Periodic Reporting for period 2 - GALVANI (Controlling epileptic brain networks with computationally optimized weak electric fields)
Berichtszeitraum: 2021-12-01 bis 2023-05-31
Epilepsy is a neurological disorder affecting 65 million people worldwide. It is defined as a brain disorder characterized by recurring and most often unpredictable seizures. In non-operable drug-resistant epilepsies, therapeutic procedures alternative to surgery (preserving brain tissue while reducing hyperexcitability in epileptic areas) are urgently needed. The Galvani project (ERC-Syg 2019) aims at developing, testing and validating innovative models and unconventional electrical stimulation methods to respond to this demand. Reaching this ambitious goal requires a synergetic approach that brings together biomathematics (computational neurosciences), biophysics (bioelectromagnetism) and medicine (epileptology), uniting the passion and background of 3 experts and their teams (Rennes, Marseille and Barcelona).
A unique research strategy has been designed to address 4 major challenges:
1) Unravel the intricate relationship between neuromodulatory low-magnitude electric fields induced by transcranial current stimulation (tCS) and the resulting neurophysiological effects induced at the level of neurons, neuronal assemblies and larger scale networks;
2) Maximize the therapeutic effects of tCS-induced weak electric fields by targeting patient-specific epileptogenic networks (ENs) in order to reduce seizure occurrence;
3) Develop optimized personalized therapeutic protocols for novel repetitive non-invasive multichannel tCS devices;
4) Assess and validate optimized protocols in a cohort of patients in order to stratify patients and objectively define potential responders.
To achieve Galvani’s objectives, the research program consists of three research tracks (RT). RT1 aims at understanding the impact of weak, persistent electric fields on brain activity and connectivity through the development of a novel class of hybrid brain models (HBMs) that combine theoretical models of bioelectromagnetism with neurophysiologically-plausible in silico models of neuronal networks. HBMs are personalized in RT2 from patient data to investigate the therapeutic effects of optimized protocols designed to significantly alter the neurodynamics of large-scale ENs. RT3 is devoted to clinical translation, with 2 major tasks: 1) development of comprehensive advanced signal processing procedures to determine patient-specific ENs responsible for seizures from clinical data and 2) clinical assessment of personalized neuromodulation protocols.
A unique research strategy has been designed to address 4 major challenges:
1) Unravel the intricate relationship between neuromodulatory low-magnitude electric fields induced by transcranial current stimulation (tCS) and the resulting neurophysiological effects induced at the level of neurons, neuronal assemblies and larger scale networks;
2) Maximize the therapeutic effects of tCS-induced weak electric fields by targeting patient-specific epileptogenic networks (ENs) in order to reduce seizure occurrence;
3) Develop optimized personalized therapeutic protocols for novel repetitive non-invasive multichannel tCS devices;
4) Assess and validate optimized protocols in a cohort of patients in order to stratify patients and objectively define potential responders.
To achieve Galvani’s objectives, the research program consists of three research tracks (RT). RT1 aims at understanding the impact of weak, persistent electric fields on brain activity and connectivity through the development of a novel class of hybrid brain models (HBMs) that combine theoretical models of bioelectromagnetism with neurophysiologically-plausible in silico models of neuronal networks. HBMs are personalized in RT2 from patient data to investigate the therapeutic effects of optimized protocols designed to significantly alter the neurodynamics of large-scale ENs. RT3 is devoted to clinical translation, with 2 major tasks: 1) development of comprehensive advanced signal processing procedures to determine patient-specific ENs responsible for seizures from clinical data and 2) clinical assessment of personalized neuromodulation protocols.
RT1:
- Development at the microscopic level (cellular), of a novel realistic model of the human neocortical tissue. The tuning of parameters allows us to reproduce epileptiform events similar to those recorded in patients;
- Development at the mesoscopic level (neural mass) of a novel layered model for the human neocortex that reproduces and explains the variety of interictal epileptic events;
- Development of a mesoscale model capable of reproducing autonomous and realistic transitions from interictal to ictal state;
- Quantification of the magnitude and spatial distribution of electric fields induced by intracranial stimulation;
- In vivo experiments in a mouse model, strongly suggesting that alternating transcranial current stimulation (tACS), at a frequency of 10 Hz, has a “therapeutic” effect (decrease of epileptic activity), as predicted by the computational model.
RT2:
- Biophysical personalization of models (including structural lesions and metallic implants);
- Development of a robust pipeline to create a personalized model of the epileptogenic focus at the single neural mass level;
- Personalization of Stereo-EEG (SEEG) data, including modeling of seizure propagation from the most epileptogenic nodes;
- Pipeline for the analysis of SEEG data during seizure, refining the classification of SEEG-recorded brain regions according to their epileptogenicity;
- Study of the stimulation of single/multiple node networks, developing metrics to quantify the reduction of seizure occurrence and the spread of seizures. Models predict the relative strength of the electric field needed for complete seizure reduction depend on patients and that the stimulation can lead to delayed seizure elimination.
