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Our previous observation of a disturbed subcortical-to-cortical gradient of activity in schizophrenia was further elucidated by examining glucose metabolism in three subcortical structures: lenticular nucleus, caudate nucleus, and thalamus. Local cerebral glucose metabolism was determined with 18F-fluorodeoxyglucose using positron emission tomography (PET) in a sample of 20 unmedicated schizophrenics and 18 normal volunteers. Repeated evaluations were performed for 12 schizophrenics following treatment with psychotropic medications and for 11 controls. Unmedicated schizophrenics had lower cortical and caudate absolute metabolic rates. Subcortical-to-cortical ratios for the lenticular nucleus and thalamus were increased in schizophrenics compared with controls, reflecting a preservation of activity in these structures relative to decreased cortical metabolism. When patients were grouped by length of medication-free period before the initial study, there was a trend for patients who had been medication free less than 6 months to have higher subcortical ratios. However, there were no consistent effects of medication in the subsample of patients whose PET studies were repeated following treatment. The results demonstrate relative hypermetabolism in structures implicated in dopamine pathways. An understanding of the physiological significance of this finding awaits the combined measurement of metabolic activity and neuroreceptors in schizophrenics.

A standardized neuropsychological battery including measures of intellectual cognitive, memory, attention-concentration, language, abstraction and mental flexibility, and sensory and motor functions was administered to 21 hemiparkinsonian patients (14 with right side and 7 with left side symptoms) and 17 controls matched for age and education. Patients were impaired in all functions except sensory. For motor functions, impairment was ipsilateral to the side of symptoms. For cognitive functions, right side symptoms were associated with verbal deficits whereas left side symptoms were associated with spatial deficits. Thus, a pattern of neuropsychological deficits consistent with the lateralization of motor symptoms may appear in the early stages of the disease.

Laterality and age of onset effects on semantic and figural memory were evaluated in 30 right-handed, left speech dominant (amobarbital test) patients with epilepsy before and after temporal lobectomy. There were no effects of focus on WAIS-R IQ scores. Early onset (less than or equal to 5 years) was associated with lower IQ and memory (WMS). Left Temporal (LT) patients showed worse semantic than figural memory preoperatively. Unexpectedly, early onset LT had marked postoperative decline of figural memory, whereas late onset LT patients showed the previously reported worsening of semantic memory. Right Temporal (RT) lobectomy patients, in contrast, improved in both semantic and figural memory regardless of age of onset. A "crowding effect" was suggested by the decline in figural memory following surgery in the early onset LT patients who remained stable or improved in semantic memory. Results indicate the need to incorporate age of onset of seizures into laterality models of memory function following unilateral temporal-hippocampal resection.

Right handers moved their eyes leftward when solving spatial problems and rightward for verbal problems when the questioner sat behind them. When facing the questioner, the same subjects moved their eyes predominantly in only one direction, either right or left, regardless of problem type. The results indicate that the cerebral hemispheres, though specialized for problem type, are also preferentially activated within the same individuals.

We report a case of a left-hander with left hemispheric language. After callosotomy, he could use the left hand to write only random letters and digits, and he became right-handed for writing. Therefore, writing by left-handers with left hemispheric language dominance may be accomplished by transcallosal transmission of the linguistic content from the left hemisphere to the right.

Recent studies show right hemisphere dominance in the mediation of emotional prosody and left hemisphere contribution to linguistic prosody in patients with cortical injury. The present study investigated emotional and linguistic functions of prosody as well as facial and musical processing in 21 patients with lateralized subcortical disease. Fourteen right hemiparkinsonians (RPD) and 7 left hemiparkinsonians (LPD) were compared to 17 normal controls (NC). Patients were impaired on receptive and expressive tests of emotional and linguistic prosody. Patients were also selectively impaired on emotional processing of facial stimuli and in the musical processing of pitch and tonal memory, though not timber. These findings suggest that monotone speech reported in PD is of multimodal origins and may involve dysfunction in neural centers involved in emotional and linguistic processing. There were no differences between RPD and LPD groups in the pattern of deficits, suggesting bilateral involvement in emotional processing at the subcortical level.

The extent of ipsilateral control of the distal limbs is not documented. In this experiment visuo-motor control of fingers was investigated in two callosotomy patients. A substantial amount of ipsilateral control was evident, especially for the left hand fingers. Ipsilateral control of the right hand was evident for the thumb and index fingers, but not for the other fingers. Left hand fingers did not vary significantly in degree of ipsilateral control.

Transient mutism has been reported following commissurotomy and callosotomy. The cause for this mutism is unknown. A case of mutism following callosotomy is presented, and the preoperative and postoperative data on neurological, physiological, and psychological functioning are discussed. The data suggest that the mutism is not caused by general intellectual deterioration, cortical lesion, or peripheral damage affecting speech production. The syndrome may result from severing interhemispheric connections in cases where both hemispheres are required for speech production.

