EU Aims – Lead Professor Declan Murphy
EU AIMs (European Autism Interventions – A Multicentre Study for Developing New Medications) is an innovative programme that will have genuine impact on academic, pharmaceutical, and regulatory stakeholders in the field of autism spectrum disorder (ASD).
There are no effective pharmacological treatments for the core symptoms of ASD, and our understanding of the pathophysiology of the disease is poor. Research is hampered by a lack of valid and reliable cellular assays and animal models; an absence of tests that demonstrate efficacy in healthy volunteers from childhood to adulthood; and the reliance of clinical trials on biologically heterogeneous groups of patients as operationally-defined by DSM/ICD10 categories. Further, even if novel treatments were developed, there is no EU platform to test them clinically. Despite these limitations, the recent identification of genetic risk factors for ASD provides unique opportunities to substantially improve this situation. AIMs therefore delivers an integrated, translational, effort to achieve key objectives for ASD research, which will deliver new research tools and standards for clinical development, and pave the way for drug discovery and clinical trials.
To implement this integrated effort, led by KCL, 13 ‘hubs’ in European institutions (with linked ‘satellites’ across the EU) have partnered with Autism Speaks (the world’s leading Autism Research Charity), three SMEs and EFPIA to: a) develop cellular assays and animal models based on confirmed genetic risks, and utilise these models to focus on translational endophenotypes for facilitating new drug discovery; b) validate biomarkers and patient group stratification to optimise conditions for clinical trials; and c) develop a sustainable EU-wide clinical infrastructure to promote research and development of new drugs. We will couple this integrated research effort with the development of new training opportunities and the implementation of new analytical approaches.
By the end of the 5 year project we expect to provide novel validated cellular assays, animal models, new fMRI methods with dedicated analysis techniques, new PET radioligands, as well as new genetic and proteomic biomarkers for patient-segmentation or individual response prediction. We will provide a research network that can rapidly test new treatments in man. These tools should provide our EFPIA partners with an added competitive advantage in developing new drugs for ASD.
Diagnostic specificity and treatment response prediction in Attention Deficit Hyperactivity Disorders: the role of frontal lobe connectivity – Dr Michel Thiebaut de Schotten
The aim of the project is to develop new tools that both help improve our understanding of the causes of Attention Deficit Hyperactivity Disorders (ADHD), and predict treatment response among patients assessed at the South London and Maudsley hospital (SLAM). Research participants will be screened for ADHD and undergo assessment with a list of neuropsychological tests, diffusion weighted MRI, resting state functional MRI before and after pharmacological stimulation. Behavioural and neuroimaging analyses will then be performed in order to test whether adults with ADHD who do not respond to stimulants have significant differences in both structural and functional ‘connectivity’ (the latter both at rest and in response to methylphenidate ‘challenge’); in contrast those who respond to treatment have abnormalities only at a functional level.
Inverness Project – Dr Susan Young
This study will investigate the clinical rates of ADHD at HMP Inverness, qualify the relationship between ADHD and substance misuse in these individuals, evaluate the ‘costs’ presented by individuals with untreated ADHD in prison in terms of service consumption, and identify appropriate treatment programmes that are likely to successfully rehabilitate prisoners into society. This will be achieved by assessing prisoners within HMP Inverness, where high rates of currently unrecognised ADHD are expected to be present and are further expected to be associated with increased substance use and greater service consumption.
