Periodic Reporting for period 4 - EPI-Centrd (Epilepsy Controlled with Electronic Neurotransmitter Delivery) Reporting period: 2021-09-01 to 2022-02-28 Summary of the context and overall objectives of the project [Problem/Issue] Drugs constitute the classical therapeutic approach to treat diseases. Newly designed drugs can be very promising during preclinical testing, but can later fail in the clinic because of their toxicity, side effects, rapid elimination and degradation, or failure to reach desired targets. A primary cause of failure is that drugs are not usually administered specifically to the region of the body affected by a problem, meaning the drugs can act elsewhere and have deleterious, undesired effects. In the case of neurological disorders, the situation is further complicated as drugs need to additionally cross the blood-brain barrier before reaching their targets in the brain. [Society] Epilepsy is an excellent example where drugs have failed in the clinic because of toxicity, side effects, and failure to cross the blood-brain barrier, despite having strong antiepileptic effects. However, controlling drug-resistant epilepsy could still be achieved with existing antiepileptic compounds if these compounds could be delivered locally. Indeed, an ideal solution would be to deliver drugs directly where they are needed, on demand. I have very successfully demonstrated this in extracted tissue samples and in rodent models using state-of-the-art organic electronic ion pumps (OEIPs), non-microfluidic devices which deliver active compounds and drugs to control epileptiform activity. [Objective] Motivated by human patients suffering from surgically untreatable and drug-resistant epilepsy, this project (EPI-Centrd) will create implantable OEIPs as a therapeutic device for Epilepsy with an equivalent impact to the Deep-Brain stimulator (DBS) in Parkinson’s disease. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The design and fabrication of an integrated probe for the therapeutic treatment of epilepsy is the overall objective of EPI-Centrd. The technical goal is successful fabrication, and the neuroscientific goal is successful implementation in tissue. The system will be tested in anesthetized and freely-moving rodents, and acutely in the clinical operating room.The technical goal (WP1):Work performed to the end of the previous period on the technical goal has resulted in the design and fabrication of an integrated probe for the therapeutic treatment of epilepsy. Essentially the technical goal of EPI-Centrd had been successfully achieved, however, as stated at the time, there remained much room for improvement in further devices iterations. As seen in the updated publication list, an advanced version of the device is now published and in operation using a fully-non-invasive technology (a patent for the new technology has additionally been filed, Patent EP 21306447).The neuroscientific goal (WP2):This goal is separated into 4 sub-goals, 1) in vitro Testing: Can the new probes control anything pathophysiological?, 2) in vivo Testing I: Can the new probes control activity more clinically-relevant? (Anesthetized rodent testing), 3) in vivo Testing II: Can the new probes control activity more clinically-relevant? (Freely-moving rodent testing), 4) Clinical Operating Room with Human Patients: Can the new probes control pathological activity in patients with drug-resistant epilepsy?.Work performed to the end of the previous period on the neuroscientific goal had completely addressed the first two points, namely that the new devices control epileptiform activity in vitro, and in vivo in anesthetized rodents. Future activities were necessary to have a closed-loop system and reservoir (under the skin, in skullcaps) for implementation in freely-moving rodents to address the third point and, if successful, preliminary clinical work to address the fourth point (WP3). As mentioned above, the completely non-invasive system developed in this reporting period has eliminated the necessity for the reservoir system. Details of the new devices can be found in the latest publications from this year (Missey et al., Frontiers in Neuroscience, 2021; Acerbo et al., Frontiers in Behavioral Neuroscience, 2021; and Missey et al., Journal of Neuroengineering, 2021). Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Although complete, iterations on the technical goal will continue. The neuroscientific goal has two remaining sub-goals, namely implementation in freely-moving rodents, and preliminary clinical work. Given the rapid success, and publications, from the work performed to the end of this period, it is unlikely that the closed-loop intervention in freely-moving rodents will be a problem to achieve by the end of the project. Current work involves a two-step model of freely moving epileptiform activity to approach clinical relevance, namely kindled rodents to create temporally on-demand seizures with spatially fixed foci, and lesioned rodents to create temporally unknown seizures with spatially fixed foci. Seizures with temporally unknown origin and with spatially unknown origin (generalized seizures) will not be investigated, as the device is designed for surgically intractable focal epilepsies. Socio-economically, the majority of surgically intractable epilepsies are focal epilepsies. The wider societal implication of a successful device, is to allow patients with surgically intractable focal epilepsies to live without fear as the condition will be controlled with the device developing in this project.