Drs. Shennan Weiss and Dura-Bernal were selected for the SUNY Downstate Seed Funding program and received $50,000 for 1 year project entitled 'An investigation of the physiological mechanisms responsible for the generation of neocortical fast ripples (>350 Hz), a biomarker of epileptogenic regions'.
Significance and Innovation
A.1 : Ascertain if neocortical fast ripples (>350 Hz) are generated and detected, by simulated macro- and microelectrode recordings, when the GABAA reversal potential becomes depolarizing: Patients with medically refractory epilepsy often require surgery to reduce their seizure burden1. Implanting intracranial macro- and micro- electrodes is used in planning these surgeries2. Fast ripples are a type of high-frequency oscillation (HFO, Fig 1) with a frequency content between (200-600 Hz), and a duration between 15-50 msec, that can be recorded in the local field potential (LFP) recorded by microelectrodes, or the intracranial EEG (iEEG) recorded by macroelectrodes. Over two decades of research suggests that fast ripples are an electrophysiological biomarker of the epileptogenic zone (EZ), defined as the brain region necessary and sufficient to generate seizures. Recent research from my laboratory suggests that neocortical fast ripples with a peak frequency content > 350 Hz are particularly of interest as potential biomarkers, because if they occur in a widespread fashion, and are outside of the region of seizure onset, then epilepsy surgery is likely to fail. It is thus important to better understand what distinct neurophysiological mechanisms are responsible for generating fast ripples >350 Hz in the neocortex. Many lines of evidence suggest that in epileptogenic tissue the GABAA reversal potential is reversed in a subset of epileptogenic neurons, and macroscale modeling suggests that the more depolarized the GABAA reversal potential, the higher the frequency of the fast ripples that are generated and detected. These hypotheses have yet to be tested in an anatomically and biophysically accurate model of neocortex.
A.2 : Determine if altering excitatory or inhibitory synaptic strength can generate fast ripples (>350 Hz): In experimental animal models of epilepsy, fast ripples first appear following traumatic brain injury or toxin exposure in the subjects that develop epilepsy. One theory suggests that fast ripple generation is dependent on a restructuring of neuronal connectivity and plasticity. Research in the hippocampus suggests that during epileptogenesis small clusters (<1 mm) of excitatory neurons are pathologically interconnected due to an increase in excitatory synaptic strength or the number of collaterals. Other experimental data suggests that during epileptogenesis a loss of inhibitory interneurons occurs. Very little is known about the network mechanisms of fast ripple generation in the neocortex, and still less is known how these network mechanisms contribute to generating higher-frequency fast-ripples > 350 Hz.
