Dopamine release and blood flow changes during induced epileptic seizures assessed with simultaneous PET-MR-EEG

Lead Research Organisation: King's College London
Department Name: Imaging & Biomedical Engineering

Abstract

Epilepsy is a brain disorder. People with epilepsy have epileptic seizures, which are brief periods of "short-circuiting" in the brain. During seizures, people may simply stare ahead and not be responsive ("absence" seizures). During other seizures, they might have abnormal movements, or fall to the ground, and injure themselves. Epilepsy is a frequent disease, affecting about 1 in 100 people in the UK.

People with epilepsy are normally treated with medication (drugs). However, these drugs only completely stop seizures in about 2 out of 3 people. It would be useful to have more drugs to treat epilepsy, particularly drugs that work in different ways to the ones that already exist.

We do not understand completely how seizures start - or stop. One possible mechanism is by neurotransmitters. Neurotransmitters are "messengers" that nerve cells in the brain use to talk to each other. Dopamine is such a neurotransmitter. Scientists have shown changes in dopamine messaging in all types of epilepsy they have studied so far.

In this project, we want to demonstrate whether seizures release dopamine in the brain. For this, patients who can trigger a harmless "absence" seizure by breathing hard (hyperventilation) will be asked to do so inside a special brain scanner.

Dopamine release can be seen with a powerful brain scanning technology, Positron Emission Tomography (PET). PET has recently become even more powerful by combining it with another technique for taking images of the brain, Magnetic Resonance Imaging (MRI). There are only two such simultaneous PET-MR machines in the UK. The second one has recently been installed in our centre at St Thomas' Hospital.

We will use MRI to get as much information as we can about patients' brains - what they look like, how they are wired, and how blood flows in them. We are especially interested in how blood flow changes when the volunteer patients have their "absence" seizures. We also want to check whether dopamine release is independent of blood flow changes.

In order to know exactly when patients have an "absence" seizure, we need yet another technique, EEG. The EEG (electro-encephalogram) allows us to see the electrical activity in the brain, which changes very clearly during an "absence" seizure from one second to the next. Over the past months, we have managed to record EEG inside the PET-MR scanner, which is quite difficult due to the strong magnetic fields inside. We therefore now have a PET-MR-EEG scanner.

PET-MR-EEG will be the ideal technique to work out whether dopamine is released at the time of seizures. We have also worked on making all three techniques as fast as possible. We therefore think that we can even work out whether dopamine is released before the seizures, or after seizures have started.

We think it will be released after seizures have started. This would mean that dopamine makes seizures stop. That would be good news for epilepsy patients, because drug companies can then develop new drugs that work through the dopamine system. Such drugs do not currently exist.

Another benefit would be to show exactly where dopamine is released thanks to the very clear MRI pictures. If we find such small areas of the brain, then surgeons may be able to target them with deep brain stimulators to try and stop seizures. Some scientists are also developing systems that can release a tiny amount of drug directly into a small brain area to stop seizures.

There are many different types of seizures, but we believe that dopamine may be a general way for the brain to stop seizures. Therefore, epilepsy patients with all kinds of seizures may benefit from this research.

We also think that many other scientists will benefit from the PET-MR-EEG technique we are developing in this proposal. Getting simultaneous information will be particularly important for diseases which come in attacks, for example migraine or stroke, but also for normal brain workings.

