Robert Cancro

Glutamate modulation of dopamine measured in vivo with positron emission tomography (PET) and 11C-raclopride in normal human subjects.

Subanesthetic doses of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist ketamine exacerbate psychosis in schizophrenic patients, and ketamine has significant abuse liability. These observations indicate that a secondary effect of ketamine may be to increase dopamine concentrations. The present study was undertaken using positron emission tomography (PET) and the dopamine (D2) radiotracer 11C-raclopride to determine whether ketamine would decrease D2 receptor availability, indicative of an increase in dopamine concentrations. Two scans were performed in seven male control subjects before and after administration of ketamine (0.5 mg/kg, IV infused over 20 min). Ketamine significantly increased cortisol levels and decreased dopamine receptor availability in the striatum (specific binding), but not in the cerebellum (nonspecific binding). In addition, the cerebellar binding subtracted from the striatal binding (to account for changes in nonspecific binding) was significantly decreased after ketamine administration. These results provide in vivo evidence for the ability of ketamine to increase striatal dopamine concentrations, consistent with the role of the NMDA receptor in modulating dopamine function.

Quantitative EEG correlates of cognitive deterioration in the elderly

We report on the quantitative analysis of the EEG (QEEG), using the Neurometric method, in large samples of normal elderly; normal subjectively impaired elderly; patients with mild cognitive impairment; patients presenting with a continuum of primary cognitive deterioration from mild to moderately severe as measured by the Global Deterioration Scale (GDS), compatible with dementia of the Alzheimers type (DAT). Neurometric QEEG measures were found to be a sensitive index of degree of cognitive impairment, especially reflected in increased absolute and relative power in the theta band, with delta increasing in later stages of deterioration. While these abnormalities were widespread, neither localized or lateralized, MANOVAs for GDS and relative power in theta reached highest significance in a bilateral temporo-parietal arc. A possible relationship between hippocampal dysfunction, cognitive deterioration, and theta abnormalities is discussed in relation to these findings. The results suggest that Neurometric QEEG features are sensitive to the earliest presence of subjective cognitive dysfunction and might be useful in the initial evaluation of patients with suspected dementia, as well as in estimating the degree of cognitive deterioration in DAT patients.

Prediction of longitudinal cognitive decline in normal elderly with subjective complaints using electrophysiological imaging

An extensive literature reports changes in quantitative electroencephalogram (QEEG) with aging and a relationship between magnitude of changes and degree of clinical deterioration in progressive dementia. Longitudinal studies have demonstrated QEEG differences between mild cognitively impaired (MCI) elderly who go on to decline and those who do not. This study focuses on normal elderly with subjective cognitive complaints to assess the utility of QEEG in predicting future decline within 7 years. Forty-four normal elderly received extensive clinical, neurocognitive and QEEG examinations at baseline. All study subjects (N = 44) had only subjective complaints but no objective evidence of cognitive deficit (evaluated using the Global Deterioration Scale [GDS] score, GDS stage = 2) at baseline and were re-evaluated during 7-9 year follow-up. Baseline QEEGs of Decliners differed significantly (p < 0.0001, by MANOVA) from Non-Decliners, characterized by increases in theta power, slowing of mean frequency, and changes in covariance among regions, especially on the right hemisphere. Using logistic regression, an R2 of 0.93 (p < 0.001) was obtained between baseline QEEG features and probability of future decline, with an overall predictive accuracy of 90%. These data indicate high sensitivity and specificity for baseline QEEG as a differential predictor of future cognitive state in normal, subjectively impaired elderly.

Volumetric analysis of the pre-frontal regions: findings in aging and schizophrenia

Frontal lobe dysfunction is thought to be involved in schizophrenia and age-associated cognitive decline. Frontal lobe volume changes have been investigated in these conditions using MRI, but results have been inconsistent. Few volumetric MRI protocols exist that divide the pre-frontal cortex into its sub-regions. In the present article, we describe a new method, which allows assessment of the superior, middle and inferior frontal gyrus, as well as the orbitofrontal and cingulate regions. The method uses multiple planes to help guide the anatomical decisions and combines this with a geometric approach utilizing readily apparent anatomical landmarks. Using this protocol, the frontal lobe volumes in young healthy subjects were contrasted with those of young schizophrenic patients and elderly healthy subjects (nine male subjects per group). The results showed that the method could be reproduced with high reliability (r(icc)> or =0.88-0.99). Schizophrenic as well as old subjects had specific significant reductions in the superior frontal gyrus and orbitofrontal regions compared with the young group. However, old and schizophrenic subjects did not differ from each another. No volume differences were observed in the other three regions assessed. Whether or not these volume reductions reflect a common pathological process remains to be investigated in future studies.

Quantitative electrophysiological characteristics and subtyping of schizophrenia.

