Familial transmission of risk factors in the first-degree relatives of schizophrenic people.

Schizophrenia is a complex illness with multiple pathophysiologic factors that contribute to its psychopathology. One strategy to identify these factors is to observe them in isolation from each other, by characterizing their expression in the relatives of schizophrenic probands. By Mendel's second law, each genetic factor should be independently distributed in a sibship, so that each can be observed by itself, uncomplicated by the general problems of the illness. Such independently distributed phenotypes are obviously useful for genetic analyses; however, they can also be considered together, to model how various brain dysfunctions may combine to produce psychoses. In addition to a sensory gating deficit linked to the alpha 7-nicotinic acetylcholine receptor locus, schizophrenics and their families have a number of other deficits, including decreased hippocampal volume on magnetic resonance images and increased plasma levels of the dopamine metabolite homovanillic acid. Although such research is far from complete, a heuristic model combining a sensory gating deficit, decreased hippocampal neuron capacity, and increased dopaminergic neurotransmission is consonant with current understanding of the neuropsychology of schizophrenia.

Co-distribution of sensory gating and impaired niacin flush response in the parents of schizophrenics.

Complex illnesses may result from the interaction or addition of multiple factors. We examined the familial co-distribution of two abnormalities common in schizophrenia: impaired auditory sensory gating and impaired flush response to niacin. In ten families, the obligate carrier parent had sensory-gating deficits, while eight of the ten parents without a family history of schizophrenia had impaired flush response. No parents had both deficits. The data are consistent with a theory suggesting the interaction of these two factors in some cases of schizophrenia.

Elementary phenotypes in the neurobiological and genetic study of schizophrenia.

This review describes the strategy of using elementary phenotypes for neurobiological and genetic linkage studies of schizophrenia. The review concentrates on practical aspects of selecting the phenotype and then understanding the confounds in its measurement and interpretation. Examples from the authors' studies of deficits in P50 inhibition and smooth pursuit eye movement dysfunction are presented. These two phenotypes share considerable similarity in their neurobiology, including a similar response to nicotine. They also appear to co-segregate with the genetic risk for schizophrenia as autosomal co-dominant phenotypes. Although most schizophrenic patients inherit these abnormalities unilinealy, i.e., from one parent, apparent bilineal inheritance produces a more severe illness, observed clinically as childhood-onset schizophrenia. The initial study showing linkage of the P50 deficit to the chromosome 15q14 locus of the alpha 7-nicotinic acetylcholine receptor is an example of the potential usefulness of these phenotypes for combined genetic and neurobiological study of schizophrenia.

Schizophrenia in Kosrae, Micronesia: prevalence, gender ratios, and clinical symptomatology.

The utility of genetic isolates for research is in part based on the assumption that the illness of interest is similar across cultures. In this report, we review the data on schizophrenia in Micronesia, a collection of small islands in the western Pacific Ocean. Significant variations in prevalence between the islands have been reported, as have male to female ratios which are strikingly high. We focus on the patients in Kosrae, one of the islands in the Federated States of Micronesia. Twenty-two schizophrenics are identified. We found a prevalence rate of 6.8 per 1000 and a male to female ratio of 6.3:1. Although, in many ways, the patients resemble their Western counterparts, 19 of the patients were episodically mute, especially when untreated or undermedicated. Possible explanations for this unusual symptom are discussed.

Neurobiological abnormalities in the relatives of schizophrenics.

The inheritance of a complex illness such as schizophrenia likely involves the segregation of genetic factors, in combination with non-genetic or environmental abnormalities. This paper reviews several family studies of biological and clinical aspects of schizophrenia, that have attempted to observe such segregation in relationship to family history of schizophrenia to identify which factors appear to be related to the transmission of genetic risk.

Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus.

