THE KINDLING PROCESS
Kindling is the process by which epileptiform activity, perceived as an afterdischarge (AD), can be elicited by applying electrical or chemical stimulation to structures of the brain (Racine & McIntyre, 1986). Goddard (1967) first demonstrated that kindling of subcortical areas, at low intensity (50 uamp) and dispersed intervals, produced an increase in the susceptibility to stimulation-induced seizures by decreasing the "convulsive threshold" (Goddard,1967,1020). Kindling also results in an increase in the spikes at secondary sites with neural connections to the initial site of stimulation (Racine & McIntyre, 1986).
Kindling experiments typically involve the surgical implantation of electrodes into the brain region of interest. Often the electrodes are placed within the left and right hemispheres of a structure (if it is bilateral) which allows the researcher to determine whether stimulation of one or the other hemisphere produces different effects. After recovery from surgery, the subject receives low levels of electrical stimulation at spaced intervals. Finally, depending on the nature of the experiment, the researchers observe the various types of behavioural and neurophysiological effects.
THE PROPERTIES OF KINDLING
The kindling phenomenon proved to be a dominant model for the study of epilepsy once ite was demonstrated that spontaneous convulsions can become a permanent behavioural manifestation (Pinel & Rovner,1978) resembling the genesis and progression of some epileptic disorders. The type of changes that can occur with kindling are manifested in behavioural, electrographic and neurochemical responses (Racine, Livingston & Joaquin,1975). Some of these processes are outlined below.
Properties of Kindling
The rate of kindling and subsequent susceptibility to seizures; however, can be altered or opposed in several ways. For example, seizure activity alone can provide temporary resistance to the occurence of later seizures (Goddard, Dragunow, Maru & MacLoed,1986). Moreover, kindling at intervals of less than 15 minutes apart will not result in motor seizure activity (Goddard, Dragunow, Maru & MacLoed, 1986). The inhibition of subsequent seizures from the occurence of convulsive activity has been shown to last for between 90 minutes, from a motor seizure elicited through a single AD, to 5 days, after a series of repeated seizures (Goddard, Dragunow, Maru & MacLoed,1986). It is suggested that this decreased susceptibility is the result of a temporary increas in the seizure threshold (Goddard, Dragunow, Maru & MacLoed,1986). The alternate stimulation of different brain regions can also alter the normal process of kindling. When this method is applied, seizure activity is much more dominant in the area which "first established connections with the motor seizure substrate (Goddard, Dragunow, Maru & MacLoed,1986,100).
A more recent study by Kline, Revilla and Hernandez (1997) has provided evidence that a "critical period" (Kline, Revilla & Hernandez,1997,130) exists early in the kindling process during which seizure progression can be altered. In this experiment the researchers implanted bipolar electrodes into distinct regions of the right amygdala of rats. Based on prior studies, the authors hypothesized that the presentation of a tone during the kindling process would differentially affect the rate and specificity of epileptogenesis. To test this hypothesis the rats were divided into 3 experimental groups: Tone, No Tone and Tone Discontinued. The results demonstrated that the acquisition of seizure activity was differentially affected depending on whather a tone was presented during kindling and where the electrode was implanted. When the stimulation was applied to the central nucleus of the amygdala the presentation of a tone resulted in a delayed kindling effect; however, the Tone Discontinued group was not significantly different from the Tone group, suggesting that the delayed effect occurs early in the kindling process (Kline, Revilla & Hernandez, 1997). Conversely, presentation of a tone, during amygdalostriatal transition area kindling, produced an increase in the speed at which seizure development occurred. Moreover, this alteration was also observed in the Tone Discontinued group. Finally, stimulation of the basolateral nucleus of the amygdala produced no significant changes in the rate of seizure progression when compared with the No Tone group. The authors propose that these findings illustrate that neural mechanisms governing the progression of epileptic activity can be differentially altered early in the kindling process without pharmacological manipulation (Kline, Revilla & Hernandez, 1997). Although, they were uncertain as to the tone's influence on neural activity and its ability to elicit these responses.
