Reprinted from Tuk Journay ov Chinicar Exvesrication, Vol. XXXIV, No. 7, pp. 1092-1100, July, 1955 Printed in U. S. A. THE REPECTS OF SLEEP AND LACK OF SLEEP ON THE CEREBRAL. CERCULATION AND METABOLISM OF NORMAL YOUNG MIEN? By RENWARD MANGOLD, LOUIS SOKOLOV, EUGENE CONNER, JEROME KLETNERMAN, PER-OLOF G. THERMAN, ann SEYMOUR S. KETY (from the Pepartment of Physiology and Pharmacology, Graduate School of Medicine, the Department of Anesthesia, Lospital 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 in attempts to explain the puzzling phenomenon of sleep. Thus sleep has been attributed to arterial anoxemia, to cerebral ischemia or anoxia, or to a generalized narcosis on the basis of one or another metabolic alteration. Little information is avail- able, however, on the subject of cerebral metabo- lism and fanetion during natural sleep. This might be explained to a great extent by the diffi- culties inherent in any experimental investigation during so labile a state as physiological sleep. Moreover, reasonably quantitative techniques for measuring the blood flow and oxygen consumption of the brain in unanesthetized animals and in man have become available only recently. [arly at- tempts (1) to obtain at least qualitative informa- tion on the cerebral blood flow in man during sleep by 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 blood flow on passage from the waking state to short or long periods of sleep. More recently, Gibbs, Gibbs, and Lennox have attempted to obtain a better understanding of the cerebral circulation during sleep by means of the thermoelectric flow recorder (3). They found no significant altera- tion in cerebral blood flow during short periods of sleep in four epileptic patients. Unfortunately, arterio-cerebral venous oxygen differences were not measured simultaneously, and no information on the important question of the oxygen consump- tion of the brain was obtained. Recently developed methods permit a more quantitative determination of the cerebral blood 1 This investigation was supported in part by a re- search grant from the Division of Research Grants and Fellowships of the National Institutes of Health, United States Public Health Service. flow and oxygen consumption during natural sleep. Tt was to obtain such information as well as to test some of the previously proposed hypo- theses that the present study was undertaken. METIH{OD Attempts to measure cerebral blood flow by means of the nitrous oxide technique (4) during sleep were made in approximately fifty, healthy, young, male volunteers varying in age from 17 to 36 years. In order to facili- tate the induction of sleep under the conditions of the study, the subjects had remained awake for a period of approximately 20 hours, or about six hours beyond their normal 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, no drugs or other special methods for inducing sleep were employed. The studies were performed in the early morning hours, most often between 4 and 6 A.M., when the tendency to fall asleep after a prolonged period of wakefulness is generally greatest (2). In most cases the subjects had been fasting for several hours; a few had eaten a light meal approximately two hours prior to the study. In each study the subject was placed in the supine position, the needles were inserted in the internal jugu- lar bulb and the femoral artery, needle electrodes for “EG recording were placed in the scalp, and a mask was strapped on the face. The subject was then permitted to rest in this position for about thirty minutes to permit any physical and emotional disturbances attending the in- troduction of the needles to subside. At