Outline

• Definition and meaning of perfusion

• CBF and autoregulation

Introduction to Perfusion in Tissues
• Microcirculation and metabolism
Ho-Ling Anthony Liu, PhD, DABR

Department of Radiological Sciences

• Vasomotor response
Graduate Institute of Medical Physics and Imaging Science
Chang Gung University • Techniques for CBF measurement
MRI Center, Chang Gung Memorial Hospital
Taiwan • Control of CBF

Perfusion: definition Vascular system

• Cerebral blood flow (CBF) delivers glucose and oxygen
to the brain, thus varies with neural activity.

Blood flow per mass of tissue • Vascular system is organized in size:

-Capillary ~ 10 µm
- Major artery ~ cm
(ml/100 g/min)

Gray matter ~ 54.5 ml/100 g/min

White matter ~ 22.2 ml/100 g/min
(Leenders et al., Brain, 1990)

Microscopic view of complex

MRA: down to mm geometry of arterioles,
Duvernoy et al., 1981
capillaries and venules

Vascular system The meaning of perfusion

• Perfusion is a general term to describe nutritive delivery
• The smallest capillaries ~ 6-8 mm, comparable to the of arterial blood to a capillary bed in the tissue.
size of red blood cells
• CBF is a specific quantity: ml (blood) /100 g (tissue) /min

• With imaging, we need “density (~1 g/ml for brain)” to

“Functional blobs” convert from voxel size to tissue mass.

A photomicrograph of monkey
visual cortex showing different
vessel density across layers

Zheng et al., 1991 Buxton, Introduction to

Functional MRI
 Cerebral Blood Volume (CBV) Blood velocity

• Cerebral blood volume (CBV) is the fraction of tissue

volume occupied by blood vessels. • Blood velocity affects perfusion:
- Large arteries: ~ 10’s cm/s
• CBV in the brain is around 4% (~0.04). - Capillary: ~ 1 mm/s

• Note: some CBV techniques may measure only fractions • Pulsatility seen in artery is largely damped out at the
of the total CBV (i.e. arterial, capillaries vs. veins). capillary level.

• Typical fractions: 5% for arterial volume and the rest • However, flow in capillary is irregular which may be due
divided equally between capillaries and veins. to the similar size of red blood cells.

• During hypoxia, capillary blood velocity increases which

increases CBF.

Mean Transit Time (MTT) Importance of Cerebral Perfusion

• CBF depends on CBV, blood velocity and vascular
architecture.
• Delivery of glucose
• Central volume principle: τ = CBV/CBF, where τ is the
mean transit time (MTT).
• Delivery of oxygen
• For CBF = 60 ml/100 g/min, CBV = 4%, MTT = 4 s.
• Clearance of CO2