Quantitative descriptors of resting electroencephalogram (EEG) (QEEG) and event-related potentials (QERP) to visual and auditory stimuli were obtained from normal subjects and 94 chronic schizophrenic patients on medication, 25 chronic schizophrenics off medication, and 15 schizophrenics with no history of medication. These schizophrenic groups showed a high incidence of neurometric features that were significantly deviant from normative values. Multivariate discriminant analysis using these features successfully separated the schizophrenic patients from normals with high accuracy in independent replication. The data from the medicated group were subjected to cluster analysis. Newly developed algorithms were used for objective selection of the most effective set of variables for clustering and the optimum number of clusters to be sought. Five clusters were obtained, containing roughly equivalent proportions of the sample with markedly different QEEG profiles. The whole sample was then classified into these clusters. Each cluster contained patients both on and off medication, but patients who had never been medicated were classified into only three of these clusters. No significant clinical or demographic differences were found between members of the five clusters; however, clear differences in QERP profiles were seen. These results are described in detail and possible physiological and pharmacological implications are discussed.

Effects of amphetamine on local cerebral metabolism in normal and schizophrenic subjects as determined by positron emission tomography

The effects of d-amphetamine (0.5 mg/kg PO) on regional cerebral glucose utilization were measured with Positron Emission Tomography (PET). Subjects included ten chronic schizophrenics and six controls who received amphetamine, and six chronic schizophrenics and nine controls who received placebo or no treatment. Amphetamine decreased glucose metabolism in all regions studied (frontal, temporal, and striatal) in normal and schizophrenic subjects. The metabolic effects of amphetamine were correlated with plasma level of the drug. Cortical atrophy was associated with a blunted metabolic response.

Brain organization in schizophrenia.

Brain metabolism was measured with positron emission tomography and [11C]deoxyglucose during baseline and during a visual task in 12 normal subjects and 18 schizophrenic patients. Global measures of metabolism for 11 brain regions were transformed into relative values by dividing them by the metabolic value for whole brain. Factor analysis was accomplished on the matrix of intercorrelations among the relative regional values for the normal and for the schizophrenic patients under baseline and under the task. Four factors that revealed independently varying metabolism in frontal, occipital, left-versus-right hemisphere, and subcortical structures were obtained. The frontal and subcortical factors discriminated between normal subjects and schizophrenic patients, whereas the occipital factor discriminated between baseline and task. Although activity in these individual regions varied significantly, it was the pattern of differences in regional metabolic activity that best discriminated between diagnostic groups and testing conditions.

Imaging of Thalamocortical Dysrhythmia in Neuropsychiatry

Abnormal brain activity dynamics, in the sense of a thalamocortical dysrhythmia (TCD), has been proposed as the underlying mechanism for a subset of disorders that bridge the traditional delineations of neurology and neuropsychiatry. In order to test this proposal from a psychiatric perspective, a study using magnetoencephalography (MEG) was implemented in subjects with schizophrenic spectrum disorder (nu2009=u200914), obsessive–compulsive disorder (nu2009=u200910), or depressive disorder (nu2009=u20095) and in control individuals (nu2009=u200918). Detailed CNS electrophysiological analysis of these patients, using MEG, revealed the presence of abnormal theta range spectral power with typical TCD characteristics, in all cases. The use of independent component analysis and minimum-norm-based methods localized such TCD to ventromedial prefrontal and temporal cortices. The observed mode of oscillation was spectrally equivalent but spatially distinct from that of TCD observed in other related disorders, including Parkinsons disease, central tinnitus, neuropathic pain, and autism. The present results indicate that the functional basis for much of these pathologies may relate most fundamentally to the category of calcium channelopathies and serve as a model for the cellular substrate for low-frequency oscillations present in these psychiatric disorders, providing a basis for therapeutic strategies.

Brain interactions in chronic schizophrenics under resting and activation conditions

The metabolic patterns of correlation among brain images obtained during resting conditions and during an eye tracking task were investigated in 12 controls and 18 chronic schizophrenics using positron emission tomography (PET) and deoxy[11C]glucose. Analyses of the interaction between brain regions revealed highly significant differences between groups under both test conditions. Schizophrenics showed lower correlations between anterior and posterior areas and between thalamus and cortical areas than the normals and less change between the baseline and the task than the normals. The schizophrenic subjects showed derangements in the pattern of interactions among brain areas, both under baseline and under activation as compared to the control group.

Cocaine craving and attentional bias in cocaine-dependent schizophrenic patients

Cocaine craving has been implicated as a major factor underlying addiction and drug relapse. From a cognitive viewpoint, craving may reflect, in part, attentional processing biased in favor of drug-related cues and stimuli. Schizophrenic individuals (SZ), however, abuse cocaine in high numbers but typically manifest baseline cognitive deficits that impair their ability to selectively allocate their attentional resources. In this study, we examined the relationship between attentional bias and craving in patients with cocaine dependence (COC; n=20), schizophrenic patients comorbid for cocaine dependence (COC+SZ; n=23), as well as two other comparison groups using a modified version of the Stroop test to include cocaine-relevant words. Results revealed that only the COC patients demonstrated Stroop interference on the cocaine-related words. Moreover, COC patients attentional processing biases were significantly associated with their cocaine craving severity ratings. COC+SZ patients, in contrast, did not demonstrate Stroop interference and manifested significantly fewer craving symptoms than their COC counterparts. These results suggest that COC+SZ patients inability to selectively encode their drug-use experience may limit and shape their subjective experience of craving cocaine and motivation for cocaine use.