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The development of psychosis in epilepsy: a re-examination of the kindling hypothesis
ELSEVIER
Behavioural Brain Research 75 (1996) 59-66
BEHAVIOURAL BRAIN RESEARCH
Research report
The development of psychosis in epilepsy: a re-examination of the kindling hypothesis Paul F. Smith * and Cynthia L. Darlington Department of Psychology and the Neuroscience Research Centre, University of Otago, Dunedin, New Zealand Received 30 September 1994; revised 1 April 1995; accepted 13 May 1995
Abstract
It is generally acknowledged that psychosis occurs with increased frequency within epileptic populations. There are several possible explanations for this over-representation: (1) psychosis may develop as a result of anti-epileptic drug or surgical treatment, or as a result of the psychosocial effects of living with epilepsy; (2) epilepsy and psychosis may, in some cases, have a common cause; and (3) chronic seizure activity may sometimes cause psychosis. The objective of this review is to evaluate the hypothesis that focal seizure activity may lead to the development of psychosis through a kindling process. There is some evidence to suggest that secondary epileptogenesis may develop following the spread of seizure activity from a primary focus, possibly via a kindling mechanism. Although it has been suggested that long-term potentiation (LTP) may result in the development of secondary epileptic foci, LTP is not necessarily implicated. The kindling hypothesis of the development of psychosis in epilepsy must address the neural mechanism by which the spread of seizures might result in psychosis. At present, the neurochemical mechanisms by which psychosis could result from epilepsy are unclear.
Keywords: Psychosis;Kindling; Epilepsy;GABAergicinhibition; Seizure
1. Introduction
1.1. Is psychosis over-represented within epileptic populations? While some researchers have argued that psychosis occurs with increased frequency within epileptic populations (e.g., [27,55,79-81]; see [88] for a review), others disagree and suggest that inadequate control groups and sampling problems have confounded most epidemiological studies (e.g., [6]; see [82] for a review). There are relatively few large epidemiological studies with agematched control groups; however, many surveys of nonselected epileptic patients have recorded an unusually high frequency of psychosis (see [12,88] for reviews). Despite the belief that psychosis is more commonly linked with temporal lobe epilepsy than other forms of epilepsy (e.g., [73,88]), some studies indicate that many * Corresponding author. Present address: Department of Pharmacology, School of Medical Sciences, University of Otago Medical School,Dunedin, New Zealand. Fax: +64 3 479-9140; e-mail: [email protected] 0166-4328/96/$15.00© 1996 ElsevierScienceB.V. All rights reserved SSDI 0166-4328(96)00157-3
patients with generalized seizures also suffer from psychosis (e.g., [10,80,81]; however, see [55]). In general, the onset of epileptic seizures has been found to precede the onset of psychotic symptoms (e.g., [ 10]; see [ 88] for a review). Recently, attempts have been made to control for the sampling biases which have undermined previous studies. Mendez et al., [55] observed interictal schizophrenic disorders (according to the DSM-III-R) in 149 patients of 1611 epileptic outpatients (9.25%). By contrast, only 23 of 2167 (1.06%) patients suffering from migraine exhibited schizophrenic symptoms. The two groups of patients were similar in age and socioeconomic background. In an age- and sex-matched comparison of epileptic patients with and without schizophrenia (n = 62 patients in each group), Mendez et al. observed that epileptics with schizophrenia had a later age of onset of seizures, more complex partial seizures, a higher frequency of auras, and fewer generalized seizures, relative to epileptics without schizophrenia. Overall, the majority of the evidence suggests that psychosis is over-represented within epileptic popula-
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tions [12]. The purpose of this review is to examine possible neural mechanisms by which psychosis may develop, with particular emphasis on the kindling hypothesis [83].
2. Neural correlates of psychosis in epilepsy A large number of studies have indicated that temporal lobe epilepsy is associated with temporal lobe pathology, for example, hippocampal sclerosis and, in some cases, neuronal loss [1,32-34,37,92]. Temporal lobe epilepsy has been correlated with an hypometabolism in the ipsilateral temporal lobe and surrounding regions [30,67], which has recently been related to impaired cognitive performance [68]. There are generally fewer studies of epileptic patients with psychosis; however, a number of investigations have suggested that the brains of psychotic epileptics show unique patterns of metabolic and structural change. Gallhofer et al. [22] reported an interictal ipsilateral hypometabolism in psychotic epileptics, which extended to the basal ganglia and the frontal cortex. Bruton et al. [ 10] compared 661 brains from four groups of epileptic patients: patients who met the DSM-III-R criteria for a diagnosis of schizophrenia, those who did not meet DSM-III-R criteria for schizophrenia but satisfied the criteria for an organic psychosis, epileptics who were inpatients but did not have psychosis, and epileptics who lived in the community and did not have psychosis. Pathological examinations were conducted without knowledge of the clinical histories and diagnoses of the patients. Surprisingly, the frequency and severity of temporal lobe pathology was similar among the four groups. Also surprising was that temporal lobe epilepsy was no more common in epileptic patients with schizophrenia, compared to the other groups; all of the schizophrenic patients had generalized seizures irrespective of whether they suffered from other types of seizures as well. The time between seizure onset and the onset of the schizophrenic symptoms ranged from 5 to 38 years [10]. Most remarkable was that the two groups of psychotic epileptics were distinguished from the nonpsychotic groups by enlarged ventricles, periventricular gliosis and excessive focal brain damage (see also [73]). These pathological changes are similar to those which have been documented in schizophrenics without epilepsy (e.g., [9]; see [72] for a review) and could not be explained by the age of the psychotic epileptic patients at death. The epileptics with schizophrenic psychosis were further distinguished from the other groups, including the non-schizophrenic psychotic group, by a large number of minute lesions on thick-walled blood vessels throughout the white matter. Again, these lesions could not be explained by age alone since the patients in two of the remaining three groups were the same age or
older at death. Bruton et al. [10] concluded that the temporal lobe pathology which is usually associated with temporal lobe epilepsy is unlikely to account for the development of schizophrenia and that other pathological changes must be responsible. While these metabolic and anatomical studies describe neural correlates of psychosis in epilepsy, they cannot demonstrate whether the metabolic or pathological changes are part of the cause or the effect of the psychosis.
