Computed electroencephalographic activity mapping in schizophrenia. The resting state reconsidered.

Several topographic mapping studies of electroencephalographic (EEG) power spectra have reported increased slow (delta) activity in the frontal regions of schizophrenic patients. Using supraorbital and lateral canthus electrodes to detect eye movement, we deleted EEG epochs during eye movement in 15 medication-free patients with schizophrenia and in 13 normal control subjects. Power spectral analysis of the 28-channel EEG demonstrated a diffuse mild increase in delta activity in schizophrenic patients compared with normal control subjects but no tendency for frontal localization of this slow activity. There were no differences between schizophrenic patients and normal control subjects in other frequency bands. These results, which replicate earlier findings of increased delta activity in schizophrenia, emphasize the importance of excluding the slow activity due to eye movement in the comparisons of summed EEG spectra. This emphasis can best be ensured by equating the summed spectra from extraocular movement channels of experimental and control groups.

Preliminary evidence of reduced combined output of dopamine and its metabolites in chronic schizophrenia.

The mean combined total body excretion of dopamine (DA) and its metabolites, measured by summing the molar excretion of DA and its metabolites in 24-hour urine samples (Sum DA), was reduced in 20 patients with schizophrenia who had not been receiving medication for at least two weeks. These patients were relatively resistant to treatment, as they were unable to live independently outside institutional settings despite conventional neuroleptic therapy. In contrast, sum norepinephrine (Sum NE), measured by summing the molar excretion of NE and its metabolites, was not reduced. These results are highlighted by expressing the data in terms of the ratio of Sum DA/Sum NE. Patients with schizophrenia had a significantly lower ratio. Treatment with haloperidol normalized the low ratio. Urinary excretion of 5-hydroxyindoleacetic acid was normal in the schizophrenic patients. These results suggest that chronic schizophrenia is more likely to be associated with a low rather than a high state of DA activity.

Increased levels of transcription factors Elk-1, cyclic adenosine monophosphate response element-binding protein, and activating transcription factor 2 in the cerebellar vermis of schizophrenic patients.

BACKGROUND: We investigated the levels of transcription factors associated with activation of the mitogen-activated protein (MAP) kinase pathway in schizophrenics using postmortem brain samples. These studies were done to determine whether our previous findings of abnormal levels of the MAP kinases in the cerebellar vermis were linked to additional downstream targets of this signal transduction pathway. METHOD: We measured the protein levels of 3 transcription factors in nuclear fractions of postmortem samples from cerebellar vermis of 10 patients with schizophrenia and 13 control subjects: Elk-1, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and activating transcription factor 2 (ATF-2). Studies in rats examined the postmortem stability and effect of haloperidol and risperidone on levels of Elk-1, cAMP, and ATF-2 proteins. RESULTS: We found a significant increase in the protein levels of Elk-1 (mean+SD, 4489+/-659 vs 2915+/-583 arbitrary densitometric units [P<.001]), CREB (mean +/- SD, 2149 1061 vs 904+/-711 arbitrary densitometric units [P=.003]) and ATF-2 (mean+/-SD, 1421 854 vs 512+/-394 arbitrary densitometric units [P=.003]) in the cerebellar vermis of schizophrenic subjects. Complementary studies in rats indicate that these findings can not be attributed to subacute treatment with antipsychotic medications. CONCLUSION: Taken together with the alterations of MAP kinases previously reported, and the findings of elevations of downstream transcription targets, we suggest that the MAP kinase signal transduction pathway contributes to the cerebellar abnormalities in schizophrenia.

Drug effect on blink rates in rhesus monkeys: preliminary studies.

Various drugs that alter central monoamine activity were given to monkeys to determine effects on blink rate. Chronic pargyline treatment raised the mean +/- SD blink rate slightly to 18.2 +/- 5.3 blinks/90 sec. When phenylethylamine was added to chronic pargyline treatment, blinks increased from a base line of 16.8 +/- 7.6 blinks/90 sec to 37 +/- 15 blinks/90 sec. Apomorphine (0.36 mg/kg) raised blinks from a base lone of 12.2 +/- 2.8 blinks/90 sec. to 41.9 +/- 10.3 blinks/90 sec. and reversed a decrease in blinking caused by haloperidol. The neurochemical basis of blinking and implications for tardive dyskinesia are discussed.

In vitro 1H-magnetic resonance spectroscopy of postmortem brains with schizophrenia.

