n o r d i c B r a i n E x Tutorial DSC Module

m a k i n g f u n c t i o n a l M R I e a s y n o r d i c B r a i n E x Tutorial DSC Module Please note that this tutorial is for the latest released nordicbrainex. If you are using an older version please upgrade. NordicNeuroLab AS Møllendalsveien 1 N-5009 Bergen, Norway Phone: +47 55 70 70 95 Email: ProductSolutions@NordicNeuroLab.com

Contents 1 Loading of perfusion data... 3 2 Coregistration... 4 3 Interacting with the results... 4 3.1 Bolus arrival time... 5 3.2 General use... 5 3.3 Merge CBV for export to neuronavigation... 7 3.4 Saving DSC data... 8 4 Parametric maps... 11 4.1 Calculation of parametric maps... 11 4.1.1 Leakage correction... 13 5 Perfusion settings... 13 5.1 DSC settings... 14 5.1.1 Motion correction... 14 5.1.2 Leakage correction... 14 5.1.3 Vessel removal... 14 5.1.4 Normalization... 14 5.1.5 Auto-detect noise threshold... 15 5.2 Output maps... 15 6 References... 15 Date modified: 2018-11-05 Page 2 of 15

1 Loading of perfusion data To start the perfusion analysis, on structural and one DSC series have to be chosen. If the DSC type is unknown, right-click to set the type (Figure 1). It is possible to select several structural series, but only one DSC dataset for each analysis. To open DSC settings, right-click and select Edit DSC Settings. For more details about the DSC settings, see section 5 Perfusion settings on page 13. Hit Next to start analysis. Figure 1: To start perfusion analysis, select one structural and one DSC series. To set the type of DSC, right-click and select the correct type from the list. To open DSC settings, select Edit DSC Settings. Hit Next to start analysis. Date modified: 2018-11-05 Page 3 of 15

Figure 2: If you select series from different studies (time points), you will get a warning. Select yes, if you do want to load series from different studies. If you select series from different studies (time points) when loading data, you will get a warning (Figure 2). This is to assure that any loading of series from different studies is only done if intended. 2 Coregistration An important step in the analysis is coregistration of the DSC series to the structural series. This will ensure that perfusion maps used as overlays are displayed in the correct position. Please see Tutorial Visualization and Interaction for details about the coregistration. 3 Interacting with the results Figure 3: Perfusion analysis is done and the normalized BV map is added as an overlay. VOIs are added in the tumor tissue the contralateral normal appearing tissue, and the mean normalized CBV value is measured. The intensity curve and histogram of the VOI is displayed. Date modified: 2018-11-05 Page 4 of 15

When the perfusion analysis is completed, the perfusion maps are generated and shown as thumbnail in the left side of the panel. Add any map as overlay or underlay to investigate the output (Figure 3). 3.1 Bolus arrival time The bolus arrival time is calculated automatically by the program, but can be edited by sliding the red line along the time curve. Click to use the new time position (Figure 4). Figure 4: The bolus arrival time is automatically calculated, but can be changed by sliding the orange line along the time curve. Use recalculate to update with the new position. 3.2 General use Display perfusion output maps as overlays or underlays: - Right-click on the thumbnail Using the Volume-of-Interest (VOI) tool to: - Measure statistical values on the parametric maps (Figure 5). - Display histogram and intensity curves (Figure 5). VOI statistics, intensity curves and histograms are displayed by selecting the icons next to the VOI name in the VOI list (Figure 5). Change CBV overlay threshold (Figure 6) to remove low CBV values from the visualized overlay. Date modified: 2018-11-05 Page 5 of 15

Figure 5: Two VOIs are added, one in tumor tissue and one in normal appearing tissue. The statistical values are measured in the two regions, and the intensity curves and histograms for the two VOIs are displayed. Date modified: 2018-11-05 Page 6 of 15

3.3 Merge CBV for export to neuronavigation Similar to for BOLD, DTI and DCE results, it is possible to save the CBV result in a format that can be used in neuronavigation systems using Merge. Settings for merge export can be defined when choosing Settings and then Export results as... in the upper left corner of the Visualization interface. The BOLD activation maps can then be exported in a format compatible with viewing on certain neuronavigation systems. Color export This will export the BOLD activation maps as separate DICOM image series that can be viewed together with the structural volume on various neuronavigation workstations. White pixels on greyscale This will export the BOLD activation maps as DICOM image series where the activated regions are shown as white pixels in the structural dataset. Figure 6: CBV threshold can be changed in the DSC tab. Here, one can also use VOI filtering and merge to neuronavigation. In order to do so, adapt your workflow to the following steps: 1. Do perfusion analysis and add the CBV map as overlay. 2. Change the threshold of the overlay by sliding on the CBV threshold slider (Figure 6). 3. Locate the area(s) of interest and add VOIs Date modified: 2018-11-05 Page 7 of 15