this point the first 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 opportunity to 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 was fed from a tank into the mask through a reducing valve in an effort to minimize the waking effect of the gas flow associated with the nitrous oxide procedure. The state of wakefulness or sleep was followed by means of con- tinuous EEG recordings in the adjacent room from the four to eight scalp electrodes previously inserted. These recordings were made continuously throughout the study 1092 1093 R tek, . my hy PLA Cy RP ni etanennniwpeenivinnt amen ilaa) AI namy tA aH \ a i Mae PA CONTROL Fic. 1. including the periods during which cerebral blood flow measurements 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 ease was the subject considered asleep until after the appearance of the characteristic sleep spindles and delta waves in the EEG record (Figure 1). When, on the basis of all these criteria, the subject was con- sidered to be in a relatively steady state of sleep, a cerebral blood flow determination was made. The above procedure was followed in all the cases in Tables LA and IB except two (P.O. and McK.) in which the order was reversed, sleep occurring throughout the first determina- tion of cerebral blood flow and the control determination performed after the subjects had been awakened and kept awake for 45 and 55 minutes, respectively. In approximately fifty attempts an uninterrupted state of sleep of sufficient depth and duration to fulfill all the criteria was achieved in only six cases. A large num- her of studies was discarded because independent review of the EMG reeord failed to confirm the presence of a steady state of sleep throughout the period of cerebral determination or revealed momentary epi- sudes of sleep rhythms during the control period. In blood flow some of those cases in which sleep did not occur, a sec- ond cerebral blood flow determination was made under exactly the same conditions as the first to form a group of “consecutive fatigued controls” with which to study the variation between two consecutive determinations in the same individual done under identical conditions but separated in time by an interval approximating that be- taveen the control and sleep determinations. {In all the studies mean arterial blood pressure was measured with a damped mercury manometer attached Blood oxygen and car- bon dioside contents were determined by the mano- metric inethod of Van Slyke and Neill (6). Total hemo- elobin concentration in arterial blood was measured in to the femoral arterial needle. MANGOLD, SOKOLOFHF, CONNER, KLEINERMAN, THERMAN, AND KETY yeramremranier Nl AL hal 0 Ara yoo 1 [ELECTROENCEPITALOGRAPTIIC PATTERN During Steere the Evelyn photometer according to a modification of the method of Evelyn and Malloy (7). Measurements of blood pH were made ancrobically at room temperature by means of a glass electrode and Cambridge potentiometer and corrected to 37° 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 dioxide tension was computed by means of the nomograms of Peters and Van Slyke (9). RESULTS [In Tables [A and IB are presented the data ob- tained in the six subjects on whom complete sleep studies could be made. The results obtained in the consecutive fatigued control studies in 13 subjects are presented in Tables ITA and IIB. It is apparent that during sleep cerebral blood flow (CBE) is increased, rising from 59 during the control state to 65 ce. per 100 g. per min. dur- ing sleep (p < 0.01) while no such statistically significant change in CBI’ was found in the con- The rise in CBF oc- curred in sleep despite a