Co-Supervisor 1A: Rina Dutta

School/Division & CAG: IoPPN, Psychological Medicine


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/rina.dutta.html

Co-Supervisor 1B: Dennis Ougrin

School/Division & CAG: IoPPN, Child and Adolescent Psychiatry


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/dennis.ougrin.html


The project is based on a randomised controlled trial (RCT) aimed to assess the impact of social media exposure

on young people’s physical and mental health. Specifically, this study will focus on the effect of social media

use on symptoms of emotional disorders, self-harm, weight, educational outcomes, social relationships and

sleep. 216 young people (5-15) at the point of their parents considering purchasing their first smartphone will

be randomly allocated to receiving either a smartphone with full functionality or a similar smartphone with

functionality limited to only text messages and phone calls. All other devices that young people have access to

will have blocked access to social media. Young people will be compared on a range of outcomes of mental

health, educational achievement and physical health. The PhD student will have the following objectives:

1. Year 1 – 4 – learn to conduct RCTs

2. Year 1 – learn to undertake and publish systematic reviews; in collaboration with industry

partners, devise a new tool aimed at measuring self-harm in young people in real time

3. Year 2 – in collaboration with industry partners, improve available devices for monitoring

physiological and physical health measures

4. Year 3 – in collaboration with industry partners, improve tools used to analyse physiological

and physical data

5. Year 4 learn the skills necessary to disseminate findings

The PhD student will have training in diagnosing mental health disorders, in conducting RCTs and developing

and testing health monitoring devices. The training will be delivered by both supervisors and industry partners.


Risk Assessment Tools and Data-driven Approaches for Predicting and Preventing Suicidal Behaviour. /

Velupillai, Sumithra; Hadlaczky, Gergö; Baca-Garcia, Enrique; Gorrell, Genevieve; Werbeloff, Nomi;

Nguyen, Dong; Patel, Rashmi; Leightley, Daniel; Downs, Johnny; Hotopf, Matthew; Dutta, Rina.

Frontiers in psychiatry / Frontiers Research Foundation, Vol. 10, No. FEB, 36, 13.02.2019, p. 36.

Randomised controlled trial of therapeutic assessment versus usual assessment in adolescents with self-harm: 2-

year follow-up

Ougrin, D., Boege, I., Stahl, D., Banarsee, R. & Taylor, E., Oct 2013, In : Archives of Disease in Childhood.

98, 10, p. 772-776

28

23.2 Discovering disease modifying therapies for Parkinson’s disease using a drug

repurposing approach.

Co-Supervisor 1A: Dr Susan Duty

School/Division or CAG: Wolfson CARD; Division of Neuroscience


KCL/KHP Website: http://www.kcl.ac.uk/ioppn/depts/wolfson/research/Duty-Lab/Duty-Lab.aspx

Co-Supervisor 1B: Dr Gareth Williams

Research School/Division or CAG: Wolfson CARD; Division of Neuroscience


KCL/KHP Website: https://www.kcl.ac.uk/ioppn/depts/wolfson/research/Williams/Index.aspx


Scientific Basis:

Parkinson’s disease is a neurodegenerative condition best known for its movement-related symptoms. Given

current treatments do not tackle the cause of the progressive symptoms, there is urgent need for better drug

treatments. Drug repurposing is an exciting drug discovery strategy that interrogates drugs already shown to be

safe in man or efficacious in one disease, for potential for use in another. By combining bioinformatics with cell

and whole animal studies, we recently used targeted repurposing to identify drugs (e.g. the anti-asthmatic,

salbutamol) to preserve dopaminergic neurones in Parkinson’s by boosting transcription of FGF-20, a protein

we discovered had protective properties. This project will adopt similar strategies to identify FDA-approved

drugs that boost production of other proteins of therapeutic interest (e.g. Neurturin; protective when infused into

patients’ brains) or suppress transcription of genes that are upregulated or risk-associated in Parkinson’s (e.g.

alpha-synuclein).

Yearly Objectives:

• Year 1: To use bioinformatics to identify drugs that boost Neurturin or suppress alpha-synuclein production

then confirm production/suppression in cell systems and brains of treated mice.

• Year 2: To investigate the therapeutic potential of Neurturin-boosting or alpha-synuclein supressing drugs in

animal models of Parkinson’s (e.g. 6-OHDA mouse)

• Year 3-3.5: To identify novel transcriptional targets for early intervention and apply bioinformatics to select

promising FDA-approved drugs to test for correction of identified early pathological changes.

Skills training:

bioinformatics; cell culture; microarray techniques; ELISA; rodent models of Parkinson’s disease; behavioural

assessments; immunohistochemistry.


Fletcher EJR, Jamieson AD, Williams G, Doherty P, Duty S (2019). Targeted repositioning identifies drugs

that increase fibroblast growth factor 20 production and protect against 6-hydroxydopamine-induced nigral

cell loss in rats. Scientific Reports. 9(1):8336

Williams G. (2012). A searchable cross-platform gene expression database reveals connections between drug

treatments and disease. BMC Genomics 13(1): 12.

29

24.2 Anxiety, somatic symptoms, and service use: Using genetics to understand links

between emotional and physical health

Co-Supervisor 1A: Prof Thalia Eley

School/Division & CAG: IoPPN, PaSS


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/thalia.eley.html

Co-Supervisor 1B: Prof Frühling Rijsdijk

School/Division & CAG: IoPPN, PaSS


KCL/KHP Website: https://www.kcl.ac.uk/people/fruhling-rijsdijk


Individuals with anxiety disorders sometimes present with high levels of physiological symptoms such as chronic

pain (e.g. abdominal or chest pain). These can not only mask the true condition and delay diagnosis, but may

also reflect different underlying causes and influence treatment outcomes. In this project, the student will use

longitudinal data from the British Twins Early Development Study (TEDS), and the Swedish Child and

Adolescent Twin Study in Sweden (CATSS) to identify and replicate trajectories of anxiety symptoms with

high and low levels of physical/somatic symptoms. Genetic influences on each will be compared. The student

will also be able to explore associations between these trajectories and medical health service use. The student

will also have access to similar data in the Genetic Links to Anxiety and Depression (GLAD) with which to

replicate findings and to extend to exploring the role of somatic/physical health symptoms in understanding

response to treatment in anxiety disorders.

The student will learn to undertake trajectory analyses using repeated measures latent class analysis. They will

also learn how to undertake structural equation model-fitting with twin data and to use genome-wide polygenic

risk scores. If keen to, they can also undertake genome-wide association analyses, but this is not the primary

analytical focus.

Year 1. Build trajectories of anxiety with high versus low levels of physical/somatic health concerns in TEDS.

Replicate in CATS.

Year 2. Undertake twin analyses of the different profiles and identify the extent to which polygenic scores from

the literature are differentially associated with these.

Year 3. Explore health service utilisation and how this varies across the two trajectory groups. Undertake twin

analyses of the associations between anxiety trajectories and service use.

Year 4. Use the GLAD sample to replicate groupings and identified and examine associations not only with

service use but with treatment seeking and outcome.


Rayner, C., Coleman, J. R. I., Purves, K. L., Hodsoll, J., Goldsmith, K., … Breen, G., Eley, T. C. (2019). A

genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in

individuals with anxiety and depressive disorders. Translational Psychiatry, 9(1), 150.

https://doi.org/10.1038/s41398-019-0481-y

Hannigan, L. J., Pingault, J.-B., Krapohl, E., McAdams, T. A., Rijsdijk, F. V., & Eley, T. C. (2018). Genetics

of co-developing conduct and emotional problems during childhood and adolescence. Nature Human

Behaviour, 2(7), 514–521. doi:10.1038/s41562-018-0373-9

30

25.2 Neuroinflammation and neuron-glia signalling through extracellular vesicles

excreted during neuronal cell death in neurodegeneration.

Co-Supervisor 1A: Manolis Fanto

School/Division & CAG: IoPPN/BCN & Neuroscience


KCL/KHP Website: https://www.kcl.ac.uk/ioppn/depts/bcn/Our-research/Neurodegeneration/Fanto-

Molecular-Mechanisms-of-Neurodegeneration/Fanto-Lab-Landing-page.aspx

Co-Supervisor 1B: Marzia Malcangio

School/Division & CAG: IoPPN/Wolfson CARD & Neuroscience


KCL/KHP Website: https://www.kcl.ac.uk/ioppn/depts/wolfson/research/malcangiolab/index


During neurodegeneration, dying neuronal cells may trigger neuroinflammatory responses or inform

neighbouring glial cells of their dying status by releasing extracellular vesicles. One of our teams has

characterised a novel form of neuronal cell death, karyoptosis, which is found in polyglutamine diseases and in

C9Orf72-based ALS/FTD, and in which the cell nucleus is degraded via association of LaminB1 with the

autophagy machinery. This is followed by the expulsion of large extracellular vesicles containing LaminB1 and

aggregated nuclear proteins.

We have preliminary data that these large microvesicles can be taken up by neighbouring cells in vitro. This

function is most likely performed by microglial cells in vivo may lead to degradation of proteinaceous aggregates

as well as trigger a neuroinflammatory response to karyoptotic cell death in the surrounds.

By using neuronal cells, either from differentiated neuroblastoma or derived from patient’s iPSC, this project

will aim

1) To characterise by proteomics the content of the vesicles excreted under karyoptotic conditions

(induced by treatment with BafylomycinA1)

2) To monitor uptake of vesicles and neuroinflammatory signalling in microglial cultures exposed to

purified karyoptotic vesicles

3) To measure degree and rate of degradation of nuclear protein aggregates transferred in vesicles from

the karyoptotic neurons to the microglial cells.

This project will merge the expertise of our two laboratories to gain fundamental cell biological insight into the

process of neuronal cell death and neuroinflammation, highly relevant to human neurodegenerative disease and

potentially other forms of injury-based neuropathology.

Year 1. Completion of Aim 1. Start culturing microglia.

Year 2. Imaging and optimization of uptake of vesicles in mircoglia (Months 13-18). Analysis of inflammatory

signalling in microglial cultures (Months 18 -24).

Year 3. Analysis of inflammatory signalling in microglial cultures (continuation) and analysis of degradation and

turnover of components identified in Aim 1 (Months 25 - 32). Thesis write up and submission (Months 36-36).


O.Baron, A.Boudi, C.Dias, M.Schilling, A.Nölle, G.Viczcay-Barrena, I.Rattray, H.Jungbluth, W.Scheper,

R.Fleck, G.P.Bates and M.Fanto (2017). Stall in canonical autophagy-lysosome pathways prompts

nucleophagy-based nuclear breakdown in neurodegeneration. Curr. Biol. 27;3626-3642.

Simeoli R, Montague K, Jones HR, Castaldi L, Chambers D, Kelleher JH, Vacca V, Pitcher T, Grist J, Al-

Ahdal H, Wong LF, Perretti M, Lai J, Mouritzen P, Heppenstall P, Malcangio M. Exosomal cargo including

microRNA regulates sensory neuron to macrophage communication after nerve trauma. Nat Commun.

8:1778, 2017

31

26.2 Electrophysiological assessment of synaptic potentiation in human visual

cortex as a biomarker for prodromal dementia.

Co-Supervisor 1A: Dr Dominic Ffytche

School/Division & CAG: IoPPN


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/dominic.ffytche.html

Co-Supervisor 1B: Dr Samuel Cooke



KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/samuel.cooke.html


Background: Synapses, the chemical junctions between brain cells, provide the route of information transfer in

the brain. They can change in strength to store memory and dysfunction of this process is thought to be the

earliest dysfunction in neurodegenerative disease. Studies of synaptic neurophysiology rely on pre-clinical

animal models as there is currently an absence of methods to explore synaptic-level alterations within specific

cortical circuits non-invasively in humans. However, recent reports of long-term potentiation (LTP)-like

enhancement of sensory evoked potentials after simple stimulation in human subjects offer promise of a

translational bridge between pre-clinical and clinical studies.

Novelty and Importance: The project would be the first to explore the detailed cortical circuitry of LTP non-

invasively in man and apply the findings to clinical populations with prodromal dementia. The importance of the

project would be in providing a new clinical measure of synaptic change at the earliest stage of dementia that

could be used to detect neurodegenerative disease before the onset of measurable symptoms and as a target for

drug trials of new dementia treatments.

Primary aim(s): To develop a clinical assay of synaptic function for use in neurodegenerative disease

Planned research methods and training provided: The project will develop novel measures of LTP in specific

visual circuits using electroencephalography (EEG) and event-related potentials (ERPs). The measures will be

based on responses to standard visual stimuli presented before and after brief periods of tetanic (high frequency)

visual stimulation. The basic methodology has already been used in the ffytche lab (see fig 1) but will be adapted

in the studentship based on pre-clinical work in the Cooke lab using monocular and binocular stimulation at

different visual field locations to investigate specific cortical circuits. The assay will be developed and tested in

patients with prodromal Alzheimer’s disease, dementia with Lewy bodies and age matched controls.

Project skills: Training will be provided in EEG acquisition and analysis, synaptic neurophysiology and clinical

assessments.

Objectives / project plan:

Year 1: Develop the synaptic plasticity assay and adapt it for clinical populations in collaboration with patients.

Explore links between visual synaptic function and measures of cognitive and higher visual function.

Year 2: Cross-sectional study of prodromal dementia cohorts and age-matched controls.

Year 3: Follow-up of participants to examine progression of synaptic and cognitive changes.


Cooke SF, Komorowski RW, Kaplan ES, Gavornik JP and Bear MF (2015) Visual Recognition Memory,

Manifested as Long-term Habituation, Requires Synaptic Plasticity in V1. Nature Neuroscience 18: 262-271.

Morrison PD, Nottage J, Stone JM, Bhattacharyya S, Tunstall N, Brenneisen R, Holt D, Wilson D, Sumich A,

McGuire P, Murray RM, Kapur S and Ffytche DH. (2011) Disruption of frontal theta coherence by Δ9-

tetrahydrocannabinol is associated with positive psychotic symptoms.

Neuropsychopharmacology 36: 827-836

32

27.2 Mechanisms of cannabis-based medicines in treating tumour-associated seizures

Co-Supervisor 1A: Gerald Finnerty

School/Division & CAG: Neurosciences


KCL/KHP Website:https://www.kcl.ac.uk/ioppn/depts/bcn/our-research/neurology/finnerty-cortical-

plasticity.aspx / https://geraldfinnerty.wixsite.com/finnertylab

Co-Supervisor 1B: Anthony Vernon

School/Division & CAG: Neurosciences


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/anthony.vernon.html


People with brain tumours have seizures that respond very poorly to anticonvulsants. New treatments are badly

needed. Cannabis-based treatments could fill the therapeutic gap, but remain controversial. A key issue for

cannabis-based treatments of seizures is that we don’t know how they work.

The student will investigate the anti-seizure mechanisms of two of the most abundant cannabis extracts, Δ9-

tetrahydrocannabidiol (THC) and Cannabidiol using ex vivo living human brain tissue. The tissue is donated by

people who are having brain tumour surgery. The live human brain tissue generates spontaneous seizure-like

discharges.

Year 1: Local field potential recordings to identify spontaneous epileptic discharges in peritumoural cortex. Wash

on Cannabidiol and THC separately and together to determine dose-response curves for their effects on seizure

discharges.

Year 2: Investigate the mechanisms of the anticonvulsant effects of Cannabidiol and THC, focusing on

excitatory circuitry. The student will use patch-clamp recording of visualised pyramidal neurons to study: i)

changes in neuronal excitability and excitatory neural circuitry; ii) whether Cannabidiol and THC block the

proconvulsant effects of glutamate release by glioma cells.

Year 3: Inhibition in the peritumoural cortex is reduced. The loss of inhibition contributes to tumour-associated

seizures. The student will assess whether Cannabidiol and THC boost inhibition to suppress seizure discharges.

Recorded neurons will be filled with a fluorescent dye and biocytin for imaging after recording has finished. The

extent of tumour infiltration in recorded human brain tissue will be assessed by labelling the tumour cells and the

excitatory and inhibitory neurons.