Inheritance of a defect in a neuronal mechanism that regulates response to auditory stimuli was studied in nine families with multiple cases of schizophrenia. The defect, a decrease in the normal inhibition of the P50 auditory-evoked response to the second of paired stimuli, is associated with attentional disturbances in schizophrenia. Decreased P50 inhibition occurs not only in most schizophrenics, but also in many of their nonschizophrenic relatives, in a distribution consistent with inherited vulnerability for the illness. Neurobiological investigations in both humans and animal models indicated that decreased function of the alpha 7-nicotinic cholinergic receptor could underlie the physiological defect. In the present study, a genome-wide linkage analysis, assuming autosomal dominant transmission, showed that the defect is linked [maximum logarithm of the odds (lod) score = 5.3 with zero recombination] to a dinucleotide polymorphism at chromosome 15q13-14, the site of the alpha 7-nicotinic receptor. Despite many schizophrenics' extremely heavy nicotine use, nicotinic receptors were not previously thought to be involved in schizophrenia. The linkage data thus provide unique new evidence that the alpha 7-nicotinic receptor gene may be responsible for the inheritance of a pathophysiological aspect of the illness.

Yohimbine impairs P50 auditory sensory gating in normal subjects.

The evoked response to repeated auditory stimuli generally decreases in amplitude, a phenomenon that demonstrates the activity of sensory gating mechanisms in the central nervous system (CNS). Gating of the P50 wave of the auditory evoked response shows such behavior in normals, but not in schizophrenic or manic subjects. In mania, diminished gating of the auditory evoked response is correlated with elevated levels of noradrenergic metabolites. In animals, yohimbine, a presynaptic alpha-2 antagonist, increases noradrenergic neuronal transmission in the CNS and diminished gating of the auditory evoked response. The aim of this experiment was to test whether yohimbine causes diminished auditory sensory gating in normal human controls. Seven normal subjects with normal P50 auditory gating were treated either with 0.4 mg/kg of oral yohimbine on one day or placebo on a different day. Each subject acted as his own control. Yohimbine, but not placebo, caused a significant but transient decrease in P50 auditory gating in these subjects. Thus, increasing CNS noradrenergic neuronal transmission in normal controls can cause a transient impairment in auditory sensory gating.

Auditory sensory gating, hippocampal volume, and catecholamine metabolism in schizophrenics and their siblings.

Schizophrenia may result from the concerted action of several pathophysiological factors. This pilot study compared the distribution of measurements of three such putative factors in 11 schizophrenics and their siblings: a neurophysiological deficit in auditory sensory gating, diminished hippocampal volume, and increased catecholamine metabolism. Abnormal auditory sensory gating was found in all schizophrenics in the 11 families studied and in 8 of their 20 siblings. Compared with the schizophrenics, the clinically unaffected siblings with abnormal auditory gating had larger hippocampal volume. There was no similar difference for the siblings with normal gating. The siblings with abnormal auditory gating also had lower homovanillic acid levels than the other siblings. The data suggest that a familial neuronal deficit, identified by diminished sensory gating, may be a necessary, but not sufficient factor in the pathogenesis of schizophrenia. Individuals with this deficit are generally clinically unaffected, except for schizophrenics, who also have other abnormalities, such as diminished hippocampal volume and increased catecholamine metabolism.

Neurophysiological and neuropsychological evidence for attentional dysfunction in schizophrenia.

The behavior of the P50 wave of the auditory evoked potential in a paired stimulus or conditioning-testing paradigm has been used as a measure of sensory gating disturbance in schizophrenia. Schizophrenics fail to decrement the P50 response to the second stimulus of the pair, so that the ratio of the test to the conditioning amplitude is elevated over normal values. The aim of this study was to compare this neurophysiological measure to neuropsychological measures of attention and memory. As expected, schizophrenics performed worse than controls on most measures. The time to complete a digit cancellation test, a measure of sustained attention, was found to be particularly longer in schizophrenics than in control subjects. Furthermore, the increased time to complete this task correlated with the increased ratio of the amplitude of the test P50 response to the conditioning response in the schizophrenics. Thus, a neurophysiological defect in sensory gating may relate to a disorder in sustained attention in schizophrenia. Although the P50 wave may come from the hippocampus, neuropsychological measures of verbal learning and memory were not correlated with alterations in the P50 ratio.

Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics.

