Periodic Reporting for period 1 - GALVANI (Controlling epileptic brain networks with computationally optimized weak electric fields) Reporting period: 2020-06-01 to 2021-11-30 Summary of the context and overall objectives of the project Epilepsy is a neurological disorder affecting 65 million people worldwide. Pharmacological treatments or surgery are ineffective in one third of the cases – 19 million people. Recent findings indicate that non-invasive brain transcranial current stimulation (tCS) is safe and of therapeutic promise in epilepsy. However, it is not yet indicated as a standard treatment due to major scientific limitations: unknown mechanisms of action, insufficient account for patient-specific factors, poor understanding of short- and long-term effects.Our ambition is to transform the care of a large fraction of patients living with drug-resistant epilepsies by solving a fundamental problem: to efficiently target and control large-scale epileptic brain networks with tCS-induced neuromodulatory weak electric fields.To proceed, GALVANI’s synergetic research strategy addresses four interdisciplinary challenges: (1) Unravel the intricate relationship between weak electric fields and their neurophysiological effects at the level of neurons, neuronal assemblies and networks; (2) Maximize their therapeutic effects by altering the neurodynamics of patient-specific epileptogenic networks; (3) Develop optimal personalized neuromodulation protocols for novel multichannel tCS technologies; (4) Test optimized protocols in a cohort of patients and objectively define potential responders.The required competences and resources are met in GALVANI, uniting the passion and background of three experts and their teams in biomathematics (computational neuroscience), biophysics (bioelectromagnetism) and medicine (epileptology).The project vision is that critical features of pathological networks can be effectively captured in a new generation of hybrid computational models developed for tailored therapy. The inflection point is to prevent epileptic seizures from a bottom-up mechanistic understanding and control of tCS effects. This will entail a paradigm shift in epileptic disorders and beyond. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Overview of the action's implementation for this reporting period Implementation:The Galvani Project has started June 1st, 2020 and its organization follows the implementation described in the Proposal. It is based on 3 major research tracks (RT). In RT1, we develop computational hybrid brain models (HBMs) able to reproduce epileptic activity and which account for biophysical aspects of neurostimulation. The grant manager and 4 post-doctoral fellows have been hired, as scheduled. One journal article is published and 3 are currently in preparation. In RT2, we develop data-driven patient-specific methods for optimizing HBMs and derive optimal stimulation protocols. A total of 11 people were hired or allocated part-time to the project (6 junior and 5 senior researchers). One journal article was submitted in December 2021 and 2 are close to submission. Two pre-prints are online. In RT3, 4 people were hired [1 engineer, 2 phD students and 1 project manager (part-time)]. We have started to collect data in patients under transcranial direct current stimulation (tDCS, referred to as Pilot Study 1, PS1) and develop methods to map epileptogenic networks. PS1 got approvals from Committee of Personal Protection (CPP) and the National Agency for the Safety of Medicines (ANSM). First patients were included in March 2021. At this time, 9 patients are included. For the simultaneous intracerebral recording-tDCS study (referred to as PS2), approval was obtained from the CPP. One journal paper was submitted in November 2021. One article and a review are in preparation. We have regular periodic distant meetings (every 4 months). As the sanitary situation improved in Autumn 2021, we also organized a 4-day person-meeting in Rennes (07-10/09/21). Thirty people could attend. To disseminate Galvani results, posters (n=11) were presented in reference conferences in the field (2021, BioEM, the 4th International Brain Stimulation Conference, the Annual Meeting of the American Epilepsy Society) and talks were given (n=7). Exchanges of visiting scientists were organized between Rennes and Barcelona (Oct. & Nov. 2021). Problems incurred:Nevertheless, delays are encountered on 3 topics. In RT1, the development of computational models at microscale is slightly delayed, since the post-doc fellow is on leave (maternity, Oct. 2021. to Jan. 2022). We also had to postpone some animal experiments because the initial Gantt chart was too optimistic and for each animal group (n=10), 3 months are required between epilepsy induction and recordings. Nevertheless, recordings and analyses under the two conditions (stim./no stim.) are in progress (n=30). In RT3, we are still waiting for the authorization of PS2 from ANSM. 