Albieri G, Barnes SJ, Alonso B, Cheetham CE, Edwards CE, Lowe AS, Karunaratne H, Dear JP, Lee KC,

Finnerty GT (2015) Rapid bidirectional reorganization of cortical microcircuits. Cereb Cortex 25:3025-3035

Borgan F, Beck K, Butler E, McCutcheon R, Veronese M, Vernon A, Howes OD (2019). The effects of

cannabinoid 1 receptor compounds on memory: a meta analysis and systematic review across species.

Psychopharmacology (Berl). 2019 doi: 10.1007/s00213-019-05283-3

33

28.2 Preventing cancer chemotherapy-induced neuropathy

Co-Supervisor 1A: Dr Sarah Flatters

School/Division & CAG: IoPPN / Wolfson CARD


KCL/KHP Website: www.kcl.ac.uk/flatterslab

Co-Supervisor 1B: Dr Angela Swampillai

School/Division & CAG: Guy’s Cancer Centre


Name of Collaborating Clinician: Nicola Peat - Clinical Specialist Physiotherapist

School/Division & CAG: Therapies Directorate, Physiotherapy



Chemotherapy-induced neuropathy (CIN) is a serious side effect of first-line chemotherapeutics for breast

cancer and glioma. There is no treatment to prevent/treat CIN, therefore CIN development often curtails cancer

treatment. CIN markedly affects patients’ quality of life due to persistent painful, neurological symptoms

following chemotherapy. Prevention would become possible with a biomarker to identify patients susceptible to

CIN accompanied with novel treatments. Additionally, knowledge of CIN incidence in different patient

populations would provide clinicians with vital information to determine personalised treatment strategies.

Research led by Dr Flatters has established mitochondrial dysfunction as causal factor in CIN rat models. Recent

data indicates mitochondrial changes in blood prior to CIN – which is being translated to patient samples as part

of SUSPECT (SUSceptibility to Pain Evoked by ChemoTherapy) study. Clinical data suggests skin

mitochondrial changes associated with development of other neuropathies, which will be explored using CIN

rat skin. This translational, interdisciplinary project has a bench-to-bedside and back approach to determine

CIN susceptibility and evaluate possible treatments underpinned by scientist-clinician-physio collaboration at

Guy’s.

Year 1/MRes: Retrospective CIN incidence audit on Guy’s breast/glioma patients. Mitochondrial assays in

CIN rat blood. Year 2: Database creation; neuropathy data collation from SUSPECT questionnaires.

Mitochondrial assessment in patient blood samples and CIN rat skin samples. Year 3/4: Evaluate preventative

therapeutic strategies in preclinical and clinical settings.

Training: Diverse range of experimental techniques, clinical audit procedures, patient database creation, data

analysis, experimental design, project organisation. Seminars at Wolfson CARD and Guy’s Cancer Centre.


Trecarichi A, Flatters SJL (2019) Mitochondrial dysfunction in the pathogenesis of chemotherapy-induced

peripheral neuropathy. International Review of Neurobiology Vol 145: 83-126

Morris KA, Golding JF, Blesing C, Evans DG, Ferner RE, Foweraker K, Halliday D, Jena R, McBain C,

McCabe MG, Swampillai A, Warner N, Wilson S, Parry A, Afridi SK. Toxicity profile of bevacizumab in the

UK Neurofibromatosis type 2 cohort. J Neurooncology 2017;131(1):117-124

34

29.2 Living Evidence on First-EpiSode of psychosis Treatments and Outcomes

(EFESTO): a living individual participant data network meta-analysis and learning

healthcare system.

Co-Supervisor 1A: Paolo Fusar-Poli

School/Division & CAG: Psychosis Studies


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/en/persons/paolo-fusarpoli(ced1ec59-cb83-4efe-b9f6-

5c41302558a7).html

Co-Supervisor 1B: Philip McGuire

School/Division & CAG: Psychosis Studies


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/philip.mcguire.html


Antipsychotic treatment at the time of a first episode of psychosis is the mainstream intervention recommended

by clinical guidelines (NICE, BAP, EPA, WPA, APA, Maudsley). Nonetheless, clinical guidelines are

infrequently updated, not readily accessible to real-world clinical practice and not personalised on the basis of

individual patterns of response and outcomes. This PhD will focus on the development of the first (i)

personalised treatment guidelines for first-episode psychosis, (ii) living updating of treatment guidelines, (iii)

implementation of living and personalised clinical guidelines in the local Electronic Healthcare Record (HER).

During Y1 the candidate will learn how to conduct living Individual Participant Data (IPD) network meta-

analyses. During Y2 the candidate will learn how to collect, clean and analyse living IPD databases. During Y3

the candidate will complete the analyses and learn how to implement living evidence-based clinical guidelines

in a learning healthcare system (LHS). During Y4 the candidate will integrate the living recommendations in

the local HER, as part of an ongoing study (Brain and Biomarker Check study), to impact clinical practice.

The candidate will have the opportunity to train on advanced evidence-synthesis, psychopharmacology, big

data, machine-learning, clinical prediction modelling, e-Health in one of the largest and most productive

research groups on early psychosis. The candidate will additionally have the opportunity to access

international networks of early psychosis research and high-quality teaching and clinical services. This PhD

will deliver the first-ever living, personalised, evidence-based recommendations for first episode of psychosis

embedded in a digital LHS, with extraordinary, real-world, global translational impact.


Lack of evidence to favor specific preventive interventions in psychosis: a network meta-analysis.

Davies C, Cipriani A, Ioannidis JPA, Radua J, Stahl D, Provenzani U, McGuire P, Fusar-Poli P. World

Psychiatry (IF=34). 2018 Jun;17(2):196-209. doi: 10.1002/wps.20526. PMID: 29856551

What causes psychosis? An umbrella review of risk and protective factors.

Radua J, Ramella-Cravaro V, Ioannidis JPA, Reichenberg A, Phiphopthatsanee N, Amir T, Yenn Thoo H,

Oliver D, Davies C, Morgan C, McGuire P, Murray RM, Fusar-Poli P.

World Psychiatry (IF=34). 2018 Feb;17(1):49-66. doi: 10.1002/wps.20490. PMID: 29352556

35

30.2 Precision medicine and mechanism: How and for whom do psychological

treatments work?

Co-Supervisor 1A: Kimberley Goldsmith

School/Division & CAG: Institute of Psychiatry, Psychology & Neuroscience/Division of Psychology and

Systems Sciences


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/kimberley.goldsmith.html

Co-Supervisor 1B: Rona Moss-Morris

School/Division & CAG: Institute of Psychiatry, Psychology & Neuroscience/Division of Psychology


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/rona.moss-morris.html

Name of Collaborating Clinician: Hazel Everitt

School/Division & CAG: Medicine, University of Southampton


Website: https://www.southampton.ac.uk/medicine/about/staff/hae1.page


Understanding how treatments work (mechanisms) and for whom (in which subgroups) is key.

Mediation and moderation analysis can answer such questions. Many mediation and outcome processes are

longitudinal in nature, and can be modelled using the structural equation modelling framework (SEM, Goldsmith

et al, 2018 doi: 10.1037/met0000154). There is strong clinical interest in modelling overarching mediation and

moderation processes, however these aspects are often studied separately and non-longitudinally. We will

extend longitudinal mediation models to incorporate moderation transdiagnostically, using data from large trials

of cognitive behavioural therapies such as the ACTIB trial for irritable bowel syndrome (Everitt et al. 2019;

10.1136/gutjnl-2018-317805). This will include methods refinement and development for latent class

moderating variable extensions, where individuals can be categorized according to clinically informative

symptom groupings.

This cross-disciplinary project (psychology, statistics, medicine) will contribute to methodological and

clinical understanding of precision medicine and mechanisms relating to transdiagnostic cognitive behavioural

treatments. There are future back-translational precision medicine implications for the application of such

treatments, whereby the biological bases of important moderating factors of treatment mechanisms could be

sought.

Skills training will include: translation of clinical questions into models/methods, R and Mplus software

packages (or equivalent), and statistical simulation methods, as well as transferrable presentation, dissemination

and collegial skills.

Years:

1. literature review, longitudinal mediator modelling of processes using the SEM framework.

2. incorporation of observed moderators, and methods for incorporating latent moderators, into mediation

models

3. simulation studies of model statistical properties and write-up of thesis.


Goldsmith KA, Chalder TC, White PD, Sharpe M, Pickles A. Tutorial: Simplex, latent growth and latent

change structural equation models for longitudinal mediation in the PACE trial of treatments for chronic fatigue

syndrome. Psychological Methods, 2018, 23(2):191-207. doi: 10.1037/met0000154.

Sibelli A, Chalder T, Everitt H, Chilcot J, Moss-Morris R. Positive and negative affect mediate the bidirectional

relationship between emotional processing and symptom severity and impact in Irritable Bowel Syndrome.

Journal of Psychosomatic Research, 2018 105: 1-13. 10.1016/j.psychores.2017.11.016.

36

31.2 Adult neurogenesis in the olfactory bulb: unlocking the secrets of newborn

neuron function

Co-Supervisor 1A: Matthew Grubb

School/Division & CAG: Centre for Developmental Neurobiology / IoPPN



Co-Supervisor 1B: Laura Andreae

School/Division & CAG: Centre for Developmental Neurobiology / IoPPN




Naturally-occurring regeneration is rare in the adult mammalian brain, where most circuits operate for lifetimes

with the same neurons that were present at birth. An exception is the olfactory bulb, whose neurons can be born

throughout adulthood. Understanding how these adult-born neurons function and integrate into existing circuits

could be critical to developing regenerative therapies for neurological disorders.

Adult-born olfactory bulb neurons include a subpopulation that release dopamine. These cells also completely

lack an axon, so must receive and send synaptic information exclusively from their dendrites. But are their

dendritic release sites just like those normally found at axon terminals, or are they molecularly specialised? And

how do these processes change as newborn neurons mature and integrate into their host circuits? We will use

genetic, imaging and electrophysiological approaches to answer these questions in a truly collaborative project.

Techniques include coupling conditional transgenic mouse lines with viral expression targeted to newborn

neurons, to selectively label these cells and delete key synaptic proteins. Immunological labelling of neurons,

including optical clearing and lightsheet microscopy, will characterise the morphology and molecular signature

of these neurons and their synapses. Finally, patch clamp electrophysiology and/or functional imaging will be

used to understand how the synapses function.

Year 1: Establish transgenic colonies, target cells with viral injections, imaging of neurons and synaptic labelling

Year 2: Examine impact of deleting synaptic proteins on development of newborn neuron synapses

Year 3: Functional characterisation using electrophysiology and imaging.


Galliano E, Franzoni E, Breton M, Chand AN, Byrne DJ, Murthy VN, Grubb MS (2018) Embryonic and

postnatal neurogenesis produce functionally distinct subclasses of dopaminergic neuron. eLife, 7:e32373.

https://doi.org/10.7554/eLife.32373

Andreae LC* and Burrone J. Spontaneous neurotransmitter release shapes dendritic arbors via long-range

activation of NMDA receptors. Cell Reports, 2015; 10(6):873-82

37

32.2 Investigating the role of TRP channels in the pathogenesis of multiple sclerosis

Co-Supervisor 1A: Dr Nicola Hamilton-Whitaker

School/Division & CAG: Wolfson CARD


KCL/KHP Website: https://www.kcl.ac.uk/ioppn/depts/wolfson/research/hamilton-lab/index.aspx

Co-Supervisor 1B: Prof Elizabeth Bradbury

School/Division & CAG: Wolfson Centre for Age-Related Diseases, IoPPN


KCL/KHP Website: www.kcl.ac.uk/bradburylab

Twitter: https://twitter.com/BradburyLab


Oligodendrocytes allow neurons to rapidly transmit information in the brain and spinal cord by wrapping myelin

sheaths around axons. The importance of oligodendrocytes is highlighted by the symptoms that result from

myelin loss occurring in Multiple Sclerosis (MS), a demyelinating disorder that causes disability in young adults.

During this PhD, the student will become trained in a range of cutting-edge skills used to investigate the

mechanisms involved in demyelinating disease processes. After obtaining a licence, the student will generate

mice that have clinically relevant demyelination similar to that found in humans with MS. They will then learn

to perform behavioural tests (e.g. rotorod tests), electron microscopy, patch-clamping, western blotting, and

immunohistochemistry to study these mice. Specifically, the PhD student will study how newly described TRP

channels are involved in oligodendrogenesis and oligodendrocyte pathology by:

Year 1 Validating mice that have TRPA1 genetically removed only in oligodendrocytes using the methods

mentioned above and comparing these mice to global TRPA1 knockouts.

Year 2 Determining whether TRPA1 cKOs have less demyelination in the cuprizone model.

Year 3 Determining whether TRPA1 cKOs have impaired remyelination in the cuprizone model.

Depending on the progress, the student will also have the opportunity to compare these results with conditional

astrocyte TRPA1 KO mice.

The Hamilton and Bradbury labs have a great track record in generating high impact results and publications,

and in training PhD students and would provide the support and platform needed to obtain the PhD.


Hamilton NB, Kolodziejczyk K, Kougioumtzidou E, Attwell D. 2016. Proton-gated Ca2+-permeable TRP

channels damage myelin in conditions mimicking ischaemia. Nature 529:523–527.

Bartus, K, Galiano J, James ND, Hernandez-Miranda LR, Dawes JM, Fricker FR, Garratt AN, McMahon SB,

Ramer MS, Birchmeier C, Bennett DL, Bradbury EJ (2016) Neuregulin-1 controls an endogenous repair

mechanism after spinal cord injury. Brain 139: 1394-1416

38

33.2 Role of autism-linked gene mutations in aggression

Co-Supervisor 1A: Prof. Robert Hindges

School/Division & CAG: IoPPN/ Centre for Dev. Neurobiology & MRC Centre for Neurodev. Disorders


KCL/KHP Website: http://tinyurl.com/jgdkxx3

Co-Supervisor 1B: Dr Marija Petrinovic

School/Division & CAG: IoPPN, Department of Forensic and Neurodevelopmental Sciences


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/marija-magdalena.petrinovic.html


Autism spectrum disorder (ASD) is a neurodevelopmental condition characterised by impairments in social

reciprocity/communication and restricted interest/repetitive behaviours. It is often exacerbated with other

conditions, including aggression (affects 2 out of 3 ASD individuals). Currently, no effective treatments for ASD

exist.

There is a very strong genetic component underlying ASD development and recent studies have identified

several risk genes playing a central role in its aetiology. However, it is unclear how individual risk gene

mutations contribute to the different phenotypes in ASD.

This project will assess the consequences of mutations with strong linkage to ASD for the structural and

functional development of neural circuits. In addition, behavioural tests will investigate the possible link

between these gene mutations and aggression. Over the course of the project, we will use previously generated

zebrafish mutants (for example Neurexin-1α knockout) and generate new mutant lines using CRISPR genome

editing to introduce single or multiple mutations in target genes. We then will structurally and functionally assess

the formation of circuits using confocal/light-sheet microscopy, combined with behavioural tests for social

interaction and aggression. Finally, we will test the effect of different drug compounds on these phenotypes.

Skills Training: zebrafish model system, CRISPR/Cas9 genome editing, confocal/light-sheet imaging,

behavioural tests.

Project objectives

Rotation/Year 1: Establishing zebrafish behavioural test for social interaction/aggression and assess existing

Neurexin-1α mutants. Generation of CRISPR mutants for high-risk genes.

Year 2: Structural and functional assessment of circuits in mutant lines.

Year 3: Behavioural assessment of mutants (social interaction/aggression). Pharmacological intervention with

subsequent structural/behavioural evaluation.


Antinucci, P., Suleyman, O., Monfries, C. & Hindges, R. (2016). Neural Mechanisms Generating Orientation

Selectivity in the Retina. Current Biology 26: 1802-1815.