As a whole, the inhibitory influences are relevant to the study of epilepsy because they suggest that if the limbic system is functioning normally, any irregular excitation of the neural circuits are suppressed by "endogenous anticonvulsant agents" (Goddard, Dragunow, Maru & MacLoed, 1986, 104) which are induced by the seizure activity.
THE LIMBIC SYSTEM
The importance of the limbic system in kindling experiments is apparent in several lines of evidence. First, many neural structures within this region are easily kindled, for example, the amygdala (Nieminen, Sirvio, Teittinen, Pitkanen, Airaksinen & Riekkinen, 1992). Secondly, because of the limbic system's
role in emotion and memory, the behavioural changes manifested through kindling provides examples of possible functions of particular discrete sites (Nieminen, Sirvio, Teittinen, Pitkanen, Airaksinen & Riekkinen, 1992). Lastly, kindling of certain sites in the limbic system produce changes which are comparable with some of the symptoms observed in partial complex seizure disorder (Adamec & Stark-Adamec,1986).
The limbic system is "a collective and functionally neutral term denoting an heterogeneous group of neural structures" (Nauta,1986,43) located at the medial edge of the cerebral hemisphere. The core components of the limbic system are the amygdala and the hippocampus, with its connection with the cortex derived primarily through the median forebrain bundle (Nauta, 1986). The limbic system can be functionally and anatomically divided into 3 subdivisions:
The limbic system's organization is largely bilaterally symmetrical and demonstrates evidence of lateral specialization (Bear, 1986). For example, right temporal lobe epileptics have more emotive symptom characteristics and left temporal lobe epileptics more often have ideative traits (Bear, 1986). There is also evidence that some limbic structures play an important role in certain types of memory (Bear, 1986). Kindling experiments investigating these considerations have focused on further definition of the unique specializations in distinct regions of limbic structures, particularly within the amygdala and the hippocampus.
BEHAVIOURAL EFFECTS OF KINDLING
Aggression
Researchers have found that defensive responses to environmental stimuli are regulated by the basal amygdala and ventral hippocampus. Specifically, in cats predisposed to defensive responses,
The hypothesis that the type of aggression adopted (defensive or predatory) is related to limbic excitability is further supported by the evidence that normally aggressive cats which have been exposed to partial kindling (no motor convulsions produced) of the amygdala adopt a more defensive behaviour when presented with an environmental stimuli and that this chnage is long-lasting (Adamec & Stark-Adamec, 1986). Because these modifications were produced without evoking motor seizure activity, Adamec & Stark-Adamc suggest that the changes in behaviour are maintained through "some form of potentiation of synaptic transmission" (Adamec & Stark-Adamec, 1986, 132) which occurs through "driving of the limbic system" (Adamec & Stark-Adamec, 1986, 132) which is not dependent on the production of epileptic convulsions.
Fear
Studies in this area of behaviour appear to indicate that the amygdala is the primary site of control over fear reactions. In one experiment (Nieminen, Sirvio, Teittinen, Pitkanen, Airaksinen & Reikkinen, 1992), electrodes were implanted in the basolateral nucleus of the left amygdala of rats and later the subjects were kindled. The researchers compared the results of kindled rats versus control rats on several tests designed to evaluate fearlfulness (open-field test, elevated plus-maze and elevated bridge); and one test designed to evaluate spatial memory (water maze task). The results showed significant differences between the two groups on evels of activity, anxiety and impaired motor coordinations; however, there were no significant differences between the groups on the performance of the memory task. The researchers therefore propose
that the basolateral nucleus of the amygdala is an important component responsible for the behavioural manifestation of the fear-response in rats (Nieminen, Sirvio, Teittinen, Pitkanen, Airaksinen & Riekkinen, 1992).