Some evidence suggests that thalamic dysfunction could explain some of the signs and symptoms of schizophrenia. We measured the absolute concentrations of amino acid metabolites in thalamus, frontal pole, and cerebellar vermis in extracts of postmortem brains from 8 schizophrenics and 10 controls using high-resolution 1H-magnetic resonance spectroscopy. The concentrations of N-acetyl aspartate, glutamate, and valine tended to be reduced in the thalamus of the schizophrenic group. Although it is difficult to ascribe significance to the "tendencies," these data may tend to support other data suggesting decreased thalamic volume or neuronal number in schizophrenia.

Mitogen-activated protein kinases in schizophrenia.

BACKGROUND: Mitogen-activated protein kinases (MAPKs) are important mediators of signal transduction from the cell surface to the nucleus and have been implicated in the integration of a variety of physiologic processes in most cells, including neurons. To investigate the possible involvement of MAPKs in schizophrenia, we compared the levels of the MAPK intermediates in postmortem brain tissue obtained from schizophrenic and control subjects. Our focus was on the cerebellar vermis because of evidence suggesting that schizophrenia is associated with abnormalities of structure, function, and signal transduction in this brain region. METHODS: Cytosolic proteins were fractionated by gel electrophoresis and subjected to Western blot analysis using polyclonal MAPK antibody, which detects total extracellular signal-regulated kinases (ERKs) 1 and 2 levels, and monoclonal MAP kinase phosphatase (MKP) 2 antibody. RESULTS: Schizophrenic subjects had increased levels of ERK2 [2763 +/- (SD) 203 vs. 2286 +/- 607 arbitrary units, U = 17, p < .05] in cerebellar vermis. The levels of a dual specificity tyrosine phosphatase, MKP2, were significantly decreased in cerebellar vermis (1716 +/- 465 versus 2372 +/- 429 arbitrary units, U = 12, p < .02) from schizophrenic patients. ERK1/MKP2 and ERK2/MKP2 ratios in cerebellar vermis, but not in other brain regions, were significantly different in schizophrenic subjects as compared to control subjects (U = 15, p < or = .027; U = 3, p < .001, respectively). CONCLUSIONS: MAPK levels are elevated in the cerebellar vermis of schizophrenic subjects. This could result from a protein dephosphorylation defect in vivo and might be involved in the pathology of the disease.

Oculomotor signs in a psychiatric population: a preliminary report.

Oculomotor signs were evaluated in 172 psychiatric patients. Schizophrenic patients demonstrated a significantly higher incidence of staring, pursuit breaks, and lateral glances than did controls or other psychiatric patients. Oculomotor signs may help to differentiate schizophrenia from affective and nonpsychotic disorders. Patients with tardive dyskinesia and patients treated with tricyclic antidepressants demonstrated a significant elevation in mean blink rate. Elevated blink rates may be on early indicator of tardive dyskinesia.

Alpha frequency in schizophrenia: an association with enlarged cerebral ventricles.

Low alpha frequency (less than 10.2 Hz) occurred more frequently in medication-free schizophrenic patients than in normal control subjects, as determined by quantitative EEG analysis. Furthermore, those patients with low alpha frequency had significantly larger lateral ventricles, as measured by CT scan, than did other schizophrenic patients (mean +/- SD ventricle-brain ratios = 9.8 +/- 1.9 versus 5.0 +/- 2.4; p less than 0.01). This finding suggests the existence of a relationship between cerebral structural pathology and the alpha rhythm that may be based on involvement of alpha-generating structures which border the cerebral ventricles. Future EEG studies of schizophrenia may resolve these questions in the context of other brain findings.

Dyskinetic movements, cognitive impairment, and negative symptoms in elderly neuropsychiatric patients.

The presence or absence of tardive dyskinesia, cognitive status, and psychopathology were assessed in a group of elderly male psychiatric patients (N = 49) in a nursing home setting. Twenty-five patients were found to have tardive dyskinesia, which was associated with a greater degree of cognitive impairment and negative symptoms. This finding was not related to obvious macroscopic organic pathologies, which were less prevalent in the dyskinetic patients. In fact, patients with frontal lesions (primarily lobotomies) had a significantly lower prevalence of tardive dyskinesia.

Treatment of schizophrenia with a vasopressin analogue.