3. Possible causes of psychosis in epilepsy What are the possible explanations for the increased frequency of psychosis within epileptic populations? First, psychosis may be a result of drug or surgical treatment used to control seizure activity, or the psychosocial experience of living with epilepsy. Second, epilepsy and psychosis may have a common cause. Third, psychosis may develop as a result of chronic seizure activity. The first possibility is difficult to exclude. The acute and chronic effects of anti-epileptic drugs on the CNS are poorly understood (e.g., [76]; see [21] and [91] for reviews). However, an increased incidence of psychiatric symptoms has been documented in patients undergoing withdrawal from anti-epileptic medication [42,55]. Continued use of some anti-epileptic drugs such as primidone and ethosuximide can cause personality changes and psychoses; many other anti-epileptic drugs cause cognitive impairment and depressed mood (see [ 18] for a review; see also the recent study by Rho et al. [71]). One possible mechanism for such effects is the reduction in folic acid levels which results from antiepileptic medication; since the folate cycle is involved in the synthesis of neurotransmitters and neuromodulators, changes in folic acid serum levels may alter the synthesis of these neurochemicals (see [70] for a review). In addition to the effects of anti-epileptic drugs on psychological state, the experience of living with epilepsy can result in anxiety and depressed mood [88]. However, while most epileptic patients receive anti-epileptic medication and experience problems in living with epilepsy, only some develop psychosis. This may be due to large differences in the type of anti-epileptic drug used, the dose regimen employed, specific drug effects, specific types of surgical intervention used, and/or differences in the problems individuals experience in coping with epilepsy. Given our poor understanding of the precise effects of drug and surgical treatments on CNS neurons (see [21] and [91] for reviews), or the neural sequelae of the psychosocial effects of epilepsy, it is difficult to exclude the possibility that psychosis in epilepsy is related to one or more of these factors. A second possibility is that epilepsy and psychosis have a common cause (see [85] for a review). Slater and Beard [80] reported that a large number of psychotic
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epileptics had a clear organic basis for their epilepsy and hypothesised that an underlying neurological disorder might be responsible both for the epilepsy and the psychosis. Trimble [88] has argued that the structural damage which occurs in temporal lobe epilepsy is largely confined to the temporal lobe, whereas the metabolic changes which have been documented in psychotic epileptics extend beyond this region; therefore, it is unlikely that the epilepsy and the psychosis share the same organic basis. However, the recent pathological study by Bruton et al.[10] demonstrates that the structural damage which occurs in psychotic epileptics may be more extensive than in non-psychotic epileptics. There are several lines of evidence which are consistent with a causal relationship between seizure activity and the development of psychosis. First, the onset of seizure activity is usually at least a decade before the appearance of psychotic symptoms (e.g., [ 10]; see [88] for a review). Second, in some studies, the frequency of seizures has been reported to decrease prior to the onset of psychotic symptoms (see [88] for a review). Third, there is some evidence from depth electrode studies that psychotic symptoms are correlated with abnormal spike wave activity in the amygdala, hippocampus and septum, and that this abnormal activity is correlated with a decrease in neocortical activity [28]. However, none of these data prove that a causal relationship exists between the occurrence of epileptic seizures and the development of psychosis, nor do they suggest a mechanism by which the psychosis may develop.
4. Secondary epileptogenesis and the kindling hypothesis If it is hypothesised that psychosis can result from seizure activity, and it is accepted that temporal lobe damage itself is not a sufficient cause, then it is necessary to explain how other parts of the CNS can be affected and by what mechanism psychosis can develop. 'Kindling' is an experimental procedure in which repeated focal electrical stimulation of the brain results in increased neuronal excitability. At first, the electrical stimulation does not produce any obvious behavioral signs and no afterdischarges in the electroencephalogram (EEG). However, gradually, over a period of days, the same electrical stimulus begins to induce afterdischarges; finally the animal exhibits generalized seizures. With continued daily stimulation, spontaneous seizures may occur (see [48] for a review). The kindling phenomenon was discovered by Alonso-DeFlorida and Delgado [-4] but was first systematically investigated by Goddard and colleagues [23,26]. The phenomenon has been demonstrated in a wide range of species, including primates, and has become a major experimental model of epilepsy (see [20,39,48,49] for reviews). Because kindling involves the spread of seizure activity from the site of stimulation to other areas of the CNS, it has been
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considered a potential mechanism by which the effects of focal epilepsy may lead to psychosis [ 82, 83 ] (see [ 88 ] for a review). Recent studies suggest that seizures evoked by application of bicuculline to a specific epileptogenic site in the deep prepiriform cortex, the area tempestas, can result in an enhanced expression of mRNA for the immediate early gene, c-fos, throughout the piriform cortex, entorhinal cortex, olfactory bulb, hippocampus and amygdala [46,50]. Since seizures evoked from the inferior colliculus did not induce c-fos expression in the limbic system, the widespread induction of c-fos in limbic areas following seizure activity in the area tempestas suggests that seizure propagation may occur more easily in some areas of the CNS than others [46,50].
4.1. Could neuronal activity in the epileptic focus be a stimulus for kindling? In order for a kindling process to be responsible for the development of psychosis, the neuronal activity within the epileptic focus would have to be similar to the type of stimulus which normally induces kindling. Numerous studies have documented neuronal activity within the human epileptic focus. Generally it has been found that synchronous bursting occurs in single neurons during a seizure (e.g., [94]). In the last decade, many studies have been performed on slices of epileptic brain tissue removed from human patients suffering from intractable epilepsy. In most cases, evoked depolarization shifts and burst discharges have been observed (e.g., [5,64,84,85]; however, see [77]). Similar results have been observed in brain slices removed from animals in which seizures have been induced experimentally (e.g., [17,63]). Many studies of epileptogenic tissue removed from humans support the hypothesis that ~,-aminobutyric acid (GABA)-induced inhibitory postsynaptic potentials are reduced [5,63,84,85]. In some cases, burst discharges have been shown to be blocked by antagonists for the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor [5,57]. In vivo studies in rats have shown that kindling is associated with the onset of rhythmic spiking at the site of stimulation [58] (see [49] for a review). Therefore, neuronal activity within the epileptic focus may approximate a stimulus for the induction of kindling. In tissue removed from kindled rats, seizure activity has been correlated with an increase in the mean open time of calcium channels associated with the NMDA receptor [44].
