Laminar organization of cellular microcircuits modulating human interictal epileptiform discharges

Interictal epileptiform discharges (IEDs) are pathological bursts of brain activity between seizures in people with epilepsy. Despite their importance in diagnosis, cognitive comorbidities and therapeutic implications as biomarkers for neurostimulation, it is unknown how IEDs arise from structured large-scale neuronal firing across human cortical lamina. We used high-density Neuropixels probes to record from epileptogenic tissue in patients undergoing resective surgery, sampling 1,152 neurons during 1,094 IEDs across nine neocortical sites. We identified microcircuits for IEDs organized by firing pattern, neocortical depth and putative cell type. Regular-spiking cells, concentrated in superficial cortical lamina, initiated and coded the amplitude of the sharp discharge and excitatory-inhibitory imbalances across neocortical lamina preceded IEDs, enabling IED prediction up to 1,000 ms in advance. Most neurons that were modulated during IEDs also encoded cognitive information and adhered to physiological rhythms at baseline. Thus, neocortical IEDs are generated from predictable laminar-cellular interactions, providing the groundwork for new neurostimulation therapies that harness the granularity of single neurons.