Maternal prenatal depression on infant brain development – Dr Michael Craig
Prenatal depression affects 10–25% of women, and there is increasing evidence that children born to ‘stressed’ mothers have a significantly increased risk for cognitive and behavioral dysfunction during childhood (including neurodevelopmental disorders such as autism and ADHD), and depression in later life. The reason for this deleterious effect on infant development is most likely a complex, and poorly understood, interaction between social and biological factors. Nevertheless preliminary animal studies suggest that one explanation may be that increased transfer of maternal ‘stress hormones’ (e.g. cortisol) across the placenta affects the development of ‘limbic’ regions such as the amygdala and hippocampus. However, to date, no one has studied in humans whether the infants of mothers with prenatal depression have abnormalities in the limbic system. We have recently developed novel imaging methods, which allow safe, reliable, measurement of healthy infant brain anatomy (including myelination), and brain function as babies process emotional sounds. We now wish to extend our work and carry out a pilot study of brain anatomy and function of infants (aged 4-6 months) born to mothers who suffered from prenatal depression. We will test the main hypothesis that these infants, compared to control infants born to non-depressed mothers, have a significant reduction in the volume of limbic structures (e.g. amygdala and hippocampus). We also wish to test the subsidiary hypotheses that these infants have (a) reduced myelination of limbic white matter tracts that connect limbic brain regions and (b) increased amygdala activation in response to negative emotional sounds (e.g. crying) and reduced activation to positive sounds (e.g. laughter). Lastly we will carry out a preliminary investigation of the relationship between any differences we find in the infants and severity of maternal prenatal depression, and cortisol levels. If successful this pilot will form the basis of future large-scale grants investigating how maternal depression, and other mental health problems, affect infant brain development – and risk for subsequent behavioural abnormalities.
Neurodevelopment and Psychosis in the 22q11.2 Deletion Syndrome
Brain, behaviour and genetics in 22q11DS
Individuals with 22q11.2 deletion syndrome (22q11DS) (previously known as velocardiofacial syndrome (VCFS), Shprintzen syndrome or DiGeorge syndrome) are vulnerable to a range of physical and mental health difficulties. 22q11DS is a genetic disorder that occurs because of a deletion, or a missing piece, at chromosome 22. In addition to physical difficulties, including heart, palate and immune function, people with 22q11DS have significantly increased rates of psychiatric and behavioural difficulties, including autism spectrum disorder (ASD),episodes of psychosis and learning difficulties. However, despite an increased vulnerability to psychiatric difficulties, the cause of these behaviours are poorly understood and it can be particularly difficult for people with 22q11DS to access mental health services.
Brain imaging studies of people with 22q11DS are limited, but available studies show differences in brain structure and function. However, most brain imaging studies of people with 22q11DS included small samples of people whose psychiatric diagnoses were not clearly identified. As such, the neural basis of 22q11DS is poorly understood and studies including larger samples of people with clear psychiatric assessments are required. The aim of this project is establish a multicentre network with the University of California, Los Angeles (UCLA) and Cardiff University. We aim to investigate the anatomy, function and connectivity of brain systems that may contribute towards psychosis and ASD in people with 22q11DS using structural and restingstate functional magnetic resonance imaging (sMRI and rsfMRI) and diffusion tensor imaging (DTI) and to identify brain, behavioural and genetic risk factors for the emergence of ASD and psychotic symptoms in children and adults with 22q11DS.
Child Health and Development Project (CHADS) – Dr Kristin Laurens
The (London) Child and Health Development Study
The Child Health and Development Study (CHADS) has been running at the Institute since 2004. The project is led by Dr. Kristin Laurens, in collaboration with a multidisciplinary team of researchers and clinicians. Our team has worked with more than 8,000 children aged 9-11 years in London via collaborating primary schools, and with over 1,500 of their primary caregivers.
Among these, over 600 families continue to participate in our longitudinal research program, which focuses particularly on tracking mental health and well-being in the children as they transition from childhood into adolescence, and then onto young adulthood.
We also work intensively with ~150 children, following this cohort with detailed laboratory assessments every two years as they develop, with questionnaire measures, interviews, structural and functional imaging, event-related potential recordings of brain function, standardised assessments of cognition, hormonal changes, genetics etc.
We work both with children who are functioning well relative to their peers, as well as with children who are experiencing early adjustment difficulties.
The overall aim of our project is to determine the factors (social, psychological, and biological) that underlie different developmental pathways of health and illness from childhood through adolescence into young adulthood. By identifying these developmental processes, we hope to be able to inform and develop new opportunities and programs that reinforce strengths in children and mitigate vulnerabilities with early intervention.