Horder J*, Petrinovic MM*, Mendez MA, Bruns A, Takumi T, Spooren W, Barker GJ, Künnecke B, Murphy

DG. (2018). Glutamate and GABA in autism spectrum disorder-a translational magnetic resonance spectroscopy

study in man and rodent models. Translational Psychiatry 8:106.

39

34.2 Targeting alpha-synuclein mediated synaptopathy

Co-Supervisor 1A: Dr. Frank Hirth

School/Division & CAG: IoPPN/Neuroscience – Clinical Neuroscience


KCL/KHP Website: https://www.kcl.ac.uk/ioppn/depts/bcn/our-research/neurodegeneration/frank-hirth-

neural-circuits/index

Co-Supervisor 1B: Dr. Richard B. Parsons

School/Division & CAG: IPS – Pharmaceutical Science


KCL/KHP Website: https://www.kcl.ac.uk/people/richard-parsons

Name of Collaborating Clinician: Prof. Dag Aarsland

School/Division & CAG: IoPPN/Old Age Psychiatry – Mental Health of Older Adults and Dementia


Website: https://kclpure.kcl.ac.uk/portal/dag.aarsland.html


Key Hypotheses and major aims: 1) -synuclein ( -syn) accumulation in aberrant form and location causes

synaptic dysfunction and subsequent neurodegeneration in synucleinopathies including Parkinson’s Disease

(PD). 2) ROCK-inhibition reverses -synuclein accumulation and is synaptoprotective.

Background: Mounting pre-clinical and clinical evidence suggests that -syn accumulation causes synaptic

dysfunction and subsequent neurodegeneration that characterise clinical symptoms and progression of disease

(e.g. Bridi & Hirth 2018). Current treatments offer only short-term amelioration but do not arrest

neurodegeneration due to impaired synaptic activity and resultant cell loss. The Rock inhibitor fasudil is able to

clear -syn aggregation in vitro, promotes synapse formation and plasticity, and attenuates neurodegeneration in

animal models overexpressing human mutant -syn. However, the underlying mechanisms are not known, nor

how long fasudil can protect against -syn mediated synaptopathy.

Project and methodology: We have established Drosophila and human cell culture models of -syn accumulation

which resemble the cytological and behavioural phenotypes that characterise the onset and progression of PD.

In years 1 and 2, molecular genetics and cell culture techniques, in combination with biochemistry,

superresolution microscopy and behavioural analysis will be used to elucidate the underlying mechanisms and

determine in which way and for how long fasudil can protect against -syn mediated synaptopathy. In years 3

and 4, the resultant findings will be validated in human patient derived tissue (in collaboration with Prof. Dag

Aarsland and Dr. Richard Killick).


Bridi JC, Hirth F (2018) Mechanisms of α-Synuclein Induced Synaptopathy in Parkinson's Disease. Front

Neurosci.12:80. doi: 10.3389/fnins.2018.00080.

Schonhofen P et al. (2018) Cannabinoid-based therapies and brain development: potential harmful effects of

early modulation of the endocannabinoid system. CNS Drugs 32: 697-712 doi:

https://doi.org/10.1007/s40263-018-0550-4

https://www.kcl.ac.uk/people/richard-parsons

40

35.2 The impact of tobacco control and vaping policies on smoking in people with

mental health and substance use problems

Co-Supervisor 1A: Dr Sara Hitchman

School/Division & CAG: Addictions Department


KCL/KHP Website: https://www.kcl.ac.uk/ioppn/depts/addictions/people/profiles/drsarahitchman

Co-Supervisor 1B: Professor Ann McNeill

School/Division & CAG: Addictions Department


KCL/KHP Website: https://www.kcl.ac.uk/ioppn/depts/addictions/people/profiles/AnnMcNeill


Smoking prevalence is higher among people with mental health and substance use problems, leading to

comorbidities and poor health. Moreover, smoking can exacerbate these problems, and there is evidence that

stopping smoking can lead to improvements in mental health. Thus, it is important to understand whether

current population health approaches to tobacco and vaping are helping people with mental health and

substance use problems stop smoking. This project will use data from the International Tobacco Control

Smoking and Vaping survey, www.itcproject.org, which includes longitudinal cohort surveys of smokers, ex-

smokers, and vapers across four countries with different tobacco and vaping policy landscapes (US, Canada,

England, and Australia). The project will aim to examine the impact of tobacco control and vaping policies,

such as health warning labels, tax, and standardised packaging on helping smokers with mental health and

substance use problems to stop smoking. Additionally, because vaping is considered to be far less harmful

than smoking, the project will also aim to consider whether tobacco control and vaping policies may

encourage smokers with mental health and substance use problems to switch to vaping, a less harmful source

of nicotine. And, among those that do switch, whether switching rather than quitting nicotine altogether can

lead to similar improvements in mental health, considering also the impact on other substance use problems.


Hitchman, S. C., Driezen, P., Logel, C., Hammond, D., & Fong, G. T. (2014). Changes in effectiveness of

cigarette health warnings over time in Canada and the United States, 2002-2011. Nicotine & Tobacco Research:

Official Journal of the Society for Research on Nicotine and Tobacco, 16(5), 536–543.

Richardson S, McNeill A, Brose LS. Smoking and quitting behaviours by mental health conditions in Great

Britain (1993-2014). Addictive Behaviours 2019 Mar;90:14-19. doi: 10.1016/j.addbeh.2018.10.011. Epub 2018 Oct

10.

41

36.2 Exploring whether bone disease is a driver and/or marker of dementia

Co-Supervisor 1A: Dr. Angela Hodges

School/Division & CAG: Institute of Psychiatry, Psychology and Neuroscience, Academic Psychiatry, MHOA

CAG


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/angela.k.hodges.html

Co-Supervisor 1B: Dr. Petra Proitsi

School/Division & CAG: Institute of Psychiatry, Psychology and Neuroscience, Basic and Clinical

Neuroscience


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/petroula.proitsi.html


Alzheimer’s disease patients (AD) have higher rates of bone fracture. This could be coincidental because AD,

falls and bone disease are common in older people. Alternatively, brain pathologies could drive bone

pathologies or vice versa or arise from common risk factors affecting both tissues. Nasu-Hakola patients with

TREM2 mutations develop fractures and dementia. TREM2 is also an AD risk gene expressed by

macrophages found in both tissues. Uncovering causal relationships has implications for patient welfare and

clinical management. This project will explore causal relationships between dementia/bone disease by:

1) bi-directional Mendelian Randomisation and statistical colocalization using high effect SNPs

(instrumental variables) for bone markers (risk factors) in AD (outcome), and vice versa (Yr1). Downstream

brain/bone molecular pathways will be investigated by eQTL analysis for any shared signals (Yr2).

2) testing association between bone disease markers (e.g. plasma bALP, Bisphosphonate prescribing)

and dementia pheonotypes (cognition, AD diagnosis, brain MRI) in TREM2 risk carriers (Yr2).

3) establishing if asymptomatic Paget’s disease is underdiagnosed or poorly managed in AD by analysing

bone disease markers (Yr3).

This project will utilise existing genetic/phenotypic data from large AD and bone disease cohorts (e.g. UK

Biobank, ADGC, CHARGE and GERAD/PERADES for AD). The student will develop high level analytical

and bioinformatics skills and gain experience of working with large datasets, coding and the use of a range of

methodological approaches. They will develop skills in problem solving and intepreting complex results, which

can be applied to any study investigating causal genetic and environmental risk factors in disease.


Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in

Alzheimer's disease

Sims, R., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W.,

Boland, A., Raybould, R., Bis, J. C., Martin, E. R., Grenier-Boley, B., Heilmann-Heimbach, S., Chouraki, V.,

Kuzma, A. B., Sleegers, K., Vronskaya, M., Ruiz, A., Graham, R. R., Olaso, R. & 31 others, 17 Jul 2017, In :

Nature Genetics.

Metabolomic correlates of central adiposity and earlier-life body mass index

Wulaningsih, W., Proitsi, P., Wong, A., Kuh, D. & Hardy, R., 18 Mar 2019, In : Journal of Lipid Research. 60,

6, p. 1136-1143

42

37.2 Understanding RNA/splicing factor transport dynamics in live developing and

degenerating neurons in culture and whole animals.

Co-Supervisor 1A: Prof. Corinne Houart

School/Division & CAG: IoPPN, Neuroscience


KCL/KHP Website: https://devneuro.org/cdn/people-detail.php?groupID=16

Co-Supervisor 1B: Prof. Jon Clarke

School/Division & CAG: IoPPN, Neuroscience


KCL/KHP Website: https://devneuro.org/cdn/people-detail.php?groupID=75


Neurons display sophisticated morphologies, with functionally distinct cellular compartments residing huge

distances apart. Axons, dendrites and synapses require protein dynamics depending on local RNA regulation

and translation. Splicing factors and spliceosome proteins are found in axons. Our latest findings indicate vital

roles for this extranuclear pool. Null zebrafish embryos for the splicing factor SFPQ and for the U1 spliceosome

protein snRNP70, fail to differentiate normal motor axons and display motility impairment. Exclusively

cytoplasmic variants of these two proteins rescue these phenotypes. Clinician colleagues found the axonal

distribution of these proteins abnormal in amyotrophic lateral sclerosis (ALS) patient-derived neurons. SFPQ

axonal mis-regulation is an early hallmark across familial and sporadic ALS.

To unveil the function of RNA/splicing factor complexes, we need to understand their local dynamics in

developing and degenerating neurons. Using zebrafish and neuronal primary culture, this project proposes to

develop cutting-edge imaging approaches (high resolution confocal and light sheet microscopy) to time-lapse

image SFPQ and snRNP70 in live neurons across development. 4D imaging datasets will be processed and

analysed using the latest approaches to molecular imaging analysis.

Year 1: Generating genome-edited zebrafish lines expressing tagged versions of SFPQ and snRNP70. Optimise

imaging approaches on transient expression models (wildtype injected with RNA coding for tagged proteins

and Cy5-UTP visualising protein and transcripts in granules)

Year 2: Imaging of neuronal development using the genome edited lines. Develop quantitative analyses of the

time-lapse datasets.

Year 3: Imaging of ALS variants (mutated versions associated to ALS patients) and test of specific transcripts

we identified as targets of SFPQ and snRNP70.


Thomas-Jinu S, Gordon PM, Fielding T, Taylor R, Smith BN, Snowden V, Blanc E, Vance C, Topp S,

Bielen H, , Nicholson GA, Pan-Vazquez A, Bond CS, Talbot WS, Blair IP, Shaw CE, Houart C. Non-nuclear

Pool of Splicing Factor SFPQ Regulates Axonal Transcripts Required for Normal Motor Development.

Neuron. 2017 Apr 19;94(2):322-336.e5

Hadjivasiliou Z, Moore RE, McIntosh R, Galea GL, Clarke JDW, Alexandre P. Basal Protrusions Mediate

Spatiotemporal Patterns of Spinal Neuron Differentiation. Dev Cell. 2019 Jun 17;49(6):907-919.e10.

43

38.2 The effects of stressful life events on the brain and subsequent development of

psychosis: A longitudinal MRI study

Co-Supervisor 1A: Dr Matthew Kempton

School/Division & CAG: Institute of Psychiatry, Psychology and Neuroscience, Division of Psychiatry, Dept

of Psychosis Studies. Psychosis CAG.


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/matthew.kempton.html

Co-Supervisor 1B: Dr Lucia Valmaggia

School/Division & CAG: Institute of Psychiatry, Psychology and Neuroscience, Division of System Sciences,

Dept of Psychology. Psychosis CAG.


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/lucia.valmaggia.html


Recent stressful life events are known to be an important factor in the development of psychosis

(Beards et al 2013) but how do the experience of these events lead to psychosis? We have shown that

particularly stressful life events such as trauma can have an observable effect on brain structure even

if in those who do not develop a psychiatric illness (Bromis et al 2018). We have recently acquired a

unique international dataset of longitudinal structural MRI scans both before and after an individual

experiences a stressful life event. The study includes healthy controls and people at clinical risk of

psychosis and during the study approximately 18% developed psychosis. The PhD candidate will be

able to investigate the effect of stressful life events on emerging psychotic symptoms and how changes

in brain structure may mediate this relationship. To clarify how stressful life events effect brain

structure in the wider population the student will analyse data from the UK-Biobank a resource of

over 10,000 MRI scans. The candidate will also have the option to interview patients in studies that

are on-going.

Year-1: Training in neuroimaging analysis and pre-processing of data (Kempton). Training in

conducting systematic review and metanalysis (Kempton and Valmaggia). Longitudinal data analysis

using STATA/SPSS (IoPPN Biostats courses). Stress and Psychosis (Valmaggia).

Year-2: Analysis of MRI and stressful life events data (Kempton and Valmaggia), Organising and

processing of UK-Biobank data (Kempton)

Year-3: Analysis of UK-Biobank data and thesis write-up (Kempton and Valmaggia)

Additional training in general PhD skills including communication and writing academic papers via

the Centre for Doctoral Studies at KCL.


Bromis K, Calem M, Reinders AATS, Williams SCR, Kempton MJ (2018). Meta-Analysis of 89

Structural MRI Studies in Posttraumatic Stress Disorder and Comparison With Major Depressive

Disorder. American Journal of Psychiatry. 2018 Oct 1;175(10):989-998.

McDonnell J, Stahl D, Day F, McGuire P, Valmaggia L.R (2018) Interpersonal sensitivity in those

at clinical high risk for psychosis mediates the association between childhood bullying victimisation

and paranoid ideation: A virtual reality study, 2018, Schizophrenia Research, 192, 89-95, DOI:

http://dx.doi.org/10.1016/j.schres.2017.04.029

44

39.2 The role of tau in -amyloid synaptotoxicity

Co-Supervisor 1A: Richard Killick

School/Division & CAG: IoPPN/Old Age Psychiatry – Academic Psychiatry


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/richard.1.killick.html

Co-Supervisor 1B: Wendy Noble

School/Division & CAG: IoPPN/Basic and Clinical Neuroscience – Clinical Neurosciences


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/wendy.noble.html


-amyloid (A) and tau are the major players of in Alzheimer’s disease. They are linked but despite

decades of research exactly how remains unclear. This is a major gap in our knowledge of the disease

and impedes our ability to treat it.

This project aims to address this. Specifically, it will investigate the role tau plays in the molecular

mechanisms underlying the toxic effects of -amyloid exerts on synapses, the structural correlate of

the memory and cognitive impairment accompanying the disease.

A “synaptotoxicity” is much reduced in the absence of tau. Hence tau must have an important role

in the process. It is a regulator of microtubules (MT) dynamics which are known to move rapidly in

and out of synapses, helping to strengthen or weaken them, a process recently shown to be under the

control of the Wnt signalling pathway, the same pathway we discovered underlies A-driven synapse

loss. We propose tau and A are linked through Wnt regulated mechanism controlling synaptic

plasticity.

The project will entail super-resolution imaging of tau proteins in synapses in living neurons from WT

and genetically engineered rodents using state-of-the-art imaging systems.

The major objectives are: Year-1, characterise the effects of A and Wnt proteins on the MT content

of synapses in WT and tau-KO neurons and examine the effects of mutated forms of tau reintroduced

into tau-KO neurons; Year-2, determine if tau-driven MT synapse entry impacts synaptic [Ca2+

]

through interactions with the ER. Year-3, determine how A and Wnt impact tau-dependent synaptic

[Ca2+

].


Sellers, K. J. et al. Amyloid beta synaptotoxicity is Wnt-PCP dependent and blocked by fasudil. Alzheimers

Dement 14, 306-317, doi:10.1016/j.jalz.2017.09.008 (2018).