Ten patients with chronic schizophrenia completed a 3-month double-blind, placebo-controlled trial with a vasopressin analogue. Modest improvement occurred, but several patients also experienced significant fluid and electrolyte imbalance.

Choline acetyltransferase in schizophrenia.

OBJECTIVE: To test the hypothesis that schizophrenia involves altered cholinergic tone in the pons, the authors studied post-mortem brain tissue from subjects with schizophrenia. METHOD: The authors used Western immunoblot to measure the concentration of choline acetyltransferase, an acetylcholine synthesizing enzyme, in the post-mortem brain tissue of 25 schizophrenic subjects and 28 nonschizophrenic comparison subjects. They also measured the concentration of glial fibrillary acidic protein, a protein from astrocytes, to examine the question of neurodegeneration. RESULTS: The pontine choline acetyltransferase concentrations of the schizophrenic subjects were 46% lower than those of comparison subjects, a significant difference. Glial fibrillary acidic protein concentrations did not differ between the two groups. CONCLUSIONS: The lower concentration of choline acetyltransferase in the pontine tegmentum of schizophrenic subjects compared with comparison subjects suggests involvement of pontine cholinergic neurons in schizophrenia.

Correlation of severity of psychiatric patients' delusions with right hemispatial inattention (left-turning behavior).

Studies associate psychotic disorders with various forms of subtle inattention to the right hemispace (left-turning behavior). The authors examined the correlation between this dopamine-related sign and severity of delusions (presumably dopaminergic symptoms) in 20 psychotic patients. Delusions were significantly correlated with severity of left-turning bias, and this neurological sign accounted for 33% of the variance in severity of delusions.

A comparison of two iatrogenic dyskinesias.

The authors compared the regions of motor involvement in levodopa-induced dyskinesia and neuroleptic-induced tardive dyskinesia. Significantly more patients with tardive dyskinesia than parkinsonian patients with levodopa-induced dyskinesia had lip and tongue movements. Patients with tardive dyskinesia had significantly higher mean AIMS scores in the orofacial region than parkinsonian patients with levodopa-induced dyskinesia. More patients with levodopa-induced dyskinesia than those with tardive dyskinesia demonstrated hyperkinesia in the lower extremities. Limb and truncal movements in levodopa-induced dyskinesia were worse in patients with more severe parkinsonism and correlated positively with the length of Parkinson's disease. These findings suggest that these dyskinesias may involve different pathophysiological mechanisms.

High prevalence of visual hallucinations in research subjects with chronic schizophrenia.

The authors examined the prevalence of visual hallucinations in severely ill hospitalized research subjects with carefully diagnosed chronic schizophrenia and found it to be high. A chart review of 100 discharged subjects revealed documentation of visual hallucinations in 32%, and a prospective examination of 43 additional subjects revealed a history of visual hallucinations in 56% (N = 24). Also, the fact that in 43% of the patients with visual hallucinations the history of visual hallucinations was first documented during the research ward work-up suggests that clinicians frequently do not inquire about visual hallucinations in patients with chronic schizophrenia.

Cerebral structural pathology in schizophrenia: evidence for a selective prefrontal cortical defect.

To replicate earlier findings of central and cortical cerebral structural abnormalities and to further examine specific prefrontal cortical irregularities in schizophrenia, the authors examined computerized tomographic (CT) scans of 71 patients with chronic schizophrenia and 30 normal volunteer control subjects for ventricle-brain ratio (VBR), third ventricle width, and prominence of cortical markings in a generalized (parieto-occipital) distribution compared with the prefrontal area. Patients showed significantly larger VBRs and third ventricle widths than control subjects. Patients also showed significantly greater prefrontal markings in terms of both the number of individuals affected and the degree of difference. The relative differences on measures of VBR and prefrontal atrophy did not appear gender related, but the difference in third ventricle width between schizophrenic and control women was greater than that between schizophrenic and control men.

Eye-blinking and cerebral ventricular size in chronic schizophrenic patients.

Spontaneous eye-blinking, a possible measure of central dopaminergic activity, was studied in 55 drug-free chronic schizophrenic patients subdivided by cerebral ventricular size. Blink rates were higher in schizophrenic patients than in normal control subjects, regardless of cerebral ventricle size. Neuroleptics lowered blink rates in patients with normal ventricles but did not affect blink rates in patients with large ventricles. Insofar as blinking is a dopaminergic parameter, these findings suggest that the dopamine hypothesis of schizophrenia is most relevant in patients with normal ventricles.

