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4 YEAR PhD IN NEUROSCIENCE

David Skuse

Behavioural and Brain Sciences Unit, Institute of Child Health

The Behavioural and Brain Sciences Unit is a 5* rated component of the Institute of Child Health, with a major research interest in the neurodevelopmental origins of normal variation in cognitive skills, in particular those concerned with social adjustment.

Unit staff are engaged in projects focused on typically developing children and adults, as well as clinically-related studies of autistic disorders. There are close links to Great Ormond Street Hospital for Children. The Unit’s research programmes are associated with a variety of inter-disciplinary collaborations, nationally and internationally.

AVAILABLE PROJECTS

1) Genetic influences on social perception

Turner syndrome patients, who have a partially or fully deleted X-chromosome, tend to experience social-cognitive problems similar to those seen in autism. In collaboration with colleagues at MIT we found that a rare allelic variant in a gene, EFHC2, influences their ability to recognise the facial expression of fear. Around 10% of males have this variant on their single X-chromosome. Recent findings indicate, in UCL male students, a significant impact on ‘theory of mind skills’.

The objective of this 3-month project would be to investigate the potential influence of the rare variant in males. Techniques learned during this placement would include an introduction to molecular genetics, functional and structural neuroimaging, and eye-tracking, as well as the measurement of evoked response potentials.

SELECTED PUBLICATIONS

Weiss LA, Purcell S, Waggoner S, Lawrence K, Spektor D, Daly MJ, Sklar P, Skuse D. Identification of EFHC2 as a quantitative trait locus for fear recognition in Turner syndrome. Hum Mol Genet. 2007 Jan 1;16(1):107-13

Skuse DH, James RS, Bishop DV, Coppin B, Dalton P, Aamodt-Leeper G, Bacarese-Hamilton M, Creswell C, McGurk R, Jacobs PA. Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function. Nature. 1997 Jun 12;387(6634):705-8.

2) Investigating the genetic basis of anti-cooperative behaviour

Why do we cooperate? Is it simply a culturally learned phenomenon, or does it have a biological- perhaps a genetic substrate? How would we prove the influence on genes on cooperation? How would we track those genes down? Experimental evidence and evolutionary models suggest that strong reciprocity, the behavioural propensity for altruistic punishment and altruistic rewarding, is of key importance for human cooperation. This has traditionally been measured in terms of Game Theory – the study of how individuals make decisions that may benefit themselves or others.

We have been studying genetic influences on cooperation using both a twin-study design and by association of behaviour during economic games with genetic variation at the molecular level. Our controversial findings indicate that genetic influences on ‘anti-cooperation’ are much stronger than those on cooperative behaviour. It seems many of us are born to be selfish and exploitative, but we are socialized to be kind and to share and cooperate. This is the opposite of what we expected to find.

A student joining this project would be working collaboratively with groups elsewhere in the world, probably including Richmond VA, Singapore, Beijing, and Israel, as well as Brazil. We are in the early phases of setting up a twin study in Sao Paulo, in order to test replication of the heritability findings made in the UK. There would be the opportunity to learn about behavioural economics, the design and analysis of twin studies, and the design and analysis of genetic association studies.

Zhong S, Israel S, Shalev I, Xue H, Ebstein RP, Chew SH. Dopamine D4 receptor gene associated with fairness preference in ultimatum game. PLoS One. 2010 Nov 3;5(11):e13765

Cesarini D, Dawes CT, Fowler JH, Johannesson M, Lichtenstein P, Wallace B. Heritability of cooperative behavior in the trust game. Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3721-6.

1. Molecular genetic and behavioural studies of autistic disorders

In the Social Communication Disorders Clinic at Great Ormond Street Hospital, we have seen children with autistic disorders for over a decade and have one of the largest research databases of ‘high functioning autism’ or Asperger syndrome, in the world. Patients coming to the clinic are routinely entered into research studies, including the exome-sequencing UK10k project run by the Wellcome Trust Sanger research centre in Cambridge.

If you have an interest in the interpretation of genetic data, at the molecular level – linking this information to phenotypic variation, and heritable risk – the project offers the opportunity to be at the ‘cutting edge’ of autism genetic research. The UK10k data will be available on our patients before the New Year (January 2012), many months before other genome sequencing is complete on other psychiatric conditions. You would work in collaboration between our research group in London and colleagues at the Sanger Centre, trying to make sense of a wealth of genetic information – this will be a considerable challenge, but could potentially result in several high-impact publications.

As an adjunct to the exome-sequencing project, you could learn about advanced techniques of 3D imaging and their analysis, with Professor Peter Hammond at the ICH. There are data sets of autistic individuals and their families awaiting analysis. This work could link with other evidence for abnormal growth of the skull and perhaps of the underlying brain in autistic disorders. It is highly novel, and could be linked to studies of genetic susceptibility or sub-phenotyping of the autistic spectrum based on an anatomical substrate.

O'Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, Karakoc E,  Mackenzie AP, Ng SB, Baker C, Rieder MJ, Nickerson DA, Bernier R, Fisher SE, Shendure J, Eichler EE. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011 Jun;43(6):585-9.

Hammond P, Forster-Gibson C, Chudley AE, Allanson JE, Hutton TJ, Farrell SA, McKenzie J, Holden JJ, Lewis ME. Face-brain asymmetry in autism spectrum disorders. Mol Psychiatry. 2008 Jun;13(6):614-23.

4. Evaluation of autistic behaviour, using novel techniques of physiological measurement and activity.

There is increasing interest in the use of biological monitoring devices to investigate differences between the individuals with a clinically diagnosed autism spectrum disorder and typical development. Domains that could be affected by autism include the following:

i) Activity:

a. at the level of motor stereotypies (e.g. hand flapping or spinning),

b. generalized overactivity (including excessive activity at night),

c. social activity – interactions with peers in unstructured social situations such as the school-yard during break-times

ii) Physiological arousal responses:

a. Hypothesis that proportion of ASD are chronically ‘over-aroused’

b. Inconsistent results from prior research

c. Interpretation of findings influenced by medication and by overall level of functioning (whether normal or low IQ subjects)

d. Experimental paradigms highly variable – usually laboratory-based and highly structured

e. Responses to sensory stimulation (e.g. sound) are of particular interest in view of revisions to diagnostic definitions pending.

Proposed project:

The aim of the proposed project will be, in the first instance, to develop miniature devices that could be worn by the subjects of the research to monitor activity and physiological arousal for defined periods of time.

Subjects:

The focus will be, in the first instance, upon typically developing young people, as a pilot study.

  • Main project will focus on schools providing education for children with autistic disorder, in the age-range 12-18 years in order to increase compliance.

Measures:

Measures will be as follows:

  • Physiological monitoring over period of up to one hour of relaxation
  • Motor (limb movement) activity monitoring on 24 hour-a-day basis if tolerated (would include overnight monitoring as proxy for evaluating sleep pattern.
  • GPS monitoring during periods of unstructured social interactions.

SELECTED PUBLICATIONS:

Levine TP, Sheinkopf SJ, Pescosolido M, Rodino A, Elia G, Lester B.

Physiologic Arousal to Social Stress in Children with Autism Spectrum Disorders:

A Pilot Study. Res Autism Spectr Disord. 2012 Winter;6(1):177-183.

Hirstein W, Iversen P, Ramachandran VS. Autonomic responses of autistic

children to people and objects. Proc Biol Sci. 2001 Sep 22;268(1479):1883-8.

More: https://iris.ucl.ac.uk/research/personal/index?upi=DHSKU85

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