Janice R. Stevens

Kindling of the mesolimbic dopamine system Animal model of psychosis

In order to examine the behavioral and physiologic consequences of chronic activation of the mesolimbic dopamine system, the nucleus of origin in the ventral tegmental area was stimulated electrically for 2 seconds daily through chronically implanted intracranial electrodes in cats at the same point where instillation of the GABA blocking agent bicuculline induced a characteristic fear, staring, searching, and withdrawal response. None of the animals developed sustained after-discharge or seizures following daily stimulation for 2 months. Progressive fearfulness, hiding, loss of social behavior, and EEG spike or slow activity in the ipsilateral nucleus accumbens developed in three of six intact animals. Two cats with prior 6-hydroxydopamine lesions of catecholamine pathways did not develop behavioral change in response to local bicuculline or daily electrical stimulation of the ventral tegmental area but demonstrated pronounced after-discharge or EEG spike propagation during the kindling procedure.

Epilepsy, psychosis, and schizophrenia Clinical and neuropathologic correlations

This study examines the relationship between epilepsy and psychosis. It compares clinical, EEG, and neuropathologic data from a group of subjects who had both epilepsy and psychosis with similar information from another group of patients who had epilepsy but no evidence of psychotic illness. We examined, blind to clinical diagnosis, gross and microscopic material from whole-brain specimens from 10 patients diagnosed with epilepsy plus schizophrenia-like psychosis, nine subjects diagnosed with epilepsy plus “epileptic psychosis,” and 36 individuals with epilepsy (21 from an epileptic colony and 15 from the community at large) who had no history of psychosis (n = 10 + 9 + 21 + 15 = 55). We abstracted case histories without knowledge of pathologic findings. Epileptic colony patients had an earlier age at onset of seizures, while epileptic colony and epileptic psychosis patients had more frequent seizures. Epileptic individuals in the community died at a younger age than did epileptic patients in long-stay hospital care. Psychotic epileptic patients had larger cerebral ventricles, excess periventricular gliosis, and more focal cerebral damage compared with epileptic patients who had no psychotic illness. Epileptic patients with schizophrenia-like psychosis were distinguished from all other groups by a significant excess of pinpoint perivascular white-matter softenings. We found that mesial temporal sclerosis and temporal lobe epilepsy occurred with equal frequency in the psychotic and nonpsychotic groups; generalized seizures occurred more frequently in the psychotic epileptics and the epileptic colony epileptics than in the community epileptic controls.

Ultradian characteristics of spontaneous seizures discharges recorded by radio telemetry in man

Abstract Twenty-four hour EEG records were recorded by radiotelemetry during free behavior from five patients with seizures for a total of 18 days and nights. Quantitative measurements of duration of epileptiform bursts, frank seizures and inter-spike and inter-seizure intervals were made from magnetic tape and ink polygraph records. Total consecutive spikes per 4 min over 24 h were enumerated automatically by a specially designed spike recognition unit. Proportional relationships were demonstrated between seizure length and pre- and post-seizure intervals. A broad or quasi normal distribution was found for diurnal seizure and interval durations in contrast to a random (Poisson) distribution for corresponding nocturnal ictal events. A relatively constant inter-ictal spike rate, interrupted every 80 to 120 min was shown for most patients during both day and night. Nocturnally, the period of spike interruption coincided with rapid eye movement (REM) sleep, and spike recurrence with slow wave sleep. A tendency for clinical ictus to occur in relation to the REM periods was apparent.

Temporal lobe epilepsy, psychopathology, and violence: the state of the evidence.

Several recent reports reaffirm the widespread impression that temporal lobe epilepsy (TLE) is frequently accompanied by psychopathology, violence, or a variety of unpleasant personality traits. However, in most of these studies, appropriate control populations were not used and the specificity of TLE in predisposing to these characteristics was not considered. When appropriate controls are employed, damage or dysfunction in the basal forebrain rather than TLE per se appears to be a significant factor in predisposing to psychopathology associated with epilepsy.

Habituation of the alpha attenuation response in children and adults with psychiatric disorders

Abstract Duration and latency of the alpha attenuation response (AAR) to 50 consecutive single light flashes presented at irregular intervals of 5–20 sec were measured in 241 adults and children, comprising five experimental and four control groups. Visual and automatic analyses were employed. Habituation of AAR duration was demonstrable for all of the adult and children groups. Schizophrenics from the University Psychiatric Service did not differ from Medical School controls, but State Hospital schizophrenics differed from both these groups demonstrating earlier attenuation (shorter latency) and more persistent response (less habituation). Adult psychopaths did not differ from Medical School patient controls. Medical School Hospital schizophrenics manifested significantly shorter latencies than adult controls. Children with hyperkinetic behavior disorders demonstrated longer durations of AAR initially and throughout the consecutive trials compared with age-matched controls. Although habituation was evident, AAR duration never decreased to a level comparable to the controlschildren. Normal children differ from adult controls in demonstrating shorter latencies of AAR as well as a much flatter habituation curve (i.e., less change between initial and final values). Comparison of amount of alpha activity for 3 sec preceding each stimulus indicated that the significant differences obtained between the groups were not due to differences or variations in background activity. The findings are considered in relation to their maturational and clinical significance.

