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Diagnosing

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Understanding

Understanding what exactly happens in an epileptic brain and why, down to a molecular level is the hub of Epinext‘s activities because it drives everything else: better diagnosis, more realistic virtual surgery and promising new approaches for therapy.

The general workflow in this task perfectly describes what makes Epinext so special:

  • Identify new cellular and molecular mechanisms that control neuronal excitability
  • Test the consequences of these findings in experiments which are directly relevant to real patient cases
  • Implement such mechanisms in virtual brain models to generate predictions which can be tested again
  • Promising predictions about new therapy approaches can finally be evaluated with real patient cases

Cellular and molecular studies

LGI1 in neuronal plasticity and epilepsy

Some forms of epilepsy like ADLTE (autosomal dominant lateral temporal lobe epilepsy) or LE (limbic encephalitis) are linked to mutations in a protein called LGI1 (leucine-rich glioma-inactivated 1). This protein plays a role in neuronal activity and Epinext will investigate how exactly it influences this activity in human patients and animals.

For practical clinical usage, Epinext will develop diagnostic tools for LGI1 antibodies and conduct animal studies to find out how LGI1-related substances can possible battle epilepsy.

Regulation of ion channel expression and robustness of excitability

Ion channels play a vital role within the brain, transporting signals between neurons. Studies have found that mutations in ion channels can be present but harmless in healthy humans, suggesting that other ion channels take over for these. Then again, such co-regulated modules of ion channels could also be the reason that some forms of epilepsy aren‘t treatable by known drugs.

Epinext will work to identify a complete regulation map of ion channels and its effect on neuronal activity, using computational modeling. This will reveal which sets of ion channels must be precisely targeted by improved anti-epileptic drugs.

Excitability disorders as disruptions of homeostatic plasticity

Epilepsy is basically a disruption in the balancing system of the brain (referred to as “homeostatic plasticity”) which ensures that the activity of all excitable neurons is kept stable. Understanding this regulatory mechanism in more detail will not only lead to further insights about the disease but also help explaining which factors are important when recovering from a brain trauma or neurosurgery.

Investigating homeostatic plasticity can be done by focusing on the visual system of our brain: There, one can easily mimic such perturbations by covering one eye and measuring the related plasticity effects in the visual cortex.

The outcome of these investigations will also shed light on related excitability disorders like cardiac arrhythmia, neuropathic pain and sensory deficits like amblyopia which affects 1-5% of humans.

Animal studies

Neuromodulation

The biological factors contributing to the emergence and propagation of seizures is still not well understood. However, computational studies predict that so-called “slow variables” play a key role. Epinext researchers will define biophysical processes behind such slow variables in the lab and then observe and record freely moving rodents to see to which extent such biomarkers can predict seizures.

Existing virtual brain models will be constantly updated and compared to the results from animal studies, resulting in sustainable biomarkers derived from systematic parameter explorations.

Functional Connectivity

Focusing on how seizures propagate through a brain, a second set of animal studies will be conducted by the Epinext team. The newly released so-called “mouse connectome” (basically a wiring diagram of a mouse‘s brain) will be simulated in The Virtual Brain software (TVB) and compared to actual animals as their brains slowly become epileptic (referred to as “epileptogenesis”) and seizures occur.

From the constant feedback-cycle between real and virtualized mice, the TVB model will become refined enough to make predictions about how seizures emerge and propagate – which can then be translated to the human brain.

Human studies

Fast oscillations as reliable markers of epilepsy

When performing epileptic surgery, i.e. resecting brain tissue from epileptogenic zones, knowing exactly where these are is obviously important to ensure a positive and safe outcome. As global patterns of neural activity, so-called High Frequency Oscillations (HFO) are considered to be good localizers for epileptogenic zones, Epinext will provide easy-to-use, reliable and quantified indices for these in a clinical setting.

Changes in functional connectivity in partial epilepsies

The Epinext team is already a global leader in studying the changes to the brain‘s network during seizures, in this case the “functional connectivity” (FC), and has established the concept of “Epileptogenic networks”. As one result, Epinext has demonstrated a connection between such FC changes and alterations of consciousness of a patient undergoing a seizure.

Building upon this knowledge, Epinext will conduct further studies to link FC changes to behavior and cognitive changes when the brain is electrically stimulated (during stereotaxic EEG) or at resting state, i.e. between seizures.

Biorelevant tools

As any epileptic patient undergoing neurosurgery must be evaluated before using EEG electrodes directly implanted into the brain surface (intracranial EEG or iEEG), the performance and sensitivity of these electrodes are of great interest.

In collaboration with partner companies Alcis and EMSE, Epinext has developed a new generation of electrodes made from organic transistors. They are extremely thin (4 microns diameter), beat any commercially available electrode on the market by a wide margin and are 100% biocompatible.

Their sensitivity allows for measuring selected molecular activity and their results from clinical tests will be fed back into computational brain modeling with The Virtual Brain software, thus improving the predictive quality of simulations.

Further development of The Virtual Brain Software in the context of epilepsy will be done in collaboration between computational neuroscientists at INS and one of Epinext’s industrial partners, Codebox.

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