significant fall in mean ar- terial blood pressure (MABP) from 94 mm. Hg to 90 mm. Hg (p < 0.05). The series of consecu- tive studies on fatigued but awake subjects showed a significant blood pressure change in quite the op- posite direction, rising from a mean of 90 mm. Hg secutive fatigued controls. in the first to 96 mm. Hg in the second determina- tion (p < 0.01). This systematic change in MABP between two consecutive control determinations does not explain, however, the decrease found in sleep since the sleep series was a mixed one, sleep sometimes occurring in the first but more often TABLE TA Cerebral circulation and metabolism during Sleep CVR MABP CBF CMRo; (A-V}02 mn, He Cerebral mm. EHg cc. /L00 2. min, cc. Oxf 100 g.. min, Vol. ©) ce. $100 g..min, RQ. Interval oT Subject Age Min. c* St Cc 5 Cc Ss Cc Ss Cc 5 Cc Ss E.R. 21 66 79 74 79 85 3.8 5.1 4.80 6.01 1.0 0.9 0.83 0.96 R. MM. 28 30 107 95 45 48 2.6 2.3 5.70 4.75 2.3 2.0 0.94 0.86 S.W. 23 23 95 91 67 72 3.6 3.4 5.35 4.75 1.4 i) 0.81 0.86 P.O. 23 45 99 96 34 Gl 3.5 3.1 6.51 5.12 1.8 1.7 0.93 1.02 H. Kk. 26 42 oF 95 53 56 3.6 2.8 6.75 6.00 1.8 1.3 1.18 1.00 Mel. 25 55 88 87 37 68 4.0 3.8 6.94 5.59 1.5 1.3 1.04 1.04 Mean 24.3 44 94.2 89.7 59.2 65.0 3.52 3.42 6.01 5.37 1.63 1.45 0.96 0.96 Stand. Error +1.02 +6 $3.9 +34 +4.9 5.3 +£0.20 +0.39 +£0.35 +0.24 +£0.18 +0.15 +0.06 +0.03 pt — —_ <0.05 <6.01 >0.7 >0.1 <0.0 >0.9 * C—Control—fatigued but awake. 7 S—Sleep. + Determined by method of paired comparison. TABLE IB Blood constituents during sleep Blood O2 content Blood CO: content Blood CO: tension Hemoglobin Vol. % Vol. % Blood pH num. 112 concentration Gm, %. Arterial Int. jugular Arterial Int. jugular Arterial Int. jugular Arterial Int. jugular Subject c* St Cc Sy Cc NS) Cc Ss Cc Ss Cc S c Ss Cc Ss c 5 E.R. 14.43 14.55 18.90 19.58 14.10 13.57 47.06 46.83 51.04 52.62 7.34 7.29 7.24 7.27 47 50 60 58 R. MM. 15.06 15.06 19.09 19.28 13.39 14.53 45.22 45.81 50.55 49.87 7AS 7.40 7.36 734 37 39 46 48 S.W. 14.25 14.43 19.81 19,97 14.46 15.22 50.31 51.28 54.65 55.38 7.33 7.34 7.30 7.30 49 49 56 57 P.O. 13.95 14.43 18.70 18.78 12.19 13.66 49.70 49,15 55.78 54.37 7.35 7.36 7.31 7.29 46 45 56 58 H.K. 14.94 14.86 20.98 20.58 14.23 14.58 52.14 54.63 60.13 60.62 7.35 7.35 7.31 7.31 49 51 60 61 Meck, 13.16 12.81 19.01 18.38 12.07 12.79 51.67 51.28 58.86 57.10 7.35 7.38 7.33 7.36 48 44 56 St Mean 14.30 14.36 19.42 19.43 13.41 14.06 49.35 49.83 55.17 54.99 7.35 7.35 7.31 7.31 46.0 46.3 55.7 55.5 Stand. Error +0.28 +0.33 +0.35 +0.33 +043 +£0.36 £1.10 41.33 +1.60 41.51 +0.02 +0.02 +0.02 +0.01 #19 41.9 +2.1 42.0 pt >0.6 >0.9 <0.1 >0.05 >0.3 >0.7 >0.9 >0.7 >0.7 >0.8 * TS + + Sleep. C—Control—fatigued but awake. Determined by method of paired comparisons. IANA) JHHIS DNIMAG WSITOUVLAN GNV NOTLVYTAONIO FOOT TABLE ttA.—Cerebral circulation and metabolism in consecutive control determinations in normal fatigued but awake subjects CVR MABP CBF CMRo2 (A-V}o1 __mm. He Cerebral Interval mm. He cc./100 g./min. cc. 02/100 g./min. Val. % cc./100 g./min. R.Q. Subject Age Min. it Ut I Il I II I II I IL I IL J.R. 27 110 86 97 63 66 3.0 2.9 4.70 4.37 1.4 1.5 0.74 1.10 A.A. 24 80 90 94 48 50 2.6 2.8 5.52 5.55 1.9 1.9 0.98 1.04 G.M, 22 70 82 86 54 53 3.0 3.3 5.63 6.28 1.5 1.6 0.98 0.94 R. O. 25 49 100 103 49 41 3.6 2.9 7.31 7.01 2.0 2.5 1.08 1.11 H.R. 24 120 81 102 52 48 4.0 3.3 7.62 6.86 1.6 2.1 0.95 0.99 J.D. 28 103 102 104 88 62 3.9 3.7 4.48 6.02 0.9 1.6 0.87 0.98 S.C. 19 125 87 89 56 68 3.7 3.4 6.57 4.77 1.6 1.3 0.86 1.15 T.F. 23 50 95 94 41 37 3.4 2.9 8.27 7.95 2.3 2.5 1.00 0.86 R. W. 22 83 88 100 a7 74 3.8 3.8 4.96 5.19 11 14 1.00 1.08 W.O'D. 18 45 109 110 100 78 5.2 4.3 5.23 5.46 11 1.4 0.98 1.04 jJ.W.D. 29 120 80 86 61 57 2.8 4.2 4.66 7.47 1.3 1.5 0.81 0.94 P.T. 24 100 89 89 88 78 4.9 4.5 5.64 5.71 1.0 1.1 1.05 1.00 L. B. 22 90 83 94 66 68 3.6 3.8 5.45 5.65 1.3 1.4 0.82 0.98 Mean 23.6 88 90.2 96.0 64.8 60.0 3.65 3.52 5.85 6.02 1.46 1.68 0.93 1.02 Stand. Error +0.9 +8 42.5 +421 +5.3 +3.8 +0.21 -+0.16 +0.34 +£0.29 +0.12 +0 12 40.03 +0.02 pt _ —_ <0.01 >0.1 >0.4 >0.5 ~0.01 <0.05 * [—First control. t I[—Second consecutive control. ¢ Determined by method of paired comparison. TABLE U1B.