Blink rates and disorders of movement.

Blink rate, a putative noninvasive marker of central dopamine activity, was assessed in medication-free patients with Parkinson's disease, progressive supranuclear palsy, Huntington's disease, and dystonia. The normal control rate of 24 blinks per minute was significantly higher than the rate of 12 and 4 blinks per minute recorded for patients with Parkinson's disease and progressive supranuclear palsy, respectively. The rates for patients with Huntington's disease and dystonia did not differ significantly from those of controls (36 and 26 blinks per minute, respectively).

Differential and region-specific activation of mitogen-activated protein kinases following chronic administration of phencyclidine in rat brain.

We have previously demonstrated elevation of the extracellular signal-regulated kinase (ERK) pathway in the cerebellum from patients with schizophrenia, an illness that may involve dysfunction of the N-methyl-D-aspartate (NMDA) receptor. Since the NMDA antagonist, phencyclidine (PCP), produces schizophrenic-like symptoms in humans, and abnormal behavior in animals, we examined the effects of chronic PCP administration in time- and dose-dependent manner on ERK and two other members of mitogen-activated protein kinase family, c-Jun N-terminal protein kinase (JNK) and p38, in rat brain. Osmotic pumps for PCP (18 mg/kg/day) and saline (controls) were implanted subcutaneously in rats for three, 10, and 20 days. Using Western blot analysis, we found no change at three days, but a significant increase in the phosphorylation of ERK1, ERK2 and MEK in the cerebellum at 10- and 20-days of continuous PCP infusion. For the experiments involving various doses of PCP, rats were infused with PCP at concentrations of 2.5, 10, 18, or 25 mg/kg/day, or saline for 10 days. We observed a dose-dependent elevation in the phosphorylation of ERK1 and ERK2 only in the cerebellum but not in brainstem, frontal cortex or hippocampus. The activities of JNK and p38 were unchanged in all investigated brain regions including cerebellum. These results demonstrate that chronic infusion of PCP in rats produces a differential and brain region-specific activation of MAP kinases, suggesting a role for the ERK signaling pathway in PCP abuse and perhaps in schizophrenia.

Mesopontine neurons in schizophrenia.

Findings reported here show that there is a significant increase in the number of neurons in the pedunculopontine nucleus in most schizophrenic patients compared to age-matched controls. Nicotinamide adenine dinucleotide phosphate diaphorase histochemistry was used to label putative cholinergic neurons in the pedunculopontine nucleus and laterodorsal tegmental nucleus, while noradrenergic locus coeruleus neurons were labeled immunocytochemically using an antibody to tryosine hydroxylase. Cell counts of these neuronal groups were carried out using a Biographics image analysis system. We found significantly increased cell numbers in the pedunculopontine nucleus of schizophrenic patients compared to controls. The number of laterodorsal tegmental nucleus neurons was increased but this was not statistically significant. However, the total cell counts for pedunculopontine and laterodorsal tegmental nuclei were significantly higher in schizophrenic subjects. The number of locus coeruleus noradrenergic neurons was similar in both groups. These results implicate the brainstem reticular formation as a pathophysiological site in at least some patients with schizophrenia. In addition, these findings suggest a developmental etiology for the disease and account for some, but not all, of the symptoms of schizophrenia, including sensory gating abnormalities, sleep-wake disturbances and, perhaps, hallucinations. Overdriving of thalamic and substantia nigra function by cholinergic afferents from the midbrain may account for some of the symptoms seen in schizophrenia. These findings suggest that, at least in some schizophrenic patients, there is an increased number of neurons in the cholinergic arm of the reticular activating system. This may explain some of the symptoms of schizophrenia and points to a prenatal disturbance as one of the possible causes of the disease.

Preliminary studies of alpha rhythm and neuropsychological impairment in schizophrenia.

Patients with chronic schizophrenia had their EEGs recorded during medication withdrawal. Neuropsychological testing was done on the same patients during a period of 'optimum' functioning during neuroleptic treatment. Correlations between alpha activity, verbal IQ and Halsted-Reitan battery performance were evident over the entire scalp. This led us to examine whether these correlations were related to the inability of a substantial proportion of these patients to generate significant alpha activity. Patients unable to generate significant alpha activity tended to have neuropsychological impairment. These preliminary results suggest that this measure of brain physiology may relate to functional impairment in schizophrenia.