L-Type calcium channel blockade reduces network activity in human epileptic hypothalamic hamartoma tissue.
OBJECTIVE
Human hypothalamic hamartomas (HHs) are associated with gelastic seizures, intrinsically epileptogenic, and notoriously refractory to medical therapy. We previously reported that the L-type calcium channel antagonist nifedipine blocks spontaneous firing and γ-aminobutyric acid (GABA)(A)-induced depolarization of single cells in HH tissue slices. In this study, we examined whether blocking L-type calcium channels attenuates emergent activity of HH neuronal networks.


METHODS
A high-density multielectrode array was used to record extracellular signals from surgically resected HH tissue slices. High-frequency oscillations (HFOs, ripples and fast ripples), field potentials, and multiunit activity (MUA) were studied (1) under normal and provoked [4-aminopyridine (4-AP)] conditions; and (2) following nifedipine treatment.


RESULTS
Spontaneous activity occurred during normal artificial cerebrospinal fluid (aCSF) conditions. Nifedipine reduced the total number and duration of HFOs, abolished the association of HFOs with field potentials, and increased the inter-HFO burst intervals. Notably, the number of active regions was decreased by 45 ± 9% (mean ± SEM) after nifedipine treatment. When considering electrodes that detected activity, nifedipine increased MUA in 58% of electrodes and reduced the number of field potentials in 67% of electrodes. Provocation with 4-AP increased the number of events and, as the number of electrodes that detected activity increased 248 ± 62%, promoted tissue-wide propagation of activity. During provocation with 4-AP, nifedipine effectively reduced HFOs, the association of HFOs with field potentials, field potentials, MUA, and the number of active regions, and limited propagation.


CONCLUSIONS
This is the first study to report (1) the presence of HFOs in human subcortical epileptic brain tissue in vitro; (2) the modulation of "pathologic" high-frequency oscillations (i.e., fast ripples) in human epileptic tissue by L-type calcium channel blockers; and (3) the modulation of network physiology and synchrony of emergent activity in human epileptic tissue following blockade of L-type calcium channels. Attenuation of activity in HH tissue during normal and provoked conditions supports a potential therapeutic usefulness of L-type calcium channel blockers in epileptic patients with HH.
Divisions of Neurology and Pediatric Neurology, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, Arizona, USA. TimothySimeone@Creighton.edu
Kristina A
KA
Simeone
Shivkumar
S
Sabesan
Do Young
DY
Kim
John F
JF
Kerrigan
Jong M
JM
Rho
Timothy A
TA
Simeone
D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D004828:Epilepsies, Partial / Q000503:physiopathology*; D005071:Evoked Potentials / Q000502:physiology; D005260:Female; D006222:Hamartoma / Q000503:physiopathology / Q000601:surgery; D006801:Humans; D007027:Hypothalamic Diseases / Q000503:physiopathology / Q000601:surgery; D007031:Hypothalamus / Q000187:drug effects / Q000503:physiopathology; D007223:Infant; D008297:Male; D009415:Nerve Net / Q000187:drug effects / Q000503:physiopathology*; D009474:Neurons / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000502:physiology; D012815:Signal Processing, Computer-Assisted; D046509:Tissue Culture Techniques; D055815:Young Adult
D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011963:Receptors, GABA-A; D009543:Nifedipine
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