How the brain transitions into a seizure is poorly understood. Recurrent seizure-like events (SLEs) in low-Mg 2ϩ /high-K ϩ perfusate were measured in the CA3 region of the intact mouse hippocampus. The SLE was divided into a "preictal phase," which abruptly turns into a higher frequency "ictal" phase. Blockade of GABA A receptors shortened the preictal phase, abolished interictal bursts, and attenuated the slow preictal depolarization, with no effect on the ictal duration, whereas SLEs were blocked by glutamate receptor blockade. In CA3 pyramidal cells and stratum oriens non-fast-spiking and fast-spiking interneurons, recurrent GABAergic IPSCs predominated interictally and during the early preictal phase, synchronous with extracellularly measured recurrent field potentials (FPs). These IPSCs then decreased to zero or reversed polarity by the onset of the higher-frequency ictus. However, postsynaptic muscimol-evoked GABA A responses remained intact. Simultaneously, EPSCs synchronous with the FPs markedly increased to a maximum at the ictal onset. The reversal potential of the compound postsynaptic currents (combined simultaneous EPSCs and IPSCs) became markedly depolarized during the preictal phase, whereas the muscimol-evoked GABA A reversal potential remained unchanged. During the late preictal phase, interneuronal excitability was high, but IPSCs, evoked by local stimulation, or osmotically by hypertonic sucrose application, were diminished, disappearing at the ictal onset. We conclude that the interictal and early preictal states are dominated by GABAergic activity, with the onset of the ictus heralded by exhaustion of presynaptic release of GABA, and unopposed increased glutamatergic responses.

Electrophysiological oscillations are thought to create temporal windows of communication between brain regions. We show here that human cortical slices maintained in vitro can generate oscillations similar to those observed in vivo. We have characterized these oscillations using local field potential and whole-cell recordings obtained from neocortical slices acquired during epilepsy surgery. We confirmed that such neocortical slices maintain the necessary cellular and circuitry components, and in particular inhibitory mechanisms, to manifest oscillatory activity when exposed to glutamatergic and cholinergic agonists. The generation of oscillations was dependent on intact synaptic activity and muscarinic receptors. Such oscillations differed in electrographic and pharmacological properties from epileptiform activity. Two types of activity, theta oscillations and high gamma activity, uniquely characterized this model-activity not typically observed in animal cortical slices. We observed theta oscillations to be synchronous across cortical laminae suggesting a novel role of theta as a substrate for interlaminar communication. As well, we observed cross-frequency coupling (CFC) between theta phase and high gamma amplitude similar to that observed in vivo. The high gamma "bursts" generated by such CFC varied in their frequency content, suggesting that this variability may underlie the broadband nature of high gamma activity.

We present a 320-channel active probe for high-spatial-resolution neuromonitoring and responsive neurostimulation. The probe comprises an integrated circuit (IC) cell array bonded to the back side of a pitch-matched microelectrode array. The IC enables up to 256-site neural recording and 64-site neural stimulation at the spatial resolution of 400 μ m and 200 μ m, respectively. It is suitable for direct integration with electrode arrays with the shank pitch of integer multiples of 200 μm. In the presented configuration, the IC is bonded with a 8 × 8 400 μ m-pitch Utah electrode array (UEA) and up to additional 192 recording channels are used for peripheral neuromonitoring. The 0.35 μ m CMOS circuit array has a total die size of 3.5 mm × 3.65 mm. Each stimulator channel employs a current memory for simultaneous multi-site neurostimulation, outputs 20 μA-250 μA square or arbitrary waveform current, occupies 0.02 mm (2), and dissipates 2.76 μ W quiescent power. Each fully differential recording channel has two stages of amplification and filtering and an 8-bit single-slope ADC, occupies 0.035 mm (2) , and consumes 51.9 μ W. The neural probe has been experimentally validated in epileptic seizure propagation studies in a mouse hippocampal slice in vitro and in responsive neurostimulation for seizure suppression in an acute epilepsy rat model in vivo .

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