Pathological high frequency oscillations associate with increased GABA synaptic activity in pediatric epilepsy surgery patients

Carlos Cepeda; Simon Levinson; Hiroki Nariai; Vannah-Wila Yazon; Conny Tran; Joshua Barry; Katerina D. Oikonomou; Harry V. Vinters; Aria Fallah; Gary W. Mathern; Joyce Y. Wu

Neurobiology of Disease (Feb 2020)

Pathological high frequency oscillations associate with increased GABA synaptic activity in pediatric epilepsy surgery patients

Carlos Cepeda,
Simon Levinson,
Hiroki Nariai,
Vannah-Wila Yazon,
Conny Tran,
Joshua Barry,
Katerina D. Oikonomou,
Harry V. Vinters,
Aria Fallah,
Gary W. Mathern,
Joyce Y. Wu

Affiliations

Carlos Cepeda: IDDRC, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA; Corresponding author at: IDDRC, Semel Institute for Neuroscience, Room 58-258, UCLA School of Medicine, 760 Westwood Plaza, Los Angeles, CA 90024-1759, USA.
Simon Levinson: IDDRC, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
Hiroki Nariai: Division of Pediatric Neurology, Mattel Children's Hospital, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
Vannah-Wila Yazon: IDDRC, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
Conny Tran: IDDRC, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
Joshua Barry: IDDRC, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
Katerina D. Oikonomou: IDDRC, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
Harry V. Vinters: Section of Neuropathology, Department of Pathology and Laboratory Medicine and Department of Neurology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
Aria Fallah: Department of Neurosurgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
Gary W. Mathern: IDDRC, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA; Department of Neurosurgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
Joyce Y. Wu: Division of Pediatric Neurology, Mattel Children's Hospital, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA

Journal volume & issue: Vol. 134

Abstract

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Pathological high-frequency oscillations (HFOs), specifically fast ripples (FRs, >250 Hz), are pathognomonic of an active epileptogenic zone. However, the origin of FRs remains unknown. Here we explored the correlation between FRs recorded with intraoperative pre-resection electrocorticography (ECoG) and spontaneous synaptic activity recorded ex vivo from cortical tissue samples resected for the treatment of pharmacoresistant epilepsy. The cohort included 47 children (ages 0.22–9.99 yr) with focal cortical dysplasias (CD types I and II), tuberous sclerosis complex (TSC) and non-CD pathologies. Whole-cell patch clamp recordings were obtained from pyramidal neurons and interneurons in cortical regions that were positive or negative for pathological HFOs, defined as FR band oscillations (250–500 Hz) at ECoG. The frequency of spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and IPSCs, respectively) was compared between HFO+ and HFO- regions. Regardless of pathological substrate, regions positive for FRs displayed significantly increased frequencies of sIPSCs compared with regions negative for FRs. In contrast, the frequency of sEPSCs was similar in both regions. In about one third of cases (n = 17), pacemaker GABA synaptic activity (PGA) was observed. In the vast majority (n = 15), PGA occurred in HFO+ areas. Further, fast-spiking interneurons displayed signs of hyperexcitability exclusively in HFO+ areas. These results indicate that, in pediatric epilepsy patients, increased GABA synaptic activity is associated with interictal FRs in the epileptogenic zone and suggest an active role of GABAergic interneurons in the generation of pathological HFOs. Increased GABA synaptic activity could serve to dampen excessive excitability of cortical pyramidal neurons in the epileptogenic zone, but it could also promote neuronal network synchrony.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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