Functional MRI (fMRI) based on the blood oxygenation level-dependent (BOLD) signal has been used by researchers over the last 25+ years to non-invasively map brain activity and to measure brain physiology. This lecture will explain the basic biophysical principles that enable the use of the BOLD signal as a surrogate measure of brain activity. Topics covered fall into the domains of BOLD-related cerebrovascular physiology (basics of neurovascular coupling) and BOLD MR physics (blood oxygenation-dependence of T2 and T2*). Building on this basic understanding will help us better interpret BOLD signals and
At the cellular level, neurons generate electrical signals to transmit information over a range of distances. This is mediated by the coordinated flow of ions across the cell membrane and the release of neurotransmitters at neuronal synapses. Returning the ionic and neurotransmitter concentration gradients to their resting levels is an energetically demanding process that is fuelled by adenosine triphosphate (ATP) consumption, and the ATP is replenished primarily by oxidative metabolism of glucose (2). In fact, the brain consumes ~25% of the body’s total glucose and ~20% of the oxygen to maintain these basal levels, despite accounting for just 2% of body mass.
The brain has no oxygen or glucose reserves and this demand must be met by the constant supply of arterial blood carrying these substrates. Glucose is dissolved in plasma and is actively transported into tissue when it enters the capillary bed. Oxygen, on the other hand, passively diffuses from plasma to tissue in the capillary bed and pre-capillary arterioles (3), however, it has very low solubility in plasma; to compensate, nearly all oxygen is transported bound to hemoglobin contained in red blood cells (RBCs) (4). Metabolic waste products, including carbon dioxide, diffuse back into the blood stream and are removed from the tissue bed by the venous drainage system. The amount of oxygen extracted at rest is ~35-45% and is remarkably uniform across the brain (5).
To meet the increased energetic demands upon neuronal activation, smooth muscle surrounding pre-capillary arterioles relaxes, driven by various signalling mechanisms (6-8), increasing the arteriolar diameter, reducing vascular resistance to flow (9), and thereby increasing flow into the vessel network. Downstream capillaries and venules passively dilate in response to the increased upstream pressure, albeit by a debated amount (9-13). This relationship between neuronal activity, energy metabolism, and CBF is known as neurovascular coupling and it provides the physiological foundation for most functional neuroimaging.
The physical basis of BOLD fMRI is dependent on the fact that the majority of oxygen in the body is transported bound to hemoglobin within blood. Each hemoglobin molecule contains four paramagnetic iron ions (Fe2+) that can each bind an oxygen molecule. The binding of oxygen to hemoglobin changes its magnetic susceptibility, χ, from paramagnetic (χ > 0) in the deoxygenated state to diamagnetic (χ < 0) in the oxygenated state (14). The susceptibilities of blood and the surrounding tissue are close to matched when the blood oxygen saturation level (SO2: the fraction of hemoglobin molecules in the oxygenated state) is near 100% as is the case typically in arterial blood (15). Where magnetic susceptibilities differ, offsets in the local B0 field arise, leading to quicker dephasing of transverse magnetization, i.e., shortened irreversible and apparent transverse magnetization relaxation times (T2 and T2*, respectively). Therefore, due to the compartmentalization of hemoglobin in RBCs and of RBCs in vessels, strong field offsets are generated in and around RBCs and vessels, resulting in intra- and extra-vascular changes in T2 and T2* that depend on SO2 (16-20). This SO2-dependence of intra- and extra-vascular T2 and T2* forms the basis of the BOLD signal, primarily exploited through T2*-weighted imaging.
Much of our understanding of BOLD MR physics has originated from early analytical and numerical modelling of transverse dephasing throughout vessel networks and related susceptibility distributions (19-23). These modelling results have shown that the dependence of the extravascular transverse relaxation rate (R2*) on deoxygenated blood volume (DBV) and the concentration of deoxyhemoglobin in blood ([dHb]) is$$R_2^* \propto DBV [dHb]^β.$$ The exponent β is in the range of 1–2 and it captures different vessel size contributions to the BOLD signal arising from diffusion of water (19,20,24-26), discussed more below. More importantly, this basic relation helps inform our interpretation of how different physiological factors may impact the BOLD signal based on how they may affect DBV or [dHb].
What ultimately enables the use of the BOLD signal as a surrogate marker of neural activity is that during the hemodynamic response to neuronal activation, there is a significantly larger increase in CBF than in oxygen consumption resulting in an oversupply of oxygenated blood (27,28), referred to as functional hyperemia. This results in a decrease of the venous concentration of deoxygenated hemoglobin, an increase in T2*, and, therefore, an increase in the measured BOLD signal (29-31). In sum, increased neural activity leads to an increased BOLD signal under normal physiological conditions.
The spatial precision with which the BOLD signal can detect neuronal activation depends on physiological factors (how finely blood flow is regulated at the microvascular level) and physical factors (which vessel/tissue compartments contribute to the observed BOLD signal). A detailed overview of microvascular blood flow regulation is beyond the scope of this lecture, but recent work, primarily using optical imaging in rodents, suggests that there is tight spatio-temporal regulation of blood flow at the level of pre-capillary arterioles that closely tracks neuronal activity (6-8,10,13,32-34).
Due to the interplay of water diffusion and the size of the field offsets generated by the vasculature, gradient echo BOLD signals are most sensitive to oxygenation changes in large vessels (20). As a result, oxygenation changes in large venous vessels relatively far downstream from the site of neural activation may elicit significant BOLD changes (35). Similarly, intravascular BOLD signal changes can also be largest in downstream vessels and may contribute significantly to the total BOLD signal at fields ≤ 3 T (36), further reducing BOLD’s spatial specificity.
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