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) Epilepsy is a multi-causal neurological disorder affecting about 1% of the population worldwide (65 million). In 2010, the WHO’s Global Burden of Disease study ranked epilepsy as the second most burdensome neurologic disorder worldwide in term of disability-adjusted life years. Almost a third of patients (29%) are untreatable: in 18.9 million patients, drugs fail and surgery is not an option or has failed too.A large body of evidence suggests that large-scale patient-specific epileptogenic networks (EN) are responsible for the generation and spread of seizures through synchronization processes between distant brain areas characterized by altered excitability. Resective surgery is the treatment of choice to suppress drug-resistant seizures, aimed at removing the key brain region(s) involved in seizure generation. This is possible provided that the EN is accurately mapped and that a viable surgical strategy can be defined. However this can only be offered to 10-20% of the potential candidates, since it can cause major functional deficits (e.g. if the target is near language areas).GALVANI’s main objective is to cover the gap of untreatable epileptic patients, providing a personalized therapeutic non-invasive brain electrical neuromodulation solution. Reaching this ambitious goal requires a synergetic approach that brings together biomathematics, biophysics and clinical epileptology. The inflection point is to achieve optimal control of seizures from a bottom-up, model-based, mechanistic understanding of dynamic weak electric field effects on target large-scale brain networks.Electrical stimulation represents one of the best opportunities available to neurologists. However, currently available options are invasive (requiring surgery). They include vagus nerve and intracranial stimulation (deep brain or cortical stimulation). In contrast, transcranial current stimulation (tCS, which includes both direct current - tDCS - and alternating current – tACS - variants) makes use of electrodes placed on the head surface to stimulate brain regions. tCS is a rapidly developing form of non-invasive brain stimulation. Its effects result from persistent, weak electric fields at low frequencies acting on cortical circuitry. Six tDCS randomized studies and several case reports suggest its potential usefulness in epilepsy. Despite heterogeneity in patient populations and methods, results are encouraging: after pioneering work, the largest studies (2013 and 2017) demonstrated a decrease in seizure frequency that was still statistically significant four weeks after treatment. These studies employed bipolar montages with large sponge electrodes, one or a few treatment sessions and no personalization. Considering that the tCS electric-field varies according to individual brain anatomical features, a patient-specific approach is absolutely required to properly engage the targeted brain regions. None of the aforementioned studies adapted their protocol to individual patients’ network targets. The ongoing Neuroelectrics clinical trial which has now completed an open-label pilot and is entering a pivotal phase, uses MRI-guided multichannel optimization in both pediatric and adult drug-resistant cortical epilepsy patients. Preliminary results indicate that a 50% median seizure reduction over two months after a 10-day multisession intervention is possible.Despite these encouraging studies, the field is in its infancy. tCS is recognized for its applicability and safety in epilepsy. However, and despite technological advances such as multichannel stimulation, it is not yet indicated as a standard treatment for non-surgical epilepsies. This situation is due to major scientific limitations: an overwhelming number of stimulation parameter combinations, unknown mechanisms of action and insufficient account for patient-specific factors, and insufficient understanding of short- and long-term effects of brain neuromodulation. Indeed, the mechanisms by which neurostimulation exerts its therapeutic effects remain elusive, particularly at very low, sub-threshold intensity. Results from long-term chronic stimulation, together with accumulated in vivo and in vitro data, suggest concurrent mechanisms of action. Acute effects result from membrane polarization, with a major downstream influence on neurotransmitter release, spike timing and spike-timing-dependent plasticity. Short- and long- term therapeutic effects could be related to neurogenesis, cortical reorganization associated to synaptic plasticity known to be both intensity- and frequency-dependent.The resulting situation is the absence of a science-based strategy for defining target networks and protocols. Stimulation parameters are usually empirically chosen based on safety considerations or clinical experience, without a strong rationale about how cortical excitability is altered by the induced electric fields, or how these effects result in plastic changes of clinical value. Thus, the qualitative nature of the methods used hinders the interpretability and reproducibility of results and there is a large margin for therapeutic improvement.To move the field forward and transform the care of a large fraction of patients living with drug-resistant epilepsy, a fundamental and interdisciplinary problem must be solved: to optimally target and control epileptic brain networks with neuromodulatory weak electric fields.The brain is a complex, plastic, electrical network and most neurological disorders ultimately result from network dysfunction. Our vision is that critical features of pathological networks can effectively be captured in personalized hybrid computational models developed to optimize non-invasively-delivered electric fields of clinical value. Our ambition is to pioneer this approach by combining science, engineering and clinical research to disentangle the mechanisms of interaction of weak electric fields with brain networks, to leverage this knowledge to manipulate them, and to make therapeutic non-invasive patient-specific brain neuromodulation procedures widely available to epileptic patients.