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Cortical High Frequency Oscillations

Cortical high‐frequency oscillations (HFOs; 100–500 Hz) have an important physiologic function in cognition and have been a subject of intense basic and clinical research in recent years.1-3 Emergence of HFOs prior to ictal discharges was documented in several in vivo and in vitro studies.45 In contrast to other epileptiform discharges, such as sharp waves or spikes, HFOs are often a reliable marker of the epileptogenic area,67 as resection of HFO‐generating areas has been shown to correlate with higher rates of seizure freedom than resection of the seizure‐onset zone alone.6 However, despite their clinical importance, the basic network dynamics of these oscillations remain only partially understood. Specifically, it is unclear how focal HFOs generated in small volumes of human cortical tissue on the scale of a cortical column289 can synchronize across large areas of the cortex. The paucity of this knowledge, in turn, hinders the development of novel approaches for monitoring the seizure onset, localization of the core epileptogenic network, and advancements of pharmacologic and/or surgical treatments.

Epilepsy affects more than two million Americans of all ages and ethnicities, including military service members, veterans and their beneficiaries (CDC, 2012). About one third of patients with epilepsy do not respond to pharmacological treatment (Kwan and Brodie, 2000) and for some, resection of the epileptogenic region remains the best treatment option (Perry and Duchowny, 2013). Intractable epilepsy has a devastating impact on patient’s quality of life, leading to the greatest burden due to epilepsy-related disability that accounts for a substantial proportion of its 15.5 billion burden on our society. Many countries restrict people with epilepsy from joining their armed forces. In the United States, in order to enroll in military service, the individual must be seizure-free from age 6 or for a period of 5 years while taking no medications for seizure control. Yet, the active members of the armed forces and veterans, who were traumatized by blunt or penetrating brain injury, carry a high risk for the development of intractable post-traumatic epilepsy decades after their initial injury (Kazemi et al., 2012).

Management of patients with intractable epilepsy is challenging due, in part, to largely unknown basic cellular mechanisms underlying epileptic seizures and the link between these basic mechanisms and the electrographic signature of epileptic seizures in the interictal and ictal periods. In this regard, high-frequency oscillations (HFOs) at 100-500 Hz (ripple and fast ripple frequency band) have been implicated in epileptogenesis in human intracranial electroencephalography (iEEG) as well as in vivo and in vitro animal models of hippocampal and neocortical epilepsy (Draguhn et al., 1998; Bragin et al., 1999). HFOs, in contrast to other epileptiform discharges, such as sharp waves or spikes, are often reliable markers of the epileptogenic area (Jacobs et al., 2010; Wu et al., 2010). Clinically, resection of areas harboring HFOs has been correlated with higher rate of seizure freedom while resection of seizure onset zone (SOZ) has not (REF). Based on the shape of putative coupling potentials (spikelets or fast prepotentials) during low-calcium ~200 Hz ripples, in vitro gap junctional coupling between axons of cortical principal neurons was suggested as the anatomical substrate of HFOs (Draguhn et al., 1998). Subsequently, Schmitz and colleagues provided electrophysiological and dye-coupling evidence for axo-axonic coupling in cortical principal cells (Schmitz et al., 2001). Our group recently provided the ultrastructural evidence for axo-axonic gap junctions in the normal rat hippocampus (Hamzei-Sichani et al., 2007; Hamzei-Sichani et al., 2012). HFOs have been associated with rearranged and aberrant network topology showing axonal sprouting (REF) and de novo synapse formation (REF). However, despite the significance of HFO detection for epilepsy treatment and preponderance of experimental evidence, there is a critical need to identify anatomical and physiological substrates of pathological HFOs and the interplay between different cortical HFO generators in human epilepsy patients. Filling[N1]  this knowledge gap is essential for identification of precise and reliable predictors of seizure onset in patients with intractable epilepsy, which, in turn, will open new avenues for the development of preventive, pharmacological and surgical treatment options for these individuals.

 [N1]Need sentence referencing potential involvement of glutamatergic synapses here.