Normalization of spiroperidol binding in the denervated rat striatum by homologous grafts of substantia nigra.

Transplantation of embryonic substantia nigra into the adult rat brain decreases the motor asymmetry that is produced by dopamine receptor supersensitivity after a unilateral lesion of the substantia nigra. The authors report that this effect of transplantation is specific to grafts of substantia nigra. They also report that, in conjunction with the decrease in motor asymmetry, these grafts cause postsynaptic dopaminergic binding sites to return to normal density as measured by tritiated spiroperidol autoradiography. Thus, in animals with brain lesions, grafts of substantia nigra produce a long-term alteration in the functional status of host brain cell receptors that is associated with a reduction in the behavioral deficit.

Brain electrical activity mapping (BEAM) in schizophrenic patients.

A new topographic approach, brain electrical activity mapping, summarizes EEG and evoked potential data as color maps. Eleven drug-free and 14 medicated schizophrenic patients and 11 normal controls were studied with this technique. Compared with controls, both schizophrenic groups had more slow activity (delta, 0 to 3.5 Hz), greatest in frontal regions, and more fast activity (beta, 20 to 31.5 Hz) in postcentral regions. Both schizophrenic groups were different from controls late in the visual evoked potential and in the middle of the auditory evoked potential. Overall, using multivariate discriminant analysis, a very significant group separation effect was found, and retrospective classification was 95% successful in discriminating both schizophrenic groups from controls. To estimate the ability of our features to assign subjects prospectively to control or patient groups, we employed "jackknifing," which resulted in overall classification success rates of 84.0% for medicated schizophrenic patients v controls and 81.8% for drug-free schizophrenic patients v controls.

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.

Antisomatostatin IgG in major depressive disorder. A preliminary study with implications for an autoimmune mechanism of depression.

IgG reactive with somatostatin 1-14 was identified in human plasma by enzyme linked immunosorbent assay. From a sample of 25 subjects, six (60%) of ten individuals with major depressive disorder demonstrated antibody reactive with somatostatin 1-14, in contrast to one (7%) of 15 controls. Overall, antisomatostatin reactivity was significantly higher in patients with major depressive disorder (0.233 +/- 0.177) than in the normal volunteers (0.084 +/- 0.039; t = 3.18, P less than .01). Antisomatostatin IgG was isolated by affinity chromatography. The recognition site for somatostatin was retained by F(ab)'2 fragments. Although there has been little previous exploration of the existence of antibodies to endogenous neuropeptides, such antibodies could prove of relevance to neuropsychiatric and other human disorders.

Anteroposterior gradients in cerebral glucose use in schizophrenia and affective disorders.

Local cerebral uptake of deoxyglucose labeled with fluorine 18 was measured by positron emission tomography in 16 patients with schizophrenia and 11 patients with affective disorder. Patients received no medication a minimum of 14 days and an average of 39.8 days. The subjects were administered the deoxyglucose 18F just before receiving a 34-minute 1/s series of unpleasant electrical stimuli to the right forearm while resting with eyes closed in a darkened, acoustically attenuated psychophysiologic testing chamber. Following monitored stimulation in the controlled environment, subjects were scanned and images converted to values of glucose use in micromoles per 100 g per minute according to Sokoloff's model. Data were analyzed with a four-way analysis of variance (ANOVA) with independent groups (normals, schizophrenics, and affectives) and repeated measures for slice level (supraventricular, midventricular, and infraventricular), hemisphere (right, left), and anteroposterior position (four sectors). Both normal subjects and patients showed a significant anteroposterior gradient in glucose use with highest values in the frontmost sector. Patients both with schizophrenia and with affective illness showed less of an anteroposterior gradient especially at superior levels, which was statistically confirmed by ANOVA. Absolute glucose levels in patients, which were actually higher in posterior regions rather than lower in frontal regions, were the largest contributors to the effect. Neither group differences in whole brain glucose use nor left-right asymmetries reached statistical significance. These results are consistent with our earlier reports of a relative hypofrontal function in schizophrenia compared with controls. This report extends this finding to affective illness, sharing a lack of diagnostic specificity with many biologic measures.

Structure and function: brain electrical activity mapping and computed tomography in schizophrenia.