—Blood constituents in consecutive control determinations in normal fatigued but awake subjects Blood O: content Blood CO» content Blood CO: tension Hemoglobin ol. % ol. % Blood pH mm, Hg concentration m. % Arterial Int. jugular Arterial Int. jugular Arterial Int. jugular Arterial Int. jugular Subject I* ily I Il I It I II i Il I II I Il I Il I Il JR. 13.65 14.03 18.18 19.09 13.48 14.72 49.25 49.25 57.73 54.03 7.36 7.38 7.34 7.32 45 44 54 54 A.A. 13.48 13.39 18.56 18.57 13.04 13.02 49.78 49.42 55.17 55.20 746 7.47 7AL 7.36 37 37 45 50 G. M. 13.48 13.48 18.60 19.20 12.97 12,92 50.24 51.34 55.74 57.23 7.44 7.43 7.38 7.36 39 40 49 52 R. O. 15.08 15.29 20.89 20.88 13.58 13.87 44.22 46.04 52.05 53.81 7.37 7.37 7.34 7.34 40 42 50 51 H.R. 13.73 14.03 19.50 19.08 12.64 11.46 46.20 44.73 52.73 51.82 7.42 7.40 7.36 7.36 38 38 48 48 J.D. 14.75 14.66 20.23 20.49 15.75 14.47 49.06 47.71 52.94 53.59 7.40 7.40 7.35 7.36 42 41 49 49 S.C. 15.08 14.66 19.85 18.95 13.28 13.98 48.25 47.86 53.89 53.57 7.39 7.34 7.34 7.32 41 46 52 53 T.F. 16.14 16.27 22.31 22.13 14.04 14.18 47.28 46.78 55.56 53.62 7.40 7.39 7.36 7.33 42 42 53 53 R.W. 12.55 12.72 17.58 18.06 12.62 12.96 47.84 46.95 52.81 52.33 7.48 7.38 7.47 7.38 34 41 38 45 W.O'D. 13.10 13.27 17.89 18.28 12.66 12.82 49.22 48.80 54.35 54.56 7.42 7.41 7.38 7.40 40 40 47 46 J. W.D. 14.24 14.24 19.65 19.47 14.99 12.00 52.35 49.87 56.24 56.74 7.34 7.36 7.33 7.31 51 46 56 56 P. T. 13.10 13.48 18.18 18.31 12.54 12.60 49.25 49.57 55.17 55.27 7.43 7.44 7.36 7.33 39 39 50 54 L.B. 13.65 13.86 18.79 19.27 13.34 13.62 45.83 46.56 50.32 52.09 7.35 7.33 7.28 7.30 43 46 52 52 Mean 14.00 14.11 19.25 19.37 13.46 13.28 48.37 48.07 54.21 54.14 7AL 7.39 7.36 7.34 40.9 41.7 49.5 51.0 Stand. Error +£0.28 +0.26 +0.37 40.32 +0.27 +0.27 +£0.59 +0.51 +0.56 +0.46 +£0.01 £0.01 +0.01 +0.01 1.2 £0.8 41.3 +09 pt >0.1 >0.3 >0.5 >0.3 >0.8 ~9.2 >0.05 >0.3 <0.05 * —First control. t [—Second consecutive control. ¢{ Determined by method of paired comparison. S60} ALUM UNV ‘NVWUAHL ‘NVWYANISIN ‘YANNOO ‘AAOIOMOS ‘TIODONVIN TABLE III Comparison between normal rested and normal fatigued young men Blood CO; Blood O2 content Blood CO: content tension Hb Vol. % Vol. % Blood pH mm. Hg CBF CMRo: CVR concen- MABP cc./100 g./ cc, Oof (A-V) 02 mm, He Cerebral tration Arte- Int. Arte- Int. Arte- Int. Arte- Int. Subject Age mm. Hg min, 100 g./min. Vol. % ce./100 g./min. R.Q. Gm. % rial jugular rial jugular rial jugular rial jugular Normal rested controls—II cases W.C. 24 95 49 2.8 5.74 1.9 0.75 13.43 18.49 12.75 48.59 52.92 7.42 7.37 40 48 H. Kk. 20 88 42 2.2 5.25 2.4 0.84 13.85 19.61 14.36 48.66 53.09 7 AA 7.39 38 46 R.C. 20 78 74 3.8 5.19 1.1 0.95 12.72 16.28 141.09 51.01 55.92 7.40 7.36 43 51 J.D.G. 22 91 80 3.8 4.77 1.4 1.08 13.94 19.29 14.52 49,20 54.36 7.44 7.35 41 51 ELL. 23 87 60 4.0 6.62 1.5 0.89 13.73 20.07 13.45 49.65 55.51 7.40 7.36 42 51 TLC, 24 88 49 2.9 5.97 1.8 0.84 12.18 17.12 11.15 46.55 51.58 7.45 7.39 35 44 L.H. 25 78 35 3.2 9,29 2.2 0.97 15.15 20.53 11.24 45.09 53.15 7.37 7.30 41 55 ALMcC. 