THE EFFECTSOF SLEEP ANDLACK OF SLEEP ONTHE CEREBRALCIRCULATION AND METABOLISMOF NORMALYOUNGMEN1

By RENWARDMANGOLD,LOUIS SOKOLOFF, EUGENECONNER,JEROMEKLEINERMAN, PER-OLOF G. THERMAN,AND SEYMOURS. KETY

(From the Department of Physiology and Pharmacology, Graduate School of Medicine, theDepartment of Anesthesia, Hospital of the University of Pennsylvania, and the Har-

rison Department of Surgical Research, University of Pennsylvania,Philadelphia, Penna.)

(Submitted for publication October 21, 1954; accepted March 21, 1955)

Numerous hypotheses have been elaborated inattempts to explain the puzzling phenomenon ofsleep. Thus sleep has been attributed to arterialanoxemia, to cerebral ischemia or anoxia, or to ageneralized narcosis on the basis of one or anothermetabolic alteration. Little information is avail-able, however, on the subject of cerebral metabo-lism and function during natural sleep. Thismight be explained to a great extent by the diffi-culties inherent in any experimental investigationduring so labile a state as physiological sleep.Moreover, reasonably quantitative techniques formeasuring the blood flow and oxygen consumptionof the brain in unanesthetized animals and in manhave become available only recently. Early at-tempts (1) to obtain at least qualitative informa-tion on the cerebral blood flow in man during sleepby means of brain plethysmography through tre-phine holes have yielded contradictory results.Later attempts with better methods of recording(2) have suggested a decrease in cerebral bloodflow on passage from the waking state to short orlong periods of sleep. More recently, Gibbs,Gibbs, and Lennox have attempted to obtain abetter understanding of the cerebral circulationduring sleep by means of the thermoelectric flowrecorder (3). They found no significant altera-tion in cerebral blood flow during short periods ofsleep in four epileptic patients. Unfortunately,arterio-cerebral venous oxygen differences werenot measured simultaneously, and no informationon the important question of the oxygen consump-tion of the brain was obtained.

Recently developed methods permit a morequantitative determination of the cerebral blood

' This investigation was supported in part by a re-search grant from the Division of Research Grants andFellowships of the National Institutes of Health, UnitedStates Public Health Service.

flow and oxygen consumption during naturalsleep. It was to obtain such information as wellas to test some of the previously proposed hypo-theses that the present study was undertaken.

METHOD

Attempts to measure cerebral blood flow by means ofthe nitrous oxide technique (4) during sleep were madein approximately fifty, healthy, young, male volunteersvarying in age from 17 to 36 years. In order to facili-tate the induction of sleep under the conditions of thestudy, the subjects had remained awake for a period ofapproximately 20 hours, or about six hours beyond theirnormal bed-time, prior to the study. They are, therefore,referred to as "fatigued." Except for making the sub-jects as comfortable as the procedure would allow, nodrugs or other special methods for inducing sleep wereemployed. The studies were performed in the earlymorning hours, most often between 4 and 6 A.M., whenthe tendency to fall asleep after a prolonged period ofwakefulness is generally greatest (2). In most casesthe subjects had been fasting for several hours; a fewhad eaten a light meal approximately two hours priorto the study.

In each study the subject was placed in the supineposition, the needles were inserted in the internal j'ugu-lar bulb and the femoral artery, needle electrodes forEEGrecording were placed in the scalp, and a mask wasstrapped on the face. The subject was then permitted torest in this position for about thirty minutes to permitany physical and emotional disturbances attending the in-troduction of the needles to subside. At this point thefirst or control blood flow determination was performed.The room was then darkened and quieted, and the sub-ject, still in the same position, was given an opportunityto fall asleep. During this period the subject was usu-ally permitted to breathe room air through a valve con-nected to the mask. In a few cases compressed air wasfed from a tank into the mask through a reducing valvein an effort to minimize the waking effect of the gas flowassociated with the nitrous oxide procedure. The stateof wakefulness or sleep was followed by means of con-tinuous EEG recordings in the adjacent room from thefour to eight scalp electrodes previously inserted. Theserecordings were made continuously throughout the study

