L-Type calcium channel blockade reduces network activity in human epileptic hypothalamic hamartoma tissue

Divisions of Neurology and Pediatric Neurology, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.
Epilepsia (Impact Factor: 4.57). 03/2011; 52(3):531-40. DOI: 10.1111/j.1528-1167.2010.02942.x
Source: PubMed


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.
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.
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.
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.

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    • "In support of this model, we observed episodes of several seconds where neurons appeared to undergo a transformation to much higher firing rates (cf. Figure 8). Since the patient was under anesthesia, it is not possible to know whether this firing definitely corresponded to a clinical seizure, however, we note that macroelectrode depth wire recordings immediately before surgical resection have also shown seizure activity within HH tissue in patients under general anesthesia (39) and that seizure-like discharges have been reported in surgically resected HH tissue slices after provocation with 4-aminopyridine (4-AP) (20). "
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