Glennon EB, Lau DWH, Gabriele MC, Taylor, MF, Troakes C, Elliott C, Killick R, Hanger DP, Perez-Nievas

BG, Noble W. (2019) Loss of bridging integrator 1 (BIN1) protein in Alzheimer's disease disrupts synaptic

structure, tau localisation and release. BioRXiv. doi: https://doi.org/10.1101/646406

45

40.2 ADHD and preterm birth: applying remote measurement technology to identify

persisting impairments and targets for intervention

Co-Supervisor 1A: Professor Jonna Kuntsi



KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/jonna.kuntsi.html

Co-Supervisor 1B: Professor Richard Dobson



KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/richard.j.dobson.html

Name of Collaborating Clinician: Professor Philip Asherson



Website: [email protected]


Remote measurement technology (RMT) is changing the way in which many conditions are assessed and

managed. For research, RMT enables detailed, frequent, long-term, real-world data collection on clinical

symptoms, impairments, health behaviours and novel digital biomarkers on large sample sizes.

A new project ‘ART’ (ADHD Remote Technology), led by supervisors Kuntsi and Dobson, is currently

underway that focuses on the development of novel remote measures for attention-deficit/hyperactivity disorder

(ADHD) and related conditions. The remote battery, incorporating active (questionnaires, cognitive tasks) and

passive (e.g. activity and sleep) monitoring using mobile and web technologies, holds promise for transforming

both research and clinical long-term monitoring of individuals with ADHD and those at risk for ADHD-like

symptoms and impairments.

The student will have the opportunity to join the ART team and take an active role in analysing data already

collected and in applying the measures to a further ‘at risk’ population as follows:

Year 1 of PhD: Analyses on existing ART project data on adolescents and adults with ADHD, and controls, to

identify novel digital biomarkers for ADHD.

Years 2-3 of PhD: A novel application of selected ART remote measures to follow up our existing ‘SPIN’ (Study

of Preterm birth and Inattention) sample of preterm-born individuals and their siblings. We previously assessed

the SPIN sample in adolescence, establishing an association between preterm birth and an increased risk for

ADHD symptoms and associated cognitive impairments. By following them up in young adulthood using RMT,

we can identify developmentally persistent impairments and investigate how they affect function in daily life,

defining targets for future interventions.


Is association of preterm birth with cognitive-neurophysiological impairments and ADHD symptoms consistent

with a causal inference or due to familial confounds?

James SN, Rommel AS, Rijsdijk F, Michelini G, McLoughlin G, Brandeis D, Banaschewski T, Asherson P,

Kuntsi J. Psychol Med. 2019 Jun 3:1-7.

RADAR-base: An Open Source mHealth Platform for Collecting, Monitoring and Analyzing data Using

Sensors, Wearables, and Mobile Devices

Ranjan Y, Rashid Z, Stewart C, Kerz M, Begale M, Verbeeck D, Boettcher S, The Hyve, Dobson R, Folarin

A, RADAR-CNS Consortium

46

41.2 Transdiagnostic mechanisms in cognitive behavioural interventions for patients

with Persistent Physical Symptoms: How do transdiagnostic psychological therapies

work?

Co-Supervisor 1A: Professor Sabine Landau



KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/sabine.landau.html

Co-Supervisor 1B: Professor Trudie Chalder



KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/trudie.Chalder.html


Persistent Physical Symptoms (PPS) such as chronic fatigue or pain are associated with increased disability

and health care costs. There is a body of evidence demonstrating that cognitive behavioural interventions can

reduce levels of symptoms and improve functioning in a range of PPS. While it is standard clinical practice to

adapt psychological therapies it is not clear which components of the interventions are transdiagnostic, that is,

address cognitive or behavioural responses shared by patients across the PPS spectrum, and which are disorder

specific. This PhD project will develop and apply methods to model the similarities and differences in

treatment mechanisms across PPS populations, in order to help clinicians identify core mechanisms and

develop new psychological interventions.

The project will provide an opportunity to develop knowledge of psychological theory and interventions and

skills in biostatistics.

The student will have access to the programme of short courses on advanced statistical methodologies

provided by the Department of Biostatistics & Health Informatics; including training in structural equation

modelling. In addition, external training can be attended if required.

In year one, the student will carry out a systematic review of mechanistic theories in PPS and approaches for

assessing transdiagnostic mechanisms, and will prepare individual participant data (IPD) from a number of

CBT trials for pooling; likely to include the PACE trial for CFS (White et al 2011) and PRINCE Secondary

trials for PPS in general. We envisage structural equation modelling and IPD meta-analysis/integrative data

analysis techniques to play an important role (years 2 and 3).


Dunn G., Emsley E., Liu H., Landau S., Green J., White I. & Pickles A. (2015) Evaluation and validation of

social and psychological markers in randomised trials of complex interventions in mental health: a

methodological research programme. Health Technology Assessment 19 (93)

http://dx.doi.org/10.3310/hta19930

Chalder T., Goldsmith KA, White PD, Sharpe M, Pickles AR. (2015) Rehabilitative therapies for chronic

fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry 2 (2):141-52.

doi.org/10.1016/S2215-0366(14)00069-8

47

42.2 Imagine a brighter future: Understanding treatment predictors and mechanisms

of a school-based positive imagery intervention to target anhedonia in adolescents.

Co-Supervisor 1A: Jennifer Lau

School/Division & CAG: IOPPN, Division of Psychology and Systems Sciences


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/jennifer.lau.html

Co-Supervisor 1B: Katherine Young

School/Division & CAG: IoPPN, Division of Psychology and Systems Sciences


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/katherine.s.young.html

Name of Collaborating Clinician: Dr Victoria Pile

School/Division & CAG: IOPPN, Division of Psychology and Systems Sciences


Website: https://kclpure.kcl.ac.uk/portal/victoria.pile.html


Depression is common and costly. Depression that starts in youth is associated with worse outcomes. We have

developed a brief therapy manual that targets mental imagery including positive future mental imagery in

adolescents with high levels of depression (Pile et al., 2018). This intervention can be implemented in schools,

increasing accessibility. A feasibility trial shows that the intervention is acceptable with clinical promise. The

aim of this PhD project is to investigate the mechanisms targeted by this intervention. In Year 1, the PhD

candidate will adapt existing tasks that measure reward anticipation using stimuli co-developed with young

people and assess these for test-retest reliability and validity against other measures of reward anticipation and

depressive symptoms. Based on these data, the candidate will select the task with the strongest psychometric

properties, and in Year 2, administer this pre-, mid-, and post-treatment within a larger clinical trial of this

intervention (of note, data collection for this trial will be shared with another funded PhD student). In Year 3,

the candidate will analyse these data, specifically, testing the hypotheses that intervening to modify positive

future mental imagery modifies reward anticipation processes and exploring whether these processes reflect

predictors of symptom change from pre to post-treatment.

The student will receive training at the heart of clinical translational neuroscience, including developing,

administering and analysing data from experimental neurocognitive tasks; conducting a randomised controlled

trial to evaluate psychological interventions and their mechanisms administered to young people; data

management including specific skills in trial statistics; and acquiring clinical skills necessary to assess young

people with depression before and after the intervention. S/he will also gain experience involving young people

in the creation of experimental tasks/stimuli; and disseminating work to academic and non-academic audiences.


Lau, Y. F., & Waters, A. (2016). Annual Research Review: An expanded account of information-processing

mechanisms in risk for child and adolescent anxiety and depression. Journal of Child Psychology and Psychiatry.

https://doi.org/10.1111/jcpp.12653

Young, K. S., Sandman, C. F., & Craske, M. G. (2019). Positive and negative emotion regulation in adolescence:

links to anxiety and depression. Brain sciences, 9(4), 76. https://doi.org/10.3390/brainsci9040076

48

43.2 Understanding neuronal migration disorders using human tissue models.

Co-Supervisor 1A: Katie Long

School/Division & CAG: Centre for Developmental Neurobiology and MRC Centre for Neurodevelopmental

Disorders, IoPPN


KCL/KHP Website: https://www.kcl.ac.uk/ioppn/depts/devneuro,

https://devneuro.org/cdn/group-overview.php?groupID=95&height=765&width=1700&ref=group-leaders,

https://devneuro.org/cndd/group-leaders-overview.php?groupID=95

Co-Supervisor 1B: Benedikt Berninger

School/Division & CAG: Centre for Developmental Neurobiology and MRC Centre for Neurodevelopmental

Disorders, IoPPN


KCL/KHP Website: https://www.kcl.ac.uk/ioppn/depts/devneuro/index.aspx

https://devneuro.org/cdn/group-overview.php?groupID=1029&height=765&width=1700&ref=group-

overview

https://devneuro.org/cndd/group-leaders-overview.php?groupID=1029


The cerebral cortex is the seat of many of the higher cognitive functions that make us human, such as our

advanced learning and speech. We know that the correct organisation of the cortex is vital for these functions,

but how this is achieved during development remains elusive. Evidence from studies on neurodevelopmental

disorders has indicated that neuronal migration is crucial to ensure that the right number of neurons end up in

the right place at the right time. A key example of such a disorder is lissencephaly, where the folding of the cortex

(the wrinkles on the outer surface) is greatly reduced. This lack of folding is associated with cognitive defects

and has been suggested to be due to an over-migration of neurons.

This project will use cutting-edge human cell and tissue culture systems to investigate how neuronal migration

is dysregulated in neurodevelopmental disorders. It will take advantage of both laboratories’ expertise,

combining the Long lab’s experience in human fetal neocortex development and explant models with the

Berninger lab’s experience in human induced pluripotent stem cells (iPSC) and organoid models. We will use a

multidisciplinary approach, including live-imaging, transcriptome analysis, confocal-imaging and cell biology.

The student will investigate:

Year 1 – Neuronal migration in human fetal neocortex explant models of lissencephaly; establishment of human

cerebral organoids from iPSCs

Year 2 – Neuronal migration in iPSC/organoid models and effect of tissue/substrate stiffness

Year 3 – Identification of mechanisms underlying defects in neuronal migration; rescue of these defects in

iPSC/organoid and human fetal neocortex models


Long KR, Newland B, Florio M, et al. Extracellular Matrix Components HAPLN1, Lumican, and Collagen I

Cause Hyaluronic Acid-Dependent Folding of the Developing Human Neocortex. Neuron. July 2018.

doi:10.1016/j.neuron.2018.07.013

Karow M, Camp JG, Falk S, et al., Berninger B. Direct pericyte-to-neuron reprogramming via unfolding of a

neural stem cell-like program. Nat Neurosci. July 2018. doi: 10.1038/s41593-018-0168-3.

49

44.2 What impact do pharmacological treatments have on self-harm and suicide in

psychosis? A pharmaco-epidemiological study.

Co-Supervisor 1A: Professor James H MacCabe

School/Division & CAG: Academic Psychiatry/ Psychosis


KCL/KHP Website: kclpure.kcl.ac.uk/portal/james.maccabe.html

Co-Supervisor 1B: Richard D Hayes

School/Division & CAG: IoPPN/ Academic Psychiatry/ Psychological medicine


KCL/KHP Website: kclpure.kcl.ac.uk/portal/richard.hayes.html


Suicide is a major, avoidable contributor to premature death in schizophrenia, with between 5 and 15% of people

with schizophrenia completing suicide. There is increasing evidence that non-adherence to antipsychotic and

mood stabilizer treatment is the largest modifiable risk factor for suicide (OR = 3.75). Furthermore, there is

evidence that clozapine has the stronger anti-suicidal effects than other antipsychotics, and that lithium has a

similar advantage among mood stabilisers. The student will study the pharmacoepidemiology of suicide and self-

harm using the Clinical Research Interactive Search (CRIS), a unique, searchable database of clinical records.

Year 1 and 2:

a) Write a systematic review of this topic

b) identify a cohort of patients with schizophrenia, schizoaffective disorder, bipolar disorder and other

psychotic disorders meeting inclusion criteria for the study,

c) document the start and stop dates of antipsychotic treatments in the cohort (the exposures)

d) record fixed and time-varying exposures that could be potential confounders

e) identify instances of non-fatal self-harm and completed suicide (the outcomes).

f) Year 2-3: analysis, which will use cox regression and other time-series analyses to examine associations

between treatment and risk for self-harm and suicide.

Year 3: Writing up and presentation at international conferences

Training: natural language processing, data linkage, data management, data governance, pharmaco-

epidemiology, advanced statistical analysis, presentation skills and academic writing.

Implications for clinical practice: Patients with established risk factors for self-harm and suicide would

preferentially be prescribed drugs which are associated with the greatest protective effects.


Wimberley T, MacCabe JH, Laursen TM, Sørensen HJ, Astrup A, Horsdal HT, Gasse C, Støvring H. Mortality

and Self-Harm in Association With Clozapine in Treatment-Resistant Schizophrenia. Am J Psychiatry. 2017;

174:990-998.

Kadra G, Stewart R, Shetty H, MacCabe JH, Chang CK, Taylor D, Hayes RD. Long-term antipsychotic

polypharmacy prescribing in secondary mental health care and the risk of mortality. Acta Psychiatr Scand. 2018;

138:123-132

50

45.2 Role of alternative splicing in diversity of mammalian neurons

Co-Supervisor 1A: Eugene Makeyev

School/Division & CAG: Centre for Developmental Neurobiology, IoPPN


KCL/KHP Website: https://devneuro.org/cdn/people-detail.php?personID=1398

Co-Supervisor 1B: Oscar Marín

School/Division & CAG: Centre for Developmental Neurobiology, IoPPN


KCL/KHP Website: http://devneuro.org.uk/marinlab/default.aspx


Brain function depends on development of multiple types of neurons characterised by distinctive structural,

physiological and molecular features. How this diversity emerges from a smaller number of progenitor states is a

fascinating biological problem. Many genes can generate more than one RNA product through alternative

splicing, a process involving non-uniform use of exons and introns. The nervous system expresses an especially

large collection of alternative isoforms, but how this molecular program contributes to the emergence of

individual neuronal identities remains poorly understood. The proposed project will address this important

question by focusing on GABAergic interneurons, a heterogeneous group containing >20 distinct categories.

Briefly, we will analyse single-cell RNA-sequencing data using state-of-the-art bioinformatics tools to detect

interneuron type-specific differences in splicing patterns and expression of RNA-binding proteins (RBPs)

known/predicted to control splicing decisions (rotation/year 1). RBPs showing the strongest correlation with

type-specific splicing patterns will be shortlisted for detailed experimental studies. To elucidate splicing

regulation mechanisms, the candidate RBPs will be over-expressed/knocked-down in neural cells in vitro and

the effect of these treatments will be assayed using reverse transcription-PCR, single-molecule RNA FISH and

immunofluorescence (year 2). Function of the most promising RBP candidate will be examined by modulating

its expression in mouse brain using appropriate viral vectors, the CRISPR-Cas9 technology or/and classical

knockouts followed by morphological, electrophysiological and behavioural analyses (years 3-4). The two

supervisors have extensive expertise in bioinformatics, biochemistry, neurobiology and mouse genetics, which

will provide an ideal training environment and will ensure successful completion of the PhD studies.


Yap K, Xiao Y, Friedman BA, Je HS, and Makeyev EV (2016) Polarizing the neuron through sustained co-

expression of alternatively spliced isoforms. Cell Rep. 15, 1316-1328.

Mi D, Li Z, Lim L, Li M, Moissidis M, Yang Y, Gao T, Hu TX, Pratt T, Price DJ, Sestan N, and Marín O

(2018) Early emergence of cortical interneuron diversity in the mouse embryo. Science 360, 81-85.

51

46.2 Emerging brain networks in babies vulnerable to neurodevelopmental

conditions (Autism Spectrum Disorder and ADHD): An MRI study of fetal and

neonatal brain.

Co-Supervisor 1A: Grainne McAlonan

School/Division & CAG: Institute of Psychology, Psychiatry & Neuroscience


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/grainne.mcalonan.html

Co-Supervisor 1B: Dafnis Batalle

School/Division & CAG: Institute of Psychology, Psychiatry & Neuroscience / BMEIS


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/dafnis.batalle.html


Abnormalities in structural and functional brain connectivity have been proposed to underpin cognitive and

behavioural difficulties of neurodevelopmental conditions (NDD) such as autism spectrum disorder (ASD and

ADHD); but, the evidence comes from individuals already diagnosed. To truly understand the biology of these

conditions we must look early, when the foundations of cognition and behaviour are established, and pathology

linked to NDD emerges. Our group at King’s is the first to use MRI to look at the brain of individuals vulnerable

to NDD in fetuses and shortly after birth. This will help us to: i) establish how genetic and/or prenatal

environmental insults disrupt the emergence and function of fundamental brain networks; and ii) determine

whether abnormalities in emerging neural networks at birth predict later outcomes. This will inform future

tailored prevention efforts, reveal new treatment targets and identify those most in need of intervention at the

earliest opportunity.