Another experiment (Rosen, Hamerman, Sitcoske, Glowa & Schulkin, 1996) corresponds with the previous findings about the role of the amygdala in fear behaviours. In this study, rats were first conditioned to be fearful of a light and then kindled in either the amygdala or the hippocampus. After kindling, the rats were retested for fear-potentiated startle. The results showed that only the subjects which had received kindling in the amygdala had a significantly increased startle response to the visual stimuli when compared with the hippocampal-kindled and control groups. To provide futher confirmation of these results, the authors conducted a second experiment to measure c-fos messenger RNA (mRNA) which highlights regions of neural activity (Rosen, Hamerman, Sitcoske, Glowa & Schulkin, 1996). The results of this experiment confirmed the behavioural evidence of the first experiment. The rats who underwent amygdala kindling showed c-fos mRNA in regions ipsilateral to the primary site of stimulation; for example, the pyriform, perirhinal, entorhinal and neocortices, the caudate nucleus, and the nucleus accumbens (Rosen, Hamerman, Sitcoske, Glowa & Schulkin, 1996). Conversely, hippocampal-stimulated rats showed c-fos mRNA in only the immediate region of the hippocampus (Rosen, Hamerman, Sitcoske, Glowa & Schulkin, 1996). From this evidence it is proposed that the sites with c-fos mRNA present after amygdala stimulation are important to the fear-potentiated startle response; whereas, hippocampal regions are probably not involved in this behavioural response to visual stimuli (Rosen, Hamerman, Sitcoske, Glowa & Schulkin, 1996).
Learning and Memory
Kindling experiments have also been utilized to determine which limbic structures play a role in learning and memory. For example, a study by
Leung, Brzozowski & Shen (1996) demonstrates the role of the hippocampus in different forms of memory. The observation that temporal lobe seizures are often associated with memory deficits (Leung, Brzozowski & Shen, 1996) is the basis of the hypothesis that kindling of the hippocampus should produce observable effects on the performance of rats on mazes designed to test different types of memory. The researchers designed two separate experiments to investigate the effects of hippocampal kindling on the retention and acquisition of cue tasks and place tasks.
In the first experiment, rats were trained on an eight arm radial maze (RAM). The place task RAM had no walls and therefore rats could learn to find the baited arms by extramaze cues within the room. The cue task RAM was walled and each maze arm was covered with a different texture material and therefore provided intramaze cues. The researchers measured reference memory errors as the number of times a rat chose an unbaited arm, and working memory errors as the number of times a rat revisited a previously entered arm. After two weeks of training, the rats had electrodes implanted in region CA1 of the hippocampus and were partially kindled. The results showed that kindled rats, compared with yoked control subjects, made significantly more errors in reference and working memory on the place task. However, there was no significant difference observed between these groups on the cue task.
In the second experiment, researchers compared acquisition versus retention of the place task. The same procedure as the place task in the first experiment was followed; although, on Day 5 after kindling, the maze was moved to a new room which manipulated the place cues, and the baited arms were randomly changed so that the rats could not have recalled the order of where the baited arms had been located. The results of this experiment showed that kindled rats, compared with control rats, experienced a significant deficit in the retention of a previously learned place task; however, they showed no difference in the rate of acquisition of a new place task.
The results from these two experiments confirm previous views regarding the role of the hippocampus. It seems that the hippocampus is involved in tasks which utilize "distal spatial information" (Leung, Brzozowski & Shen, 1996, 1021) through the formation of cognitive maps. This was demonstrated in the poorer performance of kindled rats on the place task in the first experiment. Moreover, this effect is specific to the place task and did not disrupt all working memory because there were no significant between-group differences on the cue task. The results of the second experiment also demonstrate that the hippocampus is more involved in memory for the place task, rather than the learning process, because the retention of a previously learned place task was diminished, but not the acquisition of a new place task (Leung, Brzozowski & Shen, 1996).
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