4.2. Does secondary epileptogenesis occur in humans? If kindling has relevance for the development of epilepsy in humans, then with repeated seizure activity in one area of the CNS, other areas which receive synaptic input from the epileptic focus should also develop epileptiform activity. The degree to which secondary foci develop, a phenomenon known as
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'secondary epileptogenesis', has remained controversial. Morrell [59,60] has argued that secondary epileptogenesis occurs in humans but is difficult to prove because of the possibility of multiple primary lesions. However, he has reported that in the case of cerebral tumour, where the probability of multiple lesions is low, 34% of patients exhibited secondary epileptogenesis. Hughes [35] reported that the incidence of bilateral foci increased with age and observed developing bilateral foci in 34% of his patient sample. Niediek et al. [62] found evidence of secondary foci in only 11% of their patient sample; in agreement with Morrell, they found that the secondary focus developed some years after the primary focus was identified and that these patients had a higher frequency of seizures than those without secondary foci.
4.3. Possible mechanisms of secondary epileptogenesis long-term potentiation? If the kindling process is responsible for the spread of seizure activity from one area of the CNS to another, one possible mechanism by which this process might develop is long-term potentiation (LTP). LTP is an enhancement of synaptic efficacy which follows high frequency stimulation of an afferent pathway: the postsynaptic neurons show a larger response to an excitatory stimulus than they did prior to tetanization (see [8] for a review). The enhancement of synaptic efficacy is specific to the input which has been tetanized (i.e., it is 'homosynaptic'), therefore the postsynaptic neurons respond to other afferent inputs normally. In considering how LTP might explain the development of secondary epileptogenesis through a kindling process, the first assumption is that the epileptiform activity in the primary focus is analogous to the tetanization stimulus which is used to induce LTP. This may not be the case. The tetanization of presynaptic fibers during the induction of LTP does not cause a permanent change in the excitability of those fibers [8]; however, during the development of kindling, the site of stimulation shows increased excitability [ 65 ]. A second assumption is that, because LTP is homosynaptic, it should affect only synapses which have been repeatedly activated as a result of the epileptiform activity in the primary focus. Consistent with this assumption is the finding that, during the kindling process, a secondary focus often develops at a site contralateral and homotopic to the primary focus (see [24] and [47] for reviews). However, there are several lines of evidence which argue against the hypothesis that LTP is involved in the development of secondary epileptogenesis. First, although the hippocampus develops LTP easily, it is a more difficult structure in which to induce kindling; other structures (e.g., the olfactory bulb) which kindle easily do not readily exhibit LTP (see [48] for a review). Second, LTP, while long-term, is not permanent and
decays gradually over time; however, the changes in responsiveness which are induced by kindling appear to be more permanent (see [48] for a review). Third, it has been shown that previous LTP experience results in only a small increase in the rate of kindling (see [48] for a review). While LTP remains a possible explanation for the development of secondary epileptogenesis, it is equally conceivable that epileptiform activity may be transmitted to other areas of the CNS without any change in synaptic efficacy, for example, through the modulation of intrinsic membrane properties (e.g., see [48] and [49] for reviews).
4.4. How could psychosis develop through secondary epileptogenesis? Even if secondary epileptogenesis develops through a kindling process (with or without LTP), why should the development of secondary foci lead to psychosis? Is there any evidence to support the view that secondary epileptogenesis can result in the neurochemical changes which are associated with psychosis? For decades it has been suggested that a 'biological antagonism' exists between epilepsy and psychosis, such that the neurochemical changes which promote epilepsy reduce the tendency to psychosis, and visa-versa (e.g., [54,69,70,82,86]). It has been demonstrated that postictal psychosis is correlated with a normalization ('forced normalization') of the EEG (see [93] for a review). Dopamine (DA) agonists have been demonstrated to reduce epileptiform activity (i.e., elevate seizure threshold) but exacerbate psychosis, whereas DA antagonists have been found to increase epileptiform activity but alleviate psychosis (e.g., [53]; see [70] for a review). Exactly how this 'biological antagonism' may work is unclear. However, DA, being mainly inhibitory in its actions, may reduce the hyperexcitability which causes seizures; conversely, DA antagonists may produce disinhibition which exacerbates the seizure activity (see [70] for a review). There is little direct evidence to support the hypothesis that kindling can lead to psychosis or other psychiatric disorders (see [3] and [75] for reviews). Adamec [2] observed changes in the interictal behavior of kindled cats. Wada et al. [89] reported that baboons become increasingly irritable between kindled seizures when the primary focus is the frontal cortex but not the amygdala. The most frequently cited study in relation to the possible psychiatric significance of kindling is by Stevens and Livermore [83]. Stevens and Livermore administered kindling stimuli to the ventral tegmental area (VTA) of cats: after 5-26 days, 3/6 cats developed afterdischarges in the VTA and the ipsilateral nucleus accumbens; in some cases there was spike activity in the medial geniculate nucleus. The development of these electrophysiological changes was correlated with an abrupt change in the behavior of the animals: they
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became fearful and withdrawn, sometimes behaving aggressively toward other cats. Before the experiment, however, the animals had been friendly and inquisitive. Because electrical stimulation of the VTA should result in increased DA release in the limbic system and neocortex, Stevens and Livermore [ 83 ] speculated that kindling in the VTA may result in a potentiation of DA transmission. If psychosis is related to enhanced DA transmission (e.g., [78]; see [90] for a review), then the spread of seizures to the VTA might explain how psychosis could result from secondary epileptogenesis [82,87]. Stevens [82] has suggested that increased DA release interictally might result in increased cortical inhibition, thus producing the cortical hypometabolism which has been documented in psychosis and in epilepsy with psychosis (e.g., [22]; see [82] for a review). However, while this hypothesis appears logical, it must be recognised that there are few data relating to epileptiform activity in the VTA. Stevens and Livermore's [ 83 ] observations of behavioral changes were mostly qualitative in nature and were restricted to only a small number of animals. Furthermore, in order to induce kindling in the VTA, they employed current amplitudes which were higher than those used in other kindling studies (up to 1000 #A). Goddard et al. [-26], in their original studies, consistently failed to obtain kindling in the VTA. However, consistent with Stevens and Livermore's hypothesis is the observation that amygdaloid kindling results in an enhancement of methamphetamine-induced stereotyped behavior [74]; this result could