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The more important question is whether neurons fire synchronously, or at least within short
periods of each other, during seizures. Recordings of single neurons during seizures in
humans have shown surprisingly little change in firing rates. Recently the use of multichannel
depth recordings has shown a dissociation between the widespread synchronous EEG, which
is primarily generated by synaptic currents, and very localised migrating areas of increased
and loosely hypersynchronous firing of neurons. Work on experimental models in brain slices
in vitro suggests that this dissociation is largely due to the strength of inhibitory neurons in
restraining the advancing front of neuronal hyperactivity, a process which generates large
field potentials (or EEGs). This spatial dissociation of EEG from neuronal firing is intriguing
for fundamental pathophysiology but also has potential implications for determining the
epileptogenic zone.

Histopathology. Epileptic foci are often associated with focal lesions. It is clear that
prolonged seizures cause neuronal death, which is why those chronic models of temporal lobe
epilepsy that depend on an initial status epilepticus generally are associated with substantial
losses of neurons. Excitotoxicity that results from the accumulation of intracellular calcium
is in large part due to prolonged activation of glutamate receptors, notably the NMDA variety.
What is less clear is how repeated brief seizures cause lesions in some individuals.

High frequency oscillations

The classical EEG stops at 80100 Hz, but work over the past couple of decades has shown
that important insights can be gained from much higher frequencies. These high frequency
oscillations (or activity) are often divided into sub-bands, notable ripples and fast ripples,
with a demarcation at 200300 Hz (the precise value differs between different studies).
Ripples can be seen during some normal physiological states, while fast ripples seem to be
pathophysiological.

Ripples and fast ripples (also called ‘high gamma’ by some authors) appear relatively soon
after the initial precipitating insult, at least in some experimental models, and provide a
biomarker for whether individual animals will go on to develop spontaneous seizures. They
presumably result from some of the earlier changes in the process of epileptogenesis and may
provide clues on the underlying cellular and molecular mechanisms.

Fast ripples may provide a valuable marker for the ‘epileptogenic zone’, perhaps by providing
a marker for excessive neuronal firing as distinct from excessive synaptic activity (see
hypersynchrony, above). The epileptogenic zone is the volume of brain tissue that needs to
be removed surgically to prevent seizures. The ultimate test is whether the seizures stop when
the tissue is removed. This and the other zones identified in presurgical work-up are beyond
the scope of this chapter. What is relevant is the use of fast ripples as one of the methods of
defining the epileptogenic zone. Our own recent work suggests that fast ripples can be used
in (at least experimental) cases where there is no hippocampal sclerosis to provide structural
evidence.

Detecting fast ripples is not straightforward. Obviously the bandwidth of the recording system
needs to be high enough – in the kHz range. But the recording electrodes also are critically
important. Fast ripples are best detected with intracranial, preferably intracerebral,
microelectrodes. A recent study has shown that the classical clinical macroelectrodes miss
most high frequency oscillations faster than 100200 Hz. This is probably because fast
ripples in particular synchronise over very short distances, of the order of a few hundred
microns, so they will be attenuated to below noise when recorded with electrodes with
dimensions orders of magnitude larger. Their limited spatial extent and the small amplitude
of fast ripples also make them difficult to record from the scalp.