Diminished gating of the P50 auditory evoked response to repeated stimuli is a psychophysiological feature of schizophrenia, that is also present in many relatives of patients. Animal models of auditory sensory gating indicate that nicotinic cholinergic neurotransmission is a critical neuronal substrate. The aim of this experiment was to determine if the deficit in sensory gating could be reversed by nicotine administration. Nonsmoking relatives of schizophrenics with abnormal sensory gating were selected as subjects for this initial double-blind trial, to avoid effects of psychotropic medications that might complicate trials in schizophrenic patients themselves. Nicotine-containing gum increased P50 sensory gating to near normal levels within 30 min of administration. The effect was transient; the gating of P50 returned to baseline levels within 1 hr. There was no change observed after placebo administration. In one of the subjects, the anticholinesterase inhibitor physostigmine similarly normalized P50 gating. The results are consistent with the hypothesis that nicotinic cholinergic neurotransmission may mediate a familial psychophysiological deficit in schizophrenia.

Codistribution of a sensory gating deficit and schizophrenia in multi-affected families.

Because the clinical diagnosis of schizophrenia has not generally been an adequate phenotypic marker to detect the genes that convey risk for schizophrenia, efforts have been directed toward the identification of more elementary neuronal dysfunctions in schizophrenic patients and their families. Psychophysiological studies of sensory gating and selective attention suggest that defects in these brain functions are present in schizophrenic patients and some of their relatives. This study examines one of these defects in sensory gating, failure to suppress the P50 evoked response to repeated auditory stimuli. Six pedigrees, chosen because of the presence of large sibships containing several cases of schizophrenia, were studied. A mathematical model was developed to assess the familial association of the P50 defect with schizophrenia. The model preserves the quantitative nature of the data and is suitable for use in a sample with small numbers of pedigrees comprising many individuals. It is thus suitable for the evaluation of putative phenotypes in families to be studied by linkage analysis with polymorphic genetic markers. The results suggest that the P50 defect is familially associated with schizophrenia.

Counterpoint: a sensory gating--hippocampal model of schizophrenia.

We propose a model for schizophrenia that incorporates findings of impaired auditory sensory gating with a possible structural abnormality of the hippocampus. The deficit in auditory sensory gating would be a genetic schizotaxic factor, necessary in the development of schizophrenia but not sufficient by itself. Genetic or acquired hippocampal dysgenesis or frank damage in combination with the sensory gating deficit would be necessary to produce the full-blown syndrome. We review the relevant literature and reply to Dr. E. Fuller Torrey's hypothesis.

Gating of auditory response in schizophrenics and normal controls. Effects of recording site and stimulation interval on the P50 wave.

Auditory evoked potentials were recorded using a paired stimulus, conditioning-testing paradigm from 14 schizophrenic patients and 13 normal subjects with no family history of psychotic disorder. Previous studies of the vertex P50 wave using this paradigm have demonstrated a possible sensory gating deficit in schizophrenics, as shown by their failure to diminish the response to a test stimulus presented 500 ms after a conditioning stimulus. Recordings were made at Cz, Fz, C3, T3, C4, and T4, to compare effects at different recording sites with this paradigm. Schizophrenics had significantly poorer sensory gating than normals, with the most significant difference between the groups at Cz. In addition to the 500 ms interval, subjects were also recorded at a conditioning-testing interval of 100 ms. Most schizophrenics showed normal sensory gating at the 100 ms interval, despite their abnormalities at 500 ms. The results indicate that Cz is optimal recording site for this paradigm, and that gating abnormalities in schizophrenic subjects are limited to specific interstimulus intervals.

Lack of relationship of auditory gating defects to negative symptoms in schizophrenia.

The differences between schizophrenic patients with positive and negative symptoms have been the subject of extensive investigations. Psychophysiologists have proposed that there are elementary auditory sensory processing deficits in schizophrenia, but their prevalence in particular positive or negative subtypes has not been described. Our previous studies have shown that schizophrenics have impaired auditory sensory gating relative to normal controls, as demonstrated by the P50 auditory evoked potential conditioning-testing paradigm. In this paradigm, schizophrenics fail to show the normally expected diminished response to the second or 'test' stimulus. In the present study we assessed the possible relationship of this defect to negative symptoms in 20 schizophrenic patients treated with neuroleptics. Nine patients met the Andreasen criteria for predominantly 'negative schizophrenia'. 12 normal controls with no family history of schizophrenia were also studied electrophysiologically. Negative schizophrenics showed greater impairment than patients without such symptoms on the Trails B test of organic impairment, but there were no differences between groups on electrophysiological measurements of auditory sensory gating. Both schizophrenic groups showed impaired P50 auditory gating compared to normal controls. Both groups of schizophrenics also had a significantly diminished amplitude of the N100 waveform in the conditioning response, compared to normal controls. Auditory sensory processing defects in schizophrenia appear to be independent of negative symptoms.