be explained by a kindlinginduced supersensitivity of DA receptors [74]. One argument against a kindling explanation of psychosis in epilepsy is that kindling is generally not associated with structural brain damage [19,25,26,66], although reactive synaptogenesis has been reported (see [56] for a review). Recent neuropathological studies have indicated that the development of psychosis in epilepsy is associated with structural brain damage, similar to that which has been described for schizophrenia [10]. However, these morphological changes were documented in patients who suffered seizures for years or decades, whereas kindling experiments rarely extend beyond a few months: it is possible that if kindlinginduced seizures were maintained for years, structural brain damage would be found. The evidence from metabolic studies is also inconsistent w,.'th a kindling explanation of psychosis in epilepsy. Whereas an interictal hypometabolism, ipsilateral to the epileptic focus, has been documented in psychotic epileptic patients, animal studies suggest that kindling is associated with normal or increased glucose uptake in most cases [7,19]. Again, the possibility cannot be excluded that if the kindling stimulation were continued for a sufficiently long period of time, hypometabolic changes might be found. To the extent that the neurochemical basis of psychosis is understood, at present there is no compelling evidence
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that secondary epileptogenesis results in neurochemical changes which are usually associated with the development of psychosis in humans. Psychosis is associated with widespread changes in neurotransmitter receptors, although changes in DA receptors have received the most attention (see [90] for a review); recent studies, for example, have suggested a six-fold increase in the number of D 4 receptors in the brains of schizophrenics [78]. To date, studies of DA receptors have not been performed on epileptic patients suffering from psychosis. However, precisely which neurochemical changes are responsible for psychosis in non-epileptics is still highly controversial and it is possible that there are other neurochemical disturbances which are common to these disorders irrespective of whether epilepsy is present. Studies of neurotransmitter receptors in human epileptics have shown reductions in benzodiazepine [29,41] and muscarinic acetylcholine receptors [61] in the epileptogenic temporal lobe. An increase in #-opiate receptors has been reported in the temporal neocortex, with a decrease in the amygdala ipsilateral to the epileptic focus [51 ]. Adenosine concentrations have been shown to rise during seizure activity [16], which is consistent with the hypothesis that adenosine may act as an endogenous anticonvulsant [15]. Levels of blood cortisol and cerebrospinal fluid fl-endorphins have been shown to increase during seizures Ell]; seizures may also be associated with a rise in serum levels of prolactin [52]. In animals it has been shown that kindling-induced seizures are associated with increases in thyrotropin releasing hormone (TRH) in the hippocampus and increases in prepro-TRH messenger RNA in the hippocampus, amygdala and piriform cortex; a decrease in TRH binding was found in the hippocampus and amygdala [45]. At present, none of these neurochemical changes clearly relates to the neurochemical substrates of psychosis. One neurochemical change which epilepsy and psychosis share is a dysfunction of excitatory amino acid (EAA) receptors, although the specific nature of the changes which occur remains contentious. From experimental models of epilepsy there is evidence that NMDA receptors may mediate epileptiform activity (e.g., [57]), which can be blocked by NMDA receptor antagonists (e.g., [ 31]). Some anti-epileptic drugs in clinical use have been shown to block NMDA receptors as well as potentiating GABAergic function (e.g., felbamate E71]). Recently, the hypothesis that schizophrenia involves a disorder of EAA transmission has gained popularity [43] (see [38] for a review). The glutamate hypothesis suggests that schizophrenia is associated with a decrease in glutamate concentrations in the CNS [43]. There are various lines of evidence which are consistent with this hypothesis: in some studies, a decrease in glutamate concentrations has been found in the cerebrospinal fluid of schizophrenics (e.g., [43]; see [36] for a recent review); post-mortem analyses of the brains of schizophenics
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have revealed increases in the number of EAA receptor subtypes in some areas, which may be a compensatory response to reduced glutamate levels (e.g., [ 13]; see [36] for a recent review); recent studies suggest that the number of strychnine-insensitive glycine binding sites associated with NMDA receptors is also increased in some cortical areas [36]. If both epilepsy and psychosis were associated with increased NMDA receptor function, then NMDA receptor-induced excitotoxicity might account for neuronal loss in both conditions; in this case, a kindling process might explain how chronic seizures ultimately lead to psychosis. However, there are a number of problems with this simple hypothesis given the available data. First, if schizophrenia is associated with reduced glutamate concentrations, the functional effect of the up-regulation of NMDA receptors is unclear. Second, phencyclidine, a non-competitive NMDA receptor/channel antagonist, induces a psychosis similar to schizophrenia in humans, which is consistent with the hypothesis that reduced NMDA receptor function may contribute to psychosis (see [40] for a review). The evaluation of the glutamate hypothesis of schizophrenia is still at a very early stage. However, given that EAA receptor abnormalities appear to occur in both epilepsy and schizophrenia, further research on the possible connection between EAA receptor dysfunction in epilepsy and psychosis is warranted.
5. Conclusions Overall, the evidence in favour of a causal relationship between kindling and the development of psychosis in epilepsy is not compelling. As an explanation of the high frequency of psychosis within epileptic populations, the kindling hypothesis remains to be adequately tested. The hypothesis that a reduction in GABAergic inhibition is at least partially responsible for the development of epileptiform activity remains popular (see [39] for a review). Likewise, many studies suggest that hyperexcitability may be partially mediated by NMDA receptors (e.g., [57]; see [39] for a review). Although these hypotheses do not provide any clear insight into how psychosis may arise from epileptiform activity, it is likely that chronic hyperexcitability leads to the structural brain damage observed in temporal lobe epilepsy, possibly through excitotoxicity (see [39] for a review). Psychosis may develop as the seizures become more generalized and the brain damage more widespread and severe [I0]. Some researchers have speculated that psychosis may develop as a result of a disruption of normal interhemispheric communication at both the forebrain and brainstem levels (e.g., see [14-1 for a review). Therefore, a further possibility is that, in some cases, specific types of focal seizure activity and perhaps associated cell death, result in a major disruption to the normal neural
competition between the two hemispheres, thus leading to psychosis [ 14].
Acknowledgment We thank Annabelle Jerram for her assistance and Dr. David Bilkey, Dr. Harry McConnell and Dr. Darrin Gilchrist for their critical comments on the manuscript. We would also like to thank two anonymous referees for their helpful comments. This research was supported by a Project Grant from the Health Research Council of New Zealand (to PS and CD).
