Pathophysiological Events in Neuronal Network

What is happening at the neuronal network level when neurons transition from their normal firing pattern to the interictal condition and then to the ictal state? Figure 5B depicts some of the physiologic features that accompany these changes. Now, rather than recording electrical activity from the surface of the brain, single electrodes are placed inside individual excitatory cortical neurons 1 and 2, thereby recording intracellular potentials. Much of our understanding of epilepsy mechanisms comes from such experiments using animal models (35,36).

In the normal situation, an action potential occurs in neuron 1 when the membrane potential is depolarized to its threshold level, as previously discussed. Discharges in neuron 1 may also influence the activity of its neighbor, neuron 2. For example, with a delay of several milliseconds, an action potential in neuron 1 may give rise to an EPSP in neuron 2. If cell 3, an inhibitory interneuron, is also activated by a discharge from neuron 1, then the activity in neuron 2 will be modified by an IPSP overlapping in time with the EPSP; the recorded event will be a summed EPSP-IPSP sequence. If the IPSP occurs earlier, perhaps coincident with the EPSP, the depolarizing effect of the EPSP will be diminished. In this way, we can envision inhibition as "sculpting" or modifying ongoing excitation. If this concept is extrapolated to thousands of interconnected neurons, each influencing the activity of many neighbors, it is easy to see how an increase in excitation or decrease in inhibition in the system could lead to hypersynchronous, epileptic firing in a large area of brain. Normally, neurons fire action potentials, singly or in brief runs, and excitability is kept in check by the presence of powerful inhibitory influences (the "inhibitory surround," schematized in Fig. 6). For the activity of a small group of localized, synchronously firing neurons to spread across a wide area of cortex, the local excitation must overcome this surrounding region of strong synaptic inhibition.

The intracellular correlate of the interictal focal EEG spike is called the paroxysmal depolarization shift (PDS) (37). It is called "paroxysmal" because it is arises suddenly from baseline activity and "depolarization shift" because the membrane potential is depolarized (less negative) for several tens of milliseconds. The PDS is actually a "giant EPSP," a prolonged depolarization causing the neuron to fire a burst of several action potentials riding on a large envelope of depolarization (Fig. 5B, middle and right columns). Importantly, the PDS is an NMDA-mediated event; experimentally, NMDA receptor blockers prevent PDSs and the transition from the interictal state to a seizure. The PDS is initiated or "kicked off" by a fast, non-NMDA-mediated EPSP and sustained by a prolonged, NMDA-mediated EPSP. Compared with the usual NMDA-medi-ated slow EPSP of approx 10-20 ms, the PDS is longer (30-50 ms) with many more action potentials on top of the depolarization. Note that the durations of the PDS and interictal EEG spike are similar (because they represent the same event!).

The PDS is followed by a large "post-PDS hyperpolarization" (asterisk in Fig. 5B), which serves to terminate the PDS and stop, at least temporarily, the rampant firing of action potentials. Note that a PDS in neuron 1 may activate a similar PDS in neuron 2, and so on, such that a whole network of neurons can be rapidly recruited into firing in a synchronous manner. If excitation becomes excessive or if inhibition is severely curtailed, the PDS can lead into an ictal discharge (right column). In the top trace, the post-

Paroxymal Depolarising Shift

Fig. 6. Schematic diagram of the sequence of a partial seizure. Initially, neurons fire normally with single action potentials. The hallmark of interictal firing is the paroxysmal depolarizing shift (PDS). As the PDS gradually loses its post-PDS hyperpolarization (short vertical arrow), as the firing of local neurons becomes synchronized, a seizure occurs (longer vertical arrow). The ictal electrical signature of a seizure is a persistent depolarizing plateau potential (asterisk) on which are superimposed bursts of clustered spikes. Spread of the seizure beyond the local area depends on overcoming the strong inhibitory surround adjacent to the focus. Finally, the seizure stops and normal firing resumes. Separate physiologic mechanisms regulate each of these steps (see text).

Fig. 6. Schematic diagram of the sequence of a partial seizure. Initially, neurons fire normally with single action potentials. The hallmark of interictal firing is the paroxysmal depolarizing shift (PDS). As the PDS gradually loses its post-PDS hyperpolarization (short vertical arrow), as the firing of local neurons becomes synchronized, a seizure occurs (longer vertical arrow). The ictal electrical signature of a seizure is a persistent depolarizing plateau potential (asterisk) on which are superimposed bursts of clustered spikes. Spread of the seizure beyond the local area depends on overcoming the strong inhibitory surround adjacent to the focus. Finally, the seizure stops and normal firing resumes. Separate physiologic mechanisms regulate each of these steps (see text).

PDS hyperpolarization is lost (thick arrow), allowing the neuron to generate a prolonged paroxysmal discharge. Such discharges in one neuron can easily spread to others, overwhelming the inhibitory control on the system and leading to an electrographic and clinical seizure. This interictal-to-ictal transition may occur because the post-PDS hyperpolarization is diminished owing to potentiation of EPSPs, decrement in IPSPs, inability to clear extracellular K+, a large increase in intracellular calcium, or a variety of other mechanisms.

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