Limbic kindling and animal behavior--implications for human psychopathology associated with complex partial seizures.

The latest thinking concerning the neural mechanisms of limbic kindling is briefly reviewed. It is proposed that three types of lasting neural changes accompany the increases in epileptogenicity resulting from repetitive electrical stimulation of the limbic system in animals. Two of these, long-lasting synaptic potentiation and increased susceptibility to failure, under high drive, of neurotransmitter systems antagonistic to seizure expression, are proposed to underly the lasting interictally maintained changes in species-characteristic behavior in animals. It is proposed that similar processes may occur in some humans afflicted with complex partial epilepsy, and that these processes could explain the paradoxical relationship between seizures and psychopathology.

Analysis of facial displays and verbal report to assess subjective state in the non-invasive detection of limbic system activation by procaine hydrochloride.

The problem of scalp EEG as a measure of cortical or subcortical activity is particularly relevant to complex partial seizures as the abnormal discharging is frequently limbic in origin [14, 30]. Livingston [38] has suggested that administration of intravenous procaine as a limbic activator and cortical suppressor would be of utility in diagnosing limbic involvement in complex partial seizures. While there is considerable evidence derived from experimental animal models that procaine hydrochloride is a limbic system activator that acts preferentially on subcortical epileptic foci at lower doses than on less active epileptic foci or non-epileptic tissue [2, 4], it was necessary to demonstrate that procaine activates the human limbic system. The non-invasive approach taken in the present study was to compare the published effects of direct electrical stimulation of the human limbic system [31] to the behavioural and subjects effects of intravenous procaine administration. The areas in which we obtained the most robust procaine effects (hallucinations, emotions and alimentary sensations) were also Halgren et al.'s [31] most repeatable effects. The correspondence between electrical stimulation effects and procaine administration effects was striking - with verbal report by patients matching exactly in many instances. Furthermore, analysis of facial displays proved useful in providing access to subjects state fluctuations which would otherwise have gone undetected. The data provide strong evidence that procaine hydrochloride can be used as a human limbic system activator. Future research will investigate the clinical and diagnostic significance of differential response to procaine.

The effects of procaine HCl on population cellular and evoked response activity within the limbic system of the cat. Evidence for differential excitatory action of procaine in a variety of limbic circuits.

1. The effects of intravenous injections of procaine HCl on population cellular activity in limbic tissue and overlying cortex, and on transmission of evoked activity between limbic structures was investigated in awake cats. Clear dose-related increases in cellular activity were seen in amygdala and ventral hippocampus. Changes in cellular activity in the nucleus accumbens and temporal neocortex were also dose-related, but in a complex time-dependent manner. Changes in ventromedial hypothalamus only appeared at the second highest dose of procaine. 2. Procaine facilitated transmission of evoked excitatory activity from the amygdala to the ventromedial hypothalamus, but only after a considerable delay from the time of injection. On the other hand, procaine had no effect on activity evoked in the ventral hippocampus, nucleus accumbens or temporal cortex by amygdala stimulation. 3. It was concluded that intravenous procaine functions as an excitant of limbic system cells, and that procaine alters synaptic transmission in some, but not all, output pathways from the amygdala. The neuroexcitant effects of procaine appear to be idiosyncratic, however, varying over dose with limbic and cortical area examined.

Limbic control of aggression in the cat.

Over a decade of work by Flynn and colleagues has delineated a network of limbic circuits which function to modulate the expression of predatory aggression and defence in the cat, and aspects of this work are reviewed. In particular, Flynn's work revealed a circuit involving the basomedial amygdala which functions to suppress attack, and at the same time facilitates defence. A second circuit, involving the ventral hippocampus, is involved in attack facilitation. Studies relating stable differences in excitability in these two circuits to developmentally determined behavioural dispositions toward aggression or defence are summarized. Finally, the impact of experimentally induced limbic seizures on interictally maintained expression of aggression and defence behaviourally, and on limbic excitability are reviewed. Taken together, the data indicate that the behavioural balance of attack and defence is under the tonic control of opponent limbic circuits, which are themselves biased in a measureable manner. Developmental studies indicate that adult defensiveness is determined early in life, so early as to suggest some pre-programmed neuro-developmental process. Experimentally induced seizures alter behaviour lastingly, producing an increase in defensive disposition. At the same time there is an equally lasting potentiation of interictal transmission of neural activity from the amygdala to the hypothalamus. Moreover, seizures may reduce interictal transmission of activity through the ventral hippocampus by potentiating recurrent inhibition. These effects of seizures are of interest since seizures reproduce naturally occurring differences in limbic excitability seen in naturally defensive cats.

Basic science and clinical aspects of procaine HCl as a limbic system excitant.

The literature in animals and humans which indicate that systemic procaine HCl activates limbic tissue is reviewed. Studies in cats which suggest that procaine excites limbic cells by reducing neural inhibition are then described. Evidence that power spectral analysis of high frequency EEG bands (omega or 31-55 cps) in the temporal cortical EEG reflects degree of limbic (amygdala) excitation in animals and humans is reviewed. Studies in cats are described which show that procaine selectively increases omega band activity in the amygdala and temporal cortex in a dose related fashion which parallels dose related increases in amygdaloid neural activity. Preliminary results of combining intravenous procaine and omega band analysis of scalp EEG in humans to predict therapeutic response to carbamazepine in borderline personality and affective disorder patients are then described. The effects of procaine on omega are compared to the effects of direct electrical stimulation of human limbic system in complex partial seizure patients undergoing assessment for temporal lobectomy. The results tentatively support the hypothesis that some psychiatric patients have hyperexcitable limbic systems, and those that do, show a positive behavioural response to carbamazepine.