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BEHAVIOURAL BRAIN RESEARCH
Research report
The development of psychosis in epilepsy: a re-examination of the kindling hypothesis Paul F. Smith * and Cynthia L. Darlington Department of Psychology and the Neuroscience Research Centre, University of Otago, Dunedin, New Zealand Received 30 September 1994; revised 1 April 1995; accepted 13 May 1995
Abstract
It is generally acknowledged that psychosis occurs with increased frequency within epileptic populations. There are several possible explanations for this over-representation: (1) psychosis may develop as a result of anti-epileptic drug or surgical treatment, or as a result of the psychosocial effects of living with epilepsy; (2) epilepsy and psychosis may, in some cases, have a common cause; and (3) chronic seizure activity may sometimes cause psychosis. The objective of this review is to evaluate the hypothesis that focal seizure activity may lead to the development of psychosis through a kindling process. There is some evidence to suggest that secondary epileptogenesis may develop following the spread of seizure activity from a primary focus, possibly via a kindling mechanism. Although it has been suggested that long-term potentiation (LTP) may result in the development of secondary epileptic foci, LTP is not necessarily implicated. The kindling hypothesis of the development of psychosis in epilepsy must address the neural mechanism by which the spread of seizures might result in psychosis. At present, the neurochemical mechanisms by which psychosis could result from epilepsy are unclear.
Keywords: Psychosis;Kindling; Epilepsy;GABAergicinhibition; Seizure
1. Introduction
1.1. Is psychosis over-represented within epileptic populations? While some researchers have argued that psychosis occurs with increased frequency within epileptic populations (e.g., [27,55,79-81]; see [88] for a review), others disagree and suggest that inadequate control groups and sampling problems have confounded most epidemiological studies (e.g., [6]; see [82] for a review). There are relatively few large epidemiological studies with agematched control groups; however, many surveys of nonselected epileptic patients have recorded an unusually high frequency of psychosis (see [12,88] for reviews). Despite the belief that psychosis is more commonly linked with temporal lobe epilepsy than other forms of epilepsy (e.g., [73,88]), some studies indicate that many * Corresponding author. Present address: Department of Pharmacology, School of Medical Sciences, University of Otago Medical School,Dunedin, New Zealand. Fax: +64 3 479-9140; e-mail: [email protected] 0166-4328/96/$15.00© 1996 ElsevierScienceB.V. All rights reserved SSDI 0166-4328(96)00157-3
patients with generalized seizures also suffer from psychosis (e.g., [10,80,81]; however, see [55]). In general, the onset of epileptic seizures has been found to precede the onset of psychotic symptoms (e.g., [ 10]; see [ 88] for a review). Recently, attempts have been made to control for the sampling biases which have undermined previous studies. Mendez et al., [55] observed interictal schizophrenic disorders (according to the DSM-III-R) in 149 patients of 1611 epileptic outpatients (9.25%). By contrast, only 23 of 2167 (1.06%) patients suffering from migraine exhibited schizophrenic symptoms. The two groups of patients were similar in age and socioeconomic background. In an age- and sex-matched comparison of epileptic patients with and without schizophrenia (n = 62 patients in each group), Mendez et al. observed that epileptics with schizophrenia had a later age of onset of seizures, more complex partial seizures, a higher frequency of auras, and fewer generalized seizures, relative to epileptics without schizophrenia. Overall, the majority of the evidence suggests that psychosis is over-represented within epileptic popula-
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tions [12]. The purpose of this review is to examine possible neural mechanisms by which psychosis may develop, with particular emphasis on the kindling hypothesis [83].
2. Neural correlates of psychosis in epilepsy A large number of studies have indicated that temporal lobe epilepsy is associated with temporal lobe pathology, for example, hippocampal sclerosis and, in some cases, neuronal loss [1,32-34,37,92]. Temporal lobe epilepsy has been correlated with an hypometabolism in the ipsilateral temporal lobe and surrounding regions [30,67], which has recently been related to impaired cognitive performance [68]. There are generally fewer studies of epileptic patients with psychosis; however, a number of investigations have suggested that the brains of psychotic epileptics show unique patterns of metabolic and structural change. Gallhofer et al. [22] reported an interictal ipsilateral hypometabolism in psychotic epileptics, which extended to the basal ganglia and the frontal cortex. Bruton et al. [ 10] compared 661 brains from four groups of epileptic patients: patients who met the DSM-III-R criteria for a diagnosis of schizophrenia, those who did not meet DSM-III-R criteria for schizophrenia but satisfied the criteria for an organic psychosis, epileptics who were inpatients but did not have psychosis, and epileptics who lived in the community and did not have psychosis. Pathological examinations were conducted without knowledge of the clinical histories and diagnoses of the patients. Surprisingly, the frequency and severity of temporal lobe pathology was similar among the four groups. Also surprising was that temporal lobe epilepsy was no more common in epileptic patients with schizophrenia, compared to the other groups; all of the schizophrenic patients had generalized seizures irrespective of whether they suffered from other types of seizures as well. The time between seizure onset and the onset of the schizophrenic symptoms ranged from 5 to 38 years [10]. Most remarkable was that the two groups of psychotic epileptics were distinguished from the nonpsychotic groups by enlarged ventricles, periventricular gliosis and excessive focal brain damage (see also [73]). These pathological changes are similar to those which have been documented in schizophrenics without epilepsy (e.g., [9]; see [72] for a review) and could not be explained by the age of the psychotic epileptic patients at death. The epileptics with schizophrenic psychosis were further distinguished from the other groups, including the non-schizophrenic psychotic group, by a large number of minute lesions on thick-walled blood vessels throughout the white matter. Again, these lesions could not be explained by age alone since the patients in two of the remaining three groups were the same age or
older at death. Bruton et al. [10] concluded that the temporal lobe pathology which is usually associated with temporal lobe epilepsy is unlikely to account for the development of schizophrenia and that other pathological changes must be responsible. While these metabolic and anatomical studies describe neural correlates of psychosis in epilepsy, they cannot demonstrate whether the metabolic or pathological changes are part of the cause or the effect of the psychosis.
