Neural mechanisms of positive symptoms in first-episode and prodromal psychosis.
John Grace QC PhD Scholarship 2020 - King's College London
Supervisors: Gemma Modinos, Philip McGuire.
Summary: One in four people will experience a mental health problem in their lifetime. The cost of mental ill health to the economy, NHS and society is estimated to be £105 billion a year. Schizophrenia is a mental health disorder involving psychotic symptoms such as hearing voices that aren't there. Available treatments do not work for about a third of patients and have no impact on prevention. To develop better treatments, we must understand the brain basis of how schizophrenia develops. In the brain, psychosis is associated with excess production of a chemical called dopamine, but we know little about what causes this. Recent research suggests that the dopamine excess is due to oxidative stress. Oxidative stress can lead to deficits in the chemical system GABA. GABA deficits elevate activity in key brain areas such as the hippocampus, leading to increased dopamine and psychotic symptoms. Studies also show that targeting oxidative stress early may be a new way to prevent psychosis. This project will use advanced brain imaging methods to identify the mechanisms linked to psychosis. We will study the relationship between oxidative stress, GABA and psychotic symptoms in people with early psychosis. This will help us understand the brain basis of schizophrenia and inform potential new targets for prevention.
This multimodal in vivo neuroimaging project aims to determine, for the first time:
1. The link between cortical levels of oxidative stress (glutathione) and GABA in patients with first-episode psychosis (FEP) and CHR individuals, as compared to healthy controls
2. Within the FEP and CHR groups:
a. The link between glutathione, GABA and hippocampal activity
b. The relationship between the above imaging measures and levels of positive symptoms.
Research Student: Samuel Knight
I am a PhD student at King’s College London, using multi-modal neuroimaging techniques to study the neural mechanisms of positive symptoms in early psychosis. Before starting my PhD, I completed an Honours degree in Cognitive Psychology studying memory at Victoria University of Wellington in New Zealand. During this time, I also worked as a research assistant studying memory in childhood depression and a longitudinal project on wellbeing in young adults. Most recently I completed a MSc of Neuroscience in Neuroimaging at King’s College London, where I used resting-state fMRI and 5-HT receptor information to investigate MDMA’s influence on the striatum. Since completing my MSc I have been working on a research project using EEG and cortical stimulation to treat childhood epilepsy.
Progress report year 3, 2023
The focus of my third year has been to finish the data collection for my main project, which involves recruiting and scanning individuals experiencing their first psychotic episode, those at clinical high risk for psychosis, and healthy individuals. This recruitment has been impacted by covid and the difficulty of recruiting the patient groups, but I am pleased to say that we concluded our last scan on the 19th July.
Another success this year was to publish my first paper, a review of hippocampal circuit dysfunction in psychosis: https://www.nature.com/articles/s41398-022-02115-5. I am also currently working on another paper that has come through a side project I’ve been working on while collecting the data for my PhD.
One challenge for neuroimaging is trying to understand the molecular underpinnings of effects that are measured at a different scale, for example what neurotransmitter systems underly MRI blood flow changes. My project aims to address this by spatially comparing the distribution of different neurotransmitter receptors in healthy brains and comparing this to blood flow abnormalities in patients with schizophrenia and those at clinical high risk (see below). We do this by completing a dominance analysis, which is a regression model that calculates the individual contribution of each PET receptor map in predicting blood flow alterations. By identifying which neurotransmitter systems covary with blood flow abnormalities, we might better stratify patients for treatment or identify potential targets for drug interventions.
I’ve been fortunate to present this project at the Schizophrenia International Research Society in Toronto in May, where I also received an Early Career Award. I also shared this work again at the British Association for Psychopharmacology in Manchester in July where I won a poster award. Both conferences have been fantastic opportunities to learn about the current research in the field, meet potential collaborators, and share my work.
In the year ahead I aim to publish the paper for this project, present the results at three further conferences, the International GABA symposium, European Congress of Neuropsychopharmacology, and Society for Neuroscience; I will then focus on the final analysis and writing up of my main PhD project.
Progress Report year 2, 2022
The focus of my second year has been to improve our recruitment processes (hampered by covid), to continue my training on the methodologies relevant to my PhD, and to finish and submit my first paper to a scientific journal.
COVID brought with it many difficulties for scanning patients – including a full recruitment shutdown – and due in large part to the dwindling of the pandemic, recruitment rates for my study have greatly improved. We recruited 16 participants in the last 12 months, up from 3 participants in same period in the previous year. Even after being granted an extension on recruitment until August 2023, continuing the current pace of recruitment will be important for me.
