Homeostatic Plasticity in Psychosis-related Copy Number Variation

Lead Research Organisation: University College London
Department Name: Psychology

Abstract

Psychosis has been characterised as disorder of aberrant salience, or maladaptive responses to changes in the external environment (Kapur, 2003). This model posits that psychotic symptoms start to appear when disordered dopaminergic transmission leads to the attribution of significance to stimuli that would normally be considered irrelevant. The relationship between this homeostatic deficit in the cognitive phenomenology of psychosis and homeostatic mechanisms of neural networks is not clearly understood, and can be difficult to study in vivo due to the complexity of cortical circuits. The genetic contribution to this regulatory deficit, particularly stemming from copy number genetic variants (deletions or duplications of large (~100kb+) segments of DNA), although robustly linked to psychosis in several instances, is also not mechanistically well defined.

My general hypothesis is that copy number variation (CNV) has a generic and pernicious effect on adaptive neuronal plasticity. This may be important in terms of understanding a variety of psychiatric syndromes (such as schizophrenia) in terms of abnormal gain control and cortical excitability. Aberrant salience and aberrant precision hypotheses of schizophrenia rest on abnormal gain control and its electrophysiological correlates (in particular, attenuated mismatch negativity [MMN] - an electrophysiological proxy for early auditory processing and neuronal plasticity (Baldeweg & Hirsch, 2015). I will therefore investigate this hypothesis using existing genetic and electrophysiological data from patients with psychosis, and address the same question at a synaptic level using cultured neurons induced from iPSCs with 22q11.2 deletions (which is the highest-risk CNV locus for schizophrenia).

The project primarily aims to:

Analyse existing data from a large cohort of subjects in terms of the relationship between CNVs and (attenuated) MMN in psychosis.
To generate cortical neurons from induced pluripotent stem cells (iPSCs) with copy number variants (CNVs) that are associated with an increased risk of psychosis (such as 22q11.2 deletion).
To investigate whether there are distinct cellular phenotypes in iPSC-neurons derived from 22q11.2 patients in response to changes in stimulation or extracellular conditions; i.e. how they respond to variation outside of an "attractor state" (a state of dynamic equilibrium, or least free energy).
Associate these neural network characteristics with cognitive endophenotypes of patients from whom the samples were collected (particularly in dealing with environmental variability & salience.

Techniques used:
- Genome-wide association (bioinformatics)
- Neurophysiology, analysis of EEG and evoked potential data
- Culturing human iPSCs
- Differentiating iPSCs into cortical neurons to generate neuronal networks
- Pharmacological stimulation of neuronal cultures
- Dynamic causal modelling (DCM)

Publications

10 25 50
 
Title Multi-centre MMN Genetics Dataset 
Description As a part of my first chapter/paper, I was involved in putting together a multi-centre collaborative dataset of mismatch negativity (MMN; an electroencephalographic [EEG] endophenotype for psychosis) and genetic data from patients with schizophrenia or bipolar disorder as well as healthy controls. The four centres involved were UCL, King's College London, University of Maryland in Baltimore and Harvard University in Boston. After rigorous genetic and EEG quality control, this consists of 729 participants. Both MMN and genetic data are laborious and expensive to collect, especially from patients - this is, to my knowledge, the largest dataset in the world of these phenotypes. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact This dataset will be used first by other members of our research group at the Division of Psychiatry. We are, this week, submitting a paper to Nature Neuroscience with results obtained from this data. 
 
Description UCL-Kings CNV collaboration 
Organisation King's College London
Department Maurice Wohl Clinical Neuroscience Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution I spent two years working at Deepak Srivastava's lab at King's College London. Both Deepak and my primary supervisor, Elvira Bramon, are interested in copy number variants (CNVs) - this work constituted a new collaboration between them.
Collaborator Contribution I was trained in new wet lab/tissue culture methods at King's.
Impact The results that came from this work will become the second chapter of my thesis, as well as a first-author publication.
Start Year 2018
 
Description Dear World Project 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Dear World Project is a cross-disciplinary public engagement collaboration that explores mental health, its diagnosis, and the use of labels often associated with feelings and emotions. The project has hosted a number of Dear World pop-up events, where scientists sparked conversations with passers-by about their thoughts and feelings towards the use of labels and categorisation in mental health. I participated in some of these pop-up workshops at Summer Festivals in London.

At the core of the Dear World Project was an exhibition which paired artists and researchers to explore the themes uncovered much more deeply. The research behind the project is the work of scientists at the Wellcome Centre for Human Neuroimaging and the Max Planck Centre for Computational Psychiatry at UCL, who have been paired with 7 artists and makers to explore the themes of the Dear World Project. In collaboration with the artist I was paired with, Giulia Ricci, the artwork created was a quilted Markov blanket (in reference to the statistical concept used in the theoretical portion of my work), entitled, "What is 'normal'?", aimed at raising questions about context-dependence and how the questionable used of the word 'normal' is often at the centre of how we define mental illness.
Year(s) Of Engagement Activity 2020
URL https://www.dearworldproject.org/
 
Description TEDx Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A collaborative TEDx talk on interoception and the neuroscience of theatre.
Year(s) Of Engagement Activity 2017
URL https://www.youtube.com/watch?v=UPImNPD9hws