3. Possible causes of psychosis in epilepsy What are the possible explanations for the increased frequency of psychosis within epileptic populations? First, psychosis may be a result of drug or surgical treatment used to control seizure activity, or the psychosocial experience of living with epilepsy. Second, epilepsy and psychosis may have a common cause. Third, psychosis may develop as a result of chronic seizure activity. The first possibility is difficult to exclude. The acute and chronic effects of anti-epileptic drugs on the CNS are poorly understood (e.g., [76]; see [21] and [91] for reviews). However, an increased incidence of psychiatric symptoms has been documented in patients undergoing withdrawal from anti-epileptic medication [42,55]. Continued use of some anti-epileptic drugs such as primidone and ethosuximide can cause personality changes and psychoses; many other anti-epileptic drugs cause cognitive impairment and depressed mood (see [ 18] for a review; see also the recent study by Rho et al. [71]). One possible mechanism for such effects is the reduction in folic acid levels which results from antiepileptic medication; since the folate cycle is involved in the synthesis of neurotransmitters and neuromodulators, changes in folic acid serum levels may alter the synthesis of these neurochemicals (see [70] for a review). In addition to the effects of anti-epileptic drugs on psychological state, the experience of living with epilepsy can result in anxiety and depressed mood [88]. However, while most epileptic patients receive anti-epileptic medication and experience problems in living with epilepsy, only some develop psychosis. This may be due to large differences in the type of anti-epileptic drug used, the dose regimen employed, specific drug effects, specific types of surgical intervention used, and/or differences in the problems individuals experience in coping with epilepsy. Given our poor understanding of the precise effects of drug and surgical treatments on CNS neurons (see [21] and [91] for reviews), or the neural sequelae of the psychosocial effects of epilepsy, it is difficult to exclude the possibility that psychosis in epilepsy is related to one or more of these factors. A second possibility is that epilepsy and psychosis have a common cause (see [85] for a review). Slater and Beard [80] reported that a large number of psychotic
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epileptics had a clear organic basis for their epilepsy and hypothesised that an underlying neurological disorder might be responsible both for the epilepsy and the psychosis. Trimble [88] has argued that the structural damage which occurs in temporal lobe epilepsy is largely confined to the temporal lobe, whereas the metabolic changes which have been documented in psychotic epileptics extend beyond this region; therefore, it is unlikely that the epilepsy and the psychosis share the same organic basis. However, the recent pathological study by Bruton et al.[10] demonstrates that the structural damage which occurs in psychotic epileptics may be more extensive than in non-psychotic epileptics. There are several lines of evidence which are consistent with a causal relationship between seizure activity and the development of psychosis. First, the onset of seizure activity is usually at least a decade before the appearance of psychotic symptoms (e.g., [ 10]; see [88] for a review). Second, in some studies, the frequency of seizures has been reported to decrease prior to the onset of psychotic symptoms (see [88] for a review). Third, there is some evidence from depth electrode studies that psychotic symptoms are correlated with abnormal spike wave activity in the amygdala, hippocampus and septum, and that this abnormal activity is correlated with a decrease in neocortical activity [28]. However, none of these data prove that a causal relationship exists between the occurrence of epileptic seizures and the development of psychosis, nor do they suggest a mechanism by which the psychosis may develop.
4. Secondary epileptogenesis and the kindling hypothesis If it is hypothesised that psychosis can result from seizure activity, and it is accepted that temporal lobe damage itself is not a sufficient cause, then it is necessary to explain how other parts of the CNS can be affected and by what mechanism psychosis can develop. 'Kindling' is an experimental procedure in which repeated focal electrical stimulation of the brain results in increased neuronal excitability. At first, the electrical stimulation does not produce any obvious behavioral signs and no afterdischarges in the electroencephalogram (EEG). However, gradually, over a period of days, the same electrical stimulus begins to induce afterdischarges; finally the animal exhibits generalized seizures. With continued daily stimulation, spontaneous seizures may occur (see [48] for a review). The kindling phenomenon was discovered by Alonso-DeFlorida and Delgado [-4] but was first systematically investigated by Goddard and colleagues [23,26]. The phenomenon has been demonstrated in a wide range of species, including primates, and has become a major experimental model of epilepsy (see [20,39,48,49] for reviews). Because kindling involves the spread of seizure activity from the site of stimulation to other areas of the CNS, it has been
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considered a potential mechanism by which the effects of focal epilepsy may lead to psychosis [ 82, 83 ] (see [ 88 ] for a review). Recent studies suggest that seizures evoked by application of bicuculline to a specific epileptogenic site in the deep prepiriform cortex, the area tempestas, can result in an enhanced expression of mRNA for the immediate early gene, c-fos, throughout the piriform cortex, entorhinal cortex, olfactory bulb, hippocampus and amygdala [46,50]. Since seizures evoked from the inferior colliculus did not induce c-fos expression in the limbic system, the widespread induction of c-fos in limbic areas following seizure activity in the area tempestas suggests that seizure propagation may occur more easily in some areas of the CNS than others [46,50].
4.1. Could neuronal activity in the epileptic focus be a stimulus for kindling? In order for a kindling process to be responsible for the development of psychosis, the neuronal activity within the epileptic focus would have to be similar to the type of stimulus which normally induces kindling. Numerous studies have documented neuronal activity within the human epileptic focus. Generally it has been found that synchronous bursting occurs in single neurons during a seizure (e.g., [94]). In the last decade, many studies have been performed on slices of epileptic brain tissue removed from human patients suffering from intractable epilepsy. In most cases, evoked depolarization shifts and burst discharges have been observed (e.g., [5,64,84,85]; however, see [77]). Similar results have been observed in brain slices removed from animals in which seizures have been induced experimentally (e.g., [17,63]). Many studies of epileptogenic tissue removed from humans support the hypothesis that ~,-aminobutyric acid (GABA)-induced inhibitory postsynaptic potentials are reduced [5,63,84,85]. In some cases, burst discharges have been shown to be blocked by antagonists for the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor [5,57]. In vivo studies in rats have shown that kindling is associated with the onset of rhythmic spiking at the site of stimulation [58] (see [49] for a review). Therefore, neuronal activity within the epileptic focus may approximate a stimulus for the induction of kindling. In tissue removed from kindled rats, seizure activity has been correlated with an increase in the mean open time of calcium channels associated with the NMDA receptor [44].
