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1 HST 583 October RESPIRATORY & CIRCULATORY PHYSIOLOGY FOR BRAIN IMAGERS Robert Banzett PhD Associate Prof, Physiology Program, Harvard School of Public Health CONTENTS page # I. Basics...2 A. Kinds of transport...2 B. Partial Pressure...2 C. Pressure - Flow - Volume Relationships...2 D. Fick's Law of diffusion...3 E. Some abbreviations...3 II. Cardiovascular physiology...3 A. Plan of the Circulation...3 B. The Vascular System...3 C. Regulation And Control In The CV System...4 III. Transport of O 2 and CO 2 in the blood...4 A. Blood Components...4 B. Dissociation curves...5 IV. Gas exchange at the capillary...5 A. Fick Principle...5 B. Gas profiles along the capillary...5 V. Special features of cerebral circulation...6 A. Hemodynamics...6 B. Table showing vascular parameters for dog...6 C. Cerebral microvasculature...6 D. Table: Metabolic heterogeneity...8 VI. Breathing transport of CO 2 and O 2 from the room to the blood...8 A. The lung & ventilation...8 B. Alveolar gas equations...9 VII. Basic respiratory motor control...9 A. Respiratory muscles...9 B. Kinds of breathing...9 C. Brain regions involved in breathing...9 Resp_CV_for_MRIcoursefinal.doc B3 saved 10/2/01 8:34 PM p1 of 11

2 I. Basics A. Kinds of transport 1. Bulk (convective) flow a. Powered by heart muscle or respiratory muscles b. Effective over long distance c. Distribution can be controlled 2. Diffusive transport a. Driven by concentration gradients b. Loading and unloading at capillary beds c. Distribution not controlled -- governed by concentration gradients d. Distinction between net flux and gross flux (crucial to thinking about tracer expts like H 2 15 O PET and ASL fmri) B. Partial Pressure 1. Each gas in a mix exerts pressure independent of others 2. Partial pressure = fractional concentration x barometric pressure PCO 2 = FCO 2 x P B where P is pressure, F is fraction, P B is barometric (ambient) pressure 3. Partial pressure gradient drives diffusion (essential to use partial pressure rather than percent when considering diffusion between two media having different specific capacitance, e.g., air and blood) C. Pressure - Flow - Volume Relationships 1. Resistance a. Ohm s Law Relationship of flow to resistance and driving pressure flow = (P U -P D )/R where P U =upstream pressure, P D =downstream pressure, R=resistance b. Relationship of resistance to tube size R L Poiseuille s Law -- laminar flow in long tubes 4 r where r = radius; L = length, η = viscosity 2. Relation between volume and pressure in elastic structures C=V/P or E=P/V 3. Time constant τ = RC Resp_CV_for_MRIcoursefinal.doc B3 saved 10/2/01 8:34 PM p2 of 11