The relationship between age and regional cerebral blood flow (rCBF) activation for cognitive tasks was investigated with the xenon Xe 133 inhalation technique. The sample consisted of 55 healthy subjects, ranging in age from 18 to 72 years, who were studied during rest and during the performance of verbal analogy and spatial orientation tasks. The dependent measures were indexes of gray-matter rCBF and average rCBF (gray and white matter) as well as the percentage of gray-matter tissue. Advanced age was associated with reduced flow, particularly pronounced in anterior regions. However, the extent and pattern of rCBF changes during cognition was unaffected by age. For the percentage of gray matter, there was a specific reduction in anterior regions of the left hemisphere. The findings suggest the utility of this research paradigm for investigating neural underpinnings of the effects of dementia on cognitive functioning, relative to the effects of normal aging.

Regional cerebral blood flow (rCBF) was measured with the xenon-133 inhalation technique in 15 patients with unilateral cerebral infarction and 12 matched controls. Measurements were performed during a standard resting baseline condition and during the performance of standardized verbal analogies and spatial line orientation tasks. Resting and activated CBF were lower in patients than in controls, and there were differences in the hemispheric pattern of activated CBF. Control subjects replicated earlier findings of asymmetric increase in CBF for the cognitive tasks, whereas patients showed abnormalities in lateralized CBF changes consistent with side of infarction. These findings underscore the utility of cognitive challenges in the study of rCBF in stroke. This can lead to an experimental paradigm in clinical studies of the relation between behavioral deficits and regional brain dysfunction and may also improve the utility of CBF measurements in clinical settings.

We measured regional cerebral blood flow during resting baseline and the performance of verbal and spatial tasks in 15 medicated schizophrenics and 25 matched controls. Patients did not differ from controls in resting flows but showed different blood-flow changes during task performance. Controls replicated earlier findings in normal subjects: flow increased during task performance, and the hemispheric increase was greater in the left for the verbal and in the right for the spatial task. In contrast, patients showed no flow asymmetry for the verbal task and greater left hemispheric increase for the spatial task. The latter finding is consistent with the hypothesis that schizophrenia is associated with left hemispheric overactivation for spatial tasks. In addition, schizophrenic women had unusual flow changes in that their highest flow increase was for the verbal task.

Local cerebral glucose metabolism was determined with 18-F-fluorodeoxyglucose using positron emission tomography in a sample of 12 unmedicated schizophrenics and 12 matched normal controls. The data were analyzed for absolute metabolic rates and region/whole-brain ratios using the cortical-subcortical, antero-posterior, and laterality dimensions. Lobar areas within cortical regions were also compared. Across groups, subcortical metabolism was higher than cortical metabolism. Patients had lower metabolism, cortically and subcortically, and a steeper subcortical to cortical gradient. Patients with higher scores on the Brief Psychiatric Rating Scale had higher absolute metabolism and higher left relative to right hemispheric metabolism than did patients with lesser severity. The results did not show "hypofrontality" in schizophrenia. These findings provide some support for cerebral dysfunction in schizophrenia and indicate the need for further examination of the cortical-subcortical dimension.

For 43 patients with probable Alzheimer's disease who were screened for psychiatric disorders, the interrater reliability of the Global Deterioration Scale, BPRS, and Hamilton Rating Scale for Depression was high (intraclass correlation, 0.82-0.998). As expected, the prevalence of psychiatric symptoms in this sample was low. The score on the Zung Self-Rating Depression Scale correlated with the score on the rater-administered Hamilton depression scale in patients whose Alzheimer's disease was of low severity (N = 24) but not high severity (N = 19).

Two hundred schizophrenics were compared to 200 normal controls on a measure of laterality that included handedness, footedness, and eye dominance scales. Schizophrenics showed more left-sidedness on the laterality score. The established relationship between motoric and cognitive aspects of functional brain asymmetry, found in neurological and normal populations, suggests that the leftward tendency of schizophrenics may be manifested in cognitive and conative functions as well. These results seem to corroborate previous findings indicating that schizophrenia might be related to left hemisphere dysfunction. No relationship was found between handedness and eye dominance either in the schizophrenic or the normal groups. This finding questions the assumption that eyedness-handedness nonconcordance is a pathological sign.

