Interictal Fast Ripples Recorded from a Dense Microelectrode Array in Human Epileptic Neocortex Catherine Schevon, MD, PhD; Andrew Trevelyan, PhD; Robert Goodman, MD; Guy McKhann Jr, MD; Charles Schroeder, PhD; Ronald Emerson, MD June, 2009

Multielectrode Array (MEA) NeuroPortTM, Cyberkinetics Neurotechnology Systems, Foxboro, MA (now Blackrock Microsystems, Salt Lake City, UT) Covers 4 x 4 mm area 96 contacts in a regular 10x10 grid Depth 1 mm (Layer IV/V) 400 micron spacing Active tips 35-75 μm long x 3-5 μm radius 30K samples/channel/sec Implanted in epilepsy patients undergoing chronic intracranial EEG recording, in neocortex to be included in resection Note that array is the size of a subdural electrode II III IV V VI WM I Advantages: Fine spatial/temporal resolution Regular grid spacing Limitations: Records from one small area One cortical layer per site 2

Patient MEA location Epileptogenic Zone Pathology 1 (41F) R middle temporal gyrus R mesial temporal lobe Nonspecific 2 (30M) L lateral frontal L lateral frontal and temporal N/A (MST only) 3 (39M) L lateral frontal (3x3 cm area) 4 (25F) L inferior temporal gyrus L mesial/basal/lateral temporal lobe Mild MTS

“µEEG” “Macrodischarges” Appear widespread in µEEG iEEG Microelectrode recording downsampled and aligned with clinical EEG recording “Macrodischarges” Correlate with iEEG epileptiform discharges Appear widespread in µEEG μEEG

“Microdischarges” Are they epileptiform? Are they related to interictal discharges and seizures?

HFO associated with a macrodischarge µEEG µEEG 200 µV 50 µV 100-200 Hz HFO associated with a macrodischarge 200-500 Hz 30 µV 0.8 – 2 kHz 30 µV 1 second 30 ms µEEG 200 µV µEEG HFOs with macrodischarges: common, almost all fast ripples (selective recording of Layers iv/v?), FR with MUA, at or trailing discharge peak HFOs with micros: ripple range, rare, preceded peak, no discernable MUA increase 100-200 Hz 50 µV HFO associated with a microdischarge 200-500 Hz 30 µV 0.8 – 2 kHz 30 µV 1 second 40 ms

Correlation with interictal events HFO rates high compared to previous studies; greater in epileptogenic zone Commonly seen with macrodischarges, but rarely detected with microdischarges Detections/min during sleep and association with paroxysmal µEEG features Percentage of macrodischarges and microdischarges with associated HFOs

Detections by array location Point out: 1) poisson-like distribution 2) larger area and higher rate within ez, 3) not co-located with microdcs

“HFO events” = time period during which one or more HFOs are detected 85% of events were seen at a single channel Simultaneous hfo detections have been reported before; introduce term “hfo events” Single channel event = limited to a single cortical microdomain (400 sq microns) 50 ms 40 µV

“HFO events” = time period during which one or more HFOs are detected 11% of events occurred on a large scale Almost all were found within the epileptogenic zone (ie not in Patient 1) 80% of these occurred with macrodischarges Large scale = evidence of simultaneous activity in multiple cortical domains HF activity is increased in many channels outside of detections Differences between channels suggest that multiple independent generators are responsible 400 ms 40 µV

Site to site differences during a large scale event µEEG 200 µV Site to site differences during a large scale event 100-200 Hz 200-500 Hz 0.8 – 2 kHz 50 ms µEEG 100-200 Hz 200-500 Hz 0.8 – 2 kHz 50 ms

Conclusions and Questions HFOs and microdischarges are distinct phenomena Evidence of different mechanisms underlying microdischarges and macrodischarges? Large-scale HFOs Arise from multiple simultaneous independent generators Specific markers of the epileptogenic zone? Selectively detected by sparse sampling or large sensors? Evidence of an epileptic network? Are fast ripples a primary event or a secondary local response (eg excitability)?

Co-authors and colleagues Ron Emerson Robert Goodman Guy McKhann, Jr. Charles Schroeder Andrew Trevelyan Allen Waziri Julien Besle Joe Isler Anna Ipata Elana Zion-Golumbic Sara Inati Peter Lakatos Dan Friedman Helen Scharfman Michael Goldberg

Are all HFOs created equal? Recording characteristics of Neuroport microelectrodes vs microwires or depth electrodes Selective recording from cortical layers IV and V Use of detection thresholds create the impression of a binary process 2-3 um recording tips; compare to microwires (40 um diameter disks) and depth macroelectrodes (2mm cylindrical)

Patient Implant Location MEA location Epileptogenic Zone Pathology 1 (41F) Right lateral and subtemporal regions Right middle temporal gyrus 4 cm from anterior temporal pole Right mesial temporal lobe Nonspecific, no mesial temporal sclerosis (MTS), no dysplasia 2 (30M) Left lateral frontal, mesial frontal, and lateral temporal lobes Left lateral frontal, minimum distance 2 cm superior to Broca’s area and on different gyrus Boundaries not defined but maximal area identified in left superior/lateral frontal lobe N/A (MST only) 3 (39M) Left lateral and mesial frontal lobe Left lateral frontal, minimum distance 1.5 cm superior to Broca’s area and on different gyrus Left frontal operculum (3x3 cm cortical area), superior to Broca’s area Nonspecific 4 (25F) Left lateral and subtemporal regions Left inferior temporal gyrus 2.5 cm from anterior temporal pole Left mesial and anterolateral temporal lobe Mild MTS

HFO rates Higher HFO rates (overall and max per channel) than seen with microwires or macroelectrodes but avg per channel similar HFOs more frequent in epileptogenic zone (but N of 1 outside EZ…) Almost all HFOs had a fast ripple component

HFO duration Filtered 100-500 Hz activity in subset of channels Average of all channels (what a macroelectrode would see?)