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

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.

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.

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.