Merilyne Waldo

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.

Smoking and mental illness.

Patients with mental illness have a higher incidence of smoking than the general population and are the major consumers of tobacco products. This population includes subjects with schizophrenia, manic depression, depression, posttraumatic stress disorder (PTSD), attention-deficit disorder (ADD), and several other less common diseases. Smoking cessation treatment in this group of patients is difficult, often leading to profound depression. Several recent findings suggest that increased smoking in the mentally ill may have an underlying biological etiology. The mental illness schizophrenia has been most thoroughly studied in this regard. Nicotine administration normalizes several sensory-processing deficits seen in this disease. Animal models of sensory deficits have been used to identify specific nicotinic receptor subunits that are involved in these brain pathways, indicating that the alpha 7 nicotinic receptor subunit may play a role. Genetic linkage in schizophrenic families also supports a role for the alpha 7 subunit with linkage at the alpha 7 locus on chromosome 15. Bipolar disorder has some phenotypes in common with schizophrenia and also exhibits genetic linkage to the alpha 7 locus, suggesting that these two disorders may share a gene defect. The alpha 7 receptor is decreased in expression in schizophrenia. [(3)H]-Nicotine binding studies in postmortem brain indicate that high-affinity nicotinic receptors may also be affected in schizophrenia.

Schizophrenia and nicotinic receptors

&NA; Patients with schizophrenia often cannot respond to important features of their environment and filter out irrelevant stimuli. This dysfunction could be related to an underlying defect in inhibition‐i.e., the brains ability to alter its sensitivity to repeated stimuli. One of the neuronal mechanisms responsible for such inhibitory gating involves the activation of cholinergic nicotinic receptors in the hippocampus. These receptors are diminished in many specimens of hippocampal brain tissue obtained postmortem from schizophrenic patients. In living schizophrenic patients, stimulation of cholinergic receptors by nicotine transiently restores inhibitory gating of evoked responses to sensory stimuli. Many people with schizophrenia are heavy smokers, but the properties of the nicotinic receptor favor only short‐term activation, which may explain why cigarette smoking is only a transient symptomatic remedy. This paper reviews the clinical phenomenology of inhibitory gating deficits in people with schizophrenia, the neurobiology of such gating mechanisms, and the evidence that some individuals with the disorder may have a heritable deficit in the nicotinic cholinergic receptors involved in this neurobiological function. Inhibitory gating deficits are only partly normalized by neuroleptic drugs and are thus a target for new therapeutic strategies for schizophrenia.

Elementary neuronal dysfunctions in schizophrenia

This paper describes an elementary deficit in sensory processing in people with schizophrenia. If paired sounds are presented to normal subjects, the response to the first sound, as measured by the P50 wave of the auditory-evoked potential, is much greater than the response to the second sound. The diminished response to the second sound is an example of a sensory gating mechanism that enables people to regulate their vigilance so that they can either detect all sounds in the environment or ignore most of them, in favor of narrowing the focus of their concentration. In schizophrenia, this mechanism is usually deficient; patients are in a state of hypervigilance and have diminished abilities to focus their attention. The deficiency appears to be genetically determined and to involve the brainstem control of sensory input to the hippocampus. Such sensory gating deficits may underlie more complex psychotic symptoms, such as hallucinations and delusions. Further studies of their neurobiology could lead to increased understanding of the pathophysiology of schizophrenia.

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.

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.

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.

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 assessment of sensory gating in psychiatric inpatients: Comparison between schizophrenia and other diagnoses

Gating of auditory sensory responsiveness was examined in 75 psychiatric inpatients using a conditioning-testing paradigm with the P50 wave of the auditory evoked response, in which pairs of stimuli are presented to the subject. In previous studies, most schizophrenics did not decrement the second response to the extent seen in normals. Acutely ill patients, who were representative of patients admitted to a public university teaching service and a proprietary hospital, were used to examine the extent to which diminished sensory gating is found in diagnoses other than schizophrenia. About half of these patients showed diminished sensory gating that correlated with measures of severity of illness. The data, taken together with that from other studies using this paradigm, suggest that diminished sensory gating, like several other psychophysiological abnormalities, is a trait deficit in schizophrenia, but a state deficit in many other mental illnesses.

Sensory gating deficits in psychiatric impatients: Relation to catecholamine metabolites in different diagnostic groups

Acutely ill psychiatric inpatients were examined for a deficit in sensory gating, measured as failure to suppress the P50 wave of the auditory-evoked response to the second of paired stimuli. Previously, we had found that in mania, this sensory gating deficit is correlated with increased plasma-free levels of the noradrenergic metabolite 3-methoxy, 4-hydroxyphenylglycol (pMHPG), whereas in schizophrenia, there is no correlation with catecholamine metabolism. To assess the generalizability of these findings, we examined inpatients with a broader range of diagnoses, including those with multiple DSM III-R Axis I, II, and III diagnoses. The patients were grouped into three diagnostic spectra for analysis: schizophrenic, manic, and depressive. In the schizophrenic patients, there was no relationship between pMHPG or other catecholamine metabolites and the sensory gating deficit. In manic patients, however, a positive correlation between pMHPG level and the sensory gating deficit was again observed. This relationship did not extend to the depressive patients, who uniquely showed sensory gating deficits that correlated negatively with the severity of their illness. The data suggest that sensory gating deficits are common to these three diagnostic spectra, but the deficits in each group have different relationships to catecholamine metabolism and symptom severity that may reflect differences in the underlying neuronal pathophysiology of these illnesses.