Technical Summary

The PET Centre at St Thomas' Hospital hosts the UK's second simultaneous PET-MR. We have established and validated EEG inside the scanner with phantom and volunteer studies to obtain simultaneous PET-MR-EEG.
We will use PET-MR-EEG to investigate dopaminergic neurotransmission during hyperventilation-induced absence seizures, a relatively easily accessible model of epileptic seizures generally.
Twenty controls, and 20 patients with idiopathic generalised epilepsy and hyperventilation-inducible seizures, most already identified in specialist clinics, will undergo a single-injection scan with [18F]fallypride, a high-affinity slowly equilibrating dopamine D2/D3 receptor ligand. The long scanning time (3h) will be split into three sessions for subject comfort. The tracer allows visualisation of endogenous dopamine release through receptor blockade (e.g. pilot data in Case for Support).
We will use the two early PET-MR sessions to determine subject-specific early [18F]fallypride kinetics and use the "free" simultaneous MR time to acquire structural (3DT1, DESPOT, DTI, FLAIR) and functional information (blood flow - ASL, rsfMRI) as well as sequences necessary for MR-based attenuation correction (MRAC). Until full validation of MRAC (including our own technique), a low-dose one-minute CT scan for attenuation correction will also be acquired at the Centre.
During PET-MR-EEG in the third session, subjects will be asked to hyperventilate, thus provoking absence seizures which are harmless and compatible with remaining still in the scanner. We will simultaneously record dynamic [18F]fallypride data (timing resolution in the minute range thanks to its high k2 constant), ASL (every 16s) and EEG (ms resolution) to test the hypotheses that dopamine release occurs, and occurs in response to seizures.
Volunteers scanned with and without hyperventilation will allow disentangling the EEG, blood flow, and dopaminergic neurotransmission effects of seizures and hyperventilation.

Planned Impact

A) Academic beneficiaries
The proposed project is multi-disciplinary in nature and will therefore contribute to knowledge generation, within the UK and internationally, in several disciplines.
1) In the functional neuroimaging community, researchers working on PET or MRI will benefit from the showcasing of neurotransmitter release at fast timescales, controlling for confounders. This will demonstrate a unique benefit of truly simultaneous PET-MR, answering some of the sceptics regarding its need or benefit.
2) The neurophysiology community. Since the advent of PET-CT some ten years ago, PET-EEG has been difficult due to electrode-related CT scatter issues. PET-MR-EEG stands to revive this tradition. Better deterministic or probabilistic localisation of PET/MR abnormalities likely to be the source of neuronal electrical activity stands to benefit researchers working on source localisation and inverse problem solutions.
3) Researchers working in the areas of image reconstruction, processing and statistical inference (e.g. in medicine, astronomy, geology, or security) may benefit if truly multimodal datasets are exploited e.g. for compensation of incomplete data through modelling and prior knowledge from other domains. The data will, for example, be used in a current EPSRC grant held by Dr AJ Reader in our Division.
4) The clinical research community. Our data may be used for assessing the possibility of shortening the protocol to the last 30 minutes and application in the neuropsychiatric domain. The oft-cited "killer application" for PET-MR is likely not to be in oncology but in brain assessment. A single 30-minute PET-MR-EEG including dopamine release to a stimulus could include all the information needed to, for example, optimally assign an individual to one specific therapy for depression or alcohol dependence.
B) Collaborative beneficiaries:
1) Prof. Hammers retains strong links with the CERMEP imaging centre in Lyon, France, which will enable collaboration including on large model organisms.
2) The MRC is currently funding a major expansion from two to seven simultaneous PET-MR systems in the UK as part of the Dementias Platform UK (DPUK). Prof. Hammers has co-led the imminent full integration of King's College London into DPUK, and there will be ample opportunities for translating protocols based on this project to the UK's PET-MR community.
3) To ensure maximum impact to the academic community, at the end of the project we will continue our track record of dissemination of data and methods by making the simultaneous PET-MR-EEG data available.
C) Patients
1) Experience with simultaneous protocols may benefit patients with focal epilepsies via "one-stop-shop" FDG PET-MR-EEG protocols (Ethics application under way).
2) Demonstrating that dopamine is released at the time of seizures, and whether prior to or after seizure onset, will inform the suitability of dopaminergic drugs as antiseizure drugs. Discovery of novel mechanisms has led to new classes of antiseizure drugs in the past, every time increasing chances of seizure freedom.
D) Industry/workforce
1) EEG may be included in future hardware developments, e.g. by integrating EEG connectivity into the birdcage head coil.
2) Development of drugs working on the dopamine receptor pathway by the pharmaceutical industry may be stimulated
3) Identification of e.g. localised thalamic areas with maximum effect sizes may further the development of deep brain stimulation for epilepsy
4) Similarly, companies working on closed-loop intracranial drug delivery systems may be interested in the findings if the hypothesis proves correct
5) We collaborate closely with the PET-MR manufacturer and train new researchers in the multidisciplinary skills necessary for this project
E) The wider community
1) Prof. Hammers has an excellent track record of Dissemination of Science activities. Any new research findings will underpin talks and other community activities.