1092

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including the periods during which cerebral blood flowmeasurements were being made. The mental state or

level of sleep was evaluated by means of the EEG rec-

ord on the basis of the classification of Gibbs and Gibbs(5) as well as by clinical observation including move-

ments, snoring, and response to whispered commands.In no case was the subject considered asleep until afterthe appearance of the characteristic sleep spindles anddelta waves in the EEG record (Figure 1). When, on

the basis of all these criteria, the subj ect was con-

sidered to be in a relatively steady state of sleep, a

cerebral blood flow determination was made. The aboveprocedure was followed in all the cases in Tables IA andIB except two (P. 0. and McK.) in which the order was

reversed, sleep occurring throughout the first determina-tion of cerebral blood flow and the control determinationperformed after the subjects had been awakened andkept awake for 45 and 55 minutes, respectively.

In approximately fifty attempts an uninterrupted stateof sleep of sufficient depth and duration to fulfill all thecriteria was achieved in only six cases. A large num-

ber of studies was discarded because independent reviewof the EEG record failed to confirm the presence of a

steady state of sleep throughout the period of cerebralblood flow determination or revealed momentary epi-sodes of sleep rhythms during the control period. Insome of those cases in which sleep did not occur, a sec-

ond cerebral blood flow determination was made underexactly the same conditions as the first to form a group

of "consecutive fatigued controls" with which to studythe variation between two consecutive determinations inthe same individual done under identical conditions butseparated in time by an interval approximating that be-tween the control and sleep determinations.

In all the studies mean arterial blood pressure was

measured with a damped mercury manometer attachedto the femoral arterial needle. Blood oxygen and car-

bon dioxide contents were determined by the mano-

metric method of Van Slyke and Neill (6). Total hemo-globin concentration in arterial blood was measured in

the Evelyn photometer according to a modification of themethod of Evelyn and Malloy (7). Measurements ofblood pH were made anerobically at room temperature bymeans of a glass electrode and Cambridge potentiometerand corrected to 370 C. by the factors of Rosenthal (8).Cerebral oxygen consumption, cerebral vascular re-sistance, and cerebral respiratory quotient were calcu-lated as previously described (4). Blood carbon dioxidetension was computed by means of the nomograms ofPeters and Van Slyke (9).

RESULTS

In Tables IA and IB are presented the data ob-tained in the six subjects on whomcomplete sleepstudies could be made. The results obtained inthe consecutive fatigued control studies in 13subjects are presented in Tables IIA and IIB.

It is apparent that during sleep cerebral bloodflow (CBF) is increased, rising from 59 duringthe control state to 65 cc. per 100 g. per min. dur-ing sleep (p < 0.01) while no such statisticallysignificant change in CBF was found in the con-secutive fatigued controls. The rise in CBF oc-curred in sleep despite a significant fall in mean ar-terial blood pressure (MABP) from 94 mm. Hgto 90 mm. Hg (p < 0.05). The series of consecu-tive studies on fatigued but awake subjects showeda significant blood pressure change in quite the op-posite direction, rising from a mean of 90 mm. Hgin the first to 96 mm. Hg in the second determina-tion (p < 0.01). This systematic change in MABPbetween two consecutive control determinationsdoes not explain, however, the decrease found insleep since the sleep series was a mixed one, sleepsometimes occurring in the first but more often

1093

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CEREBRALCIRCULATION AND METABOLISMDURING SLEEP

in the second of the two determinations. It seems

warranted to conclude that the decreased MABPis associated with the phenomenon of sleep. Theelevation of the blood pressure in the second ofthe consecutive controls was probably the resultof the growing discomfort on the part of the sub-ject from lying in the same position for a pro-longed period.