4.2. Does secondary epileptogenesis occur in humans? If kindling has relevance for the development of epilepsy in humans, then with repeated seizure activity in one area of the CNS, other areas which receive synaptic input from the epileptic focus should also develop epileptiform activity. The degree to which secondary foci develop, a phenomenon known as
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'secondary epileptogenesis', has remained controversial. Morrell [59,60] has argued that secondary epileptogenesis occurs in humans but is difficult to prove because of the possibility of multiple primary lesions. However, he has reported that in the case of cerebral tumour, where the probability of multiple lesions is low, 34% of patients exhibited secondary epileptogenesis. Hughes [35] reported that the incidence of bilateral foci increased with age and observed developing bilateral foci in 34% of his patient sample. Niediek et al. [62] found evidence of secondary foci in only 11% of their patient sample; in agreement with Morrell, they found that the secondary focus developed some years after the primary focus was identified and that these patients had a higher frequency of seizures than those without secondary foci.
4.3. Possible mechanisms of secondary epileptogenesis long-term potentiation? If the kindling process is responsible for the spread of seizure activity from one area of the CNS to another, one possible mechanism by which this process might develop is long-term potentiation (LTP). LTP is an enhancement of synaptic efficacy which follows high frequency stimulation of an afferent pathway: the postsynaptic neurons show a larger response to an excitatory stimulus than they did prior to tetanization (see [8] for a review). The enhancement of synaptic efficacy is specific to the input which has been tetanized (i.e., it is 'homosynaptic'), therefore the postsynaptic neurons respond to other afferent inputs normally. In considering how LTP might explain the development of secondary epileptogenesis through a kindling process, the first assumption is that the epileptiform activity in the primary focus is analogous to the tetanization stimulus which is used to induce LTP. This may not be the case. The tetanization of presynaptic fibers during the induction of LTP does not cause a permanent change in the excitability of those fibers [8]; however, during the development of kindling, the site of stimulation shows increased excitability [ 65 ]. A second assumption is that, because LTP is homosynaptic, it should affect only synapses which have been repeatedly activated as a result of the epileptiform activity in the primary focus. Consistent with this assumption is the finding that, during the kindling process, a secondary focus often develops at a site contralateral and homotopic to the primary focus (see [24] and [47] for reviews). However, there are several lines of evidence which argue against the hypothesis that LTP is involved in the development of secondary epileptogenesis. First, although the hippocampus develops LTP easily, it is a more difficult structure in which to induce kindling; other structures (e.g., the olfactory bulb) which kindle easily do not readily exhibit LTP (see [48] for a review). Second, LTP, while long-term, is not permanent and
decays gradually over time; however, the changes in responsiveness which are induced by kindling appear to be more permanent (see [48] for a review). Third, it has been shown that previous LTP experience results in only a small increase in the rate of kindling (see [48] for a review). While LTP remains a possible explanation for the development of secondary epileptogenesis, it is equally conceivable that epileptiform activity may be transmitted to other areas of the CNS without any change in synaptic efficacy, for example, through the modulation of intrinsic membrane properties (e.g., see [48] and [49] for reviews).
4.4. How could psychosis develop through secondary epileptogenesis? Even if secondary epileptogenesis develops through a kindling process (with or without LTP), why should the development of secondary foci lead to psychosis? Is there any evidence to support the view that secondary epileptogenesis can result in the neurochemical changes which are associated with psychosis? For decades it has been suggested that a 'biological antagonism' exists between epilepsy and psychosis, such that the neurochemical changes which promote epilepsy reduce the tendency to psychosis, and visa-versa (e.g., [54,69,70,82,86]). It has been demonstrated that postictal psychosis is correlated with a normalization ('forced normalization') of the EEG (see [93] for a review). Dopamine (DA) agonists have been demonstrated to reduce epileptiform activity (i.e., elevate seizure threshold) but exacerbate psychosis, whereas DA antagonists have been found to increase epileptiform activity but alleviate psychosis (e.g., [53]; see [70] for a review). Exactly how this 'biological antagonism' may work is unclear. However, DA, being mainly inhibitory in its actions, may reduce the hyperexcitability which causes seizures; conversely, DA antagonists may produce disinhibition which exacerbates the seizure activity (see [70] for a review). There is little direct evidence to support the hypothesis that kindling can lead to psychosis or other psychiatric disorders (see [3] and [75] for reviews). Adamec [2] observed changes in the interictal behavior of kindled cats. Wada et al. [89] reported that baboons become increasingly irritable between kindled seizures when the primary focus is the frontal cortex but not the amygdala. The most frequently cited study in relation to the possible psychiatric significance of kindling is by Stevens and Livermore [83]. Stevens and Livermore administered kindling stimuli to the ventral tegmental area (VTA) of cats: after 5-26 days, 3/6 cats developed afterdischarges in the VTA and the ipsilateral nucleus accumbens; in some cases there was spike activity in the medial geniculate nucleus. The development of these electrophysiological changes was correlated with an abrupt change in the behavior of the animals: they
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became fearful and withdrawn, sometimes behaving aggressively toward other cats. Before the experiment, however, the animals had been friendly and inquisitive. Because electrical stimulation of the VTA should result in increased DA release in the limbic system and neocortex, Stevens and Livermore [ 83 ] speculated that kindling in the VTA may result in a potentiation of DA transmission. If psychosis is related to enhanced DA transmission (e.g., [78]; see [90] for a review), then the spread of seizures to the VTA might explain how psychosis could result from secondary epileptogenesis [82,87]. Stevens [82] has suggested that increased DA release interictally might result in increased cortical inhibition, thus producing the cortical hypometabolism which has been documented in psychosis and in epilepsy with psychosis (e.g., [22]; see [82] for a review). However, while this hypothesis appears logical, it must be recognised that there are few data relating to epileptiform activity in the VTA. Stevens and Livermore's [ 83 ] observations of behavioral changes were mostly qualitative in nature and were restricted to only a small number of animals. Furthermore, in order to induce kindling in the VTA, they employed current amplitudes which were higher than those used in other kindling studies (up to 1000 #A). Goddard et al. [-26], in their original studies, consistently failed to obtain kindling in the VTA. However, consistent with Stevens and Livermore's hypothesis is the observation that amygdaloid kindling results in an enhancement of methamphetamine-induced stereotyped behavior [74]; this result could be explained by a kindlinginduced