Neuronal Activity & Hemodynamics

John VanMeter, Ph.D.

Center for Functional and Molecular ImagingGeorgetown University Medical Center

Outline

• BOLD contrast fMRI conceptually• Relationship between BOLD contrast and

hemodynamics • Cellular energy processes• Properties of the vasculature and blood flow• History of BOLD contrast• Relationship between neuronal glucose

metabolism and blood flow• Theories about properties of BOLD contrast

mechanisms

BOLD Contrast fMRI

• BOLD = Blood Oxygen Level Dependent contrast method

• Fundamentally BOLD contrast is an indirect measure of blood flow

• BOLD contrast as a measure of neuronal activity relies on:– Properties of the blood (deoxygenated

hemoglobin concentration)– Relationship between blood flow and

neuronal activity

Basic Model of Relationship Between BOLD fMRI & Neuronal Activity

Neuron

Neuronal Activity

• Integrative Activity– “Sum” of inputs at dendrites and/or soma

(cell body)

• Signaling Activity– Output from integrative activity resulting in

signal transmission – Action Potential generates wave of

depolarization down axon resulting in influx of Ca2+

– Subsequent release of neurotransmitter into synaptic cleft

Neurotransmitter Release

Brain Energy Budget(Rat Gray Matter)

• Majority of energy used by brain related to integrative and signaling done in neurons

• Thus, measures of energy consumption indicative of neuronal activity

Cerebral Metabolism

• fMRI cannot measure changes at the level of individual neurons

• Functional imaging techniques fundamentally rely on measures of neuronal energy components– Glucose– Oxygen

Nitty Gritty Details of Cellular Energy

• ATP - adenosine triphosphate basic unit of cellular energy

• Contains 3 phosphate groups• Hydrolysis

– Energy is released when a phosphate group is removed by insertion of a water molecule

• ATP produced from glucose (and pyruvate)

ATP from GlucoseAerobic Metabolism

• Three step process– Glycolysis

• Glucose molecule is broken down in the cell resulting in pyruvate

• 2 ATP consumed, 4 ATP produced = net increase +2 ATP

– TCA cycle (aka Krebs cycle)• Oxygen (2 molecules) extracted from hemoglobin

to oxidize pryuvate

– Electron transport chain• Ultimate output of +34 ATP molecules

ATP from Glucose Anaerobic Metabolism

• Glycolysis still occurs• Pyruvate is reduced to lactate• Fast source of ATP but inefficient

– 100 times faster than aerobic glycolysis

– Only get 2 ATP molecules!

Oxygen-to-Glucose Index (OGI)

• Aerobic processing uses 6 molecules of oxygen for every 1 molecule of glucose

• Empirical measurements at rest have shown OGI to be 5.5:1

• Implies most metabolism in neurons is aerobic but a small portion is anaerobic

Delivery of Glucose & Oxygen

• Vascular system (blood supply) is used to delivery basic components of cellular energy

• fMRI measures changes in the oxygenated state of hemoglobin

fMRI intimately linked to vascular system

Components of Vasculature

• Arteries, arterioles, capillaries delivery oxygenated (oxy) blood and glucose to cells

• Veins carry waste and deoxygenated (de-oxy) blood back to the heart

• Oxygen & glucose extraction occurs at surface of capillaries

Arteries & Veins of the Brain

Major Arteries & Veins

Blood Flow

• Increase in neuronal activity supported by increase in blood flow

• Rate varies due to vessel diameter, blood pressure, density of red blood cells, amount of O2 and CO2

– 40 cm/s in internal carotid– 10-250 mm/s in smaller arteries– 1 mm/s in capillaries

Blood Flow

• Blood flow is volume of blood delivered per unit of time

• Proportional to blood pressure difference at either end of the blood vessel divided by resistance

• Resistance determined by vessel radius• Small changes in vessel diameter

results in major changes in flow• Flow controlled in part by resistance in

vessels

Stimulation, Arteriole Dilation, Blood Velocity, Blood Pressure

• Stimulation results in dilation

• Increasing velocity of blood

• But blood pressure remains constant

Vasodilation Spatial Extent

• Winn, et al. localized neurons activated by stimulation by measuring changes in field potentials

• Changes in vasodilation are localized

Spatial Extent of Vasodilation

Why is Spatial Extent of Vasodilation Important?

• Ultimately the area over which the vasculature changes in response to neuronal activity determines spatial specificity of blood flow changes and thus a lower bound on spatial resolution for fMRI

BOLD fMRI is limited to ~1-2mm of spatial resolution

Summary

• fMRI BOLD signal arises from increase in blood flow

• Blood flow is primary means for delivering oxygen and glucose to neurons for production of energy

• Aerobic and anaerobic glycolysis implies different amounts of ATP (energy) production and oxygen requirements