A. Bragin et al., Chronic epileptogenesis requires development of a network of pathologically interconnected neuron clusters: A hypothesis, EPILEPSIA, 41, 2000, pp. S144-S152
Purpose: The "silent period" is a characteristic of human localization-rela
ted symptomatic epilepsy. In mesial temporal lobe epilepsy (MTLE), it follo
ws an initial precipitating injury, and in animal models of MTLE in which b
rain damage is artificially created, there is also a prolonged interval bet
ween injury and the onset of spontaneous seizures. The neuronal reorganizat
ion responsible for epileptogenesis presumably takes place during this sile
nt interval; however, the functional correlates of this process are poorly
understood. We have previously described high-frequency (250 to 500 Hz) osc
illations, called fast ripples (FR), in the hippocampus and entorhinal cort
ex (EC) of intrahippocampal kainic acid (KA)-injected rats and patients wit
h MTLE that are confined to the region of spontaneous seizure generation. W
e have proposed, therefore, that FR reflect the mechanisms responsible for
epileptogenesis. If this is the case. they should appear during the process
of epileptogenesis, before the appearance of spontaneous seizures. The pur
pose of the present study was to record continuously from rats after KA inj
ection to compare the temporal development of FR with spontaneous seizures.
Additional goals were to determine in these rats after spontaneous seizure
s begin (a) the volume of tissue in which FR can be recorded in hippocampus
and EC, (b) the multiple-unit and field potential correlates of FR oscilla
tions, and (c) whether there is an association of FR with mossy fiber sprou
ting.
Methods: After unilateral KA injection in the posterior hippocampus, interi
ctal field epileptic activity and single-unit activity were recorded from f
reely moving animals using multiple-contact microelectrodes in dentate gyru
s (DG) and EC. One group of animals underwent continuous recording to deter
mine the time of onset of both FR oscillations and spontaneous seizures. A
second group was implanted after behavioral seizures began to measure the a
rea within which FR could be recorded as well as their unit and field poten
tial cor relates. The neo-Timm method was used to reveal mossy fiber sprout
ing, and gray value analysis was used to measure the intensity of sprouting
in the inner molecular layer of DG.
Results: In KA-injected mts, FR were observed in hippocampal areas adjacent
to the lesion and in the ipsilateral EC ii to 14 days after injection, whe
reas spontaneous behavioral seizures occurred 2 to 4 months after injection
. Analysis of depth profiles of interictal FR in the DG and EC showed that
they were generated in local areas with a volume of about 1.0 mm(3), and un
it recordings indicated that they reflected field. of hypersynchronous acti
on potentials. FR were found in areas of DG with more intensive mossy fiber
sprouting. However, the correspondence was not absolute.
Conclusions: The electrophysiological and anatomic:al data are consistent w
ith the participation of FR oscillations, within small neuronal assemblies,
in the development of chronic epileptogenesis. It is hypothesized that sma
ll clusters of pathologically interconnected neurons develop after focal hi
ppocampal injury and that these clusters are capable of generating powerful
hypersynchronous bursts of action potentials, which initiate epileptogenes
is via a kindling effect. As the silent period progresses, a network of suc
h clusters is formed that allows the development of discharges that spread
throughout the: limbic system. When this network engages brain areas that c
ontrol motor activity, clinical seizures occur and the silent period ends.