Since CBF increased despite a decreasedMABP, cerebral vascular resistance (CVR) musthave fallen in sleep, as indicated in the change inits calculated value from 1.6 in the control deter-minations to 1.5 mm. Hg per cc. per 100 g. per

min. during sleep (p < 0.01). On the otherhand, CVRrose from a mean of 1.5 in the first to1.7 mm. Hg per cc. per 100 g. per min. in the sec-

ond of the consecutive control determinations(p -- 0.01). The fall in CVRobserved in sleepis probably associated with the phenomenon ofsleep and, for the same reasons discussed in rela-tion to the MABP, cannot be explained simply bythe systematic difference in CVR found to existbetween two consecutive control determinations.

Cerebral arterial-venous oxygen difference andcerebral oxygen consumption (CMRo2) showed no

significant changes in either the sleep or the con-

secutive control studies. Cerebral R. Q. did notchange in sleep, but the mean value, 1.02, in thesecond of the consecutive control determinationssignificantly exceeded the mean value, 0.93, ob-tained in the first determination (p < 0.05), a

finding for which no reasonable explanation is athand. Arterial hemoglobin concentrations, ar-

terial and cerebral venous oxygen and carbon di-oxide contents and pH did not change significantlyin either group. Arterial and internal jugularcarbon dioxide tensions (pCO2) were not sig-nificantly altered by sleep although it is interest-ing and possibly significant to note that these val-ues were appreciably higher in the sleep group,

even in their control state, than in the fatiguedgroup which could not sleep during the studies(p < 0.05 and p < 0.02, respectively). Simi-larly, the mean values for arterial and internaljugular blood pH were significantly lower in bothdeterminations of the sleep group than in thefatigued group which failed to sleep (p < 0.05,respectively). In the consecutive control studiesarterial pCO2 remained unchanged, but the mean

value of cerebral venous pCO2, 51 mm. Hg, in

the second determination significantly exceededthe mean value, 50 mm. Hg, in the first determina-tion (p < 0.05). This finding is probably re-lated to the tendency for the CBF to decrease inthe second determination.

In Table III, comparison is made between theresults obtained in 25 awake but "fatigued" nor-mal young men and those observed in 11 normalrested young men studied similarly by the samegroup of investigators. The values obtained inthe rested subjects agree closely with those previ-ously reported by Kety and Schmidt (4). Thesedata are taken from the control values of variousexperimental procedures provided that the con-trol determinations were made first. Thus thefatigued group includes also the first of the con-secutive control determinations in Tables IIA andIIB and the control values of those sleep cases inTables IA and IB in which the control determina-tion was first. On the basis of this comparison,no significant differences between fatigued andrested subjects could be found although the meanvalue for CBF, 64, in the fatigued group ex-ceeded the mean value, 55 cc. per 100 g. per min.,in the rested group by an amount approachingstatistical significance (p < 0.1 > 0.05).

DISCUSSION

These findings are of interest because of theirpertinence to certain theories which have been ad-vanced from time to time toward an explanation ofthe phenomenon of natural sleep. A number ofthese theories have in common the postulate thatsleep is associated with and caused by a diminu-tion in the gross nutrition or metabolism of thebrain.

Quite recently, Doust and Schneider have elabo-rated a theory which ascribes sleep to arterialanoxemia and its resultant cerebral anoxia (10).On the basis of a downward drift in the readingsof an ear oximeter, these authors concluded thatarterial oxygen saturation progressively decreasedduring the process of falling asleep and reachedlevels as low as 87 per cent during deep sleep.The lack of an attempt to confirm this surprisingresult by more direct techniques and the absenceof similar observations on non-sleeping controlsleaves open the possibility, however, that it mayhave been one of the artifacts sometimes associatedwith indirect oximetry. Our findings (Table IB)

1097

MANGOLD, SOKOLOFF, CONNER, KLEINERMAN, THERMAN, AND KETY

that both the oxygen content and hemoglobin con-centration of arterial blood were normal duringthe control period and remained unaltered duringsleep make unlikely any hypothesis which at-tributes a causal role to arterial anoxemia.

