New approaches for detection and modulation of abnormal brain networks in a preclinical model for epilepsy based on a combination of functional magnetic resonance imaging, optogenetics, chemogenetics and intracranial electroencephalography

Epilepsy is a common neurological disorder that is characterized by the occurrence of spontaneous
seizures. Unfortunately, about one third of the patients still have seizures despite treatment with
anti-epileptic drugs (AED). In addition, many patients have severe side effects due the large doses
of AED they need to take. Other treatments are required to improve the quality of life of those
patients. In order to find new therapies, more insight is necessary about how a normal brain is
transformed into an epileptic brain and how seizures come about. In this project, we will use
functional magnetic resonance imaging and intracranial electroencephalography to image how
brain networks are changing with the development of epilepsy and which networks are
responsible for the generation of epileptic seizures. Then we will try to heal the epileptic brain
and/or suppress epileptic seizures by selective modulation of specific nodes of the epileptic brain
network. To do this, we will induce expression of Designer Receptor Exclusively Activated by
Designer Drugs (DREADDs) in specific brain structures via local gene therapy. DREADDs are
receptors that are only activated by a specific drug (clozapine-N-oxide, CNO) which normally has
no effects in the mammalian body. Depending on the type of DREADD, neurons in these brain
structures can be activated or silenced via systemic administration of CNO. Using this
methodology, we aim to undo the changes causing epilepsy and/or epileptic seizures