3 D. Fick's Law of diffusion flux DA C 1 C 2 x where A=area, x=distance, C=concentration (or partial pressure), and D=diffusion coefficient (characteristic of molecule & medium) Adolf Eugene Fick (German physiologist ) Fick enjoyed mathematics during his secondary schooling, and intended to make it his career. However, an older brother, a professor of anatomy, persuaded him to switch to medicine. (Today he would enter HST!) In addition to his well known mathematical analyses of diffusion (Fick's Law) and of mass balance in oxygen consumption (Fick Principle see below), he also studied hemodynamics and muscle function, and was a leader in contact lens research! (who knew?) E. Some abbreviations Respiratory and cardiovascular physiologists traditionally measure pressure in units of the height of a column of liquid (mercury or water) that would exert that pressure in gravity field at earth's surface. Physicists and engineers usually use units of force per area (psi or kpa) 1 Torr = 1 mmhg = kpa 1 cmh 2 O = Torr = kpa 1 standard atmosphere (1 Bar) = 760 Torr = 1033 cmh 2 O = 101 kpa = 14.7 psi P means pressure, V means volume Subscripts: B is barometric, A is Alveolar, a is arterial, v is venous, I is inspired, E is expired, ET is end-tidal Dot over letter (V ) means rate (i.e., per second or per minute) V or Q = flow C = compliance ; E = elastance, R = resistance; r = radius ; L = length, η = viscosity; ρ = density II. Cardiovascular physiology A. Plan of the Circulation 1. Two circulations in series, pulmonary (right) systemic (left) a. Two pumps (right and left heart) b. Two capillary beds -- i. in systemic bed, blood delivers O 2, picks up CO 2 ii. in pulmonary it picks up O 2, loses CO 2 (pulmonary veins contain 'arterial blood') 2. Systemic circulation comprises many parallel circuits a. Allows distribution of flow where needed i. Flow controlled by resistance changes - main control sites: arterioles, precapillary sphincters ii. Arterial pressure is regulated (100 mm Hg mean) 3. Pulmonary circulation a. Entire cardiac output passes through lungs B. The Vascular System 1. Arterial tree - conducts blood away from heart, to tissues a. Large arteries (25mm - 2mm diameter) -- pressure reservoir, i. Thick-walled, elastic, not much muscle (note exception in brain) ii. Contain a very small fraction of total blood volume iii. Relatively low compliance iv. Pressure drops from 100 to 97 torr (mmhg) (i.e., resistance less than 1 torr per liter per min) b. Arterioles (approx 7micron dia, 3mm long) - flow and pressure control Resp_CV_for_MRIcoursefinal.doc B3 saved 10/2/01 8:34 PM p3 of 11

4 i. Muscular walls, diameter can be actively varied ii. Contain a small fraction of total blood volume iii. Chief site of resistance and resistance changes more than 1/2 of total resist (but note exception in brain) Distribution control Pressure drops from 97 to 30 torr (i.e., resistance approx 13 torr per liter per min) (but note exception in brain) 2. Capillaries (7 micron diameter, 1mm long) - exchange site for gases, solutes, liquid a. Characteristics i. wall comprises one layer of endothelium: Thin diffusion barrier -- fraction of a micron ii. run within a few cells of anywhere iii. contain 5% of blood volume iv. compliance is high (combination of distention and recruitment) v. total cross sectional area hundreds of times aorta vi. Pressure drops from 30 to 15 torr (i.e., resistance approx 3 torr per liter per min) 3. Venous Tree - conducts blood back to heart, volume reservoir 60% of blood is in systemic veins a. Venules & small veinsi. collection ii. thin walled iii. pressure drops from 15 to 5 torr (i.e., resistance approx 2 torr per liter per min) iv. Local volume changes consequent to flow when arterioles dilate, pressure increases downstream, thus these compliant structures will be expanded b. Veins, Great Veins - i. muscular (thin) walls, large diameter ii. venous tone controls filling pressure thus helps control SV iii. pressure drops from 5 to 4 torr (i.e., resistance approx 0.2 torr per liter per min) iv. one way valves -- the muscle pump, Harvey's skin vein experiment C. Regulation And Control In The CV System 1. Control of blood flow in individual vascular beds to meet local metabolic demand a. Arterioles dilated by local factors such as hypoxia, H +, CO 2, adenosine, K + from AP, etc. In glands, bradykinin also. Some of these may act through NO. b. Relative importance among these factors varies in different organs. Below we will cover those important to control of cerebral blood flow, Rick will go into more detail 2. Arterial Blood Pressure (i.e., pressure upstream of arterioles) is regulated a. normal mean pressure is 100 torr b. reflexes adjust cardiac output to maintain pressure as demand for flow changes c. other factors may alter pressure (emotion, posture, drugs) III. Transport of O 2 and CO 2 in the blood A. Blood Components (Blood comprises two components, liquid (plasma), and cellular (RBC, WBC, platelets) 1. Blood cells (< 1/2 of blood volume) a. Red Blood Cells (RBC or Erythrocytes) one type i % of volume in humans (defined as 'hematocrit') -- 5 x 10 9 RBC per ml of blood Resp_CV_for_MRIcoursefinal.doc B3 saved 10/2/01 8:34 PM p4 of 11