Planned research methods and training provided:

We will use conventional and novel graph theory approaches to determine if there are underlying patterns in

fetal and/or neonatal brain network organization and function which relate to childhood outcomes. Using

machine learning approaches, we will also identify predictors of specific NDD traits in childhood.

Objectives / project plan:

Year 1: Training in neuroimaging, graph theory and machine learning. Preliminary assessment of the data.

Characterisation of brain network characteristics during early development. Hands-on involvement in on-going

data collection. Training in relevant aspects of ASD and ADHD and mental health. Becoming confident in

working with participants and their families.

Year 2: Characterisation of changes associated with ASD phenotypes. Exploration of novel graph theoretical

features.

Year 3: Writing up analyses for publication. Explore novel multimodal methods (e.g. machine learning) to

identify subgroups and predict outcome.


Batalle D., Edwards, A. D. & O'Muircheartaigh, J., 2018; Annual Research Review: Not just a small adult brain:

understanding later neurodevelopment through imaging the neonatal brain. In: Journal of child psychology and

psychiatry.

Ciarrusta J, O'Muircheartaigh J, Dimitrova R, Batalle D, …, McAlonan, GM. 2019; ‘Social Brain Functional

Maturation in Newborn Infants With and Without a Family History of Autism Spectrum Disorder.’ In: JAMA

Network Open

52

47.2 Investigating hippocampal dysfunction in people at clinical high-risk for

psychosis with implications for novel drug discovery

Co-Supervisor 1A: Dr Gemma Modinos

School/Division & CAG: Institute of Psychiatry, Psychology & Neuroscience; Psychosis CAG


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/gemma.modinos.html

Co-Supervisor 1B: Dr Alice Egerton



KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/alice.egerton.html

Name of Collaborating Clinician: Prof. Philip McGuire



Website: https://kclpure.kcl.ac.uk/portal/philip.mcguire.html


Background: There are currently no interventions to prevent the onset of schizophrenia or psychosis in

people identified as being at Clinical High Risk (CHR). Growing evidence indicates that the onset of

psychosis may be driven by alterations in the hippocampus. Altered hippocampal structure and function are

consistently observed in patients with established schizophrenia as well as those at CHR. Recent research in

animal models of schizophrenia has found that administration of diazepam, a GABA-enhancing drug,

modulates hippocampal function and normalises dopamine signalling. This indicates that modulation of

hippocampal function via a GABAergic drug may be a viable therapeutic strategy for psychosis prevention in

man.

This MRI neuroimaging project in people at CHR for psychosis will investigate the effects of diazepam

administration on activity within the hippocampus (measured as cerebral blood flow) as well as the functional

connectivity between the hippocampus and wider brain networks (measured as resting-state fMRI). The

results of the project may provide proof-of-concept evidence to support the future development of novel

interventions to reduce the risk of psychosis onset.

Research methods / training: The project will provide training in recruitment and assessment of participants

at CHR for psychosis, acquisition and analysis of MRI data, statistical analysis and dissemination.

Project plan:

- Year 1: Training, participant recruitment/scanning, data collection.

- Year 2: Participant recruitment/scanning, preliminary data analysis.

- Years 3-3.5: Completion of data collection, final data analysis, thesis write-up, conference presentation

and journal publications.


Modinos G, Şimşek F, Azis M, et al. (2018) Prefrontal GABA levels, hippocampal resting perfusion and the risk

of psychosis. Neuropsychopharmacology. 43(13):2660.

Egerton A., et al (2018) Response to initial antipsychotic treatment in first episode psychosis is related to anterior

cingulate glutamate levels: a multicentre 1H-MRS study (OPTiMiSE).

Mol Psychiatry. Nov;23(11):2145-2155.

53

48.2 Wearable technology to improve the management of Psychogenic Non-

Epileptic Seizures

Co-Supervisor 1A: Dr Tim Nicholson

School/Division & CAG: IoPPN / Psychosis & Psychological Medicine


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/timothy.nicholson.html

Co-Supervisor 1B: Professor Mark Richardson

School/Division & CAG: IoPPN / Neuroscience


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/mark.richardson.html


Background: Psychogenic Non-Epileptic Seizures (PNES) are at type of Functional Neurological Disorder

(FND) and one of the commonest, but least understood, causes of severe and often chronic seizures.

Distinguishing PNES from epileptic seizures (ES) is challenging, especially as they commonly co-exist.

Reliable diagnosis is critical as psychological treatments such as Cognitive Behavioural Therapy (CBT) are

needed, rather than antiepileptic medication. Multiple converging strands of evidence indicate that wearable

technologies, such as an actigraphy watch, could improve diagnosis by identifying differential limb movement

patterns and autonomic function (e.g. heart rate, skin conductance) as well as psychometrics (real-time patient

ratings of anxiety, stress etc). Such devices can also prompt and record reliable and objective outcome

measures for both clinical trials and routine clinical use. The data could also enhance CBT by identifying

seizure triggers and warning signs. Furthermore, objective measures of seizure frequency, severity and duration

can be contrasted against subjective ratings to show meaningful improvements.

Aims: Observational study of PNES and ES patients selected from first seizure clinics investigating differences

in seizure movement patterns, autonomic function and psychometrics. Initial feasibility work would investigate

patient acceptability and generate pilot data for analytical strategies.

Techniques and skills: The student will learn how to set up and run an observational study, test current (and

potentially develop new) wearable technologies, analyse and publish high quality data.

Training: Research design, statistical analysis.

Objectives:

Yr1: Refine protocols, set up collaborations and gain ethical approval. Start feasibility work.

Yr2: Start observational study.

Yr3: Analyse and write up data/thesis/publications.


Bruno E, Simblett S, Lang A, Biondi A, Odoi C, Schulze-Bonhage A, Wykes T, Richardson MP; RADAR-

CNS Consortium. Wearable technology in epilepsy: the views of patients, caregivers and healthcare

professionals. Epilepsy Behav 2018;85:141-149.

Nicholson TR, Carson A, Edwards MR et al. Outcome measures for functional neurological disorder – a review

of the theoretical complexities J Neuropsych and Clin Neurosci 2019; in press.

54

49.2 Developing a new cognitive model and targeted psychological intervention to

reduce worry and distress in informal carers

Co-Supervisor 1A: Dr Juliana Onwumere

School/Division & CAG: Psychology and System Sciences & Psychosis


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/juliana.1.onwumere.html

Co-Supervisor 1B: Dr Colette Hirsch

School/Division & CAG: Psychology and System Sciences & Psychological Medicine and Older Adults CAG


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/colette.hirsch.html


Globally, several million people provide informal care for a relative or friend living with a health condition or

disability, or care needs due to advanced age. Though research highlights adverse physical and mental health

consequences of caregiving roles, a more nuanced understanding of carer wellbeing and development of carer-

tailored interventions to support their needs are urgently required. Worry about negative outcomes is a key

component of anxiety disorders and drives emotional distress. Understandably, carers will worry at times, but

research to date has not investigated the nature or impact of worry in carers, nor whether modifiable

psychological mechanisms that maintain worry in the general and clinical populations apply to carers. If this can

be established, then tailored psychological interventions for carers who worry excessively could reduce their

emotional distress.

This PhD will involve ground breaking research to identify factors that maintain carer worry and will form the

basis for a new model of carer worry and new targeted online intervention to help foster emotional resilience in

carers. The PhD will comprise:

a. Qualitative interviews with key stakeholders (e.g carers, clinicians) on subjective experiences of carer

worry to inform a new model of carer worry

b. Quantitative experimental study to identify modifiable psychological mechanisms that maintain worry

in carers to inform the model of carer worry

c. Development of psychological intervention to target key mechanisms that maintain worry

d. Acceptability and feasibility trial of new intervention

Training

The student will undergo specialist training in quantitative and qualitative research methods analytic

approaches.


Onwumere, J., Bonetto C., Lasalvia A., Miglietta E., Veronese A., Bellini F., Imbesi M., Bebbington, P.,

Kuipers, E, Ruggeri M. & The GET UP Group (2019). Predictors and moderators of burden of care and

emotional distress in caregivers. Results from the GET UP pragmatic cluster randomized controlled trial.

Epidemiological and Psychiatric Sciences doi: 10.1017/S2045796019000155.

Hirsch, C.R., Krahé, C., Whyte, J., Loizou, S., Bridge, L., Norton, S., Mathews, & A. (2018). Interpretation

training to target repetitive negative thinking in generalized anxiety disorder and depression. Journal of Consulting

and Clinical Psychology, 86, 1017-1030. DOI. 10.1037/ccp0000310

55

50.2 Cellular models to identify causal molecular mechanisms of early life stress (els)-

induced comorbidity

Co-Supervisor 1A: Professor Carmine Maria Pariante

School/Division & CAG: Life Science; Psychological Medicine


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/carmine.pariante.html

Co-Supervisor 1B: Dr Annamaria Cattaneo

School/Division & CAG: Psychological Medicine


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/annamaria.2.cattaneo.html


Early life stress is a major cause of morbidity in terms of both mental and physical health. Even if some stress-

related biological mechanisms have been described, such as increased cortisol levels, increased inflammation, and

changes in the microbiome, the molecular mechanisms by which these biological abnormalities affect health are

yet to be understood. In this project we will use a coherent in vitro, experimental, systematic approach, to

mimic ELS-relevant cortisol and inflammatory insults on cells from the human brain, heart, liver, pancreas and

blood immune system, to identify mechanisms underpinning the relationship between ELS and unipolar

depression, coronary heart disease and diabetes type II. We have successfully used such in vitro approaches

before (see publications).

The project consists of two main aims:

Aim 1. Mimic ELS-related insults in human cells derived from brain, heart, liver, pancreas, adipose tissue and

immune system (Year 1 of PhD), using both cortisol and the pro-inflammatory cytokine, interleukin-1 beta, and

study the effects on specific hypothesis-driven functional and biochemical mechanisms underlying the

aforementioned disorders (for example, neurogenesis, energy metabolism and insulin secretion).

Aim 2. Modulate the functional and biochemical cellular mechanisms induced by the stress-related insults

identified in Aim 1 (Year 2-3): We will activate or inhibit the identified mechanisms (from Aim 1), using

genetic tools or treatment with pharmacological drugs that can stimulate or inhibit such pathways.

Techniques and skills that will be learnt:

• Cell culture of a variety of human cell lines derived from brain (hippocampal progenitor cell line

HPC03A/07 and hypothalamic neurons derived from iPSCs), and primary cells from heart, liver,

pancreas and blood immune system (respectively, cardiomyocytes, hepatocytes, pancreatic cells

EndoC-βH and peripheral blood mononuclear cells);

• Immunostaining for the quantification of neuronal, glial and apoptotic cells;

• Single and multiplex platforms (ELISA and Meso Scale Discovery assay) for proteins level

quantification;

• qPCR for mRNA gene expression analysis.


Anacker C, Cattaneo A, Musaelyan K, Zunszain PA, Horowitz M, Molteni R, Luoni A, Calabrese F, Tansey

K, Gennarelli M, Thuret S, Price J, Uher R, Riva MA, Pariante CM. Role for the kinase SGK1 in stress,

depression, and glucocorticoid effects on hippocampal neurogenesis. Proc Natl Acad Sci U S A. 2013 May

21;110(21):8708-13.

Borsini A., Alboni S., Horowitz M.A., Tojo L. M., Cannazza G., Su K., Pariante C.M., Zunszain P. A..

Rescue of IL-1β−induced reduction of human neurogenesis by antidepressants and omega-3 fatty acids. Brain

Behaviour and Immunity. 2017, 65:230-238.

56

51.2 Enhancing patient benefits from IAPT psychological therapy services through

machine learning informed decision-making tools and personality measurement

Co-Supervisor 1A: Adam Perkins

School/Division & CAG: IoPPN/Academic Psychiatry, Psychological Medicine and Integrated Care


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/adam.perkins.html

Co-Supervisor 1B: Allan Young



KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/allan.young.html

Name of Collaborating Clinician: Professor Anthony Cleare



Website: https://kclpure.kcl.ac.uk/portal/anthony.cleare.html


Improving Access to Psychological Therapies (NHS-IAPT) provides evidence-based psychotherapies for

depression and anxiety using “stepped-care” where patients are allocated to low/high intensity treatment

based on illness severity (Clark, 2011). Although IAPT serves a wide population (Clark, 2018), doubts remain

about its implementation. Guidelines for therapy-allocation decisions are lacking and there is high variability in

services provided and patient benefits derived (Richards et al., 2012). Offering clinicians evidence-based tools

to aid decision-making could optimise service delivery. This project aims to develop such a tool through

harnessing machine learning technology, IAPT data and existing evidence-base to develop a decision-making

tool. The student will analyse a large dataset of existing longitudinal IAPT data, augmented by personality

scores obtained via an evidenced online personality questionnaire (Patrick et al., 2019). Secondarily, we aim to

elucidate the causal role of biology on clinical outcomes through neuroimaging experimentation with a subset

of volunteer patients. Depending on project findings, this PhD has potential for translation into services to

enhance the delivery of psychological therapies that maximise patient benefits.

Year 1: establish collaboration with stakeholders, undertake training (see below) and obtain data access, all

preparations for machine learning analyses.

Year 2: complete machine learning analyses and undertake primary research study.

Year 3: complete all data analyses and write-up.

Training has been identified to facilitate skills development in ethics of reproducible research, open data

scientific practices, machine learning and predictive modelling approaches, software programming, personality

measurement and neuroimaging techniques (functional, structural, spectroscopic).


Perkins, A. M., Strawbridge, R., Arnone, D., Williams, S. C., Gasston, D., Cleare, A. J., ... & Corr, P. J.

(2019). Towards a neuroscience-based theory of personality: within-subjects dissociation of human brain

activity during pursuit and goal conflict. Personality Neuroscience, 2.

Wolke SA, Mehta MA, O'Daly O, Zelaya F, Zahreddine N, Keren H, O'Callaghan G, Young AH, Leibenluft

E, Pine DS, Stringaris A. Modulation of anterior cingulate cortex reward and penalty signalling in medication-

naive young-adult subjects with depressive symptoms following acute dose lurasidone. Psychological medicine.

2019 Jun;49(8):1365-77.

https://kclpure.kcl.ac.uk/portal/adam.perkins.html

57

52.2 Does cognitive behaviour therapy for psychosis alter psychophysiological

mechanisms associated with distressing psychotic symptoms?

Co-Supervisor 1A: Dr Emmanuelle Peters

School/Division & CAG: Psychology Department, Psychology & Systems Science Division, previously

Psychosis CAG (now Croydon Specialist Psychosis and Neurodevelopmental)


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/emmanuelle.peters.html

Co-Supervisor 1B: Dr Matteo Cella

School/Division & CAG: Psychology Department, Psychology & Systems Science Division


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/matteo.cella.html


Psychotic experiences (PEs), such as hearing voices or having unusual beliefs, are not always associated with

distress or requiring care. Psychological explanations of psychosis suggest that it is how individuals appraise, and

cope with, their PEs, rather than their presence, that leads to distress. Biological explanations suggest that the

body’s ability to adapt flexibly to stress plays a role in the subjective experience of PEs. Cognitive Behaviour

Therapy for psychosis (CBTp) aims to reduce distress by changing how people appraise, and respond to, their

PEs. This project seeks to identify the signatures of distress, across both psychological and physiological levels,

which can determine whether PEs become clinically significant, and how they reduce through therapy.

