Using Multi-electrode Array Recordings to detect unrecognized electrical events in epilepsy

Transcription

1 Using Multi-electrode Array Recordings to detect unrecognized electrical events in epilepsy December 1, 2012 Catherine Schevon, MD, PhD Columbia University New York, NY American Epilepsy Society Annual Meeting

2 Disclosures NIH/NINDS K08-NS48871 Epilepsy Foundation New Therapy Project American Epilepsy Society Annual Meeting 2012

3 Learning Objectives What is a (human) seizure? Do neural firing patterns agree with predictions from simple in vitro models? How does surround inhibition affect seizure localization? How does EEG relate (spatially) to neural firing? Are there different components of the seizure onset zone? American Epilepsy Society Annual Meeting 2012

4 NINDS Epilepsy Research Benchmarks Benchmarks Area II: Develop new therapeutic strategies and optimize current approaches to cure epilepsy B.1 Develop and validate biomarkers and surrogate markers to localize the epileptogenic networks and aid in the discovery and testing of new antiepileptic therapies C.1 Determine factors and approaches associated with best outcomes for surgical therapies

5 Extracellular Intracellular Recruitment phase Bursting phase Penicillin model in vitro and in vivo Matsumoto and Ajmone-Marsane, Science 1964 Goldensohn and Purpura, Science 1963

6 Hypersynchronization Timofeev and Steriade, Neuroscience 2004

7 What is the relationship between the ictal EEG and neural firing? What neural firing patterns characterize human seizures?

8 Micro-electrode recordings in humans Utah array 4 x 4 mm 96 1 mm microelectrodes Records neural firing and field potentials 7 patients 72 seizures (in 5 patients)

9 Recruitment phase Bursting phase 19F, right posterior temporal complex partial seizure

10 A different type of seizure? Early seizure Late seizure Single neuron raster plot showing heterogeneous changes in firing rates during a seizure Truccolo et al, Nature Neuroscience 2011 Single neuron firing not synchronized with epileptiform discharges Wyler et al, Annals of Neurology 1982

11 EEG is the gold standard Neural activity is the gold standard Seizures can be characterized by heterogeneous neuronal participation Heterogeneous firing indicates that the seizure is located elsewhere

12 Inhibitory surround intrinsic cortical mechanism that opposes epileptiform activity Prince & Wilder, 1967 Dichter & Spencer, 1969a,b Liang & Jones, 1997, 1998 Schwartz & Bonhoeffer, 2001 LFP MUA 3 mm LFP MUA Penumbra

13 Seizure model in a mouse neocortical slice Occipital coronal slices Mg 2+ washed out to enhance excitation while preserving inhibition Ca 2+ imaging: fluorescent calcium dye that is taken into neurons as they fire, causing them to flash Voltage clamp (-30 mv): Upward = inhibition, downward = excitation Schevon et al, Nature Communications 2012 Courtesy Andrew Trevelyan, Univ Newcastle, UK

14 Inhibitory response to upstream excitation Ictal wave fronts generate powerful feedforward inhibition Trevelyan et al, J Neuroscience 2006

15 Superimposed LFP traces LFP MUA 3 mm LFP MUA EEG

16 Penumbra Seizure focus Schevon et al, Nature Communications 2012

17 Propagation speeds: MUA vs LFP v = 0.83 mm/sec Schevon et al, Nature Communications 2012

18 Seizure onset zone, revisited

19 What do these recordings mean? Need EEG feature that reflects high intensity, synchronized firing rather than strong synaptic potentials, which may be inhibitory

20 Rationale for Ictal ECoG High Frequency Oscillations as Localizing Biomarker EEG Hz Intra Timofeev and Steriade, Neuroscience 2004

21

22 Impact on Clinical Practice Inhibitory surround distorts seizure localization: EEG cannot distinguish between excitatory (focus) and inhibitory (penumbra) potentials Seizure onset zone is a complex entity Penumbra may become arbitrarily large due to the difference between slow seizure propagation and fast synaptic distribution Arguably, resecting penumbra cannot contribute to seizure control EEG biomarkers (eg HFOs) Need to be validated against gold standard of neural firing Late-onset, sustained ictal HFOs may be a good indicator of the seizure focus

23 Acknowledgments Ronald Emerson (Cornell University, NY) Andrew Trevelyan (Newcastle University, UK) Guy McKhann Jr Robert R Goodman Joshua Cappell Shennan Weiss Garrett Banks Columbia Epilepsy Center faculty and fellows Rafael Yuste And especially. The patients who volunteered their participation and support

24 Non-recruitment in the SOZ The ictal penumbra MUA (x10) LFP 0.2 mv 1 s

25 Rationale for Ictal ECoG High Frequency Oscillations as Localizing Biomarker Correlation between synchronized multiunit firing and ECoG high gamma (> Hz) increases during seizures

26 Pt 1 Pt 2 Pt 3 EEG Ictal focus The extent of late-onset, sustained high frequency bursting advances more slowly than does the extent of lowfrequency activity Ictal HFOs (sustained or high rate) have been studied by other groups: Jacobs et al, Epilepsia 2008 Modur et al, Epilepsia 2011 Akiyama et al, Epilepsia 2011