5 ii. Biconcave discs 7 microns in diameter (large surface and easily deformed) iii. Packed with hemoglobin (Hb) to carry O 2 and CO 2 (15g Hb per 100cc blood - 50% of body iron) b. White Blood Cells & Platelets - not important here 2. Plasma a. Water -- 93% by weight b. Proteins -- 7 % by weight c. Gasses d. Other stuff (Electrolytes, Nutrients, Wastes, Hormones, etc) B. Dissociation curves 1. Oxygen (see figure at end of notes) a. O 2 capacity saturates at PO 2 of normal arterial blood b. 99% of O 2 in arterial blood is bound to hemoglobin c ml O 2 is dissolved per 100torr PO 2 therefore breathing 100% O 2 increases arterial O 2 very little d. rise in CO 2 or temperature or H + concentration reduces binding of O 2 slightly 2. Carbon Dioxide (see figure at end of notes) a. Capacitance for CO 2 does not saturate and is much greater than for O 2 b. Does not saturate in physiologic range c. CO 2 is carried in 3 major forms i. dissolved as molecular CO 2 (10% of total) ii. as bicarbonate ion CO 2 + H 2 O H 2 CO 3 HCO 3 + H + (60% of total) iii. as carbamino compounds (bound to Hb) (30% of total) rise in O 2 reduces binding of CO 2 slightly IV. Gas exchange at the capillary A. Fick Principle 1. V O 2 = C.O. (CaO 2 - CvO 2 ) where C.O. is cardiac output; Ca, Cv are arterial & venous content 'FICK Principal (also applies to CO 2 glucose, or whatever) a. V O 2 of 70kg human is about 250 ml/min b. C.O. is about 5 liters/min c. CaO 2 is normally 0.2 ml O 2 per ml blood, mixed venous CvO 2 is about 0.15 B. Gas profiles along the capillary 1. Upstream end of capillary has gas levels equal to arterial blood (usual: PaCO 2 = 40, PaO 2 = 100) 2. O 2 falls and CO 2 rises along capillary, the final values being determined by metabolic rate and flow (Fick principle). (diagram of axial O 2 and CO 2 profiles) 3. Increased local O 2 needs are met by a combination of increase in flow and increase in O 2 extraction a. O 2 extraction is normally reflected in changes in venous PO 2, because arterial PO 2 is normally constant due to regulation by the respiratory system. b. Brain seems to be unusual: when local demand increases, O 2 extraction actually falls (venous PO 2 rises) because flow is increased more than necessary to meet demand. Resp_CV_for_MRIcoursefinal.doc B3 saved 10/2/01 8:34 PM p5 of 11

6 V. Special features of cerebral circulation A. Hemodynamics 1. Brain arteries are different a. even large arteries have ample smooth muscle b. pressure drop in arteries preceding arterioles is much greater (half the drop in the circuit occurs before arterioles!! B. Table showing vascular parameters for dog 1. most volume is in small vessels - greatest in capillaries, lots in venules & veins 2. capillary equilibration time is over 2 sec some vascular parameters for 10 kg dog/ 80g brain vessel class 1st 2nd arterioles 3rd capillaries 4th venules 5th pressure drop torr blood flow ml/sec blood velocity cm/sec radius (avg) mm xs area sqmm length (avg) mm volume cubic mm number 18 6,400 71,000, total xs area sqmm total volume cubic mm total volume ml transit time (avg) sec from moskalenko 'Biophysical aspects of cerebral circulation' 1980 C. Cerebral microvasculature (figures from Neurophysiological basis of cerebral blood flow control, s. Mraovitch & R Sercombe 1996) 1. Small Arteries a. Pial arteries lie on surface (in arachnoid space) b. arterioles branch off and dive at 90 angle into cortex. c. All arterial generations have smooth muscle and are innervated Larger arteries have elastic lamina and multiple smooth muscle layers. Arterioles lack elastic lamina, have 1-3 layers of sm muscle d. vasa vasorum not seen nourished by CSF? 2. Veins/venules follow same geometry, but are not paired with arteries/arterioles 3. Capillaries form mesh. a. about 6 micron internal diameter, 0.2 micron wall. b. capillary density (number per unit tissue) proportional to local metabolism -- each neuron is within a couple cell diameters of a capillary c. closed capillaries are not seen -- flow rate in open capillaries increases with demand, rather than recruiting capillaries as in many tissues d. Tight junctions form 'blood brain barrier' i. gasses pass easily ii. H 2 O diffusion impeded -- important for MRI signal iii. most large molecules (like drugs, neurotransmitters and hormones) do not pass Resp_CV_for_MRIcoursefinal.doc B3 saved 10/2/01 8:34 PM p6 of 11