22 85 50 2.7 5.36 1.7 1.03 16.90 21.16 15.80 43.42 48,92 7.33 7.28 43 57 D.F. 19 85 54 4.3 7.89 1.6 0.92 15.08 19.56 11.67 43.90 51.19 7.34 7.28 42 56 L.H. 19 83 69 4.5 6.51 1.2 0.91 16.16 19.88 13.37 48.37 54.29 7.35 7.30 46 37 N.Y. 22 93 41 2.5 6.11 2.3 0.95 17.16 21.86 15.75 47.53 53.31 7.39 7.35 43 52 Mean 21.8 86.5 54.8 3.34 6.25 1.68 0.92 14.57 19.44 13.20 47.45 53.11 7.39 7.34 41.3 51.6 S.E. +£0.63 #17 +4.3 +0.23 +0.40 +£0.13 +0.03 +0.50 +0.49 +0.53 +0.73 +0.60 0.01 +0.01 +0.9 41.3 Normal fatigued controls—25 cases M.S. 36 95 70 5.0 7.15 14 1.07 14.23 20.20 13.08 49.19 56.83 7.38 7.32 44 37 J. F. 25 107 56 4.2 7.45 1.9 0.91 13.48 19.38 11.93 51.23 58.02 7.39 7.37 44 53 T.I. 24 90 60 3.4 5.60 1.5 0.90 13.10 18.92 13.32 48.12 53.27 7.44 7.33 38 52 A.P.H. 17 89 70 3.2 4,56 1.3 0.82 12.35 18.13 13.57 50.06 53.99 7.40 7.38 42 47 S. D. 22 81 60 4.4 7.24 1.4 0.96 13.86 19.10 11.86 42.67 49.60 7.35 7.32 40 49 S.S.K. 34 98 57 3.7 6.45 1.7 0.96 13.65 18.86 12.41 44.96 51.15 7.31 7.27 45 56 J. Fr. 26 79 74 4.2 5.69 1.0 0.94 12.35 17.00 11.31 48.29 53.61 741 7.34 39 50 P.K. 22 83 62 3.4 5.59 1.3 0.95 13.89 18.80 13.21 52.28 57.57 — —_— — —_ H.R. 26 97 53 3.6 6.75 1.8 1.18 14.53 20.98 14.23 52.14 60.13 7.35 7.31 49 60 E.R. 21 79 79 3.8 4.80 1.0 0.83 14.03 18.90 14.10 47.06 51.04 7.31 7.24 47 60 S. W. 23 95 67 3.6 5.35 1.4 0.81 13.86 19.81 14.46 50.31 54.65 7.33 7.30 49 56 R.M. 28 107 45 2.6 5.70 2.3 0.94 15.09 19.09 13.39 45.22 50.55 7.43 7.36 37 46 J.R. 27 86 63 3.0 4.70 1.4 0.74 13.65 18.18 13.48 49.25 $7.73 7.36 7.34 45 54 A.A. 24 90 48 2.6 5.52 1.9 0.98 13.48 18.56 13.04 49.78 55.17 7.46 7.41 37 45 G. M. 22 82 54 3.0 5.63 1.5 0.98 13.48 18.60 12.97 50.24 55.74 7.44 7.38 39 49 R.O. 25 160 49 3.6 7.31 2.0 1.08 15.08 20.89 13.58 44.22 52.05 7.37 7.34 40 50 H.R. 24 81 52 4.0 7.62 1.6 0.95 13.73 19.50 12.64 46.20 52.73 7.42 7.36 38 48 J.D. 28 102 88 3.9 4.48 0.9 0.87 14.75 20.23 15.75 49.06 52.94 7.40 7.35 42 49 S.C. 19 87 56 3.7 6.57 1.6 0.86 15.08 19.85 13.28 48.25 53.89 7.39 7.34 41 52 T.F. 23 95 41 3.4 8.27 2.3 1.00 16.14 22.31 14.04 47.28 55.56 740 7.36 42 53 R. W. 22 88 77 3.8 4.96 1.1 1.00 12.55 17.58 12.62 47.84 $2.81 7.48 7.47 34 38 W.O’D. 18 109 100 5.2 5.23 1.1 0.98 13.10 17.89 12.66 49.22 54.35 7.42 7.38 40 47 J.W.D. 29 80 61 2.8 4.66 1.3 0.81 14.24 19.65 14.99 §2.35 56.24 7.34 7.33 51 56 P.T. 24 89 88 4.9 5.64 1.0 1.05 13.10 18.18 12.54 49.25 55.17 743 7.36 39 50 L. B. 22 83 66 3.6 5.45 1.3 0.82 13.65 18.79 13.34 45.83 50.32 7.35 7.28 43 52 Mean 24.4 90.9 63.8 3.70 5.94 1.48 0.94 13.86 19.18 13,27 48.41 54.20 7.39 7.34 41.9 51.2 S.E. +0.9 +1.9 2.9 0.14 +0.22 +0.08 +0.02 +0.18 +0.23 +0.19 +0.51 +0.54 +0.01 +0.01 +0.9 41.0 p* >0.05 >0.1 >0.05 >0.1 >0.3 >0.1 >0.6 >0.1 >0.5 >0.8 ~0.3 >0.2 >0.9 >0.8 >0.6 >0.8 * Determined by method of significance of difference between two means. ONIYAdC WSITOUVLAW GNV NOILVINOUID TVadadHo daa ts 9601 1097 in the second of the two determinations. It seems warranted to conclude that the decreased MABP is associated with the phenomenon of sleep. The elevation of the blood pressure in the second of the consecutive controls was probably the result of 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 decreased MABDP, cerebral vascular resistance (CVR) must have fallen in sleep, as indicated in the change in its 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 other hand, CVR rose from a mean of 1.5 in the first to 1.7 mm. Hg per ce. per 100 g. per min. in the sec- ond of the consecutive control determinations (p ~ 0.01). The fall in CVR observed in sleep is probably associated with the phenomenon of sleep and, for the same reasons discussed in rela- tion to the MABP, cannot be explained simply by the systematic difference in CVR found to exist between two consecutive control determinations. Cerebral