If not the first, then certainly one of the earliestrecorded theories of sleep attributed this phenome-non to an ischemia of the brain. By recordingchanges in intracranial volume in two subjectswith cranial defects, Mosso (1) concluded thatsleep was associated with a decrease in cerebralblood volume. Tarchanoff (11) supported thisview by observing a blanching of the pial vesselsin puppies when sleep occurred. A large num-ber of investigators, however, were unable to cor-roborate the findings of Mosso or found insteadevidence of cerebral vascular engorgement (12-16). None of these observations yielded informa-tion on cerebral blood flow which is certainly dif-ferent from and not necessarily correlated withcerebral blood volume. Only in the case of Gibbs,Gibbs, and Lennox, whose thermoelectric tech-nique would probably have indicated if it did notmeasure gross changes, had observations relatedto cerebral blood flow in sleep been made (3).These authors were unable to demonstrate anychange during sleep in the function which theystudied.

The present studies show a moderate but sta-tistically significant increase in cerebral blood flowassociated with sleep. This occurred in the faceof the slight but significant fall in arterial bloodpressure seen in these subjects and consistentlyobserved by numerous previous investigators (17-19) and was the result, therefore, of a decreasedresistance to flow somewhere in the brain. Sincethe intracranial pressure is usually found to riseduring sleep (14, 15), and since the present stud-ies demonstrate no change in hemoglobin concen-tration in the blood, factors of decreased externalpressure or lessened viscosity appear to be ruledout, and it seems warranted to conclude that thereis a relaxation in cerebrovascular tone duringsleep. This supports previous observations whichsuggested a cerebral hyperemia during sleep (12-16). The cause of this cerebrovascular relaxationremains obscure. It cannot be attributed tochanges in arterial oxygen or carbon dioxide ten-sion since these remained relatively unaltered be-tween control and sleep, nor was it in response to

an increase in cerebral metabolism which was alsounaffected. The usually plausible hypothesis ofa decrease in neurogenic vasoconstrictor tone isrendered less tenable by the failure to demonstratea normal vasoconstrictor tone in the cerebral ves-sels of man, or at least one mediated by the knownsympathetic inflow to the head (20).

Examination of the data in Table III revealsthat the results in normal rested young men werealmost identical with those in the original report ofthe method (4). When considered as a singlegroup, the subjects who had remained awake forseveral hours beyond their normal bedtime andwere, therefore, "fatigued," did not differ signifi-cantly in any respect from the rested young men.Within the "fatigued" group, however, arterialand cerebral venous carbon dioxide tensions weresignificantly higher and pH significantly lowerin those subjects who slept than in the subjectswho were unable to sleep under the conditions ofthe experiment (Tables IB and IIB). These dif-ferences, indicative of a mild respiratory acidosis,were apparent not only during sleep but even dur-ing the control period when the sleep subjectswere awake. Comparable changes have been ob-served previously during sleep (2, 21), and Mills(22) has found elevations of alveolar carbon diox-ide tension during the night or early morning ir-respective of whether the subjects were awake orasleep. He attributes these changes to a normaldiurnal rhythm in alveolar carbon dioxide ten-sion which is independent of sleep. Our resultsindicate also that the respiratory acidosis can oc-cur in the absence of sleep and that sleep per secauses little if any change in carbon dioxide ten-sion and pH of the blood, but they raise an inter-esting question of whether sleep can occur in theabsence of the respiratory acidosis. It was thisfinding which distinguished the subjects whoslept from those who could not sleep under iden-tical experimental conditions. Despite the evi-dence of respiratory depression, no significantanoxemia was observed in these subjects, norwas it to be expected. As Mills has also observedin his studies (22), the degree of carbon dioxideretention was insufficient to account for any ap-preciable fall in arterial-oxygen saturation, cer-tainly not to the levels on which Doust andSchneider (10) based their anoxemic theory ofsleep.