7 iv. Ions do not pass v. Molecules with special carriers (e.g., glucose and amino acids) can pass. vi. high electrical resistance vii. contains active Na + / K + transporters that pump K + out of csf viii. bbb permeability subject to active regulation 4. Brain Metabolism a. brain energy i. brain power consumption is 20 watts or 250cal/min (whole body 1275 cal/min) More that 50% of energy budget for pumping. large amount for transmitter reuptake & storage -- some of this transport may be coupled to Na + / K + pump Spike activity of whole brain approx 7X10-5 cal/gm/sec or about 2% of brain energy budget some O 2 consumption is for neurotransmitter synthesis (2%?) metabolism hetrogeneous mean -50% to +100% in grey matter; i.e., 4 fold.-- see table below ii. brain is mainly dependent on glucose, but can use ketone bodies during fasting may account for 50% of brain energy glucose in brain is rapidly incorporated into AA in tricarboxilic acid cycle (i) esp glutamate -- which is precursor to transmitters glutamine, GABA, (ii) (iii) also others precursor to dopamine, norepi, etc. Ach is derived from acetyl co-a iii. brain is mainly dependent on aerobic metabolism in normal steady state local glucose metabolism is tightly coupled to local O 2 metabolism Brain ATP stores (3µmols/gm) would last 6-9 sec. phosphocreatine stores add 10 sec b. Fick applied to brain V O 2 =Q (CaO 2 - CvO 2 ) where Q is blood flow; Ca, Cv are arterial & venous content i. V O 2 of 1500g human brain is about 50 ml/min ii. Q is about 700ml/min iii. CaO 2 is normally 0.2ml O 2 per ml blood, CvO 2 of brain is about 0.13 iv. brain weight is 1500gm or 2% BW, brain V O 2 is 20% whole body V O 2 (up to 50% in 0-10 yr olds) B 3 calculates from these figures 700ml/min CBF (14% of C.O.) or 0.47ml/min/gram of brain 5. CerebroVascular control a. Metabolic regulation -- negative feedback acts to maintain levels of O 2 and CO 2 in brain tissue i. strongest control exerted by CO 2 (different from most of body, where O 2 dominates) CO 2 dilates vessels -- increases flow CO 2 probably acts via vascular intracellular H + concentration -- may be in smooth muscle cells, endothelium, or both ii. O 2 changes can also have a potent effect O 2 decrease (hypoxia) dilates vessels -- increases flow O 2 probably acts through adenosine levels (produced when ATP degraded for energy) O 2 probably acts through K + channels that are controlled by intracellular ATP levels b. Non-metabolic control -- feedforward -- increased blood flow not directly related to metabolism i. spilled transmitters from active synapses ii. metabolic precursors Resp_CV_for_MRIcoursefinal.doc B3 saved 10/2/01 8:34 PM p7 of 11