Experience Sampling Method (ESM) is a methodology allowing ‘in-the-moment’ measurement of PEs,

thoughts, and emotions within their social and environmental context. Developments in technology also allow

for wearable devices to record biological stress indicators, such as heart rate variability (HRV) and electrodermal

activity (EDA). We will assess HRV, EDA, and ESM concurrently in individuals with benign PEs and compare

them to patients with distressing PEs pre- and post-CBTp. This will allow us to determine: (1) factors that lead

to benign or distressing outcomes of PEs; (2) how CBTp may affect the physiology of distress. This will improve

our understanding of the psychobiology of symptoms, inform future therapies and contribute to devices that can

monitor symptoms and track therapeutic change.

Year 1: Training in ESM, HRV and EDA; ethical permissions; therapy observations; setting up recruitment;

draft systematic review

Year 2: Recruitment; training in multi-level modelling statistics; submit review paper; analyse and draft 1st study

paper

Year 3: Finish recruitment, analyse study 2, write up thesis


Peters, E., et al., Clinical, socio-demographic and psychological characteristics in individuals with persistent

psychotic experiences with and without a "need for care". World Psychiatry, 2016. 15(1): p. 41-52.

Cella, M., et al., Using wearable technology to detect the autonomic signature of illness severity in

schizophrenia. Schizophrenia Research, 2018. 195:537-542.

58

53.2 Stress Vulnerability in Sexual Minorities: Genetic and Environmental

Influences

Co-Supervisor 1A: Dr Qazi Rahman

School/Division & CAG: IoPPN / Psychology and Systems Sciences / Psychology


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/qazi.rahman.html

Co-Supervisor 1B: Dr Edward D. Barker

School/Division & CAG: IoPPN / Psychology and Systems Sciences / Psychology


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/ted.barker.html


Stress vulnerability has been implicated in the higher burden of psychiatric disorders among sexual minorities

(lesbian, gay, and bisexual) but never investigated directly. Understanding the psychophysiology underlying this

minority stress is important because poor mental health in sexual minorities results in worse quality of life, slower

recovery from stress, and increased healthcare utilization.

Aims: This PhD will compare physiological and psychological responses to laboratory stressors in sexual minority

and heterosexual male/female controls (non-twins). Importantly, this PhD will also test identical twins

concordant and discordant for sexual orientation in order to tease apart genetic and non-genetic influences. The

use of discordant identical twins permits quantitative tests of whether group differences in stress responses are

due to environmental factors while minimizing the contribution of genetics.

Techniques, skills and training: This project will use experimental and physiological techniques in a genetically

sensitive design and provide advanced training in; bespoke development of laboratory stressors (e.g., stigma

induction tasks); psychophysiological measurement (e.g., electrodermal activity; cortisol release); multilevel

modelling; twin modelling; and research with under-represented populations in biomedical research (recruiting

sexual minorities and twins).

Objectives, Year 1: Develop and experimentally validate laboratory tasks; recruit twin and non-twin samples;

pilot testing; and acquire training in multilevel and twin statistics.

Objectives, Years 2/3; Testing of all groups; use multilevel and twin modelling to quantify group differences in

stress responses and test whether these are due to genetic and non-genetic factors in comparisons of concordant

and discordant twin pairs; identify psychological factors that mediate/moderate these differences; write-up and

dissemination.


Timmins, L., Rimes, K. A., & Rahman, Q. (2018). Minority stressors, rumination, and psychological distress in

monozygotic twins discordant for sexual minority status. Psychological Medicine, 48(10), 1705-1712.

https://doi.org/10.1017/S003329171700321X

Association between maladaptive parenting and child self-control over time: cross-lagged study using a

monozygotic twin difference design. Cecil CA, Barker ED, Jaffee SR, Viding E. Br J Psychiatry. 2012

Oct;201(4):291-7. doi: 10.1192/bjp.bp.111.10758

59

54.2 Investigation of the cell biological basis for polypharmacy and their risks and

benefits for Alzheimer’s disease

Co-Supervisor 1A: Prof. Dr. Lawrence Rajendran



KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/lawrence.rajendran.html

Co-Supervisor 1B: Prof. Robert Stewart

School/Division & CAG: IoPPN/Academic Psychiatry, MHOAD


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/robert.stewart.html


In this state-of-the-art project, we combine cell biology with epidemiology & deep learning (Artificial

Intelligence) to discover unstudied mechanisms of FDA-approved CNS drugs on neurons and microglia. A high-

content screen of 320 FDA-approved CNS drugs on iPSC-derived neurons, microglia and co-cultures is to

ascertain effects on main phenotypes associated with Alzheimer’s disease (AD) both in neurons (amyloid

production, endosomal trafficking, lysosomal clearance, Tau phosphorylation) and iPSC-microglia (amyloid

clearance, synaptic pruning, cytokine profile), with hits validated through co-cultures and through deep-

learning-aided drug interactions.

Clinical effects of these drugs will be evaluated using the SLaM NIHR BRC Clinical Record Interactive Search

(CRIS) data resource with detailed clinical data on all SLaM services of 15,000 patients with new dementia

diagnoses, and prognostic markers including routine cognitive function trajectories and markers of frailty such

as hospitalisations, mortality. Access to Primary Care data resources (e.g. CPRD) will be used to ascertain

associations with dementia incidence for cross-testing hypotheses.

This work can identify drugs that could modulate the risk for AD and also lead to repurposing for Alzheimer’s,

for which there is currently no cure. In addition, A.I (artificial intelligence)/ deep-learning assisted validation of

drug-mechanism studies should help discover potential new drugs/ pathways for AD therapy.

• M1/M2: Literature search Rajendran and Stewart Labs

• M6/7: Training & Establishment of assays in iPSC-derived neurons & microglia / Introduction to

CRIS

• M18: Screen & analysis and replication

• M28: Clinical epidemiology & cross-testing

• M35 : Machine-learning/ DL-assisted validation & the in-silico prediction

• M38 : Writing & submission of Thesis/ Papers


Rosa C. Paolicelli, Ali Jawaid, Christopher Henstridge, Andrea Valeri, Mario Merlini, John Robinson, Edward

Lee, Jamie Rose, Stanley Appel, Virginia M.-Y. Lee, John Q. Trojanowski, Tara Spires-Jones, Paul E. Schulz

and Lawrence Rajendran*

TDP-43 Depletion in Microglia Promotes Amyloid Clearance but also Induces Synapse Loss Neuron 2017

Perera G, Pedersen L, Ansel D, Alexander M, Arrighi HM, Avillach P, Foskett N, Gini R, Gordon MF,

Gungabissoon U, Mayer M-A, Novak G, Rijnbeek P, Trifirò G, van der Lei J, Visser PJ, Stewart R. Dementia

prevalence and incidence in a federation of European electronic health record databases: the European

Medical Informatics Framework resource. Alzheimer’s & Dementia 2018; 14: 130-139.

60

55.2 Developing a microfluidic model of headache “pain”

Co-Supervisor 1A: Dr Ramin Raouf

School/Division & CAG: Wolfson CARD / IoPPN


KCL/KHP Website: https://www.kcl.ac.uk/ioppn/depts/wolfson/research/raouf-lab

Co-Supervisor 1B: Professor Peter J. Goadsby

School/Division & CAG: Basic and Clinical Neuroscience/ IOPPN


KCL/KHP Website: https://www.kcl.ac.uk/ioppn/depts/bcn/Our-research/Neurology/goadsby-holland-

headache-group/Lab-group-members.aspx


Scientific Background:

Migraine headache remains an unmet clinical challenge with significant impact on quality of life for the

sufferers. Headache pain is mediated by the peripheral axons of trigeminal neurons innervating cranial

structures and craniofacial blood vessels, while centrally synapsing onto the brainstem nuclei. Several

neurotransmitters and neuropeptides such as CGRP and neurokinin-1, that are released during migraine

headache, regulate pain transmission and the blood vessels but the basic mechanisms of generation of headache

pain are largely unknown.

Building upon a novel microfluidic based cell culture platform developed in Raouf lab, the objective of this

project is to develop a microfluidic model that recapitulates the nociceptive neuronal circuit headache pain,

i.e., an in vitro model of headache. Using this microfluidic co-culture platform the candidate will investigate

sensitization of trigeminal neurons and modulation of synaptic transmission between the trigeminal and brain

stem neurons. The project will be based at the Wolfson Centre for Age-Related Diseases, Guy’s Campus.

Year 1 /2: Techniques: cell culture, microfluidic culture, viral tracing, calcium imaging. The prospective

candidate will learn cell culture and cell imaging techniques and characterize the co-cultures.

Year 3/4: Techniques: Pharmacology and patch clamp recording. The objective of the year is to investigate

the regulation synaptic transmission by CGRP and other modulators. Stretch goal would be to differentiate

neurons that innervate cranial meninges and compare their properties to the neurons innervating the skin.

Translational Significance: Understanding the molecular mechanisms that are involved in headache pain will

lead to generation of more effective therapeutics. The microfluidic based cell models offer a novel approach to

investigate the basic mechanisms of headache pain signalling, and hence, identify novel targets that can be used

for drug discovery development.


Vysokov, N., McMahon, S.B. & Raouf, R. 2019, The Role of NaV channels in synaptic transmission after

axotomy in a microfluidic culture platform, Scientific Reports, https://doi.org/10.1038/s41598-019-49214-w

(in press)

Ho, T.W., Edvinsson, L., and Goadsby, P.J. 2010, CGRP and its receptors provide new insights into migraine

pathophysiology. Nature Review Neurology 6(10), 573-582.

61

56.2 Molecular basis of visual learning

Co-Supervisor 1A: Beatriz Rico

School/Division & CAG: Neuroscience, Dept of Neurodevelopmental Neurobiology, MRC Centre for

Neurodevelopmental Disorders



Co-Supervisor 1B: Adil Khan

School/Division & CAG: Neuroscience, Centre for Developmental Neurobiology, MRC Centre for

Neurodevelopmental Disorders


KCL/KHP Website: www.khanlab.net


Animals are remarkably adept at learning new and arbitrary associations between objects, places, and events,

and this ability is essential for survival in an ever-changing environment. The ability to learn is believed to

depend on the plasticity of cortical circuits, which produce neural activity that is adapted to the current goal of

the animal. In the mammalian cerebral cortex this plasticity depends on the interactions between two main

types of neurons, excitatory pyramidal cells and inhibitory interneurons. Increasing evidence suggests that

interneurons play a key role in fine-tuning and enhancing cortical plasticity. This is particularly relevant in

neurodevelopmental disorders, where strong evidence implicates a misbalance between excitation and

inhibition. However, there is little understood about the molecular codes orchestrating these network

dynamics and what happens when they fail during development or adulthood. Novel methods and tools have

opened the possibility of studying the molecular underpinnings of cortical plasticity, by measuring and

manipulating the activity of networks of neurons in mice learning a novel task, while at the same time

perturbing defined molecular pathways.

The aim of this project will be to investigate the molecular players involved in plasticity and whether

comparable molecular codes are involved in plasticity during development and adulthood. To explore this, we

will investigate how genetic mouse models with altered inhibitory circuits accomplish the learning of a novel

task. We will use a multidisciplinary approach, combining loss of function experiments (cre-loxP, shRNA,

CRISPR-Cas9) and in-vivo calcium imaging from neural populations as mice learn a visual discrimination task.

Over-arching objectives, Year 1: Learn experimental techniques, including synaptic connectivity analysis and

mouse behaviour. Acquire pilot data for candidate genes. Year 2: Acquire synaptic data from genetic

disruptions. Year 3: Perform in-vivo imaging with genetic disruptions.


Favuzzi E*, Deogracias R*, Marques-Smith A, Maeso P, Exposito-Alonso D, Kroon T., Baglia M.,

Fernandez- Maraver E, Rico B. Distinct molecular programs regulate synapse specificity in cortical inhibitory

circuits, Science, 263:413 (2019).

Khan, A.G., Poort, J., Blot, A., Chadwick A., Sahani, M., Mrsic-Flogel, T.D., Hofer, S.B. (2018). Distinct

learning-induced changes in stimulus selectivity and interactions of GABAergic interneuron classes in visual

cortex. Nature Neuroscience 21(6):851-859

62

57.2 Nonconformity to gender-related expectations and ideals: Investigation of

interpersonal difficulties and mental health

Co-Supervisor 1A: Dr Katharine Rimes

Research School/Division: Dept of Psychology, Institute of Psychiatry, Psychology and Neuroscience.


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/katharine.rimes.html

https://www.kcl.ac.uk/ioppn/depts/psychology/research/ResearchGroupings/LGBT-Mental-Health.aspx

Co-Supervisor 1B: Dr Patrick Smith

School/Division & CAG: Dept of Psychology, Institute of Psychiatry, Psychology and Neuroscience.


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/patrick.smith.html


“Gender nonconformity” is often used to refer to nonconformity to society’s gender-related expectations

regarding preferences for activities/relationships/appearance or one’s gender identity. Childhood gender

nonconformity is more common in people who identity as a sexual or gender minority in adulthood but is also

reported by others. There are also societal gender-related ideals regarding physical attractiveness. Childhood

nonconformity with gender-related stereotypical expectations or physical ideals is associated with increased

mental illness in childhood and adulthood. This may be due to increased risk for bullying, interpersonal

difficulties, family relationship problems or abuse. The resulting distress and reduced confidence may trigger

coping responses with unhelpful consequences that increase risk for mental health problems. Little is known

about effective interventions or how different components of childhood gender nonconformity are associated

with specific interpersonal difficulties, coping strategies or mental illness.

Objectives:

Years 1 & 2

• Systematic review: Relationship between childhood gender nonconformity and interpersonal difficulties

e.g. bullying, social exclusion.

• Longitudinal study: analysis of secondary data from birth cohort study investigating the relationship

between childhood gender nonconforming behaviour and self-harm/suicidality in young adulthood and

possible mediation by interpersonal difficulties.

• Large retrospective study with adults: Associations between different components of childhood gender

nonconformity, types of interpersonal difficulties, unhelpful coping strategies and mental health problems.

Year 3

Pilot study investigating acceptability of brief intervention to improve social support/inclusion for gender

nonconforming young people delivered via short videos, co-produced with young adults and informed by

research and theory.

Skills training:

Systematic reviews; Advanced statistical analysis; Clinical intervention development and evaluation.


Villalta, L., Smith, P., Hickin, N., & Stringaris, A. (2018). Emotion regulation difficulties in traumatized

youth: a meta-analysis and conceptual review. European child & adolescent psychiatry.

https://doi.org/10.1007/s00787-018-1105-4

Warren, A-S., Goldsmith, K. A., & Rimes, K. A. (2019). Childhood gender-typed behavior and emotional or

peer problems: A prospective birth-cohort study. Journal of Child Psychology and Psychiatry, 60(8), 888-896.

https://doi.org/10.1111/jcpp.13051

63

58.2 The impact of diet on early adversity, brain maturation and mental health in

young adolescents

Co-Supervisor 1A: Dr Ana Rodriguez-Mateos

School/Division & CAG:Deoartment of Nutritional Sciences, School of Life Course Sciences


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/ana.rodriguez-mateos.html

Co-Supervisor 1B: Professor Paola Dazzan



KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/paola.dazzan.html


Adolescence is a crucial developmental period for the emergence of mental health problems in vulnerable

individuals. Risk for these disorders is dramatically increased by exposure to early adversity, such as childhood

maltreatment, adverse life events and area-level disadvantage. Recent evidence suggest that diet is an

important factor affecting mental health. A recent systematic review in children and adolescents has

highlighted the crucial association between healthy dietary patterns and lower levels of depression. However,

most of this evidence is based on the use of dietary self-reporting, such as food frequency questionnaires, an

approach that is highly inaccurate. In contrast, biomarkers of food intake provide an objective assessment of

dietary intake. In this work, data from two existing cohorts in 400 adolescents (MRC funded EA-BRAIN

project), will be used to investigate relationships between biomarkers of food intake, early adversity, early

brain developmental trajectories, immune biomarkers, and psychopathology.

Specific objectives are:

1) To analyze biomarkers of food intake in plasma and urine samples from 400 adolescents using targeted

metabolomics (YEAR 1).