• Clearance of heat
CBF1 = 2 CBF2
MTT1=1/2 MTT2

Buxton, Introduction to
Functional MRI

CBF and Autoregulation Coupling of microcirculation and

• Cerebral blood flow, pressure and volume are metabolism
maintained at a certain level to provide adequate blood
• CBF is never uniform throughout the brain even under
supply to the brain.
resting conditions.
• CBF depends on arterial pressure (Pa) and
• This may reflect proportional difference in the local
cerebrovascular resistance (CVR): CBF = Pa/CVR
metabolic rate.
• If vessel size remains constant, increase in arterial
• The link between local activity of tissue (and hence the
pressure must results in increase in CBF.
metabolic needs) and CBF in the tissue may occur with a
feedback mechanism.
• However, under normal conditions, CBF is kept
constant. This may be regulated by vasomotor responses
of small arteries and arterioles.
 Microvascular response
• Possible mechanisms for vasomotor response in CBF
regulation:
(1) Metabolic mechanism:
- Vasodilator metabolites are produced constantly
- When arterial pressure drops and flow decreases, the
concentration of the metabolites increases
- This may be caused by reduced washout, or
- by increased production as a secondary effect of
reduced tissue PO2
(2) Myogenic mechanism:
- When intravascular pressure rises (or falls), the arteriole
is stimulated to contract (or dilate), for the smooth
muscle cell to maintain a constant wall tension in
arterioles.
Endothelial cells and vasomotor
response
• Endothelial cells may cause relaxation by the
release of an endothelial-derived relaxing factor
(EDRF).
• Flow increments cause the release of EDRF.
• Endothelial cells may serve as a pressure sensor in
the autoregulation.
Measuring CBF: Nitrous Oxide
• Measuring global CBF
• Human subject inhales NO2 for several mins and arterial
and venous of NO2 concentrations are sampled frequently.
• NO2 freely diffuses in whole brain and reach a equilibrium
state w/ a time constant τ.
• Since τ = V/F, V is whole brain volume and τ is a measure
of global flow, F.
Buxton, Introduction to
Functional MRI
Microvascular response
(3) Neurogenic mechanism:
- Blood vessels are contacted by nerves which may
play a role in cerebral autoregulation.
(4) Flow-dependent mechanism:
- Dilatation of vessels is graded according to the
magnitude of increase in flow velocity.
One or several mechanisms may be involved in CBF changes,
and it may be difficult to distinguish one from another
factors.
Measuring CBF: Microsphere
technique
• Apply radioactive microspheres small enough to
pass through the arterioles but large enough to stay
in capillary.
• Inject the microspheres in a feeding artery and
respective local CBF can be measured by counting
brain sections.
• Not feasible for in-vivo human studies.
Measuring CBF: Diffusible vs.
Intravascular Tracers
• Tracers used in brain imaging can be divided into:
-Diffusible: freely diffuses to whole brain volume
-Intravascular: remains in the blood (4% of brain
volume)
• Diffusible tracer equilibrates slowly (~100 s), thus is a
good tool for CBF measurement.
• Intravascular tracer equilibrates quickly (~4 s) and
then remains in the blood, thus is a good tool for CBV
measurement.
Measuring CBF: Radioactive Xenon
• Xe-133 is a radioactive tracer which is freely diffusible
in the brain.
• The agent is typically administered by inhalation.
• After equilibrium, inhalation stops and the clearance
is monitored by NM camera. The time constant for
clearance is 1/CBF.
Buxton, Introduction to
Functional MRI
Perfusion MRI
• Dynamic susceptibility contrast (DSC) MRI:
- Inject paramagnetic contrast agent (e.g. Gd-based)
and dynamically acquire T2 or T2*-weighted images.
- CBV, CBF and MTT can be obtained after some
calculations.
• Arterial spin labeling (ASL) MRI:
- Label inflowing blood water using RF pulses, and use
the labeled spins as the diffusible tracer.
- CBF can be obtained when T1 is provided.
Control of CBF: Vasodilatory agents
• In addition to H+, other positive charged ions (cations)
exhibits a strong vasodilatory effect: Cation hypothesis
(Lassen, 1991).
• Increased K+ and decreased Ca++ in fluid space around
arterioles both produce dilitation.
• Adenosin molecules and nitric oxide (NO) both also
induce vaso-dilatation (they play key roles in brain
activity).
Measuring CBF: PET techniques
• Use O-15 water (half-life ~ 2mins), a PET tracer which
is freely diffusible in the brain.
• Method1 : Inject O-15 water as a bolus and measure
the activity integral of the early phase (~first 40 s after
injection).
• Method 2: Inhale C15O2 which exchanges with oxygen
to produce O-15 water in the blood. Measure the
activity at the equilibrium state.
Control of CBF: Vasodilatory agents
• CBF depends on arterial pressure (Pa) and
cerebrovascular resistance (CVR): CBF = Pa/CVR
• As pressure changes, CVR changes in compensatory
way by dilating or constricting the arterioles.
•With a constant Pa, 100% increase in CBF (i.e. 100%
decrease in CVR) can be caused by only 19% increase in
arteriole radius.
• CO2: Raising arterial CO2 level from 40 mmHg to 60
mmHg nearly doubles the global CBF.
•The large CBF response may serve to increase clearance
rate of CO2 and provide some control of pH changes.
CBV vs. CBF
• CBF increase is caused by decrease in CVR which is done
by vasodilatation (increase in CBV).
• A general form: (V/V0) = (F/F0)α
• A simple example:
- with laminar flow, F is proportional to r4
- if all vessels dilate, CBV is proportional to r2
- thus α = 0.5
• The relationship is actually complicated, considering
different mechanisms for CBV changes in arteriole and veins.
• Classical data by Grubb et al. (1974) showed α = 0.38 in
steady-state.
THANK YOU!

Tapei 101, Taiwan