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Imaging large scale neuronal networks in epilepsy

English title Imaging large scale neuronal networks in epilepsy
Applicant Seeck Margitta
Number 140332
Funding scheme SPUM
Research institution Clinique de Neurologie Hôpitaux Universitaires de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.05.2012 - 31.10.2016
Approved amount 2'017'244.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Neurology, Psychiatry

Keywords (5)

Epilepsy ; Neuroimaging; Electrophysiology; EEG; MRI

Lay Summary (English)

Lead
Lay summary
Epilepsy is a frequent neurological disease that affects up to 1% of the population in most of the Western countries, with devastating consequences, in particular for younger people. Due to recurrent impaired consciousness or falls, the patients may encounter learning difficulties, remain excluded from the job market and even encounter an increased mortality. Thus, if we better understand from where the epilepsy comes, we might be able to offer more targeted treatment possibilities, be it with surgery or neurostimulation of selected structures. In the context of the grant, we further improved the localizing properties of multichannel EEG (with up to 256 scalp electrodes, electric source imaging [ESI]), functional MRI and so-called diffusion-tensor imaging (DTI), which aims at visualizing the fibers connecting one brain structure with the others. Thanks to a large data base obtained during the first phase of the grant, we could show a) that ESI has an excellent localizing value in patients admitted for possible surgery, and b) that the fMRI shows a network which resembles the one found with intracranial EEG or ESI, but with a much higher precision. DTI also turned out to be promising. However, in order to fully use this technique, we needed a data base of healthy controls, which is now accomplished. Our first observations confirm that DTI/DSI is capable to show physiological or aberrant fiber bundles in patients and this can be reliably done, with similar results, in all MR machines of the three centers (University Hospitals of Geneva, Lausanne, and Berne).
While we focused very much on epileptogenic abnormalities when there is no clinical seizure (called the interictal state), we will now extend our studies to visualize the seizure activity and determine if the spread follows what is suggested by the interictal ESI, fMRI or DTI findings. If this is true, we might not need to see the patient’s seizure to know where the epilepsy comes from or which epilepsy disease the patient suffers from, but just record a short piece of EEG. We will also probe the increased value to very performing MRIs (7T) which show much more precisely the brain anatomy. Our studies will not only include patients who are worked up for possible surgery and/or adults, but also patients with other forms of epilepsy, including young children seen mainly by our neuropediatric colleagues. Furthermore, we like to know what happens if the brain is at “rest” in our patients. In healthy subjects, distinct areas are activated (or inactivated) and supposedly this is a sign of mental health. While we do not expect a major anomaly in this resting network, there might be subtle changes which explain attention or memory difficulties in our patients. Finally, we make use of those patients who have to undergo brain surgery and find out which components in the MRI relate to tissue composition in small structures in the mm range. Any result from this analysis will be extremely helpful for other patients who suffer different neurological diseases (dementia, multiple sclerosis) and usually have no brain surgery. The mouse model, developed by the fourth group, resembles very much what is found in patients and will help us to better understand epilepsy on the cellular level. Like in our previous grant, most of our studies aim to explain the neuronal activity at the individual level, which is required for a tailored care, albeit we will also try to find “laws” in larger patient groups vs control subjects. With our common efforts, we hope to substantially decrease the number of patients who do not respond to drug treatment, which is currently still around 30%.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
159780 The two faces of neuroplasticity - In vivo study of brain plasticity induced by epileptic seizures and electroconvulsive therapy 01.04.2016 Project funding (Div. I-III)
124089 Imaging large scale neuronal networks in epilepsy 01.05.2009 SPUM
155950 A Bayesian Inference Approach to Intracranial EEG Seizure Dynamics 01.11.2014 Project funding (Div. I-III)
169198 Local and global brain connectivity alterations in focal epilepsy: Effects of disease, surgery and neuromodulation 01.02.2017 Project funding (Div. I-III)
146633 Non-invasive analysis of language network connectivity by EEG, fMRI, and DTI for the planning of brain surgery 01.10.2013 Project funding (Div. I-III)
159705 Temporal dynamics of whole-brain neuronal networks 01.05.2015 Project funding (Div. I-III)
122073 Localization of functionally vital cortex in the individual patient: correlation between invasive and non-invasive methods 01.12.2008 Project funding (Div. I-III)
150828 Development of Advanced Translational High-Field MRI 12.05.2014 R'EQUIP
180365 Predict and Monitor Epilepsy After a First Seizure: The Swiss-First Study 01.02.2019 Sinergia

Abstract

This research project aims to continue our efforts in characterizing the initiation and spread of epileptic activity in the brain with multimodal non-invasive imaging techniques. During the last research period we successfully developed and applied different imaging techniques to a large number of epileptic patients and demonstrated the ability of these techniques to not only localize the epileptogenic zone with high precision, but to also describe pathways and nodes of propagation of epileptic activity in large-scale neuronal networks. One of these methods is Electric Source Imaging (ESI) based on high-density EEG. In a retrospective study of a large sample of 152 operated patients we showed that ESI reaches a sensitivity of more than 80% in correct focus localization even in difficult cases like non-lesional epilepsy. A second method is the combination of high-density EEG and fMRI in simultaneous recordings. In different studies we demonstrated the importance of combining these two imaging techniques in order to achieve the required spatial and temporal resolution to adequately follow the fast dynamics in epileptogenic networks. Different analysis methods were developed that enhanced the sensitivity and clinical yield of this technique. The third imaging method that was studied is diffusion spectrum imaging (DSI). Substantial work was devoted to the reproducibility of DSI results in the same subject recorded with the different scanners at the three different centers. Analysis of the first patients showed promising results, i.e aberrant fibers may explain part of the “incorrect” localized discharges. Besides the different imaging studies in patients, our project also studied the anatomical and neurophysiological characteristics of a mouse model with cortical heterotopias and seizures. Several pilot studies suggested that there is a novel mechanism of epileptogenesis, that is due to an inherited mutation of the microtubule-associated protein. Interestingly, compound heterozygous mutations of this gene were found in one family with bilateral subcortical heterotopy, severe epilepsy, and mental retardation. In total, 14 publications resulted from this first grant period of around 2.5 years and 4 papers are submitted or in revision. Most papers were written by the clinical research candidates, demonstrating their successful scientific progress through this project. The prolongation of this project will allow us to continue the fruitful collaboration and further application of our tools, which should lead to an increase of our database of patients in whom multimodal imaging was done. The Swiss-EPINET consortium that was created on the basis of this SPUM-project between the University Hospitals of Geneva, Berne and Lausanne, allowed us to establish a common recording protocol and create a central database which can be exploited by the different partners for testing different analysis techniques, for selecting and comparing patients with particular syndromes, focus localization, or distinct neuropsychological or psychiatric profiles. Besides the continuation of the studies of the patients with the outlined methods, we will also include new approaches, such as the detailed analysis of structure (subfields) and the connections of the medial temporal lobe of patients with and without a focus in that region, using ultra high field 7T scanner. This will also help to inform data obtained by ESI or fMRI, or vice versa. A recently installed group in the Neurology Clinic of the CHUV (Lausanne), specialized in advanced volumetric and diffusion analysis of the MRI will join the research team.
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