Publications

10 25 50
 
Title "PEbrain": explaining common epilepsy surgeries and the role of PET and MR imaging in preparing for surgery 
Description I obtained this grant together with some team members to create a life-sized 3D printed brain with removable parts to illustrate the role of imaging in the preparation for epilepsy surgery. Prototypes have been printed and look great. 
Type Of Art Artefact (including digital) 
Year Produced 2020 
Impact Not yet - will update once final product deployed. 
 
Description Dementias Platform UK MR-PET Partnership
Amount £860,793 (GBP)
Funding ID MR/N025792/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2016 
End 03/2020
 
Description King's College London Medical Engineering Centre of Research Excellence
Amount £12,100,395 (GBP)
Funding ID 203148/Z/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2017 
End 04/2022
 
Description Wellcome / EPSRC Centre for Medical Engineering fellowship scheme
Amount £84,064 (GBP)
Funding ID N/A - Wellcome / EPSRC Centre for Medical Engineering, School of Biomedical Engineering and Imaging Sciences, King's College London 
Organisation King's College London 
Sector Academic/University
Country United Kingdom
Start 10/2019 
End 09/2020
 
Description 29. Professions in the community. Outreach event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Interactive 10-minute meetings with groups of pupils, Rudolf Steiner School Kings Langley, Hertfordshire, UK, 21st of November 2017 (1 hour, interaction with approx. 15 students)
Year(s) Of Engagement Activity 2017
 
Description 31. NIHR Cardiovascular Medtech and In vitro diagnostic Co-operative (MIC) Imaging Sciences Public and Patient Involvement (PPI) Panel: Presentation of planned and ongoing research projects & discussion with the panel (1.5h, about 10 patients and interested laypersons). London, UK, 18th of July, 2018 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact NIHR Cardiovascular Medtech and In vitro diagnostic Co-operative (MIC) Imaging Sciences Public and Patient Involvement (PPI) Panel: Presentation of planned & ongoing research projects & discussion with the panel (1.5h, about 10 patients and interested laypersons). London, UK, 18th of July, 2018
Year(s) Of Engagement Activity 2018
 
Description 33. Spare Parts: Parts to Spare. Panel discussion on brain surgery for Epilepsy as part of the "Spare Parts" season at Science Gallery London, UK, 30th of April, 2019 (approx. 100 participants). Initiated by me, and I was one of the discussants: https://london.sciencegallery.com/events/spare-parts-parts-spare 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Panel discussion on brain surgery for Epilepsy as part of the "Spare Parts" season at Science Gallery London, UK, 30th of April, 2019 (approx. 100 participants). Initiated by me, and I was one of the discussants.
We had a philosopher, two clinicians, a facilitator and a patient who had had (successful) brain surgery for epilepsy. While most of the audience were general public, there were many patients or patient group / charity representatives, too.
Year(s) Of Engagement Activity 2019
URL https://london.sciencegallery.com/events/spare-parts-parts-spare
 
Description Chinese student visit 20th of July 2017, led by Dr McGinnity, organised by Dr Ran Yan 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Dr McGinnity gave a talk and a lab tour to 8 excellent pharmaceutical students from Hangzhou and Beijing universities in China
Year(s) Of Engagement Activity 2017
 