A computerized topographic technique that maps brain electrical activity is applied to the investigation of neurophysiological abnormalities in medicated and drug-free schizophrenic patients. This topographic approach uses EEG and evoked potentials to provide functional measures of electrophysiological abnormalities. Neurophysiological differences between schizophrenic patients and controls are delineated which add further evidence that frontal lobe dysfunction may be relevant to our understanding of schizophrenia. An initial investigation employs computed tomography to examine the relationship of structural anatomical pathology in schizophrenia with the functional abnormalities that may be defined using brain electrical activity mapping. When schizophrenic patients with and without frontal cortical atrophy were compared, electrophysiological differences were delineated that overlay frontal cortical regions. This preliminary work suggests that in schizophrenia, abnormal electrophysiological function is associated with definable gross morphological abnormalities of the brain.

Increased temporal lobe glucose use in chronic schizophrenic patients.

Temporal lobe glucose metabolic rate was assessed in 21 off-medication patients with schizophrenia and 19 normal controls by positron emission tomography with 18F-deoxyglucose. Patients with schizophrenia had significantly greater metabolic activity in the left than the right anterior temporal lobe, and the extent of this lateralization was in proportion to the severity of psychopathology.

Positron emission tomography in schizophrenic patients with and without neuroleptic medication.

Positron emission tomography using [18F]2-fluoro-2-deoxy-D-glucose was performed in nine chronic schizophrenic patients both when medication-free and when medicated with neuroleptics. Total brain cortex, temporal cortex, and basal ganglia glucose use was significantly increased with medication; however, there was no change in anterior/posterior metabolic gradients.

Cerebral asymmetry and cerebellar atrophy in schizophrenia: a controlled postmortem study.

The authors examined volumetric occipital asymmetry and evidence of anterior vermian atrophy in the postmortem brains of 12 schizophrenic and 32 control subjects. Although they found no difference in the mean occipital asymmetry they found that for the schizophrenic subjects abnormal occipital asymmetry and vermian atrophy were inversely related.

Perinatal loss and parental bereavement.

The authors studied 25 middle-class pregnant women and their husbands who had experienced perinatal losses (16 miscarriages, seven stillbirths, and two neonatal deaths) within the previous 2 years. The Perinatal Bereavement Scale was designed to determine whether parents who have experienced a late perinatal loss (stillbirth or neonatal death) display more unresolved grief during a subsequent pregnancy and during the postnatal period than parents who have experienced a miscarriage. A three-factor repeated measures analysis of variance indicated significantly greater grief for the late-loss group, for the mothers, and during the pregnancy preceding the birth of the viable child.

Clinical correlates of decreased anteroposterior metabolic gradients in positron emission tomography (PET) of schizophrenic patients.

The finding in schizophrenic patients of a reversal of the normal frontal to posterior pattern of brain metabolic activity with positron emission tomography (PET) is of interest, but its relevance to psychopathology is unknown. Using PET, the authors studied 21 patients with chronic schizophrenia and 21 age- and sex-matched control subjects. Although eight of the 21 patients and only one of the control subjects showed a relatively lower anteroposterior metabolic gradient, no clinical correlates of this finding were noted. In addition, cerebral atrophy, as determined by CAT scan, was not associated with this aberrant metabolic pattern.

Brain-imaging approaches in psychiatry: early developmental considerations.

Recent advances in the neurosciences have provided important new approaches to understanding mental illness. Historically, the application of these approaches has followed patterns that parallel the scientific process of repeated testing and reexamination. In the investigation of schizophrenia, this process has focused particular attention on the frontal lobes. Special considerations should be weighed in assimilating and integrating these new approaches into our field.

The alcohol facilitation effect on memory: a dose-response study.

Sixteen normal male subjects participated in four sessions where they studied a set of pictures followed by either placebo, 0.025, 0.50, or 1.0 ml/kg alcohol. Later, when sober, recognition memory was tested. These doses resulted in peak blood alcohol concentrations (BAC) of 0.00, 0.018, 0.034, and 0.067 g/100 ml, respectively. The 1.0 and 0.50 ml/kg doses significantly improved memory for pictures studied before drinking. Alcohol appears to enhance memory directly rather than indirectly via a reduction in interference. It is suggested that a particular phase of the rising blood alcohol curve (0.02-0.03 g/100 ml) facilitates trace consolidation. The facilitating and possibly excitatory effects of alcohol may be important for understanding the rewarding aspects of drinking.

Resolution of parental bereavement after a perinatal loss.

This is a follow-up study of 25 middle-class, expectant, married couples who had experienced a perinatal loss (16 miscarriages, seven stillbirths, and two neonatal deaths) within the previous 2 years and who subsequently gave birth to a healthy child. The Perinatal Bereavement Scale (PBS) had been previously completed during the 8th month of the subsequent pregnancy and at 6 weeks postnatally. In this study, the PBS was completed 16 months after the birth of the subsequent child. The hypothesis was that the parents who experienced a late perinatal loss (stillbirth and neonatal death) would display more unresolved grief 16 months after the subsequent child was born compared to parents who had experienced an early loss (miscarriage). The late group mothers had significantly higher PBS scores than either the early group mothers or early group fathers at 16 months postnatally.

