Seymour S. Kety

THE NITROUS OXIDE METHOD FOR THE QUANTITATIVE DETERMINATION OF CEREBRAL BLOOD FLOW IN MAN: THEORY, PROCEDURE AND NORMAL VALUES

In 1945 the authors reported the determination of cerebral blood. flow in man by the use of nitrous oxide in low concentration, a technique which permitted for the first time quantitative clinical measurement of this important physiologic function (1). Since that time numerous modifications have been made in the procedure (2) and the underlying theory has been subjected to extensive experimental evaluation. The present report constitutes a description of the technique as we have now employed it in over 300 determinations, an examination of its underlying theory and validity, and values obtained with its use in 34 studies on 14 normal young men.

THE EFFECTS OF ALTERED ARTERIAL TENSIONS OF CARBON DIOXIDE AND OXYGEN ON CEREBRAL BLOOD FLOW AND CEREBRAL OXYGEN CONSUMPTION OF NORMAL YOUNG MEN

A method for measuring quantitatively the volume of cerebral blood flow in man by inhalation of nitrous oxide (1) found its first application in a study of the cerebral circulatory effects of low CO2 tension achieved by hyperventilation; of high CO2 tension, and of high and low 02 tensions obtained by inhalation of appropriate gas mixtures (2). Only the first part of this study, the effects of active and passive hyperventilation, has been published in detail (3). The purpose of the present paper is to present the remainder of these findings and to derive from them, together with those of the hyperventilation experiments, evidence bearing on the intrinsic control of the human cerebral circulation as revealed by quantitative measurements.

Biogenic Amines and Emotion

The studies discussed here have shown a fairly consistent relationship between the effects of drugs on biogenic amines, particularly norepinephrine, and affective or behavioral states. Those drugs which cause depletion and inactivation of norepinephrine centrally produce sedation or depression, while drugs which increase or potentiate brain norepinephrine are associated with behavioral stimulation or excitement and generally have an antidepressant effect in man (Table 1). From these findings, a number of investigators have formulated the concept, designated the catecholamine hypothesis of affective disorders (6), that some, if not all, depressions may be associated with a relative deficiency of norepinephrine at functionally important adrenergic receptor sites in the brain, whereas elations may be associated with an excess of such amines. It is not possible either to confirm or to reject this hypothesis on the basis of currently available clinical data. Although there does appear to be a fairly consistent relationship between the effects of pharmacological agents on norepinephrine metabolism and on affective state, a rigorous extrapolation from pharmacological studies to pathophysiology cannot be made. Confirmation of this hypothesis must ultimately depend upon direct demonstration of the biochemical abnormality in the naturally occurring illness. It should be emphasized, however, that the demonstration of such a biochemical abnormality would not necessarily imply a genetic or constitutional, rather than an environmental or psychological, etiology of depression.Whereas specific genetic factors may be of importance in the etiology of some, and possibly all, depressions, it is equally conceivable that early experiences of the infant or child may cause enduring biochemical changes and that these may predispose some individuals to depressions in adulthood. It is not likely that changes in the metabolism of the biogenic amines alone will account for the complex phenomena of normal or pathological affect.Whereas the effects of these amines at particular sites in the brain may be of crucial importance in the regulation of affect, any comprehensive formulation of the physiology of affective state will have to include many other concomitant biochemical, physiological, and psychological factors. Although in this review of the relationship of biogenic amines to affective state relatively little has been said concerning the intricate set of environmental and psychological determinants of emotion, the importance of these factors must be stressed. The normally occurring alterations in affective state induced by environmental events is well known to all, from personal experience. The interactions between such environmental determinants of affect, various physiological factors, and the complexity of psychological determinants, including cognitive factors derived from the individuals remote and immediate past experiences, have received only limited study under adequately controlled conditions. It may be anticipated, however, that this will prove to be a particularly fruitful area for future research, for only within such a multifactorial framework may one expect to understand fully the relationship of the biogenic amines to emotional state.

Effects of amino acid feedings in schizophrenic patients treated with iproniazid.

Large oral doses of individual amino acids were given three or four times daily for periods of 1 week to schizophrenic patients, some of whom were maintained on iproniazid. Marked alterations in behavior in some patients were associated with the administration of l-methionine and of l-tryptophan.