Description Hot stuff - when radioactivity is good for you. Exhibit curated by Sam Terry at the Royal Society's Summer Exhibition 
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 Dr McGinnity and Prof Hammers participated in this Summer Exhibition stand for about 4 shifts. Interactions with general public.
86% of respondents rated the content of the exhibition as "Great" or "Good".
71% of respondents agreed that they learnt how radioactivity is used to treat disease.
91% of researchers said that taking part in Hot Stuff has helped them to prepare for or encourage their involvement in other public engagement activities.
Year(s) Of Engagement Activity 2018
URL https://royalsociety.org/science-events-and-lectures/2018/summer-science-exhibition/exhibits/hot-stu...
 
Description Interview by Dubai TV at New Scientist Live, 10 October 2019 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I was selected to give an interview to Dubai TV at New Scientist Live, 10 October 2019.
Episode covered in "The London Show", Dubai TV, available at https://vimeo.com/366639264/3103ba383b (coverage ~4min50 - 6min50)
Year(s) Of Engagement Activity 2019
URL https://vimeo.com/366639264/3103ba383b
 
Description New imaging studies to improve the understanding of epilepsy: a watermelon study 
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 Stand in St Thomas' hospital during British Science Week, London, UK, 18th of March 2016 (3 hours). Mentioned with picture in April 2016 Divisional Newsletter
Year(s) Of Engagement Activity 2016
URL http://www.kcl.ac.uk/lsm/research/divisions/imaging/newsevents/Newsletter.aspx
 
Description Pint of Science intervention by Dr McGinnity: "Positrons and Protons; Picture this!" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Interactive 40-minute presentation as part of an evening during "Pint of Science" event "Inside-Out! Observing your insides, from the outside", 16 May 2017, Horse and Stables pub, London, UK. About 60 participants.
Year(s) Of Engagement Activity 2017
URL https://pintofscience.com/
 
Description Public Engagement Grant ""PEbrain": explaining common epilepsy surgeries and the role of PET and MR imaging in preparing for surgery" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Obtained Centre for Medical Engineering / King's College London grant
""PEbrain": explaining common epilepsy surgeries and the role of PET and MR imaging in preparing for surgery" to build a 3D brain model specifically for explaining and discussing epilepsy surgery. Awarded 18 Nov 2019.
This is for designing and building a life-sized 3D printed brain that can be partly taken apart to reveal imaging abnormalities. Prototype exists - once ready, this will be used to reach hundreds of people.
Year(s) Of Engagement Activity 2019
 
Description Public Engagement event - New Scientist Live. ExCel London, UK, 10 October 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact New Scientist Live is one of the biggest science shows in the country, and our School of Biomedical Engineering and Imaging sciences had one of the largest stands there (120m2 stand).
I was a whole-day volunteer at King's College London on 10 October and greeted about 2,500 visitors that day. We had well over 10,000 visitors in total, and many repeat visitors who reported that our stand was the best!
Year(s) Of Engagement Activity 2019
 
Description School visits - Professionals that live in our community 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Professionals build a mini-stand - I used University / Funder / Department logos. Short intro, then pupils select professionals to talk to for 10 mins, bell rings, they change.
Pupils exchange about these events afterwards.
In 2015 I had more visitors but in 2016 more focussed ones - one of them (from an ethnic minority) has now arranged for work experience at my institution.
Year(s) Of Engagement Activity 2015,2016
 
Description Tour of the PET Centre (Dr Colm McGinnity) as part of "Discover Chemistry at King's College London" 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Six groups of 5-6 students each visited
Year(s) Of Engagement Activity 2017
 
Description Two pints of brain, dissected during life. "Pint of Science" session by Alexander Hammers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Interactive 40-minute presentation as part of an evening during "Pint of Science" event "Inside-Out! Observing your insides, from the outside", 16 May 2017, Horse and Stables pub, London, UK. About 60 participants.
Year(s) Of Engagement Activity 2017
URL https://pintofscience.com/