4. Select VOI filtering and use include/exclude on VOI(s) to locate the region relevant for merge (it is possible to skip this step) 5. Verify the output in real time in the MPR. 6. Select Merge to create a new series. 7. Stop VOI filtering to continue. While in VOI filtering mode, some of the application s functionality is blocked. To access all functionality, VOI filtering mode must be stopped (hit Stop, see). Figure 7: Merge CBV for neuronavigation: Step 1: add the CBV map as overlay. Step 2: Threshold the CBV. Step 3: Locate the area of interest and create a VOI. Step 4: Select VOI filtering to include/exclude regions. Step 5: Verify the output in real in the MPR. Step 6: Select Merge to create new series. Note that multiple VOIs can be included or excluded to include/exclude multiple regions from the merged series. 3.4 Saving DSC data There are several different ways of saving the DSC data. Save the derived maps to the database: - Right-click on the thumbnail and select Save - Right-click on the thumbnail and select Save and send to send it to a remote entity (e.g. PACS) Create a new DICOM series with perfusion maps as overlay (see Figure 8): - Add a perfusion map (e.g. blood volume) as an overlay - Right-click in MPR and select Create snapshot, Slice selection or Slice all. - This will create a new secondary capture slice package that can be saved to the database and sent to PACS. If choosing Merge in the Interaction panel, the selected CBV overlaid on the structural datasets can be merged into a new DICOM series. By right clicking on any of the three planes of the current volume in the MPR, choosing Create snapshot will open the Slice editor window of the current slice. Create snapshot of MPR will open the Slice editor window of the three current planes of the MPR, as well as the visualized activations in the 3D viewer. Date modified: 2018-11-05 Page 8 of 15

Copy will copy the current slice to the clipboard, so it can be pasted into other programs (like word etc.). See Figure 8. In the Slice editor window (See Tutorial Visualization and Interaction ), accessed by right clicking on any of the three planes in the MPR and choosing Slice selection (and clicking on Slice) or Slice all, slices can be: Saved to the database Saved and sent to a remote entity (for example PACS) Added to report (Select View slices by right-clicking on the new thumbnail after saving to database) Saved as AVI-file (Select View slices by right-clicking on the new thumbnail after saving to database) Send, accessed by right clicking on series thumbnail in the Data panel will send the series to a remote entity (for example PACS). Read more about saving sessions in Saving data to database and PACS in Tutorial Handling Image data. Add to report (bottom left of any plane in the MPR) can be chosen to add the current slice to Report (see Report in Tutorial Visualization and Interaction ). Saving the session can be done by choosing File -> Save Session. This will save the entire session (all loaded and acquired datasets) to the database. The session name that you entered will appear in the session table on the Select patient data window. Read more about saving sessions in Saving, loading and sending a Session in Tutorial Handling Image data. Date modified: 2018-11-05 Page 9 of 15

Figure 8: Slice selection from the axial MPR has been selecting, displaying the VOIs and the VOI statistics, as well as the histogram for the CBV and the intensity curves for the DSC dynamic series for the two VOIs. This frame can be send to PACS by selecting 'Save and send'. Date modified: 2018-11-05 Page 10 of 15

4 Parametric maps Figure 9: The parametric maps are displayed under derived data on the left side of the visualization screen. Right-click to interact (view as underlay / overlay, save to database, view slices etc.). 4.1 Calculation of parametric maps The resulting parametric maps appear as icons on the left side of the screen under Derived Data (Figure 9). The parametric maps that are obtained are calculated using standard formulas and assumptions. The first step is to obtain the contrast agent concentration as a function of time. It is obtained using the assumption that the * change in relaxation rate is proportional to the concentration of contrast agent: R = r CA with the relation between MR signal and relaxation rates, SI0 ln * SI( t) R2 ( t) =, TE 2. Combining this Date modified: 2018-11-05 Page 11 of 15

the concentrations can be found. Then the following parametric maps are obtained: Normalized blood volume (ncbv) * The pixel values are initially set equal to rcbv = R ( t) dt. If leakage correction is turned on, the pixel values are then leakage corrected (see explanation of leakage correction below). Finally, the map is normalized. Relative blood volume (rcbv) Same as ncbv, but not normalized. Uncorrected ncbv This map displays the normalized blood volume without leakage correction. Uncorrected rcbv This map displays the relative blood volume without leakage correction. Leakage map This map displays the degree and type of leakage. Pixels close to zero (black) represent low degree of leakage. Positive (red) or negative (blue) pixel values represent T1-dominant or T2-dominant leakage, respectively. Mean transit time (rmtt) 2 The relative MTT values are calculated from the following relation: Normalized Blood Flow (ncbf) rmtt t R = R * 2 * 2 dt dt The blood flow values are calculated based on this relation, followed by normalization. rcbf = rcbv rmtt Relative Blood Flow (rcbf) Same as ncbf, only without normalization. Time to peak (rttp) Relative time of maximum concentration expressed in seconds. Date modified: 2018-11-05 Page 12 of 15