Eye blinking and rapid eye movement: Pulsed photic stimulation of the brain

Abstract Abnormalities of blinking observed in patients with parkinsonism and schizophrenia led to this examination of spontaneous blinking in a number of mammalian species. Spontaneous blink rate, like the duration of rapid eye movement (REM) sleep, is relatively constant for each individual and species. Significantly higher blink rates were found in diurnally active animals than in nocturnal species. In contrast, REM durations are significantly longer in nocturnally active mammals. This observation led to the hypothesis that blinking during waking and REM during sleep may both serve to periodically excite the visual pathway. This hypothesis was tested by recording multipleunit activity and evoked potentials elicited by blinking and REMs in day-light and darkness from cats bearing chronically implanted electrodes in visual cortex and subcortical nuclei of the visual pathway. Both blinking and REMs evoked light-modulated potentials in the primary visual pathway and in the suprachiasmatic nucleus and medial terminal nucleus of the accessory optic tract, regions which have been implicated in photic regulation of biological rhythms.

Endogenous conditioning to abnormal cerebral electrical transients in man.

Ten subjects with epilepsy were trained to press a lever to avoid a mildly painful shock each time paroxysmal epileptiform activity occurred in their own electroencephalogram. All subjects learned to avoid the shock as long as they could hear the electroencephalogram and respond to the characteristic change in sound accompanying each spike-wave burst. When the audio component of the electroencephalogram was eliminated, only one subject was able to respond to the purely subjective effect of his own paroxysmal activity.

Electroencephalographic studies of conditional cerebral response in epileptic subjects.

Abstract Classical conditioning techniques were employed to investigate the effect of conditioned “excitation” and “inhibition” upon the occurrence of epileptiform activity in the EEG of patients with convulsive disorders. Four patients with high voltage spike-wave response regularly elicited by photic stimulation were subjected to repeated pairing of the S-W inducing light with a neutral tone. Despite more than 500 paired presentations of the two signals, and persistence of the S-W response to the light, no evidence of conditioning the S-W to follow the tone was obtained. However, presentation of tone signals unreinforced by light (differential stimulus and extinction of CS) after numerous paired sound-light trials resulted in a highly significant increase in occurrence of S-W to the unreinforced stimuli. Nineteen epileptic patients with sustained photic driving responses to specific flash frequencies were subjected to a conditioning procedure in which the attempt was made to condition the occipital driving response to follow a previously neutral tone. Little evidence of conditioned driving was obtained. However, again the unreinforced signals (differential and extinction stimuli) provoked a significant increase in incidence of sharp, paroxysmal, slow and epileptiform changes in the EEG. Retardation of the light stimulus (Trace reflex) also enhanced the propensity to pathological EEG discharge in both groups. These EEG abnormalities were similar to the focal or diffuse pathological findings noted from these patients during previous EEG studies. The exaggeration of paroxysmal activity by unreinforced stimuli is considered in relation to theories of “conditioned expectation” and Pavlovian “conditional inhibition”. Slowing of scalp frequencies during non-reinforcement may be a crucial factor contributing to the potentiation of abnormal EEG patterns.

Endogenous spike discharges as conditioned stimuli in man

Abstract Focal high voltage spike or wave-spike complexes recorded from scalp or intracranial sites in patients with epilepsy between frank epileptic attacks are typically unassociated with either objective or subjective clinical change. Even bilaterally synchronous discharges, when of relatively brief duration, pass without the least evidence to subject or observer. To determine whether these abnormal discharges affect subject state or behavior, we have employed a Pavlovian conditioning paradigm in which the spontaneously arising pathological cerebral electrical activity serves as the conditioning stimulus followed by a noxious stimulus. Eighteen patients with repeated discrete focal or diffuse spike discharges received from 40 to 180 “reinforcements” with cutaneous shock, bright flickered light or unpleasant sound stimulus following consecutive spike bursts. Test trials were interspersed with reinforced trials. Key depression, skeletal muscle activity and several autonomic variables were recorded throughout. Changes in these functions with respect to epileptiform paroxysms were determined before, during and after conditioning. Controls for sensitization and progressive change in physiological state during each experiment were incorporated. All subjects demonstrated well-developed unconditioned skeletal and/or autonomic responses. One subject developed a transient avoidance response to his own right temporal spike discharge. Five patients developed change in cardiac or respiratory rate with spontaneous spike discharges following conditioning. It is concluded that spontaneous epileptiform EEG transients have little influence upon ongoing behavior or subjective state and can be conditioned to act as internal signals only with great difficulty. The findings are contrasted with results of central conditioning studies utilizing an external source for cerebral stimulation and possible clinical implications are considered.

Psychomotor Epilepsy and Schizophrenia: A Common Anatomy?*

Publisher Summary This chapter focuses on psychomotor epilepsy and schizophrenia. The contrasting distribution of dopamine and norepinephrine terminals to striatum and cortex, and the relative influence of neuroleptic agents on these monoamines, on psychotic symptoms, and on convulsive threshold shows that the limbic striatum, which receives input from limbic cortex, amygdala, and hippocampus, serves a gating function for impulses arising in these structures similar to those that can obtain for caudate-putamen for pathways converging thereon from neocortex. Disturbance in this function, related to faulty production of, or inactivation of, local monamines in limbic striatum, can influence the threshold for transmission of peculiarly limbic affective, interpretative, and behavioral patterns transmitted by predominantly cholinergic pathways from cortical structures to final common paths in consciousness and behavior. The epileptogenic effect of neuroleptic agents is maximum in the weakest antipsychotic neuroleptics. Although both psychomotor seizures and schizophrenia share a similar clinical phenomenology of altered affect, distorted percepts, and stereotyped behaviors, which can originate in or be interpreted through limbic and temporal structures, the two disorders are derangements of separate anatomical and biochemical systems.