Partial kindling and emotional bias in the cat: lasting aftereffects of partial kindling of the ventral hippocampus. II. Physiological changes.

The first study revealed that evocation of repeated afterdischarges (ADs) in the perforant path-dentate system of the ventral hippocampus of cats induced a lasting increase in defensive sensitivity to species-characteristic threats. This study examined interictally maintained changes in physiological properties of two limbic pathways which covaried with the behavioral changes. It was found that ADs which spread to the amygdala and ventromedial hypothalamus induced a lasting (30-60 days) increase in evoked transmission of excitatory activity from the amygdala to the ventromedial hypothalamus. This change is consistent with the role of the amygdalo-hypothalamic pathway in defensive behavior in the cat. Lasting increases in the EPSP component of the dentate field potential induced by perforant path stimulation were found, as well. Countering this increase in hippocampal excitability were long-lasting increases in recurrent inhibition. The increase in recurrent inhibition in the hippocampus was interpreted to mean that the ability of the hippocampus to transmit neural activity at high rates was lastingly impaired. This finding is also consistent with the proposed role of the ventral hippocampus in modulating predatory aggression and defense. It was concluded that interictally maintained changes in defensiveness were dependent on a form of lasting synaptic potentiation of excitatory activity from the amygdala to the ventromedial hypothalamus, and an equally lasting attenuation of function due to increased recurrent inhibition in the ventral hippocampus.

Partial kindling and emotional bias in the cat: lasting aftereffects of partial kindling of the ventral hippocampus. I. Behavioral changes.

Repeated electrical evocation of afterdischarges in the perforant-path ventral hippocampal system of the cat produces lasting changes in species characteristic behavioral responses to environmental threat. After 7 to 12 afterdischarges, cats showed greatly enhanced defensive (withdrawal) responses to rats, and mildly enhanced defensive responses toward mice. Measures of predatory attack which negatively correlate with withdrawal from rats were also changed in a direction consistent with the increase in withdrawal tendency. There was little effect of afterdischarges on the same parameters of attack on mice. Thus the stimulation seemed to attenuate predatory aggression by increasing defensive sensitivity to the threat posed by prey self-defense, and not by reducing predatory motivation per se. The change in defensiveness was not restricted to the predatory test situation, however. Tests of defensive response to conspecific threat vocalizations revealed an increased defensive responding to this stimulus as well. On the other hand, there was no change in social responsiveness shown toward a highly familiar human. Given the sudden onset (1 hr to 24 hr after the last afterdischarge), the long-lasting nature of the change (30-60 days) which persisted in the absence of seizures, and the generality of expression of the behavioral change, it was concluded that the afterdischarges produced an interictally maintained alteration in a defensive personality characteristic of the cats.

The subjective marijuana experience: great expectations.

Participants' expectations of marijuana effects are frequently cited as unmeasured post hoc explanations of variability in response to the drug, or of the data which fail to conform to the experimenters' expectations of the drug's effects. Twenty-four male volunteers, experienced in the use of marijuana, participated in research involving the administration of coltsfoot, placebo, and marijauna to investigate whether expectancy of marijuana effects could be measured and related to observed effects. Data for the Expectancy Questionnaire were derived from the Marihuana Effects Questions filled out when potential participants volunteered for the study and were compared to the High Questionnaire filled out after drug administration sessions. Expectancy was shown to have a quantifiable effect on the drug experience (both placebo and marijuana), even in an experimental situation. Prior frequency of occurrence of specific effects was positively related to both the intensity and duration of the effects in the laboratory. The data are discussed in terms of the learned components in getting stoned, and in terms of the social nature of cannabis intoxication.

Power spectral analysis of EEG drug response in the kindled rat brain.

The specificity of procaine as a limbic epileptic focus activator was investigated in rats kindled in the amygdala. Power spectral analysis of spontaneous EEG was employed to assess the effects of two doses of procaine HCl (60 and 100 mg/kg) on the kindled and unkindled amygdala. Analysis revealed a dose-dependent increase in power in the 1--15 c/sec frequency band of the EEG. Power increases were greater in the kindled than in the unkindled amygdala of the same rat, and exceeded power changes induced in unkindled controls. The effects of procaine on the EEG persisted past the day of injection, but returned to baseline by the fifth day. Changes in power over days following an injection of procaine differed in the kindled and unkindled amygdala amygdala of the same rat. The kindled amygdala showed an increase on the day of injection, followed by a steady decline to baseline. The unkindled amygdala showed a delayed rise in power on day 2 and then a decline to baseline levels over days. Comparison of spectral changes induced by drug and by electrically triggered seizures suggested that procaine induces EEG patterns which are seizure-like in the absence of seizures. The data are consistent with the view that procaine may be a useful focus specific activator in the detection of limbic epilepsy.