2) To investigate associations between biomarkers of food intake, dietary patterns, early adversity, brain

maturation and mental health (YEAR 2)

3) To analyze other plasma and urinary biomarkers related to mental health disorders and investigate their

relationship with diet and mental health (YEAR 3)

The student will learn a wide range of techniques in the areas of analytical chemistry (in particular mass

spectrometry, chromatography), metabolomics, bioinformatics, and dietary assessment methods


Rodriguez-Mateos A, Istas G, Boschek L, Feliciano RP, Mills CE, Boby C, Gomez-Alonso S, Milenkovic D,

Heiss C. Circulating Anthocyanin Metabolites Mediate Vascular Benefits of Blueberries: Insights From

Randomized Controlled Trials, Metabolomics, and Nutrigenomics.J Gerontol A Biol Sci Med Sci.

2019;74(7):967-976. doi: 10.1093/gerona/glz047.

Fusté, M., Pauls, A., Worker, A., Reinders, A. A. T. S., Simmons, A., Williams, S. C. R., Haro, J. M.,

Hazelgrove, K., Pawlby, S., Conroy, S., Vecchio, C., Seneviratne, G., Pariante, C. M., Mehta, M. A. &

Dazzan, P. Brain structure in women at risk of postpartum psychosis: an MRI study. Translational psychiatry

2017; 7, 12, p. 1286.

64

59.2 Healthy ageing and cognitive decline: How important is remembering through

our own eyes?

Co-Supervisor 1A: Dr Charlotte Russell

School/Division & CAG: Department of Psychology, IoPPN


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/charlotte.russell.html

Co-Supervisor 1B: Dr Caroline Catmur

School/Division & CAG: Department of Psychology, IoPPN


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/caroline.catmur.html


Episodic memory, our memory for personally experienced events, is central to our identity and sense of self.

This complex cognitive process is among the first to show age-related decline. Decline in this long-term

memory system is linked to poorer quality of life, an increased risk of dementia and functional decline in daily

activities. These impacts make it crucial to understand how episodic memory changes with age and which

changes are associated with a diagnosis of Mild Cognitive Impairment (MCI). This is important as MCI

increases the risk of developing dementia. Our recent work has shown that there is a specific decline in

remembering from one’s own perspective as we age (Russell et al, 2019). Here we are interested in

investigating both the extent and the implications of this deterioration of self-perspective in episodic memory.

We then will examine whether targeting this skill with transcranial direct current stimulation (tDCS) will lead

to improvements in our tasks and in memory.

Skills training will be provided in both neuropsychological testing and neurostimulation.

Objectives:

Year 1: Development, running and analysis of two behavioural studies with healthy

ageing participants and younger control participants. Commence patient recruitment.

Year 2: Based on data from Year 1 - develop, run and analyse behavioural study

comparing MCI patient and control participants. Commence neurostimulation

interventions with both patients and healthy groups.

Year 3: Complete and analyse neurostimulation interventions. Write-up thesis.


Russell C., Davies S., Li K., Musil A.S., Malhotra P.A., Williams A.L. (2019) Selfperspective in episodic

memory after parietal damage and in healthy ageing. Neuropsychologia.;124:171-181.

Santiesteban, I., Kaur, S., Bird, G. & Catmur, C. (2017). Attentional processes, not implicit mentalizing,

mediate performance in a perspective-taking task: Evidence from stimulation of the temporoparietal junction.

NeuroImage, 155 : 305-311.

65

60.2 Investigating pain mechanisms in wound healing and pathological keloid scars

Co-Supervisor 1A: Tanya Shaw

School/Division & CAG: FoLSM, SIMS, Department of Inflammation Biology


KCL/KHP Website: https://www.kcl.ac.uk/research/profile/shaw-lab

Co-Supervisor 1B: Franziska Denk

School/Division & CAG: IoPPN, Wolfson Centre for Age-Related Diseases


KCL/KHP Website: franziskadenk.com


Our immune and nervous systems are vital for the protection of our bodies. Abnormal neuroimmune

interactions often lead to disease, particularly in barrier tissues like skin. For example, keloid scars are partly

due to immune and inflammatory cells not responding as they should to a wound. The resulting fibrotic lesion

is not just unsightly, but frequently extremely painful.

One mystery is why some patients with keloids experience no symptoms beyond scarring, while others suffer

from excruciating pain. This project would investigate why this might be. We hypothesize that painful keloid

scars are more likely to release substances that sensitise neurons, and importantly, that blocking these

substances might reduce pain.

You will receive training in both neuroscience and immunological techniques and will work with human

tissue/cells and animal models.

The aims are to:

Year-1: test whether keloid fibroblasts from painful scars release more interleukin 6 (IL6) or nerve growth

factor (NGF) than those from non-painful ones.

Year-2: use conditioned medium experiments to investigate whether blocking IL6 or NGF will reduce

neuronal sensitisation in vitro and/or alter the fibrotic reaction of fibroblasts.

Year-3: use transgenic mice in which fibroblasts cannot make IL6 or NGF to demonstrate that these factors are

a major source of persistent pain.

This work will put you in contact with the very patients who could potentially benefit directly from your

research; if your project demonstrates the involvement of IL6 or NGF, it may be relatively straightforward to

block them in the scar tissue and thus block pain.


Shaw, T.J. and Martin, P. (2016).Wound repair: a showcase for cell plasticity and migration. Curr Opin Cell

Biol 42, 29-37.

Hore Z, Denk F (2019). Neuroimmune interactions in chronic pain – An interdisciplinary perspective. Brain,

Behavior, and Immunity 79, 56-62.

66

61.2 Using virtual reality to investigate sense of body ownership and agency in

patients with functional neurological disorder.

Co-Supervisor 1A: Dr Paul Shotbolt

School/Division & CAG: Institute of Psychiatry, Psychology and Neuroscience/ Academic

Psychiatry/Psychological Medicine

KCL/KHP E-mail:[email protected]

KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/paul.shotbolt.html

Co-Supervisor 1B: Dr Sukhi Shergill

School/Division & CAG: Institute of Psychiatry, Psychology and Neuroscience/ Academic

Psychiatry/Psychosis


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/sukhi.shergill.html


Functional Neurological Disorder (FND) is the second commonest diagnosis in neurology clinics and causes

significant disability (Carson & Stone, 2015). Motor FND symptoms are subjectively reported by patients as

involuntary (Edwards, 2012). This may be mediated by altered sense of body ownership and agency, also

found in schizophrenia (Shergill 2014).

Previous studies of these constructs, using experimental paradigms such as the rubber hand illusion, have led to

conflicting results. In this project, novel VR environments will be used. We anticipate that their immersive

nature plus the ease of manipulation to change experimental conditions will allow more valid investigation.

The hypotheses are that, compared to controls, patients with FND and schizophrenia will; 1. be more

susceptible to manipulation of sense of body ownership. 2. show reduced agency over the movements of an

avatar.

25 individuals diagnosed with FND, 25 with schizophrenia and 25 healthy controls recruited. Body ownership

and agency assessed in two VR environments; a ‘virtual mirror’ avatar (participants see an avatar in front of

them that follows their movements), and a ‘virtual body illusion’ (participants see a projected true image of

their body from the back).

Skills Training

1. assessment of FND/schizophrenia patients 2. VR design 3. all aspects of relevant research methods and data

analysis.

Objectives:

Year 1: Systematic review of agency / body ownership in FND and other clinical populations. Finalise design

and VR environments, prepare final protocol, regulatory approval, start recruitment.

Year 2: Run and complete study, secondment with Mesmerise

Year 3: Write up thesis and publications, disseminate results.


Specialist inpatient treatment for severe motor conversion disorder: a retrospective comparative study.

McCormack R, Moriarty J, Mellers JD, Shotbolt P, Pastena R, Landes N, Goldstein L, Fleminger S, David AS.

J Neurol Neurosurg Psychiatry. 2014 Aug;85(8):895-900

Functional magnetic resonance imaging of impaired sensory prediction in schizophrenia.

Shergill SS, White TP, Joyce DW, Bays PM, Wolpert DM, Frith CD. JAMA Psychiatry 2014 Jan;71(1):28-

35.

67

62.2 Adolescent psychopathology and disrupted decision making about the future:

An investigation of behavioural and neural processes.

Co-Supervisor 1A: Professor Edmund Sonuga-Barke

School/Division & CAG: Institute of Psychiatry, Psychology and Neuroscience, Child & Adolescent

Psychiatry Department


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/edmund.sonuga-barke.html

Co-Supervisor 1B: Jacqueline Phillips Owen

School/Division & CAG: Institute of Psychiatry, Psychology and Neuroscience, Child & Adolescent

Psychiatry Department



Adolescents’ decisions significantly impact later life chances. The ability to realistically contemplate future

outcomes is a critical determinant of effective decision-making. If processes of prospection are disrupted or

distorted this is likely to lead to bad decisions creating long-term disadvantage.

Given this, it is surprising how little is known about the links between adolescent psychopathology and future

orientated decision-making ability. Even less is known about the neural processes that underpin such links.

Adolescents affected by psychopathology often underachieve in later life and these adverse outcomes may be

in part shaped by either disruptions to decision-making or even an unwillingness to engage in future-oriented

thinking at all. Building on our successful pilot work, supported by start-up monies provided by the BRC to

Professor Sonuga-Barke, this project will examine the effects of three types of psychopathology: anxiety,

depression and attention deficit-hyperactivity disorder on the quality of future-thinking abilities. It will

involve the use of experimental methods combined with EEG to understand the underlying behavioural and

neural processes. The project will provide excellent training combining as it does a wide range of methods used

in mental health and neuroscience research. Students will develop their data analysis, writing and presentation

skills and will learn systematic reviewing/meta-analysis.

Yearly objectives:

Year 1: To develop a study protocol, obtain ethical approvals and conduct a pilot study.

Year 2: To complete a literature review and focus on data collection.

Year 3: To complete data collection and focus on analyses and writing-up.


Sonuga-Barke EJS, Cortese S, Fairchild G, Stringaris A (2016). Trans-diagnostic neuroscience of child and

adolescent mental disorders: Differentiating decision-making in attention-deficit/hyperactivity disorder,

conduct disorder, depression and anxiety. Journal of Child Psychology & Psychiatry, 57, 32-349.

Kariuki S, Newton CRJ, Abubakar A, Bitta MA, Odhiambo R, Phillips_Owen, J (2018). Evaluation of

Psychometric Properties and Factorial Structure of ADHD Module of K-SADS-PL in Children From Rural

Kenya. Journal of Attention Disorders. https://doi.org/10.1177/1087054717753064

68

63.2 Regulation of neural stem cell quiescence by non-coding RNA

Co-Supervisor 1A: Rita Sousa-Nunes

School/Division & CAG: IoPPN, Centre for Developmental Neurobiology


KCL/KHP Website: https://devneuro.org/cdn/group-

overview.php?groupID=88&height=1254&width=2220&ref=group-leaders

Co-Supervisor 1B: Marc-David Ruepp

School/Division & CAG: IoPPN, Department of Basic and Clinical Neuroscience


KCL/KHP Website: https://www.kcl.ac.uk/ioppn/depts/bcn/dri/lab-groups/index.aspx


Background. Regulated proliferation of stem cells is required for growth, maintenance and repair of tissues.

Many stem cells undergo periods of reversible cell-cycle arrest accompanied by low biosynthetic activity,

termed quiescence. Quiescence prevents stem cell exhaustion and proliferation-induced mutations. Neural

stem cells (NSCs) are mostly quiescent in the adult mammalian CNS. Their (re)activation also regulates

learning, memory and mood. Cancer cells too can undergo quiescence, rendering them refractory to chemo-

and radiotherapies. Despite its importance, quiescence remains poorly understood at cellular and molecular

levels.

The Sousa-Nunes laboratory has discovered a novel, evolutionarily conserved, post-transcriptional mechanism

of controlling NSC quiescence/activation: subcellular compartmentalisation.

Aims. 1. Identification of mRNA species accumulating over time in quiescent NSC subcellular

compartments.

2. Determination of the processing status of these mRNA.

Models. Mouse primary adult hippocampal NSC cultures for transcriptomic studies; validation of key findings

in vivo in mouse and Drosophila, enquiring into evolutionary conservation.

Training. The student will acquire diverse ‘wet’ and ‘dry’ skills (already established among the two

laboratories): subcellular fractionation, RNA isolation, RNAseq, small molecule fluorescent in situ

hybridisation, molecular biology, lentiviral-mediated gene delivery, immunohistochemistry, confocal

microscopy, genetics, and bioinformatics.

Year 1: Total RNAseq on fractions of active and quiescent NSCs

Year 2: Validation of RNAseq results in vitro and then in vivo

Year 3+: Characterization of levels and activity of mRNA export machinery

Deciphering molecular mechanisms of compartmentalisation using validated targets


Sousa-Nunes R, Lee LL, Gould AP (2011) Fat cells reactivate quiescent neuroblasts via TOR and glial insulin

relays in Drosophila. Nature 471:508-12.

Ruepp MD#, Aringhieri C#, Vivarelli S, Cardinale S, Paro S, Schümperli S, Barabino SML (#equal contribution)

(2009) Mammalian pre-mRNA 3’ end processing factor CF Im68 functions in mRNA export. Molecular Biology of the

Cell, 20:5211-5223.

69

64.2 Illuminating the darkness: Developing neuroimaging biomarkers for bipolar

depression

Co-Supervisor 1A: Dr Paul Stokes, Reader in Mood Disorders & Psychopharmacology

School/Division & CAG: Institute of Psychiatry, Psychology & Neuroscience, Division of Academic

Psychiatry. Psychological Medicine and Older Adults CAG

KCL E-mail: [email protected]

KCL Website: https://kclpure.kcl.ac.uk/portal/paul.r.stokes.html

Co-Supervisor 1B: Professor Anthony Cleare,

School/Division & CAG: Institute of Psychiatry, Psychology & Neuroscience, Division of Academic

Psychiatry. Psychological Medicine and Older Adults CAG

KCL Email: [email protected]

KCL Website: https://kclpure.kcl.ac.uk/portal/anthony.cleare.html


Overview: Depressive symptoms experienced by people with bipolar disorder cause a great deal of distress and

increase risks of self-harm. People who experience bipolar depression find that they don’t enjoy their lives and

experience difficulties with motivation and processing emotions. Although bipolar depression is an important

clinical challenge for which we have few treatments, we know relatively little about how abnormalities in brain

signalling may cause symptoms. This project will use state of the art functional MRI (fMRI) neuroimaging

techniques to examine abnormalities in reward, motivation and emotional processing brain systems in people

with bipolar depression. We will compare how these systems function in bipolar depression in comparison to

people with unipolar depression and healthy people. This project aims to develop a neuroimaging biomarker

for bipolar depression which can be used to examine the effect of new treatments.

Training: This project, supervised by two leading experts in mood disorders and neuroimaging, provides a

fantastic range of training opportunities. The student will receive training in the clinical assessment of people

with mood disorders, functional and structural MRI neuroimaging, and image analysis. The project provides

great opportunities to learn the practicalities of participant recruitment and fMRI imaging in mood disorders.

Objectives:

Year 1: Understand fMRI methodology, systematically review neuroimaging studies, gain expertise in

recruiting and imaging participants.

Year 2: Develop expertise in fMRI, and experience in neuroimaging and behavioural data analysis.

Year 3 / 4: Consolidate skills, complete imaging analysis, present results at an international conference,

submission of thesis and study publications.


Hidalgo-Mazze D, Berk M, Cipriani A, Cleare A, Di Florio A, Dietch D, Geddes J, Goodwin GM, Grunze H,

Hayes JF, Jones I, Kasper S, Macritchie K, McAllister-Williams RH, Morriss R; Nayrouz S, Pappa S, Soares

JC, Smith DJ, Suppes T, Talbot P, Vieta E, Watson S, Yatham LN, Young AH, Stokes PRA. Treatment-

resistant and Multi-therapy resistant criteria for bipolar depression: A consensus definition. British Journal of

Psychiatry January 2019; 214 (1) 27-35

Wise T, Marwood L, Perkins AM, Herane-Vives A, Williams SCR, Young AH, Cleare AJ*, Arnone D*(2018)

(*Joint Senior Authorship). A Morphometric Signature of Bipolarity in Unmedicated Major Depression. Acta

Psychiatrica Scandinavica, 138, 73-82.