8 D. Table: Metabolic heterogeneity from Neurophysiological basis of cerebral blood flow control, S. Mraovitch & R Sercombe 1996 monkey brain gluc metab mol/100g/min as % mean auditory aud cort % med genic % inf colliculus % sup olive % cochlear nucl % visual visual cort % lat genic 39 81% sup collic % limbic parietal cort 47 98% nucl accumb 36 75% amygdala 25 52% hippocamp 25 52% mammilary b % pontine grey 28 58% motor sens-mot cort 44 91% caudate-put % globus pall 26 54% subst nigra 29 60% cerebell cort 31 64% cerebell nucl 45 94% mean grey 48.1 white matter corpus callo 11 int capsule 13 cerebell white 12 VI. Breathing transport of CO 2 and O 2 from the room to the blood (note: normal average values are shown following most equations) A. The lung & ventilation 1. Lung volumes (values are gender, age, size, and smoking history dependent) a. Biggest breath you can take is about 4.5 liters b. Average breath at rest is 0.5 liters (V T or tidal volume) (2.5 liters remains in lung at the end of a normal expiration (EEV or FRC) c. At rest people breathe about times per minute 2. Concept of minute ventilation V E = V T x f 7 lit/min = 0.5 lit x 15 breaths/min where V T is amount of air in one breath, f is respiratory frequency. a. When a respiratory physiologist asks "how much was she breathing?" V E is a much better number to give than f i. One can achieve V E of 7 lit/min with 2 breaths of 3.5 liters or with 35 breaths of 0.2 liters b. Maximum ventilation in exercise is about 10X resting Maximum voluntary ventilation is about 20X resting 3. Concept of dead space volume and alveolar ventilation Resp_CV_for_MRIcoursefinal.doc B3 saved 10/2/01 8:34 PM p8 of 11

9 a. Alveoli gas exchange unit (air is brought within microns of capillary blood) b. Conducting airways (essentially no gas exchange due to thick walls, low blood flow) c. deadspace volume can be measured or estimated from body height and weight (150ml 'normal') d. V A = (V T - V DS ) x f 5 lit/min = (.5 lit -.15 lit) 15 breaths/min e. V A is an even better number to give your friendly (but demanding) physiologist, because it is most directly related to gas exchange. if V T = 3.5 lit. and f = 2, V A = 6.6 lit/min; if V T = 0.2 and f = 35, V A = 1.75 f. Equivalence of end-tidal PCO 2 with alveolar PCO 2 and arterial PCO 2 B. Alveolar gas equations 1. Equations for O 2 and CO 2 V O 2 = V A ( FIO 2 - FEO 2 ).3=5( ) V CO 2 = V A (FECO 2 - FICO 2 ) Note usual FI values are those of air (78.1% N 2, 20.9% O 2, 0.9% Ar, 0.03% CO 2 ) 2. Amount of O 2 consumed per minute, V O 2, and CO 2 produced per min, V CO 2, are set by metabolic demand, not by respiratory system 3. in steady state, usually about 0.8 liters of CO 2 is produced from 1 liter of O 2 - range from.7 (burning fat to 1 burning carbs). In unsteady state V CO 2 can vary greatly due to gain or loss from body stores of CO 2, which are huge compared to O 2 stores. VII. Basic respiratory motor control (respiration is, I think, unique in having a completely automatic motor control as well as completely voluntary motor control) A. Respiratory muscles 1. Skeletal muscles -- require neural drive (not autorhythmic) B. Kinds of breathing 1. Automatic breathing or 'Spontaneous breathing' a. occurs during sleep, anesthesia, and probably most of waking hours i. Negative feedback chemoreceptor systems exist to regulate arterial PCO 2 and arterial PO 2. The gain of these systems is such that CO 2 is more tightly regulated (but this has the effect of keeping PO 2 nearly constant as well). ii. Other, less important, mechanoreceptor feedback systems assist chemoreceptor systems. 2. Voluntary breathing a. Learned voluntary breathing patterns are used in speech b. subjects can do complex tracking tasks with breathing muscles 3. Behavioral breathing a. involuntary changes in breathing are driven by emotion, body temperature, and other inputs b. e.g., hyperventilation (breathing more than needed for CO 2 exchange) is common in stressful situations. c. Probably very common in scanner subjects. C. Brain regions involved in breathing 1. Brainstem respiratory motor centers (from animal experiments) a. Principle origin is thought to be in the medulla (respiratory related neurons are distributed in a ventrolateral column extending from the spino-medullary junction to the retrofacial nucleus just below the pons) b. contributions from the pons come from the region of the parabrachial nucleus Resp_CV_for_MRIcoursefinal.doc B3 saved 10/2/01 8:34 PM p9 of 11