We examined the possibility that neurofibrillary tangles (NFTs) were heterogeneous in postmortem hippocampus from 22 patients with or without senile dementia of the Alzheimer type. Intraneuronal NFTs and extracellular, or "ghost," NFTs were recognized in situ by only one or the other of two monoclonal antibodies. The first monoclonal antibody, RMO87, stained only intraneuronal NFTs and is specific for phosphate-dependent epitopes in tau and the two high molecular weight neurofilament proteins. The second monoclonal antibody, 2.2B10, is specific for glial fibrillary acidic protein, and it stained only the RMO87-negative extracellular NFTs. Treatment of sections with alkaline phosphatase or sodium dodecyl sulfate, and the isolation of NFTs from hippocampus, did not expose RMO87 binding sites in extracellular NFTs. These observations indicate that neurofilament-like and tau-like epitopes can be lost from NFTs in situ, and that at least two populations of morphologically and immunochemically distinct NFTs exist.

The rate of local cerebral glucose metabolism was measured in subjects receiving a verbal (n = 4) and a spatial (n = 4) task. The verbal task produced greater metabolism in Wernicke's area relative to the right hemispheric homotopic region, whereas the spatial task produced greater metabolic activity in the right hemispheric homotopic region. Broca's area and its right hemisphere counterpart showed symmetrical activity during the verbal task, but there was a significant asymmetry to the right during the spatial task. Lateralized task effects were also obtained in the frontal eye fields, supporting a hypothesized neural network linking cognitive activity with motor orientation.

Regional cerebral blood flow (rCBF) was measured during resting baseline and the performance of a verbal and a spatial task in 19 unmedicated schizophrenics and 19 matched controls. Abnormalities in rCBF were evident in schizophrenics both for resting and activated measures. Resting flows were higher in the left hemisphere for schizophrenics, supporting the hypothesis of left hemispheric overactivation. This effect was stronger in the more severely disturbed patients. The pattern of rCBF changes during activation with the verbal and spatial tasks was also different in schizophrenics. Laterality of flow changes further supported the hypothesis of left hemispheric overactivation. Furthermore, whereas normals had greater increase in flow for the spatial than the verbal task, schizophrenics showed the reverse pattern. This effect also was more pronounced in the severely disturbed patients. Comparison with an earlier sample of medicated schizophrenics suggested that neuroleptics restore symmetry of resting flows before they produce symptomatic relief. Medication did not affect the abnormalities in pattern of rCBF changes during activation with cognitive tasks.

Regional cerebral blood flow was measured during resting baseline and the performance of a verbal and a spatial task in 14 medicated depressives and 25 matched controls. Overall resting flows did not differ, nor were there hemispheric or anteroposterior differences between patients and controls for resting flows. Differences between patients and controls were evident during cognitive activity, and the effects were different for male and female patients. Depressed female patients had higher than normal flows in all conditions, whereas depressed male patients had lower than normal resting flows, which increased to normal during cognitive activity. Their anterior flows increased for the verbal task but not for the spatial task.

Repeated applications of the 133Xe inhalation technique for measuring regional CBF (rCBF) were made during consecutive resting conditions in a sample of young healthy subjects. Subjects were grouped by order and by sex [nine had resting studies as the initial two measurements in a series of four measurement (six men, three women) and six had these measurements later (two men, four women)]. Three flow parameters were examined: f1 (fast flow) and IS (initial slope) for gray matter CBF, and CBF-15 for mean CBF (gray and white matter over 15-min integration), as well as w1, the percentage of tissue with fast clearing characteristics. With all groups combined, there were no significant differences between the two resting measurements, and high test-retest correlations were obtained for the flow parameters and w1. Analyses by order and sex grouping revealed, for the flow parameters, significant interactions of test-retest difference with order. Repeated initial studies showed reduced CBF from the first to second measurement, whereas resting studies performed later in the series showed no reduction. Interactions for test-retest difference with sex indicated that reduced CBF in serial measures was more pronounced for women. No hemispheric or regional specificity to account for these effects was found. Correction for PaCO2 differences did not alter these results. The results resemble data regarding habituation effects measured for other psychophysiologic measures, and suggest that reduction in CBF for consecutive measurements made on the same day may reflect habituation. This underscores the importance of controlling for effects of habituation on serial measurements of CBF and metabolism.

Two of the hypotheses on regional brain dysfunction in schizophrenia that have received some support in studies of cerebral blood flow (CBF) and cerebral metabolic rate (CMR) are: (1) left hemispheric dysfunction and overactivation (laterality) and (2) frontal lobe deactivation or failure to activate (frontality). Although these hypotheses are not mutually exclusive, their relative importance for providing clues to neural underpinnings of symptoms specific to schizophrenia depends on their ability to predict variation in symptomatology. A potentially efficient strategy for such study is to start with physiological parameters of laterality and frontality, and correlate them with measures of severity of clinical symptoms specific to schizophrenia. For two schizophrenic samples reported earlier, we derived laterality (left-right hemispheres) and frontality (frontal-posterior regions) measures of CBF (Study 1) and CMR (Study 2), and correlated them with symptom specificity, defined as the difference in severity of symptoms specific and nonspecific to schizophrenia assessed by the Brief Psychiatric Rating Scale. In both studies, low but significant positive correlations were obtained between the specificity score and laterality for CBF in Study 1 and for CMR in Study 2, but not frontality. The results suggest that in these samples disturbances in lateralized activity are more prominently associated with the phenomenology of schizophrenia than disturbed frontal lobe activity.