Sensory gating in schizophrenics and normal controls: effects of changing stimulation interval.

Auditory evoked potentials were recorded using a paired click, conditioning-testing paradigm in 10 schizophrenics and in 10 normal subjects with no family history of psychotic disorder. The paradigm is used to demonstrate central nervous system gating of responsiveness to auditory stimuli by examining the extent to which the response to the conditioning stimulus diminishes the response to a test stimulus occurring a short time later. Recordings were made at conditioning-testing intervals of 500 msec, 150 msec, and 75 msec to determine subjects' gating of responsiveness to stimuli repeated at various intervals. The schizophrenics had conditioning-testing ratios indicative of poor gating of the auditory P50 wave at the 500-msec and 150-msec intervals, but most patients had good sensory gating at the 75-msec interval. Normal subjects showed good sensory gating at all three intervals. Results suggest that although sensory gating mechanisms responsible for changes in neuronal response at longer intervals are chronically defective in schizophrenics, other gating mechanisms functioning at shorter intervals appear to be intact and function well in most patients. The results may lead to increased specification of the neurobiological basis of sensory abnormalities in schizophrenia.

MAOI treatment response: multiaxial assessment.

While studying the effectiveness of the MAOI isocarboxazid for the treatment of depression, we noted that many patients experienced a reduction of symptoms without equivalent improvement in other areas of their lives. We evaluated four outcome areas: symptoms, work, family functioning and social functioning. After 6 weeks on medication, symptoms improved the most, significantly more so than the other three areas. For the group of patients who completed 24 weeks on medication, all four outcome areas were further improved compared to the 6-week levels, with the improvement in work functioning reaching statistical significance. We conclude that the assessment of treatment outcome is more complex than the simple measurement of symptom reduction, and that different outcome areas are likely to improve at different rates and to different extents.

Defects in auditory sensory gating and their apparent compensation in relatives of schizophrenics.

Auditory sensory processing is defective at several stages in schizophrenics, as revealed by electrophysiological recordings. The purpose of this study was to assess the relationship between two of these defects in schizophrenics and their relatives. One defect is illustrated by the failure to gate the P50 wave of the auditory evoked potential in the conditioning-testing paradigm. In this paradigm, paired clicks are presented to the subject. Normals suppress or gate the P50 response to the second or test click. Schizophrenics fail to suppress the test response. This defect has been related to schizophrenics' inability to filter out noise in their environment. A second defect is illustrated by schizophrenics' lower than normal N100 wave, which has been related to failure to attend to particular features of interest in the stimulus. The question addressed in this study was whether these two defects inevitably occur together. While they do occur together in schizophrenics, even in very good prognosis, mildly ill subjects, they do not occur together in the relatives of schizophrenics. The defect in the gating of P50 occurs in half these relatives, but N100 amplitudes are not diminished. Instead, relatives with abnormal P50 gating have N100 amplitudes which are larger than normal. One interpretation of the data is that the relatives with the sensory gating defect can compensate for that defect at a subsequent stage of information processing, as demonstrated by their large amplitude N100 wave, whereas schizophrenic patients cannot.

Premenstrual mood changes and gating of the auditory evoked potential.

To assess the effect of the menstrual cycle on a measure of brain physiology known to be affected in psychiatric illness, auditory-evoked electroencephalographic potentials were recorded from 12 women on the day prior to menstruation and nine days after the initiation of their cycle. Eight were normal college students, and four were patients in a premenstrual syndrome clinic. The women showed significant changes in self-ratings of mood between the two recordings. The P50 wave of the auditory-evoked response was evaluated in a conditioning-testing paradigm, in which stimuli were presented in pairs, allowing assessment of putative excitatory and inhibitory processes involved in the gating of central nervous system sensory responsiveness to auditory stimuli. The auditory-evoked potentials were unchanged between the two recording periods. There was also no difference between the women and age-matched male controls. The data suggest that these central nervous system functions are not responsive to hormonal fluxes in menstruation. Since inhibitory gating of the P50 wave is lost in the manic phase of manic-depressive illness, the data also suggest that premenstrual mood changes in normal women do not share electrophysiological properties of mania.