10 c. cerebellum probably also contributes, but less well studied 2. Voluntary breathing is initiated in the cortex. (Colebatch et al., 1991; Maskill et al., 1991; Ramsay et al., 1993; Fink et al., 1996) a. During speech (Murphy et al., 1997), swimming, playing musical instruments we use this system, although it may be so well-trained we are unaware of it b. can be used to control breathing at will during experiments 3. Respiratory Sensation & Dyspnea 4. Dyspnea (perception of discomfort related to breathing) a. Activates anterior insula, and probably other cerebral areas (Banzett et al., 2000b; Peiffer et al., 2001) REFERENCES Cerebral regions activated by breathing Banzett, R.B., H.E. Mulnier, K. Murphy, S.D. Rosen, R.J. Wise and L. Adams (2000b). Breathlessness in humans activates insular cortex. Neuroreport 11: Colebatch, J.G., L. Adams, K. Murphy, A.J. Martin, A.A. Lammertsma, H.J. Tochon-Danguy, J.C. Clark, K.J. Friston and A. Guz (1991). Regional cerebral blood flow during volitional breathing in man. J Physiol 443: Fink, G.R., D.R. Corfield, K. Murphy, I. Kobayashi, C. Dettmers, L. Adams, R.S. Frackowiak and A. Guz (1996). Human cerebral activity with increasing inspiratory force: a study using positron emission tomography. J. Appl. Physiol. 81: Maskill, D., K. Murphy, A. Mier, M. Owen and A. Guz (1991). Motor cortical representation of the diaphragm in man. J Physiol 443: Murphy, K., D.R. Corfield, A. Guz, G.R. Fink, R.J. Wise, J. Harrison and L. Adams (1997). Cerebral areas associated with motor control of speech in humans. J. Appl. Physiol. 83: Ramsay, S.C., L. Adams, K. Murphy, D.R. Corfield, S. Grootoonk, D.L. Bailey, R.S. Frackowiak and A. Guz (1993). Regional cerebral blood flow during volitional expiration in man: a comparison with volitional inspiration. J Physiol 461: TEXTS Any good textbook of medical physiology will cover most of this material. Human Physiology: The Mechanisms of Body Function, Arthur Vander, James Sherman, Dorothy Lucian 864 pages 8th edition Book&CDROM (2000) Amazon Price: $ McGraw-Hill Higher Education; ISBN: This is a readable and reliable text covering all systems -- We have used it for years in my department. Resp_CV_for_MRIcoursefinal.doc B3 saved 10/2/01 8:34 PM p10 of 11

11 a v CO2 data from Comroe 'Physiology of Respiration' 0.2 a 0.1 v O2 0 Partial pressure (torr) Figure: O 2 and CO 2 dissociation curves for whole blood. Normal arterial and venous values at rest are marked with a and v Resp_CV_for_MRIcoursefinal.doc B3 saved 10/2/01 8:34 PM p11 of 11

I. Overview of physiologic events in active brain tissue that could be detected in functional imaging

I. Overview of physiologic events in active brain tissue that could be detected in functional imaging HST.583: Functional Magnetic Resonance Imaging: Data Acquisition and Analysis Harvard-MIT Division of Health Sciences and Technology Course Instructor: Dr. Robert Banzett. HST 583 - Fall 2004 RESPIRATORY