La neutralidad del dinero

To recap from section 2.2, the transverse relaxation rate T2, is the time constant for phase coherence loss among spins oriented at a given angle to the static magnetic field due to spin- spin interaction. This process causes a loss of transverse magnetisation and MRI signal decay. T2* accounts for the additional signal loss due to magnetic field inhomogeneity and this process is exploited in BOLD-weighted imaging. Note, T2 is always greater than T2*.

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Sensitivity to blood oxygenation arises in T2*-weighted MRI because the image intensity is generally subject to attenuation caused by deoxyhaemoglobin (dHb), a paramagnetic relaxation enhancer introduced into venous blood vessels as tissues extract oxygen during aerobic metabolism. Increasing the concentration of oxygenated blood in tissue leads to dilution of venous dHb, reducing the attenuation of the T2*-weighted signal. The subsequent increase in signal intensity is referred to as the BOLD response. However, increases in CBF also cause compliant venous vessels to dilate and increase the tissue volume fraction occupied by dHb. This partially counteracts the diluting effect of the CBF increase. If the rise in CBF is due to neuronal activity, as assumed in the explanation above, then the rise in the cerebral metabolic rate of oxygen consumption CMRO2 and oxygen extraction fraction (OEF) of tissue will accelerate the production of dHb and further counteract the dilution effect (Hoge et al., 1999). The BOLD signal is reliant on the fact that the CBF increase following a neural stimulus is typically over twice the increase in CMRO2 (Fox & Raichle, 1986). As neural activity and CBF increase, the fraction of oxygen extracted by tissue decreases, and this phenomenon forms the basis of BOLD. The dHb reduction with higher regional venous oxygenation due to OEF reductions leads to an increase in the BOLD signal (Buxton, 2013). BOLD is an indirect measure of neuronal activity, but has been a key tool in studying functional networks due to its superior ability to localise resting state functional connectivity and evoked responses.

In comparison to ASL, BOLD has a much higher SNR, making it easier to detect very small changes, especially in sub-cortical and frontal regions which can suffer from signal dropout and blurring (Detre & Wang, 2002). A main limitation of BOLD is that it is not possible to quantify activity changes due to its reliance on the relative mismatch between CBF and CMRO2 upon neuronal activation. The BOLD signal is a complex interaction between changes in haematocrit, cerebral blood volume (CBV), CBF, OEF and CMRO2, and contrast is dependent on signal decay resulting from changes in the amount of deoxyhaemoglobin present in the vasculature (Blockley, Griffeth, Simon, & Buxton, 2013). Signal dependence on the interplay between these physiological variables means that it is challenging to interpret the exact meaning of the BOLD signal in terms of brain function. If neuronal or vascular physiology is abnormal, then the BOLD signal is not reliable in determining group differences and the signal can be misleading where baseline physiology is altered (Iannetti & Wise, 2007). For example, a study is designed to compare BOLD responses in young versus older adults to a visual stimulus. CBF is known to decline with age so a significantly reduced BOLD signal may occur in the older group despite potentially unchanged neural activity. Alternatively, declining neural function may require

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increased energy resources in this older group resulting in a similar or higher BOLD signal compared with the younger group. Either way, it is unclear from the BOLD signal alone whether electrical activity, vascular responses or both are causing the between group differences. Therefore, when investigating brain function in any group with suspected or known abnormal vascular physiology or neuronal function, it is helpful to acquire additional data to calibrate the BOLD signal and make meaningful conclusions about data.

Another limitation of BOLD is the effect of the draining of dhb from capillaries to veins on spatial specificity. This issue is most pronounced in studies which elicit a large BOLD response as a portion of the blood draining into large vessels downstream of activation will have originated in the activated area and combine with blood draining from other activated regions, meaning that there will be a measured BOLD response from both the site of activation and larger downstream vessels. When the true area of activation is small, dhb is diluted with blood from non-activated areas quite quickly which reduces the non-specific signal (Kim & Ogawa, 2012). To overcome this problem, a high statistical threshold can be used in analysis to select the most strongly activated areas, or predefine regions of interest (ROIs). Alternatively, where simultaneous BOLD and ASL data have been acquired (see 2.10), the overlap of responses can be selected as the ROI, as the ASL signal does not suffer from this draining vein contribution. Lastly, the susceptibility to physiological noise (see 2.17) and thermal noise caused by the motion of free electrons in the system, makes BOLD non-specific in terms of neuronal activity (Ugurbil, 2016).

Despite these limitations, BOLD is a useful tool in quantitative fMRI, as demonstrated in this thesis, where calibrated fMRI (see 2.13) can be used alongside ASL to determine relative changes in CMRO2, as well as determining the baseline OEF (OEF0) and CBV. These applications are discussed in the following sections.

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Figure 2.6 Diagram showing the components of the BOLD signal. Image taken from: Iannetti & Wise (2007).