Sites of Seizure Origin

Over the last decade a hypothesis has been developed by Browning12 suggesting that there are two sites of seizure origin in the rat: the forebrain and the brainstem (Figure 1.4).12-58-59 Convulsions mediated by the forebrain involve face and forelimb clonus

Brainstem Seizures

- running and bouncing clonus

- tonic flexion/extension or tonic-clonlc

- high threshold

- overrides forebrain seizure

- activated by corneal and transauricular

Generalized activation of spinal cord by brainstem structures Induces tonic-clonlc (flexion/extension) sequence.

FIGURE 1.4

A schematic depiction of the two seizure origin sites in the rat as proposed by Browning.12 Although the activation indicated is for electroshock, both forebrain and brainstem seizures may be induced by chemical convulsants. Animals with a complete brain transection at the precollicular level, indicated by the dotted line, still respond to corneal electroshock with tonic-clonic convulsions.62 Similarly, rats with such precollicular transections also respond to systemic chemical convulsant administration with appropriate forebrain electrographic seizures.58 In seizure naive animals the two seizure origin sites function independently, but with repeated seizures (kindling) each area begins to influence the seizure response of the other. The brainstem structures activate the spinal cord which contains all the neuronal mechanisms necessary to generate tonic-clonic convulsions.49

Generalized activation of spinal cord by brainstem structures Induces tonic-clonlc (flexion/extension) sequence.

FIGURE 1.4

A schematic depiction of the two seizure origin sites in the rat as proposed by Browning.12 Although the activation indicated is for electroshock, both forebrain and brainstem seizures may be induced by chemical convulsants. Animals with a complete brain transection at the precollicular level, indicated by the dotted line, still respond to corneal electroshock with tonic-clonic convulsions.62 Similarly, rats with such precollicular transections also respond to systemic chemical convulsant administration with appropriate forebrain electrographic seizures.58 In seizure naive animals the two seizure origin sites function independently, but with repeated seizures (kindling) each area begins to influence the seizure response of the other. The brainstem structures activate the spinal cord which contains all the neuronal mechanisms necessary to generate tonic-clonic convulsions.49

and may include rearing and falling in the case of kindled limbic seizures.12 Forebrain convulsions can occur independently of the brainstem as intact electrographic forebrain seizures can be induced after complete forebrain transection.58 While forebrain convulsions may be induced by low, systemic doses of chemical convulsants or low electrical stimulation currents applied directly to the limbic system through depth electrodes, the most sensitive site for activation is the deep prepyriform cortex or the area tempestas.59 At low stimulation currents corneal electroshock also activates the forebrain selectively inducing minimal clonic seizures (Table 1.1). Such minimal clonic seizures are considered an experimental model of absence (petit mal) sei-zures.6 815 Repeated corneal electroshock stimulation with low currents induces corneal kindling which may serve as a model of complex partial seizures1855 as does amygdala kindling, as described in Chapter 3. In contrast, transauricular stimulation does not activate the forebrain and does not induce face and forelimb clonus.141855

The brainstem is the proposed site of origin for tonic-clonic convulsions.12 Although direct electrical stimulation of the reticular formation produces tonic-clonic convulsions,6061 the most convincing evidence is that rats with complete precollicular brain transections at the level indicated in Figure 1.4 still respond to maximal electroshock stimuli with generalized tonic-clonic convulsions.62 The pon-tine reticular formation is the site considered most likely to generate the tonic-clonic convulsions1259 and the nucleus reticularis pontis oralis is proposed to be essential for the occurrence of THE as induced by electroshock, audiogenic seizures, or pentylenetetrazol.4048 63-65 High doses of chemical convulsants or high currents of electrical stimulation are proposed to activate directly the neuronal substrates in the brainstem that mediate tonic-clonic convulsions.1262 The wild running and generalized tonic-clonic convulsions associated with audiogenic seizures in genetically epilepsy-prone rats are also proposed to involve only the brainstem site of seizure origin.12 Repeated maximal electroshock at 3-d intervals using high currents induces a kindling effect in that the tonic-clonic convulsion response becomes increasingly severe.25

The forebrain and brainstem possess separate mechanisms for seizure origin with separate thresholds for seizure initiation. Either seizure origin site may generate seizures in the absence of the other site.5862 Although the brainstem threshold is higher, once initiated it overrides forebrain seizures and only the tonic-clonic convulsions are observed (Figure 1.4).12 Initially, in seizure-naive, normal experimental animals the forebrain and brainstem mechanisms function separately. However, with repeated seizures the separation of the two seizure origin sites erodes. For example, in kindled amygdala seizures the incidence of THE is significantly enhanced in comparison to nonkindled rats.65 Genetically epilepsy-prone rats given repeated audiogenic seizures that exhibit generalized tonic-clonic convulsions solely by way of brainstem mechanisms eventually also exhibit face and forelimb clonus as mediated by forebrain mechanisms.66 When subjected to amygdala kindling, genetically epilepsy-prone rats develop spontaneous generalized tonic-clonic convulsions.67 These studies indicate that the interaction between forebrain and brainstem seizure sites are facilitated in genetically epilepsy-prone rats. Thus, not only do both seizure origin sites demonstrate kindling,8 16 25 but the kindling influences seizure activity mediated by the other site.65-67

Once activated by an electroshock stimulus the brainstem neural substrate that mediates generalized tonic-clonic convulsions is proposed to induce a generalized activation of the spinal cord (Figure 1.4).45 49 Although all of the neuronal mechanisms necessary to emit tonic-clonic convulsions are in the spinal cord it is the supraspinal brainstem neural substrate that activates the spinal cord51 and it would appear that supraspinal brainstem nuclei and not the spinal cord are the site of action of antiepileptic drugs.33 49 The hypothesis of two separate origins of seizure activity indicates that the antiepileptic drugs act on the individual seizure origin sites,55 rather than the spread of seizure activity from the "oscillator" as originally proposed.2631 This raises the interesting possibility that the site of action of drugs in tonic-clonic convulsions is the brainstem.68

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