Human cerebral blood flow and oxygen consumption as related to aging

Abstract A review of available information on over-all cerebral blood flow and oxygen consumption in man obtained by means of the nitrous oxide technique reveals a distinct correlation of these functions with age. There is a rapid fall in the circulation and oxygen utilization of the brain from childhood through adolescence followed by a more gradual but progressive reduction throughout the remaining age span. The factors responsible for these changes and whether one or the other is primary appear to be suitable subjects for continued investigation.

THE EFFECTS OF INCREASED INTRACRANIAL PRESSURE ON CEREBRAL CIRCULATORY FUNCTIONS IN MAN

The effect of increased intracranial pressure on cerebral blood flow has been the object of very few clinical studies. In accordance with the MonroeKellie-Cushing Doctrine, it would be presumed that increased intracranial pressure would increase cerebrovascular resistance and thereby decrease cerebral blood flow. However, Williams and Lennox (1) in 1939 concluded on the basis of cerebral arteriovenous oxygen differences that cerebral blood flow was practically unaffected by a rise in cerebrospinal fluid pressure. Courtice (2) also working with humans and using a similar technique came to a different conclusion: that there was a slowing of blood flow through the brain in certain types of brain tumor associated with increased intracranial pressure. More recently Ferris (3), using a plethysmographic meas-

THE BLOOD FLOW, VASCULAR RESISTANCE, AND OXYGEN CONSUMPTION OF THE BRAIN IN ESSENTIAL HYPERTENSION

The vascular bed of the brain should occupy a prominent place among the regions of interest to the clinical investigator who would seek to define the circulatory disturbances associated with hypertension. The vulnerability of cerebral arteries in chronic hypertensive disease has long been recognized. Statistical surveys demonstrate that about 15% of deaths in hypertension are the result of cerebrovascular lesions (1 to 3). Many hypertensive patients experience symptoms such as headache, dizziness, and tinnitus, which are probably referable to the brain. Furthermore it has been suggested :that some of the etiological factors in hypertension may be of cerebral origin. Knowledge of the cerebrovascular resistance and cerebral blood flow in human hypertension has been extremely limited. The well-recognized changes observed in retinal vessels, in the absence of more specific information, have been presumed to reflect similar phenomena in the cerebral vascular bed. Measurement of cerebral blood flow in this disease has been limited to studies of cerebral arteriovenous oxygen differences (4, 5) which become an index of blood flow only after cerebral metabolism can be measured or shown to be normal. The nitrous oxide method for the quantitative measurement of human cerebral blood flow (6, 7) found its first application to clinical disease in a study on five patients with various degrees of arterial hypertension (8). The present study represents a more complete investigation on 13 additional patients.

Schizophrenics' offspring reared in adoptive homes

THIS is the first of a projected series of reports on what Dr. Kety, Dr. Wender and I call the Adoptees Study.l The one that Dr. Kety presented we call the Extended Family Study and the one that Dr. Wender presented we call the Adoptive Parents Study. The names may help to distinguish the studies in future discussions of them. This is a preliminary as well as a first report, since we are still very much in the midst of our extensive research activities. We will be finding and examining subjects for at least another year. In June 1967 we began the third year of this project. The reader will observe a strong resemblance, as well as important differences in conception and method, between the Adoptees Study and the study reported by Heston. We want to point out that our study was conceived and planned years before we learned of Heston’s remarkable feat, and it was well under way for some time before Heston’s report appeared. Although all our studies attempt to assess the relative contributions of heredity and environment to schizophrenia, the major focus of the Adoptees Study is somewhat different. Here we are trying to obtain evidence that a diathesis-stress theory of schizophrenia is correct. What we would like to do is to detect and describe some behavioral and psychological aspects of that inherited diathesis. Paul Meehl would call it the “schizotype”, which is a perfectly good name for it.

O-methylation, the Principal Route of Metabolism of Epinephrine in Man

Evidence is presented which indicates that the principal pathway of metabolism of epinephrine in man is O-methylation to metanephrine. The extent of the conLversion to metanephrine, a physiologically inactive compound, indicates that the enzyme responsible for this reaction, catechol-O-methyl transferase, is the enzyme mainly involved in the termination of action of epinephrine in man.

CEREBRAL BLOOD FLOW AND OXYGEN CONSUMPTION IN HYPERTHYROIDISM BEFORE AND AFTER TREATMENT

The unexpected results of this early study inspired Sokoloff to study the effects of thyroxine on brain metabolism.