Title: Neocortical Pathological High Frequency Oscillations Are Associated with 1 Frequency-dependent Alterations in Functional Network Topology 2 3

47 Synchronization of neural oscillations is thought to integrate distributed neural 48 populations into functional cell assemblies. Epilepsy is widely regarded as disorder of 49 neural synchrony. Knowledge is scant, however, regarding whether ictal changes in 50 synchrony involving epileptogenic cortex are expressed similarly across various 51 frequency ranges. Cortical regions involved in epileptic networks also exhibit 52 pathological high frequency oscillations (pHFOs>80 Hz), which are increasingly utilized 53 as biomarkers of epileptogenic tissue. It is uncertain how pHFO amplitudes are related to 54 epileptic network connectivity. By calculating phase-locking values among intracranial 55 electrodes implanted in children with intractable epilepsy, we constructed ictal 56 connectivity networks and performed graph theoretical analysis to characterize their 57 network properties at distinct frequency bands. Ictal data from 17 children were analyzed 58 using a hierarchical mixed-effects model adjusting for patient-level covariates. 59 Epileptogenic cortex was defined in two ways: (1) a hypothesis driven method using the 60 visually-defined seizure-onset zone; and (2) a data-agnostic method using the high 61 frequency amplitude of each electrode. Epileptogenic cortex exhibits a logarithmic 62 decrease in inter-regional functional connectivity at high frequencies (>30 Hz) during 63 seizure initiation and propagation, but not at termination. At slower frequencies, 64 conversely, epileptogenic cortex expressed a relative increase in functional connectivity. 65 Our findings suggest that pHFOs reflect epileptogenic network interactions, yielding 66 theoretical support for their utility in the pre-surgical evaluation of intractable epilepsy. 67 The view that abnormal network synchronization plays a critical role in ictogenesis and 68