The role of superficial and deep layers in the generation of high frequency oscillations and interictal epileptiform discharges in the human cortex.

Describing intracortical laminar organization of interictal epileptiform discharges (IED) and high frequency oscillations (HFOs), also known as ripples. Defining the frequency limits of slow and fast ripples. We recorded potential gradients with laminar multielectrode arrays (LME) for current source density (CSD) and multi-unit activity (MUA) analysis of interictal epileptiform discharges IEDs and HFOs in the neocortex and mesial temporal lobe of focal epilepsy patients. IEDs were observed in 20/29, while ripples only in 9/29 patients. Ripples were all detected within the seizure onset zone (SOZ). Compared to hippocampal HFOs, neocortical ripples proved to be longer, lower in frequency and amplitude, and presented non-uniform cycles. A subset of ripples (≈ 50%) co-occurred with IEDs, while IEDs were shown to contain variable high-frequency activity, even below HFO detection threshold. The limit between slow and fast ripples was defined at 150 Hz, while IEDs' high frequency components form clusters separated at 185 Hz. CSD analysis of IEDs and ripples revealed an alternating sink-source pair in the supragranular cortical layers, although fast ripple CSD appeared lower and engaged a wider cortical domain than slow ripples MUA analysis suggested a possible role of infragranularly located neural populations in ripple and IED generation. Laminar distribution of peak frequencies derived from HFOs and IEDs, respectively, showed that supragranular layers were dominated by slower (< 150 Hz) components. Our findings suggest that cortical slow ripples are generated primarily in upper layers while fast ripples and associated MUA in deeper layers. The dissociation of macro- and microdomains suggests that microelectrode recordings may be more selective for SOZ-linked ripples. We found a complex interplay between neural activity in the neocortical laminae during ripple and IED formation. We observed a potential leading role of cortical neurons in deeper layers, suggesting a refined utilization of LMEs in SOZ localization.

Bursting of excitatory cells is linked to interictal epileptic discharge generation in humans.

Knowledge about the activity of single neurons is essential in understanding the mechanisms of synchrony generation, and particularly interesting if related to pathological conditions. The generation of interictal spikes-the hypersynchronous events between seizures-is linked to hyperexcitability and to bursting behaviour of neurons in animal models. To explore its cellular mechanisms in humans we investigated the activity of clustered single neurons in a human in vitro model generating both physiological and epileptiform synchronous events. We show that non-epileptic synchronous events resulted from the finely balanced firing of excitatory and inhibitory cells, which was shifted towards an enhanced excitability in epileptic tissue. In contrast, interictal-like spikes were characterised by an asymmetric overall neuronal discharge initiated by excitatory neurons with the presumptive leading role of bursting pyramidal cells, and possibly terminated by inhibitory interneurons. We found that the overall burstiness of human neocortical neurons is not necessarily related to epilepsy, but the bursting behaviour of excitatory cells comprising both intrinsic and synaptically driven bursting is clearly linked to the generation of epileptiform synchrony.

Laminar distribution of electrically evoked hippocampal short latency ripple activity highlights the importance of the subiculum in vivo in human epilepsy, an intraoperative study.

OBJECTIVE: The goal of this study was to define the pathology and anesthesia dependency of single pulse electrical stimulation (SPES) dependent high-frequency oscillations (HFOs, ripples, fast ripples) in the hippocampal formation. METHODS: Laminar profile of electrically evoked short latency (<100 ms) high-frequency oscillations (80-500 Hz) was examined in the hippocampus of therapy-resistant epileptic patients (6 female, 2 male) in vivo, under general anesthesia. RESULTS: Parahippocampal SPES evoked HFOs in all recorded hippocampal subregions (Cornu Ammonis 2-3, dentate gyrus, and subiculum) were not uniform, rather the combination of ripples, fast ripples, sharp transients, and multiple unit activities. Mild and severe hippocampal sclerosis (HS) differed in the probability to evoke fast ripples: it decreased with the severity of sclerosis in CA2-3 but increased in the subiculum. Modulation in the ripple spectrum was observed only in the subiculum with increased fast HFO rate and frequency in severe HS. Inhalational anesthetics (isoflurane) suppressed the chance to evoke HFOs compared to propofol. CONCLUSION: The presence of early HFOs in the dentate gyrus and early fast HFOs (>250 Hz) in the other subregions indicate the pathological nature of these evoked oscillations. Subiculum was found to be active producing HFOs in parallel with the cell loss in the hippocampus proper, which emphasize the role of this region in the generation of epileptic activity.

Reorganization of Large-Scale Functional Networks During Low-Frequency Electrical Stimulation of the Cortical Surface.

We investigated the functional network reorganization caused by low-frequency electrical stimulation (LFES) of human brain cortical surface. Intracranial EEG data from subdural grid positions were analyzed in 16 pre-surgery epileptic patients. LFES was performed by injecting current pulses (10mA, 0.2ms pulse width, 0.5Hz, 25 trials) into all adjacent electrode contacts. Dynamic functional connectivity analysis was carried out on two frequency bands (low: 1-4Hz; high: 10-40Hz) to investigate the early, high frequency and late, low frequency responses elicited by the stimulation. The centralization increased in early compared to late responses, suggesting a more prominent role of direct neural links between primarily activated areas and distant brain regions. Injecting the current into the seizure onset zone (SOZ) evoked a more integrated functional topology during the early (N1) period of the response, whereas during the late (N2) period - regardless of the stimulation site - the connectedness of the SOZ was elevated compared to the non-SOZ tissue. The abnormal behavior of the epileptic sub-network during both part of the responses supports the idea of the pathogenic role of impaired inhibition and excitation mechanisms in epilepsy.