70

65.2 Imaging glutamate with GluCEST: investigating the mechanistic action of

ketamine in depression

Co-Supervisor 1A: James Stone

School/Division & CAG: Neuroimaging, Affective Disorders


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/james.m.stone.html

Co-Supervisor 1B: David Lythgoe

School/Division & CAG: Neuroimaging


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/david.lythgoe.html


Changes in glutamatergic neurotransmission have been hypothesised to underlie a number of different mental

illnesses including depression, schizophrenia and autism. Most studies to date have used Proton Magnetic

Resonance Spectroscopy (1H-MRS) to measure glutamate levels in the brain. This method, although having

good temporal resolution, is of poor spatial resolution – it is necessary to define an a-priori region of interest

which is usually of 20mm3 or larger. This makes comparison of data between different studies more

problematic because many centres will have slightly different protocols for region of interest placement.

GluCEST (Glutamate Chemical Exchange Saturation Transfer) is a novel method, possible only at ultra-high

(7T) MRI field strengths. This method yields a high-resolution image, with each voxel intensity correlating

with the glutamate concentration.

Ketamine has emerged as a novel treatment for depression with a glutamatergic mechanism of action. One 1H-

MRS study has suggested that patients with lower levels of glutamate in the anterior cingulate have a more

marked response to ketamine.

In this study, the student will develop GluCEST imaging methods at the 7T scanner at St Thomas’ Hospital.

Initial development will include comparison of GluCEST data to 1H-MRS data acquired from the same

region. In the second part of the PhD the student will use GluCEST imaging in patients with depression prior

to ketamine treatment – testing the hypothesis that those patients who respond to ketamine have lower levels

of brain glutamate than those who fail to respond.

Year 1: Development of GluCEST imaging methods at 7T including healthy volunteer scanning complete

systematic review of glutamate imaging in depression.

Year 2: Commence GluCEST imaging in patients, present data at British Association of Psychopharmacology.

Year 3: Finalise data collection, analyse data and write up.


Stone J, Kotoula V, Dietrich C, De Simoni S, Krystal JH, Mehta MA. Perceptual distortions and delusional

thinking following ketamine administration are related to increased pharmacological MRI signal changes in the

parietal lobe. J Psychopharmacol. 2015 Sep;29(9):1025-8.

Wise T, Taylor MJ, Herane-Vives A, Gammazza AM, Cappello F, Lythgoe DJ, Williams SC, Young AH,

Cleare AJ & Arnone D. (2018) Glutamatergic hypofunction in medication-free major depression: Secondary

effects of affective diagnosis and relationship to peripheral glutaminase. J. Affect. Disord., 234, 214–219.

71

66.2 Aggression and Irritability in Neurodevelopmental Disorders: A Translational

Approach

Co-Supervisor 1A: Prof. Andre Strydom

School/Division & CAG: Institute of Psychiatry, Psychology and Neuroscience (Behaviour and

Developmental disorders CAG)


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/en/persons/andre-strydom(ac4f7c9a-cea3-4fa7-bfce-

3e8b5866ce8c).html

Co-Supervisor 1B: Dr Diana Cash

School/Division & CAG: IOPPN/ Neuroimaging Department/ BRAIN Centre for Preclinical Imaging


KCL/KHP Website: https://brain-imaging.org/; https://kclpure.kcl.ac.uk/portal/diana.cash.html


Aggression is a common form of challenging behaviour among individuals with neurodevelopmental disorders

(NDDs) such as autism and schizophrenia. Aggressive behaviours have a serious negative impact on both

affected individuals and their families, and society (e.g. school exclusion, costly care, and criminal justice

system involvement) - yet we lack effective treatments. Development of better interventions is urgently

needed, but our poor understanding of causal mechanisms hampers this.

In this project, we will combine human and rodent studies to examine neurobiological underpinnings of NDD-

associated aggression. The student will work with both humans and rodents carrying mutation in NRXN1 gene

to examine the brain biology of aggression in NDD, these mutations are associated with schizophrenia,

intellectual impairment, and autism in humans. The student will use EEG and MRI/MRS as translational tools

to examine brain structure, function and biochemistry in-vivo. Thus, we aim to define the brain systems

involved in aggression in NDD in patients and then establish whether these signatures can be recapitulated in

mice carrying the same genetic mutation. This back-translation into animal models coupled with cutting-edge

methods (e.g. 3D imaging in transparent brains (CLARITY), optogenetics, electrophysiology) will help to

identify underlying mechanisms and generate treatment targets.

Skills Training: ethics, patient assessment, human/rodent MRI, EEG and behavioural tests,

immunohistochemistry, microscopy, optogenetics

Overarching objectives for the project

Rotation/Year 1: Patient recruitment/assessment; behavioural tests for social interaction/aggression in a mouse

model

Year 2: Structural/functional assessment of patients/ mouse model

Year 3: Data analysis; pharmacological intervention in a mouse model with subsequent structural/behavioural

evaluation


Thygesen, J. H., Wolfe, K., Mcquillin, A., Viñas-jornet, M., Baena, N., Brison, N., ... Vogels, A. (2018).

Neurodevelopmental risk copy number variants in adults with intellectual disabilities and comorbid psychiatric

disorders. British Journal of Psychiatry, 212(5), 287-294. https://doi.org/10.1192/bjp.2017.65

Walker SE, Wood T, Cash D, Mesquita M, Williams SCR, Sandi C (2018) Alterations in brain

microstructure in rats that develop abnormal aggression following peripubertal stress. Eur. J. Neurosci. 1-45.

doi:10.1111/ejn.14061

72

67.2 Autism Spectrum Disorders and eating disorders: exploration of the benefits

and costs of a tailored clinical pathway

Co-Supervisor 1A: Prof Kate Tchanturia

School/Division & CAG: Psychological Medicine, IoPPN


KCL/KHP Website: www.katetchanturia.com / https://kclpure.kcl.ac.uk/portal/kate.tchanturia.html

Co-Supervisor 1B: Prof Sarah Byford

School/Division & CAG: Health Service & Population Research, IoPPN


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/s.byford.html


Anorexia Nervosa (AN) and Autism spectrum disorders (ASD) often coexist. Epidemiological and clinical

audit data suggest that 35-37% of adults with AN might have comorbid ASD. Patients with AN and

undiagnosed ASD are often treated with standard eating disorder treatment programmes without tailoring the

environment or treatment strategies to their dual diagnosis, which might explain why studies show longer

admissions and poorer treatment outcomes for patients with both conditions.

We have recently launched a novel ASD/AN clinical pathway. However, there is a need to evaluate whether

the additional cost of this tailored pathway can be justified in terms of savings from reduced use of other health

services (e.g. admissions) and benefits to patients. This will be a mixed-methods project (qualitative and

quantitative components) and will be tailored to the candidate’s interests. Objectives: Yr1 systematic review

and quantitative data collection, Yr2 quantitative/economic analysis and qualitative data collection, Yr3

qualitative analysis and write-up.

This project will provide an excellent training opportunity for a PhD student to access and develop expertise in

two complementary disciplines (KT clinical scientist practitioner; SB health economist) and make a unique

contribution to an undeveloped area. The student will be encouraged to develop transferable skills and be an

active part of two vibrant research departments in the IoPPN, whilst working closely with clinicians and the

world-class National Eating Disorder Service. Strengths of the project include the breadth offered in studying

ASD and AN and qualitative and quantitative methods, and the opportunity to have real impact on clinical

and NHS policy.


Westwood H, Tchanturia K (2017) Autism Spectrum Disorder in Anorexia Nervosa: An Updated Literature

Review Current Psychiatry Reports doi: 10.1007/s11920-017-0791-9

Barrett B, Mosweu I, Jones CRG, Charman T, Baird G, Simonoff E, Pickles A, Happe F, Byford S (2015).

Comparing service use and costs among adolescents with autism spectrum disorders, special needs and typical

development. Autism, 2015, 19, 562-569 doi: 10.1177/1362361314536626

73

68.2 Using smartphone-based personal sensing to understand and predict risk of

psychotic relapse at the individual level.

Co-Supervisor 1A: Stefania Tognin

School/Division & CAG: IoPPN / Academic Psychiatry / Psychosis


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/stefania.1.tognin.html

Co-Supervisor 1B: Andrea Mechelli

School/Division & CAG: IoPPN / Academic Psychiatry / Psychosis


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/a.mechelli.html


Psychosis is a debilitating disorder characterised by a range of symptoms including false beliefs, false

perceptions and disorganised thinking. Although antipsychotic medication can lead to rapid improvement in

the acute-phase, most patients subsequently relapse. A key challenge in the clinical management of psychosis is

that we have limited understanding of the factors that lead to a relapse; this means that doctors are unable to

optimise treatment of individual patients based on their level of risk. To address this challenge, we have

developed a smartphone app which allows the close monitoring of people across multiple contexts, time-points

and locations in real time (Urban Mind; www.urbanmind.info). In this project we will use an adapted version

of the Urban Mind app to measure daily social stress in a total of 450 patients with a first episode of the illness.

The main hypothesis is that daily social stress predicts future risk of psychotic relapse over a 12-month period.

The results will be used to develop a predictive model linking real-time measures of daily social stress with risk

relapse. The candidate will receive training in the recruitment and assessment of patients, data management,

smartphone data analysis and write up of scientific manuscripts.

Year-1:

• Training on recruitment and assessment

• Recruitment and baseline assessment of 50 participants

Year-2:

• Recruitment and baseline assessment of 50 participants

• Start of 12-month follow-up assessments

• Training on statistical analysis of the smartphone data

• Statistical analysis of baseline data

Year-3:

• Completion of 12-month follow-ups

• Statistical analysis of 12-month follow-up data

• Thesis writing-up

• Dissemination


Bakolis I, Hammoud R, Smythe M, Gibbons J, Davidson N, Tognin S, Mechelli A (2018). Urban Mind: Using

Smartphone Technologies to Investigate the impact of Nature on Mental Wellbeing in Real Time. Bioscience

68(2):134-45.

Reilly TJ, Mechelli A, McGuire P, Fusar-Poli P, Peter J Uhlhaas (in press). e-Clinical High Risk for Psychosis:

Potential of Digital Innovations For Preventive Psychiatry.JMIR Mental Health.

74

69.2 Investigating markers of neuroprogression in Anorexia Nervosa.

Co-Supervisor 1A: Professor Janet Treasure

School/Division & CAG: Psychological Medicine, IOPPN


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/janet.treasure.html

Co-Supervisor 1B: Dr Hubertus Himmerich

School/Division & CAG: Psychological Medicine, IOPPN


KCL/KHP Website: https://kclpure.kcl.ac.uk/portal/hubertus.himmerich.html

Name of Collaborating Clinician: Dr. Sandrine Thuret

School/Division & CAG: Basic and Clinical Neuroscience, IOPPN


Website: https://kclpure.kcl.ac.uk/portal/sandrine.1.thuret.html


Aim: To examine hippocampal function and neurogenesis in eating disorders.

Background: Calorie restriction (CR) – i.e. intermittent fasting – (without malnutrition) has been found to impact

on adult hippocampal neurogenesis (AHN) and function. The translational prediction drawn from this is that people

with eating disorder will show anomalies in hippocampal structure and function. This may contribute to the chronic

course and treatment resistance described in the staging model of anorexia nervosa

Hypothesis: Reduced hippocampal neurogenesis and functional anomalies will be found in the severe enduring

stage of anorexia nervosa but will be not be found in people with binge spectrum disorders.

Protocol: This project involves a multimethod assessment in patients with diverse forms of eating disorders in

different stages of the disorder (acute, chronic and recovered).

Participants: Recruitment of n=40 clinical subjects in each group.

1. Patients with anorexia nervosa (AN), acute (within one-year onset) & chronic illness (> 7 years of illness) and at

stages of renutrition (BMI<16, BMI>16, BMI>18) (Year 1-2.5).

2. Patients with binge spectrum disorders in active acute and chronic phase of illness and after recovery). ) (Year 1-

1.5)

Assessment Measures:

1. Self-report measures of specific eating disorder psychopathology and comorbid features (depression, anxiety,

OCD).

2. Hippocampal cognitive function. Memory and Learning test.

· Mnemonic Similarity Test (MST; pattern separation)

· Fear learning/unlearning paradigm (Eley KCL EDIT).

3. Blood markers influencing neurogenesis

· Growth factors and cytokines (BDNF, TNF-alpha and IL-6).

Skills: Clinical assessment and engagement (Year 1-2). Experimental medicine synthesis (year 2-3). Application for

further translational funding and dissemination (year 3-3.4)


Kan C, Treasure J. Recent Research and Personalized Treatment of Anorexia Nervosa. Psychiatr Clin North Am.

2019 Mar;42(1):11-19. doi: 10.1016/j.psc.2018.10.010. Epub 2018 Dec 22. Review. PubMed PMID: 30704633

Dalton B, Leppanen J, Campbell IC, Chung R, Breen G, Schmidt U, Himmerich H. A longitudinal analysis of

cytokines in anorexia nervosa. Brain Behav Immun 2019, Epub ahead of print.

75

70.2 The effect of mitochondrial transport and function on synaptic integrity during

ageing.

Co-Supervisor 1A: Alessio Vagnoni



KCL/KHP Website: https://bit.ly/2Np93aN

Co-Supervisor 1B: Deepak Srivastava



KCL/KHP Website: https://tinyurl.com/SrivastavaLab-KCL


Proper distribution of mitochondria is essential for maintaining neuronal homeostasis and many studies have

substantiated a role for defective mitochondrial transport and function in the pathogenesis of age-related

neuronal dysfunction. We have discovered a remarkable age-dependent decline in the axonal transport of

mitochondria in adult neurons of Drosophila. We showed that reduced transport contributes to the broader

decline of neuronal homeostasis that occurs during ageing while upregulation of this process appears to be

beneficial in older neurons. Synaptic loss is a hallmark of neurodegenerative and neurodevelopmental

disorders. However, how reduced transport influences synaptic stability and function throughout ageing is

surprisingly unknown. The PhD student will use cutting-edge microscopy approaches to uncover how

manipulating mitochondrial transport and function impacts on synaptic structure in intact Drosophila during

ageing.

Objectives

• Year 1 (or rotation project): Testing methods to optically clear whole adult Drosophila for high-

resolution microscopy. The student will use established clearing methods such as ScaleS and FlyClear

and 3D reconstruction of neuronal architecture by light-sheet microscopy.

• Year 2: Visualising neuronal structure and synaptic connections during ageing and after

RNAi/CRISPR-mediated reduction of mitochondrial subunits leading to transport and functional

impairment.

• Year 3: Studying how synaptic connections are shaped following treatments that restore mitochondrial

transport during ageing.

• Year 4: Testing whether augmenting transport mitigates the loss of synaptic structure in Drosophila

mutants that display reduced synaptic connectivity, for instance neurexin mutants. Writing papers and

thesis.

The student will be trained in: Drosophila genetics, molecular biology and biochemistry; advanced imaging

and image analysis/quantification.


Mattedi F, Vagnoni A (2019) Temporal Control of Axonal Transport: The Extreme Case of Organismal Ageing.

Front. Cell. Neurosci., 23 August 2019 https://doi.org/10.3389/fncel.2019.00393

Deans PJM et al. (2017) Psychosis Risk Candidate ZNF804A Localizes to Synapses and Regulates Neurite

Formation and Dendritic Spine Structure. Biol Psychiatry, Jul 1;82(1):49-61.

https://doi.org/10.1016/j.biopsych.2016.08.038

theme 2 neurosciences, psychiatry and mental [email protected] projects listed in this...

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