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Exploring better ways to arrest seizure activity

Brain tumours arise from the abnormal growth of cells in the brain (neurons), with roughly 500 people every year in Ireland diagnosed with a tumour that arises from cells inside the brain. These ‘primary tumours’ can give rise to severe symptoms as the tumour grows into the surrounding brain tissue.

Seizures are a frequent and severe symptom for patients with brain tumours and are poorly controlled with current medical and surgical treatments. Brain tumour patients with seizures report lower quality of life both physically and mentally compared to patients without seizures. There is also the significant risk that brain tumour patients may experience status epilepticus, which is a life-threatening medical emergency in which seizure activity continues for an extended amount of time (> 5 minutes) and requires urgent treatment, often in an intensive care unit, in order to limit further damage to the brain.

Work in the Cunningham Laboratory in Trinity aims to develop better ways to arrest seizure activity in patients with tumour related seizures. This is important in cases where seizures are difficult to treat with conventional anti-seizure drugs or in circumstances where surgery may not be an option.

Brain tumours arise from the abnormal growth of cells in the brain (neurons), with roughly 500 people every year in Ireland diagnosed with a tumour that arises from cells inside the brain. These ‘primary tumours’ can give rise to severe symptoms as the tumour grows into the surrounding brain tissue.

Seizures are a frequent and severe symptom for patients with brain tumours and are poorly controlled with current medical and surgical treatments. Brain tumour patients with seizures report lower quality of life both physically and mentally compared to patients without seizures. There is also the significant risk that brain tumour patients may experience status epilepticus, which is a life-threatening medical emergency in which seizure activity continues for an extended amount of time (> 5 minutes) and requires urgent treatment, often in an intensive care unit, in order to limit further damage to the brain.

Work in the Cunningham Laboratory in Trinity aims to develop better ways to arrest seizure activity in patients with tumour related seizures. This is important in cases where seizures are difficult to treat with conventional anti-seizure drugs or in circumstances where surgery may not be an option.

Professor Mark Cunningham, Ellen Mayston Bates Professor of Neurophysiology of Epilepsy

One theory examining how seizures arise due to a brain tumour is related to an increased level of a chemical messenger, or neurotransmitter, around the tumour. Professor Mark Cunningham and his team are focused on examining the role of a particular type of neurotransmitter (glutamate) in a region called the peritumoural zone.

Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS) and as such the glutamate receptors play a vital role in the mediation of excitatory synaptic transmission.

A receptor is a protein expressed in the membrane of brain cells to which specific molecules, in this case glutamate, can bind. When glutamate binds to its receptor it causes the flow of positively charged ions into the brain cell and this acts to excite the cell.

In the healthy brain, the levels of glutamate released from neurons is tightly regulated. In brain tumours, however, glutamate levels are elevated, which leads to increased glutamate concentrations, in turn overexciting neurons in the peritumoural zone which acts to generate seizures. The source of this glutamate is the brain tumour cells that express increased levels of a transporter pump that moves glutamate out into the extracellular environment in excessive amounts, driving neurons to behave in a hyperexcitable manner. This in turn causes more glutamate to be releases by these brain cells.

As glutamate levels grow, the environment around the brain cells becomes excitotoxic and glutamate kills the healthy brain cells that surround the tumour. The glutamate released can also act on the brain tumour cells to activate processes that allow these tumour cells to grow and move into the space previously occupied by the now dead brain cells. Thus, tumour growth and seizure generation in the peritumoural regions are inextricably linked by the ability of tumour cells to hijack the glutamate system to sustain its survival and growth.

An important aspect of the work taking place in the Cunningham Lab is to also understand the contributions of the receptors that glutamate acts on to excite neurons. By selectively targeting these receptors we can hope to stop seizures from occurring. We will also be able to limit the growth of the tumour. The team is also interested in one receptor called the AMPA receptor, which is highly sensitive to glutamate. Activation of this receptor can cause a profound excitation of neurons.

The team is also exploring gene therapy approaches that would allow us to express an ion channel in peritumoural brain cells that is sensitive to glutamate and when activated by glutamate this ion channel acts to suppress excitation of neurons and limit seizure generation.

How will the team examine these research questions?

In the Cunningham laboratory, the team has the unique expertise of working with live human tissue as a means of conducting research that gets as close to the patient as possible. Previous work from our group has demonstrated that we can record the electrical activity of large groups of neurons in slices of human brain tissue that is obtained from patients undergoing surgery to remove epileptic brain regions.

This technique allows us to record and study seizure activity generated by the microcircuits of neurons in the slices of peritumoural tissue that we keep alive in the lab. We can test our hypothesis using a combination of electrophysiological, pharmacological and gene therapy techniques.

Earlier this year, Professor Cunningham’s team obtained ethical permission to start work with samples of peritumoural tissue, removed from patients with brain tumours and seizures. This work will be carried out in conjunction with colleagues in RCSI and the Department of Neurosurgery at Beaumont Hospital and under the auspices of the SFI funded ‘FutureNeuro’ project.

This is a seizure event as recorded from a slice of live human brain tissue – the black trace is the raw data recorded as, what is termed – the local field potential (LFP). The local field potential underlies the signal that is recorded by the electroencephalogram (EEG). The LFP signal is produced by hundreds of thousands of brain cells (and supporting cells) in the tissue acting to produce this organised and high synchronised electrical activity. The coloured trace shows a representation of the raw data but in the frequency domain. The fast activity can be seen at the start; this initial activity is sometimes termed ‘tonic’ and then followed by second stage during which the activity slows and transforms to what is sometimes referred to a ‘clonic’ activity. We use our ability to record this activity in the lab to understand more about the mechanisms that cause seizure generation and to examine the action of novel therapies on this activity.