arterial-veous oxygen difference and cerebral oxygen consumption (CM Ro.) showed no significant changes in cither the sleep or the con- secutive control studies. Cerebral R. Q. did not change in sleep, but the mean value, 1.02, in the second of the consecutive control determinations significantly exceeded the mean value, 0.93, ob- tained in the first determination (p < 0.05), a finding for which no reasonable explanation is at hand, Arterial hemoglobin concentrations, ar- terial and cerebral venous oxygen and carbon di- oxide contents and pH did not change significantly in either group. Arterial and internal jugular carbon dioxide tensions (pCO,) 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 fatigued group which could not sleep during the studies (p < 0.05 and p< 0.02, respectively). Simi- larly, the mean values for arterial and internal jugular blood pH were significantly lower in both determinations of the sleep group than in the fatigued group which failed to sleep (p < 0.05, respectively). In the consecutive control studies arterial pCO, remained unchanged, but the mean value of cerebral venous pCO,, 51 mm. Hg, in MANGOLD, SOKOLOFF, CONNER, KLEINERMAN, THERMAN, AND KETY the second determination significantly exceeded the mean value, 50 mm. Ifg, in the first determina- tion (p< 0.05). This finding is probably re- lated to the tendency for the CBF to decrease in the second determination. In Table 11[, comparison is made between the results obtained in 25 awake but “fatigued” nor- mal young men and those observed in 11 normal rested young men studied similarly by the same The values obtained in the rested subjects agree closely with those previ- ously reported by Kety and Schmidt (4). These values of various experimental procedures provided that the con- trol determinations were made first. Thus the fatigued group includes also the first of the con- secutive control determinations in Tables ITA and IIB and the control values of those sleep cases in Tables JA and IB in which the control determina- tion was first. On the basis of this comparison, no significant differences between fatigued and rested subjects could be found although the mean value for CBI, 64, in the fatigued group ex- ceeded the mean value, 55 ec. per 100 g. per min., in the rested group by an amount approaching statistical significance (p < 0.1 > 0.05). group of investigators. data are taken from the control DISCUSSION These findings are of interest because of their pertinence to certain theories which have been ad- vanced from time to time toward an explanation of the phenomenon of natural sleep. A number of these theories have in common the postulate that sleep is associated with and caused by a diminu- tion in the gross nutrition or metabolism of the brain. Quite recently, Doust and Schneider have elaho- rated a theory which ascribes sleep to arterial anoxemia and its resultant cerebral anoxia (10). On the basis of a downward drift in the readings of an ear oximeter, these authors concluded that arterial oxygen saturation progressively decreased during the process of falling asleep and reached levels as low as 87 per cent during deep sleep. The lack of an attempt to confirm this surprising result by more direct techniques and the absence of similar observations on non-slecping controls leaves open the possibility, however, that it may have been one of the artifacts sometimes associated with indirect oximetry. Our findings (Table TB) CEREBRAL CIRCULATION AND that both the oxygen content and hemoglobin con- centration of arterial blood were normal during the control period and remained unaltered during sleep make unlikely any hypothesis