Vessel Map Displays the vessels found during the vessel removal. 4.1.1 Leakage correction The method used in nbx for leakage correction is described in the article by Bjørnerud et al (2011). In brief, the method uses the tail of the residual function to estimate the leakage. The residual function is defined through the equation C(t) = AIF(t) R(t) where C is the measured concentration, AIF is the artierial input function and R is the residual function. The residual function describes the fraction of contrast agent that is left in a voxel at the time t after a pulse of contrast agent enters the voxel. The concentration is thereby equal to the convolution between the input concentration, the arterial input function, and the residual function. Basically, if the residual function does not approach 0 after a long time, there is leakage. The leakage may be a T1 type or a T2 type, giving a residual function ending above or below 0. Either way, the leakage correction is done by finding the mean value of the residual after a preset time T C and multiplying it with the time that has passed after T C. The value found is subtracted from the initial estimate of the CBV. In the case leakage correction is done, the flow is recalculated as the peak of the residual function, TTP is set equal to the time of the residual peak and MTT is recalculated as the ration between blood volume and flow. 5 Perfusion settings Figure 10: In perfusion settings, the user can decide which preprocessing and analysis settings to use, and which output maps to display. Date modified: 2018-11-05 Page 13 of 15

Perfusion settings (Figure 10) can be opened from the loading frame by right-clicking on the DSC series, or from the visualization interface by right-clicking on the DSC source data thumbnail. In the perfusion settings, the user can decide which preprocessing and analysis settings to use, and which output maps to display. 5.1 DSC settings The settings for DSC are global settings, meaning that changes done at one time will be saved and applied to all future analysis until the settings again are changed. 5.1.1 Motion correction When checked this turns on motion correction of the DSC image series, meaning that all the image volumes are coregistered to the first image volume. These parameters are saved internally so that the user can display them at a later stage by right-clicking on the icon of the perfusion series and choose Motion Correction Results. The coregistration is performed using an iterative method based on a measure of similarity. Step sizes are calculated from the gradients of the similarity measure (the mutual information metric), and once the step size of the rotation and translation parameters is small enough, the iteration process is halted, and the estimated rotation and translation parameters are applied to the source volume using a cubic interpolation approach. Due to the limited geometrical resolution of such image series only in-plane rotations and translations for axial slices are done. 5.1.2 Leakage correction In tissue where contrast agent is leaking out of the vessels into the extra- or intracellular space the blood volume will not be correctly estimated. The remedy for this phenomenon is what is termed as leakage correction. If not corrected for, this leakage can lead to either under- or overestimation of the normalized blood volume. Leakage correction will correct the output maps mean transit time (MTT), time to peak (TTP), blood volume (CBV) and blood flow (CBF). Additional explanations can be found in Section 4 Parametric maps on page 11. 5.1.3 Vessel removal A patented method for vessel removal has been implemented in the software that identifies pixels that most likely are affected by the contrast agent in a vessel. These pixels will not be included in the formation of the output maps. The Vessel Map contains the pixels excluded. 5.1.4 Normalization Normalization is done by defining the normal tissue in the volume, and dividing all pixels on the value of the normal tissue. The normal tissue in a normalized CBV map should thus have an average value close to one. The normal tissue is found by segmenting the brain using a clustering algorithm. First, pixels with values lower than the noise level threshold are excluded. The remaining pixels are segmented based on their baseline signal intensity, and the pixels with the highest values are assumed to be lesion and are excluded. To exclude blood vessels from healthy brain tissue, a second segmentation is performed based on the already calculated BV values, where the highest values are excluded as blood. The output maps blood volume (CBV) and blood flow (CBF) are normalized. When normalization is done, the average CBV value of the normal tissue is equal to 1, while tumor tissue typically has a higher CBV value. Date modified: 2018-11-05 Page 14 of 15

If normalization is used, CBV and CBF output maps are indicated with a n prefix for normalized. All maps that have not been normalized are indicated with a r prefix for relative. 5.1.5 Auto-detect noise threshold If checked, an automatick noise threshold is performed, and if unchecked, the user can set the noise threhold manually using a slider (Figure 11). The noise threshold affects the performance of the normalization and leakage correction, so a warning will be given when manual noise threshold is selected. If brain tissue is removed by the nosie threshold, the normalization and leakage correction might not work optimally (i.e. noise threshold should not be used for segmenting the data). Figure 11: Noise-threshold can either be detected automatically, or the level can be changed using a slider. 5.2 Output maps In the Output maps tab (Figure 10), the user can select which output maps to display. Details on how these parametric maps are calculated are given in section 4 Parametric maps. 6 References Bjornerud A, Sorensen AG, Mouridsen K and Emblem KE (2011) T 1- and T 2* -dominant extravasation correction in DSC-MRI: Part I Theoretical considerations and implications for assessment of tumor hemodynamic properties. Journal of Cerebral Blood Flow & Metabolism 10:2041-53. Date modified: 2018-11-05 Page 15 of 15