**3.4.1 Functional Diffusion Maps**

More recently Functional Diffusion Maps (fDMs) were developed as a new application of DWI that can be used as a surrogate biomarker for brain tumor cellularity (Ellingson, Malkin et al. ; Moffat, Chenevert et al. 2005). fDMs obtained computationally allow establishing the correlation between water diffusivity and cellularity mainly to predict the effectiveness of tumor treatment on a voxel-by-voxel pixel analysis. These color based maps are obtained by comparing diffusion MR images at two time points, before and after therapy, to evaluate quantitatively the therapeutic-induced changes in ADC values of the tumor. These maps are depicted in three colors by segmenting the tumor in different regions depending on the magnitude and directions of the ADC changes, allowing the use of this computational analysis as a surrogate marker of the early tumor response to the treatment as depicted in figure 7.

Fig. 7. fMD map involving coregistration of images before and after the treatment. A threecolor overlay of postprocessed and analyzed maps show ADC values in the tumor that are unchanged (green), significantly increased (red), or significantly decreased (blue). These regions may be associated to unresponsive (green) or responsive (red, blue) regions. Data can be also represented in a scatter plot allowing quantitative assessment of ADCs changes (Moffat, Chenevert et al. 2006). Reproduced with permission.

Some authors have concluded that fDMs as obtained from the analysis of longitudinal diffusion images appear as a potent tool to detect the therapeutic response of tumors

Currently, there are three principal methods to measure hemodynamic perfusion parameters by using MRI: T2\*-weighted DSC, ASL, and T1-weighted DCE acquisitions, respectively. Any of them involves the serial acquisition of images through the brain as magnetically labelled blood passes through it. The labelling procedure can be either based on an exogenous contrast material, typically a paramagnetic complex of gadolinimum (Gd), or on an endogenous magnetic label. Among them, T2\*W dynamic susceptibility imaging is probably the most consolidated method to carry out MR perfusion in clinical environments not only in brain oncology but also in many other pathologies, mainly

Nowadays, PWI employing DSC techniques is one of the most relevant procedures of functional MRI with an increasing number of clinical applications depending on software and hardware availability. DSC enhanced images allow for the evaluation of regional cerebral hemodynamics by analyzing changes in the intensity of the MR signal during the first pass (and often second) of a narrow and concentrated bolus of an exogenous CA, through the brain microvascular bed. This technique is often called *bolus tracking* and performs perfusion measurements employing very rapid imaging to capture the first pass of a rapidly injected intravenous contrast material (Rosen, Belliveau et al. 1990), exploiting the T2\* susceptibility effects induced by the large local concentrations of the agent rather than the T1 shortening effects routinely used in contrast enhancement by conventional MRI. For accurate assessment of the circulation it is necessary to measure signal drop during the passage of the bolus with sequences endowed with high sensitivity and temporal resolution to the magnetic susceptibility changes occurring in the tissue during the pass of the agent. One approach is to use EPI sequences enabling acquisition times of less than one second because the whole raw data set of an image is acquired after a single spin excitation. EPI is merely a read-out technique and can be combined with any technique of spin excitation (such as spin-echo or gradient echo). Due to the special readout scheme of EPI, and because major parts of k-space are affected by T2\*, each EPI

In the brain, the first-pass extraction of the agent is zero when the blood-brain barrier (BBB) is intact, and the complete intravascular compartmentalization of the contrast creates strong, microscopic magnetic susceptibility gradients. These gradients cause dephasing of spins as the spins diffuse through the vessel. In general, pulse sequences without complete refocusing of static field inhomogeneities, as such gradient-echo (GE) will suffer a general signal loss due to the presence of microscopic field disturbances in the vessels. In terms of relaxivity, the shortening of T1 values affects only those protons near the unpaired electron clouds of the agent. This is a short-range effect. A distinct feature of the signal loss on T2\*W images is that all protons near the CA are affected because the magnetic susceptibility effect spreads far beyond the immediate vicinity of the agent. This is considered a long-range effect. However, direct damage of the BBB in a tumor may cause a disruption in it and a leakage of contrast material, a circumstance indicating that the factors responsible of the

Experimentally, the contrast medium at high concentrations (narrow bolus), induces T2\* shortening yielding firstly a signal loss, followed by a recovery as the agent is diluted in

**4.2 Techniques and methods** 

neurodegenerative diseases.

**4.2.1 Dynamic Susceptibility Contrast** 

sequence is inherently T2\* sensitive.

observed MR signal may be more complex.

through the early detection of induced changes in their morphology (Moffat, Chenevert et al. 2006; Hamstra, Galban et al. 2008). A patient with a brain tumor that shows significant changes in its ADC values after treatment is supposed to be responsive to therapy. There is the hypothesis that the water liberated by cell necrosis as induced by therapy is the major mechanism for the induced ADC increase. So, the magnitude of change in tumor water diffusion as detected by MRI is related to the quantity of cells killed by therapy and hence, to its efficacy. These changes precede the volume changes in the tumor by several weeks, providing the main justification for DWI as an early predictor of treatment response in individual patients. Even more, no changes in diffusion coefficient indicate a therapeutically unresponsive tumor suggesting the prescription of an alternative therapeutic option.