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CEREBRALCIRCULATION AND METABOLISMDURING SLEEP

Another hypothesis on the nature of sleep sug-gests that this state is some endogenous narcosisassociated with an overall decrease in metabolicactivity in the central nervous system which per-mits the replenishment of certain substrate storespresumably depleted by the active metabolism ofthe waking state. That sleep is quite differentfrom anesthesia or coma is clearly demonstratedby the data on cerebral oxygen consumption(Table IA). Whereas coma (23, 24) or anes-thesia (25) are associated with profound de-creases in the utilization of oxygen by the brain,this function in sleep is not significantly differ-ent from its level in the waking state.

Thus the state of sleep should be added to agrowing list of conditions, like schizophrenia (23)and performance of mental arithmetic (26), inwhich a good correlation between energy conver-sion and functional activity commonly found inother organ systems appears to be absent. Thisresult is compatible with the current vogue ofviewing the brain as a calculating or communicat-ing mechanism which, in contradistinction to ma-chines which do mechanical work, utilizes by farthe greater part of its energy requirements merelyin keeping its circuits alive and sensitive; thepresence of a message, its functional usefulness orrationality adds only infinitesimally to the totalload. Equally adequate, however, are hypothe-ses found more on traditional biological conceptsthan on electronic analogues. Thus, when thebrain is considered as a great number of functionalunits, many of which may be reciprocally relatedwith regard to activity, then increased activity inone group of units may result in decreased ac-tivity in others. Under such conditions, differentfunctions could result in an altered pattern ofdistribution of the activity without measurablechanges in the net overall oxygen consumption ofthe brain. Or, even more simply, is it not con-ceivable that the primitive functions of the brain,namely, the regulation of unconscious vegetativefunctions in the body, consume so much of thetotal cerebral oxygen requirements that they ob-scure the metabolic effects of the later phylo-genetic functions found in conscious waking be-havior, such as thought and reason?

These studies have not elicited, nor were theydesigned to elicit information bearing on the moresubtle functional, biochemical, or electrical al-

terations in sleep. They do, however, render un-tenable those hypotheses which attribute this im-portant phenomenon to an anoxemia, to cerebralischemia, to narcosis, or to a generalized depres-sion in cerebral metabolism.

SUMMARY

1. Studies of cerebral blood flow, cerebral vas-cular resistance, and cerebral oxygen consump-tion, as well as mean arterial blood pressure, he-moglobin concentration, blood gases, and bloodpH, were made before or after and during naturalsleep in six subjects, during two consecutive de-terminations under identical conditions in 13 sub-jects, during a state of fatigue in 25 subjects, andalso in 11 normal rested controls.

2. The mean values obtained in the rested sub-jects were almost identical with the original nor-mal values reported for the method.

3. The fatigued subjects showed no differencesfrom the rested controls except for an elevationin cerebral blood flow which approached statisti-cal significance.

4. During natural sleep there was a statisticallysignificant increase in cerebral blood flow, statisti-cally significant decreases in cerebral vascular re-sistance and mean arterial blood pressure, and nochanges in cerebral oxygen consumption, hemo-globin concentration, and arterial oxygen content.

5. The fatigued subjects who slept were distin-guished from those who were unable to sleep bysignificantly higher values of carbon dioxide ten-sion and lower values of pH in arterial and cere-bral venous blood even during the control period.These findings suggest some relationship betweenrespiratory acidosis and the process of fallingasleep.

6. The results of these studies make less tenablethose hypotheses which attribute sleep to arterialanoxemia, cerebral ischemia, or to a generalizednarcosis or other depression in cerebral metabolicrate.

ACKNOWLEDGMENTS

The authors wish to express their appreciation to MissCarolyn Doernbach, Miss Hilda Klotz, and Mrs. IsabelVan den Noort for their technical assistance.

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MANGOLD,SOKOLOFF, CONNER, KLEINERMAN, THERMAN,AND KETY

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