supersensitivity of DA receptors [74]. One argument against a kindling explanation of psychosis in epilepsy is that kindling is generally not associated with structural brain damage [19,25,26,66], although reactive synaptogenesis has been reported (see [56] for a review). Recent neuropathological studies have indicated that the development of psychosis in epilepsy is associated with structural brain damage, similar to that which has been described for schizophrenia [10]. However, these morphological changes were documented in patients who suffered seizures for years or decades, whereas kindling experiments rarely extend beyond a few months: it is possible that if kindlinginduced seizures were maintained for years, structural brain damage would be found. The evidence from metabolic studies is also inconsistent w,.'th a kindling explanation of psychosis in epilepsy. Whereas an interictal hypometabolism, ipsilateral to the epileptic focus, has been documented in psychotic epileptic patients, animal studies suggest that kindling is associated with normal or increased glucose uptake in most cases [7,19]. Again, the possibility cannot be excluded that if the kindling stimulation were continued for a sufficiently long period of time, hypometabolic changes might be found. To the extent that the neurochemical basis of psychosis is understood, at present there is no compelling evidence
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that secondary epileptogenesis results in neurochemical changes which are usually associated with the development of psychosis in humans. Psychosis is associated with widespread changes in neurotransmitter receptors, although changes in DA receptors have received the most attention (see [90] for a review); recent studies, for example, have suggested a six-fold increase in the number of D 4 receptors in the brains of schizophrenics [78]. To date, studies of DA receptors have not been performed on epileptic patients suffering from psychosis. However, precisely which neurochemical changes are responsible for psychosis in non-epileptics is still highly controversial and it is possible that there are other neurochemical disturbances which are common to these disorders irrespective of whether epilepsy is present. Studies of neurotransmitter receptors in human epileptics have shown reductions in benzodiazepine [29,41] and muscarinic acetylcholine receptors [61] in the epileptogenic temporal lobe. An increase in #-opiate receptors has been reported in the temporal neocortex, with a decrease in the amygdala ipsilateral to the epileptic focus [51 ]. Adenosine concentrations have been shown to rise during seizure activity [16], which is consistent with the hypothesis that adenosine may act as an endogenous anticonvulsant [15]. Levels of blood cortisol and cerebrospinal fluid fl-endorphins have been shown to increase during seizures Ell]; seizures may also be associated with a rise in serum levels of prolactin [52]. In animals it has been shown that kindling-induced seizures are associated with increases in thyrotropin releasing hormone (TRH) in the hippocampus and increases in prepro-TRH messenger RNA in the hippocampus, amygdala and piriform cortex; a decrease in TRH binding was found in the hippocampus and amygdala [45]. At present, none of these neurochemical changes clearly relates to the neurochemical substrates of psychosis. One neurochemical change which epilepsy and psychosis share is a dysfunction of excitatory amino acid (EAA) receptors, although the specific nature of the changes which occur remains contentious. From experimental models of epilepsy there is evidence that NMDA receptors may mediate epileptiform activity (e.g., [57]), which can be blocked by NMDA receptor antagonists (e.g., [ 31]). Some anti-epileptic drugs in clinical use have been shown to block NMDA receptors as well as potentiating GABAergic function (e.g., felbamate E71]). Recently, the hypothesis that schizophrenia involves a disorder of EAA transmission has gained popularity [43] (see [38] for a review). The glutamate hypothesis suggests that schizophrenia is associated with a decrease in glutamate concentrations in the CNS [43]. There are various lines of evidence which are consistent with this hypothesis: in some studies, a decrease in glutamate concentrations has been found in the cerebrospinal fluid of schizophrenics (e.g., [43]; see [36] for a recent review); post-mortem analyses of the brains of schizophenics
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have revealed increases in the number of EAA receptor subtypes in some areas, which may be a compensatory response to reduced glutamate levels (e.g., [ 13]; see [36] for a recent review); recent studies suggest that the number of strychnine-insensitive glycine binding sites associated with NMDA receptors is also increased in some cortical areas [36]. If both epilepsy and psychosis were associated with increased NMDA receptor function, then NMDA receptor-induced excitotoxicity might account for neuronal loss in both conditions; in this case, a kindling process might explain how chronic seizures ultimately lead to psychosis. However, there are a number of problems with this simple hypothesis given the available data. First, if schizophrenia is associated with reduced glutamate concentrations, the functional effect of the up-regulation of NMDA receptors is unclear. Second, phencyclidine, a non-competitive NMDA receptor/channel antagonist, induces a psychosis similar to schizophrenia in humans, which is consistent with the hypothesis that reduced NMDA receptor function may contribute to psychosis (see [40] for a review). The evaluation of the glutamate hypothesis of schizophrenia is still at a very early stage. However, given that EAA receptor abnormalities appear to occur in both epilepsy and schizophrenia, further research on the possible connection between EAA receptor dysfunction in epilepsy and psychosis is warranted.
5. Conclusions Overall, the evidence in favour of a causal relationship between kindling and the development of psychosis in epilepsy is not compelling. As an explanation of the high frequency of psychosis within epileptic populations, the kindling hypothesis remains to be adequately tested. The hypothesis that a reduction in GABAergic inhibition is at least partially responsible for the development of epileptiform activity remains popular (see [39] for a review). Likewise, many studies suggest that hyperexcitability may be partially mediated by NMDA receptors (e.g., [57]; see [39] for a review). Although these hypotheses do not provide any clear insight into how psychosis may arise from epileptiform activity, it is likely that chronic hyperexcitability leads to the structural brain damage observed in temporal lobe epilepsy, possibly through excitotoxicity (see [39] for a review). Psychosis may develop as the seizures become more generalized and the brain damage more widespread and severe [I0]. Some researchers have speculated that psychosis may develop as a result of a disruption of normal interhemispheric communication at both the forebrain and brainstem levels (e.g., see [14-1 for a review). Therefore, a further possibility is that, in some cases, specific types of focal seizure activity and perhaps associated cell death, result in a major disruption to the normal neural
competition between the two hemispheres, thus leading to psychosis [ 14].
Acknowledgment We thank Annabelle Jerram for her assistance and Dr. David Bilkey, Dr. Harry McConnell and Dr. Darrin Gilchrist for their critical comments on the manuscript. We would also like to thank two anonymous referees for their helpful comments. This research was supported by a Project Grant from the Health Research Council of New Zealand (to PS and CD).
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