In November 2021 I was fortunate to be sponsored by MHRUK and KCL to attend the GABA symposium and Magnetic Resonance Spectroscopy (MRS) training workshop. MRS is a neuroimaging technique that uses the nuclear magnetic resonance phenomena – what enables us to make images with an MRI machine – to quantify the number of molecules of interest in an area of the brain. As my PhD aims to make connections between the levels of at least two molecules, glutathione and GABA (see summary above), MRS is an important tool for measuring differences between our patient/control groups. The conference was an invaluable opportunity to learn from world-leading experts in these methods, as well as present my own study and gain important feedback on our use of MRS.
A major task this year has been finishing my review on hippocampal circuit dysfunction in psychosis. The hippocampus is a region involved with many important cognitive processes (memory, emotion, stress), and is among the brain regions most susceptible to dysfunction in psychosis. I am trying to measure hippocampal hyperactivity as part of my PhD, so this literature review has been important in consolidating what is known about the vulnerability of the hippocampus in psychosis, as well as ways in which this dysfunction could be targeted with new treatments. I had been working to incorporate reviewer feedback and have just resubmitted.
In the year ahead, I aim to redouble my recruitment efforts and to complete a new experimental paper.
A challenge in neuroimaging is understanding how measures at different spatial scales relate to each other, for example resting cerebral blood flow and the underlying neurotransmitter systems. My next piece of work aims to integrate these types of information so as to examine the neurotransmitter systems involved in resting cerebral blood flow patterns in individuals at clinical high-risk of psychosis. I have also had an abstract accepted for presentation at the upcoming European College of Neuropsychopharmacology Congress in Vienna in October 2022.
Progress Report year 1, 2021
My project aims to explore the link between the positive symptoms of psychosis and several possible neural mechanisms: oxidative stress, hyperactivity of the hippocampus, and excitatory/inhibitory imbalance (figure 1).
Figure 1. Oxidative stress-GABA-psychosis pathway for positive symptoms in early psychosis. The high-metabolic costs of fast-spiking inhibitory GABAergic parvalbumin-positive interneurons (PVI) results in a heightened vulnerability to oxidative stress (A). This susceptibility of PVI to oxidative damage may lead to the excitatory-inhibitory balance tipped in an excitatory direction (B) in susceptible brain regions, including the hippocampus. This hyperactivity within the hippocampus (C) leads to downstream aberrant dopaminergic activity via the ventral tegmental area (D) and positive psychotic symptomology.
As part of the wider STRESSGAP project led by my supervisor, data collection for my project had already started before the start of my PhD, so the early months were spent getting up to speed with the recruitment procedures, training in the assessments, and familiarising myself with the neuroimaging modalities.
Due to COVID-19, recruitment has slowed; all research was shut down during the initial months of the year. However, in spite of these challenges, data collection is on track. I have presented my study to early intervention services in south London and attend weekly clinical review meetings to seek out potential participants. Now that data collection has resumed, I have recruited and assessed my first participants.
Recruiting participants involves screening for our exclusion criteria, assessing participants, and the neuroimaging scan. Our assessments include a battery of clinical assessments such as the PANSS – used to measure psychotic symptoms – though we also use clinical questionnaires for anxiety, depression, as well as various tests of cognitive ability. I’ve now been trained in all these procedures and assessments. In addition, I’ve received training as a phlebotomist to take blood samples from our participants. Blood samples are required to ensure safety during our scanning visit, but also for us to measure certain genes of interest and blood markers of oxidative stress.
Another area of progress this year has been familiarising myself with the neuroimaging modalities I am using in my study. Two main methods are being used: Magnetic Resonance Spectroscopy (MRS) and Arterial Spin Labelling (ASL). MRS allows us to look at particular molecules of interest in a particular brain region, in our case GABA (the brain’s main inhibitory neurotransmitter) and glutathione (the body’s main antioxidant). ASL on the other hand is a measure of regional cerebral blood flow; looking at these changes in the hippocampus can give us an idea of whether the region is hyperactive.
Finally, as a contingency project to work on during the data collection shutdown, I have been writing a literature review. I explore the how hippocampal neurodevelopmental critical periods are relevant in the development of psychotic symptoms and what this can teach us about new targets for treatment. This is particularly relevant to my PhD project as I am measuring some of these potential targets in early psychosis and in those at high risk for developing psychosis.
My aims for the coming months are to finish my literature review and submit it for publication, to continue recruitment, and to develop my skills in neuroimaging. In November a training workshop and symposium is being run by the leading authorities on our MRS methodology, and MHRUK has generously made my attendance possible. In addition to receiving the training, I will present some of our pilot data.