Cherrier et al. BMC Cancer 2010, 10:1 http://www.biomedcentral.com/1471-2407/10/1 3 seconds of fixation. Three, 18 second fixation blocks (cross-hair) were intermixed in the sequence. The run was thus composed of 3 fixation blocks (18s each) + 3 repeti- tions of the route perspective movie (46+3s each) + 3 repetitions of the survey perspective movie (46+3s each) in for a total run time or 348 s (116 volumes, TR = 3). Imme- diately following encoding subjects were tested on their knowledge of the complex environment during the recog- nition task (see below). Subjects were informed that their memory for the environment would be subsequently tested but active responses were not required during encoding. Recognition task (RECOG) During the recognition run subjects viewed still images of the previously studied environment and determined if objects within the environment were; (i) correctly posi- tioned (previously seen items in appropriate environ- mental locations), (ii) spatially rearranged (previously seen items shuffled within the environment), or (iii) they could not tell (do not know). A total of 64 images were presented; 32 from the route perspective (4 blocks of 8 images, each block preceded by 3 s of fixation) and 32 images from the survey perspective (4 blocks of 8 images, each block preceded by 3 s of fixation). Each set of 8 images contained four spatially correct images and four foils or incorrect choices with the order randomized. Four, 18 s fixation blocks (cross-hair) were intermixed in the sequence. The entire run was thus composed of 4 fixation blocks (18s each) + 4 route perspective picture blocks (48+3s each) + 4 survey perspective picture blocks (48+3s each) in a quasi-random order for a total run time of 480s (160 volumes, TR = 3). Following the fMRI session subjects were asked to draw the environ- ment to ensure they had completed the task appropri- ately (data not scored). Mental Rotation Matching Task (MATCH) Participants were shown black and white complex, three dimensional (3D) figures taken from the Shephard and Metzler Mental Rotation test [24,25] or complex and abstract two dimensional (2D) figures in black/white/ gray. Participants were asked to determine if the figures (i) matched exactly or, (ii) they did not match or, (iii) did not know. Incorrect matches for the three-dimen- sion figures were either mirror images or a different configuration whereas a match was the same image side by side, although the images may have been rotated in space. For the 2D- images, a match was the same image side by side, whereas a mis-match involved one of the figures having additional details or missing details. Stimuli were presented using Eprime® software http:// www.pstnet.com/products/e-prime/ and responses were recorded using magnet compatible buttons. For 3D-fig- ures a total of 15 figures were presented (3 blocks of 5 images, each block preceded by 6 seconds of Page 3 of 8 instruction) and for 2D-figures a total of 18 images were presented (3 blocks of 10 images, each block preceded by 6 seconds of instruction). Four, 18 s fixation blocks (cross-hair) were inter-mixed in the sequence. The entire run was thus composed of 4 fixation blocks (18 s each) + 6 figure matching blocks + 6 instruction periods for a total run time of 468 second scan (156 volumes, TR = 3). BOLD imaging Structural and functional MRI were performed on a 1.5 T MR imaging system (General Electric, Waukesha, WI). Whole brain axial anatomic (21 images, TR/TE 200/2.2 ms) and functional (21 images, TR/TE 3000/ 50 ms, flip angle 90°, 64 × 64 matrix, in-plane resolution of 3.75 × 3.75 mm, slice thickness 6 mm with 1 mm spaces) images were collected using a two-dimensional gradient-echo, echo-planar pulse sequence. Functional image analysis Functional data were processed using tools from the FMRIB Software Library (http://www.fmrib.ox.ac.uk and Smith et al., 2004) in essentially 6 steps (see Table 1): STEP 1) Independent components analysis based artifact detection and component removal, STEP 2) first-level analysis of individual paradigms for each subject; STEP 3) second-level fixed-effects analysis of individual sub- ject’s time1 vs. time2 scans; STEP 4) group mixed-effects general linear model comparison of ADT treated and CTR groups and, STEP 5) group mixed-effects compari- son of baseline (time1) vs. treatment (time2) activation changes in each group for the individual tasks; STEP 6) Using paradigm specific ROIs defined by STEP 5 (i.e., a unique ROI for ENCODE, RECOG and MATCH) the average change in the z-score between time1 and time2 was determined for each subject and task. STEP 1: Motion correction [26], spatial smoothing with a 7 mm at half-maximum Gaussian kernel and low pass (sigma = 2.8 s) and high pass (sigma = 75 s) filters were applied. Absolute motion varied from 0.1 to 1.2 mm and relative motion varied between 0.04 and 0.22 mm. Data were then analyzed using probabilististic independent components analysis (ICA) (MELODIC) [27] to identify extreme scanning artifacts and the corre- sponding components were removed. 4-10 components removed from 4 of 24 ENCODE scans (1 ADT and 1 CTR subject) and 2 or 24 MATCH scans (1 CTR sub- ject). No RECOG scan needed correction. STEP 2: The initial 6 volumes of each functional series were dis- carded to allow T1 equilibrium. For each task three separate explanatory variables (EVs) plus 6 motion para- meters of no interest were modeled. For each subject and each task, four individual contrasts were designed to determine task-related activation, deactivation, and the difference between route/survey in the EMT and 3D/2D in the MATCH tasks. STEP 3: Each subject’s