Catecholamine content of intracerebral adrenal medulla grafts.

The rotational behavior which is produced by substantia nigra lesions can be decreased by adrenal medulla grafts adjacent to the denervated striatum. Perhaps these grafts secrete dopamine that diffuses into the striatum. In the present study, we measured concentrations of catecholamines in adrenal medulla grafts as compared with the normal adrenal medulla. The grafts were found to have high but extremely variable concentrations of dopamine. In hosts with substantia nigra lesions, concentrations of dopamine in the adrenal medulla grafts were decreased. Substantia nigra lesions, however, tended to increase concentrations of epinephrine in the grafts, while norepinephrine and total catecholamine concentrations were not significantly affected. It is concluded that at least some adrenal medulla grafts contain concentrations of dopamine sufficient to account for their behavioral effects.

Development of O4+/O1- immunopanned pro-oligodendroglia in vitro.

In this study, O4+/O1- pro-oligodendroglia isolated by immunopanning from cerebral hemispheres of P3-P5 rats were evaluated during their maturation in culture. Immunopanning yielded 3-4 x 10(5) cells/cerebrum, with 98% O4+ and 6% O1+. There was heterogeneity in the morphologies of immunopanned cells ranging from simple bipolar cells to more complex multipolar cells. As a first step in determining potential differentiative responses of mature oligodendroglia, we examined glial fibrillary acidic protein (GFAP) expression in response to fetal bovine serum (FBS) by cultures established from O4+/O1- immunopanned cells grown for 1, 14, or 21 days, exposed to 20% FBS for 6-7 days and fixed and immunostained on days 7, 21 or 28 in culture (DIC). When immunopanned cells were exposed to FBS following 1 day in serum-free medium, 88% expressed GFAP and when immunopanned cells were cultured for 14 days prior to FBS exposure, 78% expressed GFAP. By contrast, when cells were cultured for 21 days prior to FBS exposure (when a majority of the cells expressed O1 and myelin basic protein (MBP)), only 19% of the cells expressed GFAP (p < 0.001). Cells that were O4+/GFAP- even in the presence of FBS often exhibited a mature oligodendroglial morphology. Among immunopanned cells that responded to FBS by expression of GFAP, both process-bearing (similar to type 2 astroglia) and flattened, polygonal (similar to type 1 astroglia) GFAP+ cells were observed. These results confirm the utility of immunopanning for the isolation of pro-oligodendroglia and demonstrate that oligodendroglia that develop in vitro from O4+/O1- immunopanned cells become resistant to GFAP induction by FBS.

Dysfunction in a prefrontal substrate of sustained attention in schizophrenia.

Regional brain metabolism was measured in normal subjects and patients with schizophrenia while they performed an auditory discrimination task designed to emphasize sustained attention. A direct relationship was found in the normal subjects between metabolic rate in the middle prefrontal cortex and accuracy of performance. The metabolic rate in the middle prefrontal cortex of patients with schizophrenia, even those who performed as well as normals, was found to be significantly lower than normal and unrelated to performance. The findings point to a role of the mid-prefrontal region in sustained attention and to dysfunction of this region in schizophrenia.

A probable neuroleptic effect on platelet monoamine oxidase in chronic schizophrenic patients.

Platelet monoamine oxidase activity (MAO) was studied serially over time in 16 chronic schizophrenic patients when medication free and then when medicated. Thirteen of the 16 patients had significant decreases in platelet MAO activity following neuroleptic drug treatment. The change in MAO activity was found to be correlated with response to treatment and to dose of medication.

The Genain Quadruplets: electrophysiological, positron emission, and X-ray tomographic studies.

Four 51-year-old monozygotic quadruplets concordant for schizophrenia, originally studied at the National Institute of Mental Health 25 years ago, were restudied with topographic electroencephalography (EEG), evoked potentials (EPs), computed tomography (CT scans), polysomnographic sleep recordings, and positron emission tomography (PET) with 18F-2-deoxyglucose. EEG and EP findings were consistent with those from other groups of patients with schizophrenia and showed great similarity within the quadruplets. CT scans revealed uniformly small lateral ventricles. PET scans replicated earlier findings of relatively low glucose use in the frontal lobes but did not show strong familial concordance.