RT3:
- Development of signal processing algorithms to quantify markers of epilepsy;
- Classification of brain regions according to their epileptogenicity degree;
- Quantitative definition of the topology of epileptogenic networks (ENs) and propagation networks (PNs);
- First pilot study (PS1) of direct current tCS (tDCS) to test its efficacy and better define networks involved in functional changes (source localization), using high resolution electroencephalography and magnetoencephalography recordings. Ten patients were included and 7 have completed the whole protocol;
- Second pilot study (PS2), to quantify the immediate impact of weak electric fields on brain activity and investigate the impact of personalized tCS (direct and alternating current) to validate predictions of biophysical models regarding the effects of weak fields on neural network dynamics. To date, 3 patients were included.
- Development at the microscopic level (cellular), of a novel realistic model of the human neocortical tissue. The tuning of parameters allows us to reproduce epileptiform events similar to those recorded in patients;
- Development at the mesoscopic level (neural mass) of a novel layered model for the human neocortex that reproduces and explains the variety of interictal epileptic events;
- Development of a mesoscale model capable of reproducing autonomous and realistic transitions from interictal to ictal state;
- Quantification of the magnitude and spatial distribution of electric fields induced by intracranial stimulation;
- In vivo experiments in a mouse model, strongly suggesting that alternating transcranial current stimulation (tACS), at a frequency of 10 Hz, has a “therapeutic” effect (decrease of epileptic activity), as predicted by the computational model.
RT2:
- Biophysical personalization of models (including structural lesions and metallic implants);
- Development of a robust pipeline to create a personalized model of the epileptogenic focus at the single neural mass level;
- Personalization of Stereo-EEG (SEEG) data, including modeling of seizure propagation from the most epileptogenic nodes;
- Pipeline for the analysis of SEEG data during seizure, refining the classification of SEEG-recorded brain regions according to their epileptogenicity;
- Study of the stimulation of single/multiple node networks, developing metrics to quantify the reduction of seizure occurrence and the spread of seizures. Models predict the relative strength of the electric field needed for complete seizure reduction depend on patients and that the stimulation can lead to delayed seizure elimination.
RT3:
- Development of signal processing algorithms to quantify markers of epilepsy;
- Classification of brain regions according to their epileptogenicity degree;
- Quantitative definition of the topology of epileptogenic networks (ENs) and propagation networks (PNs);
- First pilot study (PS1) of direct current tCS (tDCS) to test its efficacy and better define networks involved in functional changes (source localization), using high resolution electroencephalography and magnetoencephalography recordings. Ten patients were included and 7 have completed the whole protocol;
- Second pilot study (PS2), to quantify the immediate impact of weak electric fields on brain activity and investigate the impact of personalized tCS (direct and alternating current) to validate predictions of biophysical models regarding the effects of weak fields on neural network dynamics. To date, 3 patients were included.
Transcranial current stimulation (tCS) is a rapidly developing technique of non-invasive brain stimulation. Its effects result from persistent, weak electric fields at low frequencies acting on neurons and neuronal circuitry. tCS is recognized for its applicability and safety in patients suffering from epilepsy. However, it is not yet indicated as a standard treatment for non-surgical epilepsies. This situation results from the absence of a science-based strategy for defining target networks and protocols. Currently, 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, network effects, and how these effects result in plastic changes.
Galvani's main objective is to improve the care of incurable epileptic patients, providing a personalized therapeutic solution based on non-invasive brain electrical neuromodulation. 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 (Figure 1).
Until the end of the project, expected results will show that the critical features of pathological epileptic networks can effectively be captured in personalized hybrid brain models (HBMs) developed to optimize non-invasively-delivered electric fields of clinical value. Our ambition is to combine science, engineering and clinical research to disentangle the mechanisms of interaction of weak electric fields with brain networks, and to develop non-invasive patient-specific therapeutic procedures.
Galvani's main objective is to improve the care of incurable epileptic patients, providing a personalized therapeutic solution based on non-invasive brain electrical neuromodulation. 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 (Figure 1).
Until the end of the project, expected results will show that the critical features of pathological epileptic networks can effectively be captured in personalized hybrid brain models (HBMs) developed to optimize non-invasively-delivered electric fields of clinical value. Our ambition is to combine science, engineering and clinical research to disentangle the mechanisms of interaction of weak electric fields with brain networks, and to develop non-invasive patient-specific therapeutic procedures.