which at- tributes a causal role to arterial anoxemia. If not the first, then certainly one of the earliest recorded theories of sleep attributed this phenome- non to an ischemia of the brain. By recording changes in intracranial volume in two subjects with cranial defects, Messo (1) concluded that sleep was associated with a decrease in cerebral Tarchanoff (11) supported this view by observing a blanching of the pial vessels blood volume. in puppies when sleep occurred. A large num- her of investigators, however, were unable to cor- roborate the findings of Mosso or found instead evidence of cerebral vascular engorgement (12- 16). None ot these observations yielded informa- tion on cerebral blood flow which is certainly dif- ferent from and not necessarily correlated with Only in the case of Gibbs, Gibbs, and Lennox, whose thermoclectrie tech- nique would probably have indicated if it did not cerebral blood volume. measure gross changes, had observations related to cerebral blood flow in sleep been made (3). These authors were unable to demonstrate any change during sleep in the function which they studied. The present studies show a moderate but sta- tistically significant increase in cerebral blood flow associated with sleep. This occurred in the face of the slight but significant fall in arterial blood pressure seen in these subjects and consistently observed by numerous previous investigators (17- 19) and was the result, therefore, of a decreased resistance to flow somewhere in the brain. Since the intracranial pressure is usually found to rise during sicep (14, 15), and since the present stud- ics demonstrate no change in hemoglobin concen- tration im the blvod, factors of decreased external pressure or lessened viscosity appear to be ruled out, and it scems warranted to conclude that there is a relaxation in cerebrovascular tone during sleep. This supports previous observations which suggested a cerebral hyperenua during sleep (12- 1G). remains The cause of this cerebrovascular relaxation Tt cannot attributed to changes in arterial oxygen or carbon dioxide ten- obscure. he sion since these remained relatively unaltered be- tween control and sleep, nor was it in response to METABOLISM DURING SLEEP 1098 an increase in cerebral metabolism which was also unaffected. The usually plausible hypothesis of a decrease in neurogenic vasoconstrictor tone is rendered less tenable by the failure to demonstrate a normal vasoconstrictor tone in the cerebral ves- sels of man, or at least one mediated by the known sympathetic inflow to the head (20). Examination of the data in Table III reveals that the results in normal rested young men were almost identical with those in the original report of the method (4). When considered as a single group, the subjects who had remained awake for several hours beyond their normal bedtime and ” did not differ signifi- cantly in any respect from the rested young men. Within the “fatigued” group, however, arterial and cerebral venous carbon dioxide tensions were significantly higher and pH_ significantly lower in those subjects who slept than in the subjects were, therefore, “fatigued, who were unable to sleep under the conditions of the 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 subjects were 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 or asleep. He attributes these changes to a normal diurnal rhythm in alveolar carbon dioxide ten- sion which is independent of sleep. Our results indicate also that the respiratory acidosis can oc- cur in the absence of sleep and that sleep per se causes 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 the absence of the