Modeling Inhibitory Neuron Firing in Epilepsy Treatment

Modeling Desynchronized Inhibitory Neuron Firing in a Seizing Dentate Gyrus: A Novel Treatment for Epilepsy • Epilepsy is a neurological disorder characterized by repeated seizures and occasionally losses of consciousness • Seizures result from synchronous bursts of electrical activity in the brain where certain neurons experience heightened activity caused by excitement in their axonal environment 1 Discussion/ Conclusions Results Introduction • Dentate Gyrus seizure network code generated raster plot • Seizure characterized by high activity and synchronous firing • Changing synaptic weights successfully stopped seizure Fig. 2 Seizure graph generated by altering parameters • We modeled treatments that promote GABAergic inhibition such as Clonazepam • Seizure propagation was halted by ~800 ms Fig. 3 Graph generated by doubling synaptic connection weights to model Clonazepam treatments Fig. 1 Normal vs Epileptic neuron firing 2 • Repeated seizures→ more synchrony/stronger synaptic connections → even more seizures 3 • No cure, but current treatments include: • Prescription drugs such as Clonazepam that increase GABAergic inhibition, halting seizure activity • Deep Brain Stimulation (DBS), which uses electrical currents to regulate brain activity and disrupt seizures • Problems with prescription drugs: • Overactivating inhibitory pathways might lead to absence seizures • 30-40% of patients do not respond to drug treatment • Still promotes synchrony between networks; patient remains seizure prone • We propose a potential alternative treatment for epilepsy that involves asynchronously activating inhibitory neural networks to both combat overexcitation and decrease the strength of synaptic connections caused by synchronous firing, thus reducing the likelihood of future seizures. • Alternate treatment turned out to be relatively ineffective in shutting down seizure • Opportunity for future investigation • Depolarization block observed in HIPP cells potentially lowers efficacy of treatment • We then modeled asynchronous inhibitory neuron firing • Initial beneficial effect, but seizure continued to propagate Fig. 4 Graph generated by asynchronously stimulating inhibitory cells • Then tested the effects of activating each type of inhibitory cell individually • Only basket cells were able to stop seizure Fig. 5 Stimulating Mossy Cells Only Fig. 6 Stimulating Basket Cells Only Fig. 7 Stimulating HIPP Cells Only • Tested different durations of basket cell inhibition: • Minimum duration for successful stoppage of seizure was 650 ms Fig. 8 Stimulating Basket Cells for 650 ms Methods Fig. 9 Stimulating Basket Cells for 600 ms • Changed direction – attempted to • Based program off Dentate Gyrus • Modeled GABAergic treatments by altering 4 stop seizure by activating different neural network model (Python 3) the seizure code types of inhibitory cells in the • Made parameter and function • Doubled synaptic connection dentate gyrus (Mossy, Basket, edits to the code from inhibitory to weights HIPP) • Increased sodium ion excitatory granule cells • Stimulated all the cells in the channel conductance, • Modeled asynchronous activation of network of each individual cell type percent cell death, and inhibitory neurons by altering the seizure and compared the effects on the axon sprouting code differently network • Stimulated various different • Provided input current to individual • Modeled stimulation of all neurons in the dentate-cell cells to stimulate them inhibitory interneurons at the same time for network to produce a seizure. asynchronously the same duration Fig. 10 Voltage Graphs of Each Cell Type during proposed treatment simulation • A more precise form of DBS was also investigated • Stimulating inhibitory basket cells for at least 650 ms found to be most effective • Future technological advances might be capable of activating select inhibitory networks or cells