Neil Baker

Sensory Physiology and Catecholamines in Schizophrenia and Mania

Hypersensitivity to sensory stimulation is a prominent characteristic of both schizophrenia and mania. Neurophysiological recordings suggest a common deficit in a central neuronal sensory gating mechanism which regulates sensitivity to repeated auditory stimuli. Dopamine and norepinephrine are hypothesized to have major roles in these illnesses, but their role in aberrant sensory processing has not yet been proved. Presumptive evidence for effects of catecholamines on sensory processing comes from psychophysiological studies of normal subjects challenged with stimulants who show decreased sensory gating, and studies of psychotic patients treated with neuroleptics who show improved function. Studies of similar phenomena in animals show comparable effects of catecholamines on sensory processing, both behaviorally and at the single neuron level. In this study, gating of auditory evoked potentials (EPs) during treatment of both illnesses was compared with plasma dopamine and norepinephrine metabolites. Comparisons of medicated and unmedicated states showed that schizophrenic patients have a fixed deficit in sensory gating, which is a familial trait, unchanged by medication. During acute illness, they have an additional transient hypersensitivity to stimuli, manifested as smaller EPs, which seems to be mediated by dopamine. Manic patients have only the deficit in sensory gating, which is transient and seems to be mediated by norepinephrine. Thus, similar neurophysiological deficits in the two psychoses are associated with different biochemical abnormalities, which may explain similarities in acute symptoms and differences in other aspects of the illnesses, such as their response to treatment.

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.

Auditory sensory gating and catecholamine metabolism in schizophrenic and normal subjects

Diminished neuronal response to repeated sensory input is a sensory-gating phenomenon that has been found to be deficient in schizophrenic patients. For example, schizophrenic patients fail to decrease the amplitude of the P50 wave of the auditory evoked potential to the second of paired click stimuli. In some studies, however, normal subjects have also failed to decrease their P50 responses. The aim of this study was to determine if accommodation to the recording situation over time would affect the gating of the P50 response. The gating of the P50 wave is measured as the ratio of the amplitude of the second response to the amplitude of the first. Three successive auditory evoked potentials were compiled, each from trains of 32 pairs of stimuli. Twelve normal subjects and 12 schizophrenic patients were studied. Unconjugated catecholamine metabolites were measured from venous samples drawn before and after the electrophysiological recording. Between the first and third trials, the normal subjects significantly increased their gating of P50. This increase in gating of P50 was related to decreased levels of the noradrenergic metabolite 3-methoxy-4-hydroxyphenylglycol. No similar phenomenon was observed in the schizophrenic patients, a number of whom had a further decrease in P50 gating over the three trials. Transient failure to observe gating of P50 in normal subjects may be related to increased state-dependent noradrenergic activity, which is known to disrupt sensory gating. This mechanism does not seem to account for the more persistent failure of sensory gating in schizophrenia.

Reproducibility of the measurement of plasma noradrenergic and dopaminergic metabolites in normal subjects

The object of this study was to determine the reproducibility of the measurement of plasma catecholamine metabolites in normal control subjects and to assess the influence of factors such as time of day, diet, activity, blood pressure, and mood on the variance of these measures. Plasma free homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid (VMA) were simultaneously measured by high performance liquid chromatography with electrochemical detection. Samples were collected from 15 doctors and nurses at 8 a.m. and at noon on 2 separate days. After the fasting 8 a.m. sample, the subjects ate a regular hospital breakfast. Activity in their usual tasks on an inpatient psychiatric unit was monitored electronically by an activity meter. Levels of each metabolite were not significantly different between days at the respective assay times and were highly correlated for individuals. MHPG showed a significant increase from morning to noon, while HVA showed a significant decrease. Activity, dietary intake of tyrosine and tyramine, blood pressure, pulse, scores on the Profile of Mood States, age, and sex were not related to plasma levels. The results demonstrate that measures of dopamine and norepinephrine metabolites have significant reliability in normal subjects in a setting used for research studies with psychiatric patients.

Candidate for Inherited Neurobiological Dysfunction in Schizophrenia

Schizophrenia is a mental illness that affects approximately 1% of the population. It generally begins in early adulthood and continues as a chronic illness for the individuals lifetime. It is characterized by hallucinations, which are unreal sensory sensations such as hearing voices that converse about oneself, and by delusions, which are unreal beliefs. The delusions are often paranoid; e.g., one is being spied on by the police. These symptoms are called positive symptoms and may show fluctuation over time. The periods of exacerbation are called acute psychotic episodes. While they can be partly treated with tranquilizing medication, the effects are generally not complete. In addition, the patient suffers negative symptoms, so called because they are an absence of normal behavior, rather than a clearly abnormal behavior like the hallucinations and delusions. The most common negative behavior is social isolation or reclusiveness. The combination of negative and positive symptoms generally results in severe mental disability. The inheritance of schizophrenia has been long hypothesized, but the evidence for a particular genetic mechanism has not been forthcoming.Epidemiologic studies show clustering of the illness in families (1), and twin adoption studies demonstrate that inherited biological elements are likely to be important in the pathophysiology of the illness (2). However, monozygotic twin concordance rates are rarely higher than 70%. Frequently, relatives show some signs reminiscent of the illness, such as severe shyness, suspiciousness, or magical thinking, but the relationship of these symptoms to schizophrenia is not clear. This state is termed schizotypy. It has been proposed that there must be an inherited schizotaxic factor which predisposes persons to either schizotypy or, in the presence of other genetic or environmental factors, to schizophrenia (3). However, this schizotaxic factor has not yet been identified. Were it to be identified, however, it might be a better candidate for genetic analysis than schizophrenia itself. Such a factor would be a basic element in the pathophysiology of schizophrenia and would be present in some form in relatives of schizophrenics as well. Among basic elements in the pathophysiology of schizophrenia, attention has been directed to problems in the regulation of responsiveness to sensory stimuli. These problems are apparent in first-person accounts of the illness, in which patients describe being unable to filter out extraneous sensory stimuli. They find noises around them very difficult to ignore. Consequently, they seem unable to pay attention to the important parts of their environment. For example, while talking to a

Stability of plasma catecholamine metabolites in outpatient schizophrenics

for tardive dyskinesia vulnerability, we conducted a post hoc analysis of plasma AA levels and BPRS symptoms. Subjects were 53 randomly selected young male chronic schizophrenic inpatients having three to 20 years of neuroleptic treatment. Pearson correlation coefficients were calculated between LNAA levels and ratios as compared to BPRS individual item scores and BPRS factor scores. Most of the LNAAs were found to have significant positive correlations with psychotic symptoms. TYR had only positive correlations with depression and anxiety. The branched chain amino acids (valine, isoleucine, and leucine) also showed positive correlations with depressive symptoms. Though PHE, TYR, and TRP have been the primary focus of this line of research, fasting HIS (a precursor of histamine which is a probable neurotransmitter) was found to have significant negative correlations with the following BPRS items: mannerisms, conceptual disorganization, grandiosity, unusual thought content, disorientation, total BPRS score; and the factors of thought disorder, activation, and hostility/suspiciousness. A positive correlation was found for blunted affect. Postloading levels, however, did not show any significant associations. These preliminary findings suggest that future research in the AAs and mental illness should include a broader range of AAs such as HIS and their relationships to symptomatology .