respiratory acidosis. Jt was this finding which distinguished the subjects who slept from those who could not sleep under iden- tical experimental conditions. Despite the evi- dence of respiratory depression, no significant anoxemia was observed in these subjects, nor was it to be expected. As Mills has also observed in his studies (22), the degree of carbon dioxide retention was insufficient to account for any ap- preciable fall in arterial-oxygen saturation, cer- tainly not to the levels on which Doust and Schneider (10) based their anoxemic theory of sleep. 1099 Another hypothesis on the nature of sleep sug- gests that this state is some endogenous narcosis associated with an overall decrease in metabolic activity in the central nervous system which per- mits the replenishment of certain substrate stores presumably depleted by the active metabolism of the waking state. That sleep is quite different from anesthesia or coma is clearly demonstrated by 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 a growing list of conditions, like schizophrenia (23) and performance of mental arithmetic (26), in which a good correlation between energy conver- sion and functional activity commonly found in other organ systems appears to be absent. This result is compatible with the current vogue of viewing the brain as a calculating or communicat- ing mechanism which, in contradistinction to ma- chines which do mechanical work, utilizes by far the greater part of its energy requirements merely in keeping its circuits alive and sensitive; the presence of a message, its functional usefulness or rationality adds only infinitesimally to the total load. Equally adequate, however, are hypothe- ses found more on traditional biological concepts than on electronic analogues. Thus, when the brain is considered as a great number of functional units, many of which may be reciprocally related with regard to activity, then increased activity in one group of units may result in decreased ac- tivity in others. Under such conditions, different functions could result in an altered pattern of distribution of the activity without measurable changes in the net overall oxygen consumption of the brain. Or, even more simply, is it not con- ceivable that the primitive functions of the brain, namely, the regulation of unconscious vegetative functions in the body, consume so much of the total 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 they designed to elicit information bearing on the more subtle functional, biochemical, or electrical al- MANGOLD, SOKOLOFF, CONNER, KLEINERMAN, THERMAN, AND KETY terations in sleep. They do, however, render un- tenable those hypotheses which attribute this im- portant phenomenon to an anoxemia, to cerebral ischemia, 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 blood pH, were made before or after and during natural sleep in six subjects, during two consecutive de- terminations under identical conditions in 13 sub- jects, during a state of fatigue in 25 subjects, and also 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 differences from the rested controls except for an elevation in cerebral blood flow which approached statisti- cal significance. 4. During natural sleep there was a statistically significant increase in cerebral blood flow, statisti- cally significant decreases in cerebral vascular re- sistance and mean arterial blood pressure, and no changes 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 by significantly 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 between respiratory acidosis and the process of falling asleep. 6. 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