The relation between anxiety and cortical activity was compared in two samples of normal volunteers. One group was studied with the noninvasive xenon-133 inhalation technique for measuring cerebral blood flow (CBF) and the other with positron emission tomography (PET) using 18Flurodeoxyglucose (18FDG) for measuring cerebral metabolic rates (CMR) for glucose. The inhalation technique produced less anxiety than the PET procedure, and for low anxiety subjects, there was a linear increase in CBF with anxiety. For higher anxiety subjects, however, there was a linear decrease in CBF with increased anxiety. The PET group manifested a linear decrease in CMR with increased anxiety. The results indicate that anxiety can have systematic effects on cortical activity, and this should be taken into consideration when comparing data from different procedures. They also suggest a physiologic explanation of a fundamental behavioral law that stipulates a curvilinear, inverted-U relationship between anxiety and performance.

Forty-eight schizophrenics (24 paranoids, 24 nonparanoids) and 24 matched controls (12 men and 12 women in each group) were asked to detect the differences between 30 pairs of altered pictures presented successively (15 pairs) and simultaneously (15 pairs) in a counterbalanced order. Overall performance, as measured by reaction time and response quality, was better for controls than for schizophrenics. However, schizophrenics, like right hemisphere brain-damaged patients who presumably rely on their left hemisphere, reacted faster in the successive presentation procedure while the controls reacted equally fast in both conditions. These results support the hypothesis that schizophrenics tend to overactivate their left dysfunctional hemisphere. Twenty-four depressed patients, tested in the same procedure, showed a pattern of results similar to that of controls, suggesting that the results obtained for schizophrenics are not a general characteristic of psychosis.

Here we review our recent "epitope analyses" of a few of the fibrous intraneuronal inclusions that are distinctive hallmarks of human neurodenerative conditions using a large library of monoclonal antibodies (MAbs) raised to normal neuronal cytoskeletal proteins. Analyses of the low (NF-L), middle (NF-M), and high (NF-M), and high (NF-H) molecular weight neurofilament (NF) proteins with greater than 500 MAbs enumerated epitopes shared by NF proteins and the intraneuronal neurofibrillary tangles (NFTs) that occur in the hippocampus and brainstem of Alzheimer's disease (AD) subjects. We identified the NF-H multi-phosphorylation repeat domain, i.e. repeats of Lys-Ser-Pro-X (where X is a small uncharged amino acid and Ser acts as a phosphate acceptor), as the determinant recognized by 15/16 MAbs that detected NFTs in sections of AD hippocampus, and 11 of the same 16 MAbs recognised NF-M multi-phosphorylation repeats. Further, the antigen binding regions of these MAbs were shown to comprise 13 separate classes based on their differential binding to 12 synthetic peptides derived from the NF-H and NF-M multi-phosphorylation sites, NF subunits of 10 diverse mammalian and sub-mammalian species, and normal human tau (tau). None of these anti-NF MAbs recognized NFTs in the brainstem of subjects with progressive supranuclear palsy (PSP), but NFTs in AD brainstem sections were reactive with five of these MAbs. Both PSP and AD brainstem NFTs were recognized by MAbs specific for tau and paired helical filament antigens.(ABSTRACT TRUNCATED AT 400 WORDS)

Three experiments are reported on visual field asymmetries in the perception of emotional expressions on the face. In experiment I full faces expressing six different emotions were presented unilaterally for exposure durations, allowing the subject to judge whether the facial expression was positive or negative. Right-handed subjects judged all expressions except happiness as more negative when presented in the left visual field (LVF). This effect was smaller for left-handers and was absent in left-handers who use the non-inverted writing posture. In experiment II subjects were presented with happy, sad and "mixed" chimeric faces, projected to each visual field, for durations allowing only the detection of the existence of a face. LVF presentations produced greater differential rating of emotional valence for the three types of stimuli. In experiment III chimeric faces containing happy and sad expressions were presented unilaterally for durations allowing the subject to perceive the existence of two expressions on the face. The subjects were required to decide whether the mood expressed in the face was predominantly negative or positive. RVF presentations resulted in a bias toward positive judgments. These results indicate right hemispheric superiority for the perception and processing of emotional valence and a left hemispheric perceptual bias toward positive aspects of emotional stimuli.