John Metz

Sustained human chemosignal unconsciously alters brain function.

The human chemosignal, Δ4,16-androstadien-3-one modulates psychological state without being consciously discernible as an odor. This study demonstrates that Δ4,16-androstadien-3-one (androstadienone) alters cerebral glucose utilization both in subcortical regions and in areas of the neocortex not exclusively associated with olfaction. These widely distributed changes are consistent with modulation of an integrated neural network for regulation of emotional and attentional states. This is the first study to demonstrate the effects of a sustained chemosignal on brain metabolism and to show that they are similar to those of long acting chemical substances that affect psychological states. Moreover, this provides the first evidence that a human chemosignal has distributed effects on cortical processes and brain metabolism even when it is not detected consciously.

Fluoxetine effects on cerebral glucose metabolism

In a counterbalanced, double-blind, placebo-controlled trial, 40 mg of fluoxetine was administered to four healthy adult volunteers (three men, one woman; age range 20-39 years), 90 min before injection of 6-7.5 mCi of [18F]-2-deoxyglucose to measure cerebral metabolic rate of glucose (CMRglu). Subjects were engaged in a visual monitoring task shortly before and during scanning with a PETT-VI tomograph. Global CMRglu did not differ when placebo (8.93 +/- 0.96 mg 100 g-1 min-1) was compared to fluoxetine (8.22 +/- 0.86 mg 100 g-1 min-1; paired t-test = 0.82, df = 3, p < 0.48). However, statistical parametric mapping of differences in CMRglu between placebo and fluoxetine conditions revealed regional effects of fluoxetine shown by decreased metabolism in the amygdaloid complex, hippocampal formation and ventral striatum, and by increased metabolism centered in the right superior parietal lobe (Brodmann area 7). Parametric mapping for use in PET studies of glucose metabolism represents a significant new tool for studying drug effects in humans.

Basal ganglia regional glucose metabolism asymmetry during a catatonic episode

The pathophysiology of catatonic symptoms remains unknown, although several anatomical sites, including the basal ganglia (Kleist et al. 1960) and brainstem (Blasco et al. 1986), have been implicated. We have attempted to study the physiological substrate of these symptoms by employing positron emission tomography (PET) in the first PET study of a patient with catatonia. The patient was a 22-year-old black woman admitted to our research unit with a DSMIIf diagnosis of schizoaffect~ve disorder. She had a 4-year history of episodes of psychoses associated with auditory hallucinations and loose associations. She had been treated with antipsychotic medications during most of this period. On admission, she showed labile effect with racing thoughts, hypersexuality. and paranoid delusions. During a s-week drug-free period. she became increasingly psychotic and catatonic. Despite a subsequent week of lithium treatment (1200 mg daily, lithium level 0.8 mEqiliter), she continued to show mutism, posturing, waxy flexibility, and decreased psychomotor activity. In this state, she underwent a first PET scan. Seventeen days later, while on the same dose and blood level of lithium, she was retested in the PET procedure. At this time, there was no evidence of catatonia.

Descriptive studies of H-reflex recovery curves in psychiatric patients

The rate of recovery of the H-reflex, an electrical evoked monosynaptic spinal cord reflex, was abnormally high (fast) in over 20% of unmedicated psychotic patients of all major diagnostic classes. A few patients had significantly lower H-reflex recovery curves. Chronic neuroleptic treatment produced relatively lower recovery curves, whereas fluoxetine, a specific serotonin uptake blocker, produced relatively higher curves.

Des-tyrosine-γ-endorphin: H-reflex response similar to neuroleptics

Abstract In a study of eight schizophrenic patients, des-tyrosine-γ-endorphin was found to significantly reduce secondary facilitation of the H-reflex recovery curve. This result is similar to the effect found after treatment with classical neuroleptic medication. The effect is different from that produced by lithium carbonate or anti-depressants. This suggests that des-tyrosine-γ-endorphin and neuroleptics have a similar pharmacological action in man.

Effect of chlorpromazine on H-reflex recovery curves in normal subjects and schizophrenic patients

This study sought to determine the effect of chlorpromazine (CPZ) on a physiological measure, the H-reflex recovery curve (HRRC) and to determine whether the effect is different in normal subjects and schizophrenic patients. Eleven normal control subjects and 14 patients were administered 12.5 and 25.0 mg CPZ by IM injection. On the average, HRRCs measured 90 min after the injections were lower compared to pre-injection levels in both groups, at both doses. In general, the higher dose was more effective in both groups. Half of the patients, however, failed to respond to 12.5 mg, indicating that some schizophrenics are less sensitive than normals to CPZ. These results indicate that excessive dopamine activity or sensitivity may underlie abnormally high HRRCs in unmedicated psychotic patients.

Pharmacologic Challenge in ERP Researcha

In 1968, Sam Sutton (1969) wrote a critical review on the subject of experimental design in event-related potential (ERP) research and defined the “triangular experimental paradigm.” He argued that in the ideal ERP experiment, all three corners of a triad-stimulus events, physiological events, and psychological events-should be studied simultaneoirsly. He astutely noted that it was more common, and much easier, to examine only two corners at a time. Unfortunately, what is lost in the two-corner approach, he noted, is the ability to assess critical sources of variance in an ERP experiment. He was pointing to the value of using independent sources of information in construct validation. Concepts emphasized in his review, like the need for experimental control over “subject option” and the need for greater refinement in behavioral assessments during ERP recording were to heavily influence the field for the next two decades as they still do today. In this paper, we shall review the strategy of examining different classes of variables simultaneously for the purposes of obtaining converging evidence about the nature of ERP response to pharmacologic challenge and understanding the pathophysiology of psychosis. Advantages and problems in extending the triangular research paradigm to include more levels of the physiological corner of the triad will be demonstrated. We shall use our own study of acute challenge with the psychotomimetic N,N-dimethykryptamine (DMT) to illustrate how information simultaneously derived from multiple levels of independent measurement can potentially provide insight for interpreting behavioral and physiological response to a drug. In this case, the multilevel approach involved combining behavioral and neurotransmitter/neuroendocrine data with ERP and Hoffman-reflex (H-reflex) measures before and after administration of DMT alone or DMT in conjunction

Effect of 5-hydroxytryptophan on H-reflex recovery curves in normal subjects and patients with affective disorders ☆

The effect of the serotonin precursor DL-5-hydroxytryptophan (5-HTP) on the Hoffmann reflex recovery curve (HRRC) was studied in normal subjects and patients with affective illness. 5-HTP significantly decreased the HRRC in normal controls and in depressed and manic patients receiving treatment with lithium or antidepressants. 5-HTP increased the HRRC in unmedicated depressed and manic patients. These results provide further evidence for a serotonergic abnormality in the affective disorders.

Positron emission tomography in central nervous system drug discovery and development

Genetics, neuroscience, and imaging science have advanced greatly in the last few years. These advances can be brought together and applied in creative new ways to make available better drugs for treating neuropsychiatric disorders and for getting candidate drugs through the development process faster. One particular approach, built around [18F]fluordeoxyglucose positron emission tomography, is described.

Brain imaging in psychoses. structural and functional findings

Recent brain imaging studies in the psychoses outlining developments in our understanding of both structural and functional abnormalities are reviewed. Emphasis is placed on methodological issues that complicate this area of research while attention is drawn to the most promising technologies