D-KEFS Verbal Fluency Test. The Verbal Fluency Test measures letter and category

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1 e-methods Neuropsychological testing. D-KEFS Verbal Fluency Test. The Verbal Fluency Test measures letter and category fluency. In this study, we used the letter fluency task, which requires subjects to generate words that begin with a target letter for one minute. The letter fluency scaled score for the total correct responses is the dependent variable we used. D-KEFS Trail-Making Test. The Trail-Making Test is a visual-motor sequencing task that measures cognitive flexibility. In the number-letter switching condition, the subject connects numbers and letters in order while switching between the number and letter categories (e.g., A-1-B-2 ). The number-letter switching completion time scaled score is the dependent variable we used. D-KEFS Twenty-Questions Test. The Twenty-Questions Test measures reasoning ability, including categorization, abstraction, incorporation of experimenter feedback and hypothesis testing. The subject is shown a set of images of common objects, and is asked to identify an unknown target object by forming a series of yes/no questions. The subject is instructed to minimize the number of yes/no questions asked before successfully identifying the object. The total questions asked scaled score, which reflects the efficiency of the yes/no questions, was the dependent variable we used. Other neuropsychological tests that were included in our study for control and descriptive purposes include the Armed Forces Qualification Test 1 which we used to describe pre- and post-injury general intelligence; the Boston Naming Test (BNT 2 ) for object naming; the Token Test (TT 3 ) for basic verbal comprehension; and the Visual

2 Object and Space Perception Battery (VOSP 4, 5 ) for object and space perception. The pre-injury AFQT was administered to our participants at induction to the military prior to their service in Vietnam. It is composed of the following subtests: vocabulary knowledge, arithmetic word problems, object-function matching, and mental imagery. The AFQT has been standardized within the U.S. military and is highly correlated with general intelligence test scores 6. CT image acquisition and analysis. During Phase 3, we acquired axial computed tomography (CT) scans of participants at the Bethesda Naval Hospital on a General Electric Medical Systems Light Speed Plus CT scanner in helical mode. Images were reconstructed with an in-plane voxel size of 0.4 x 0.4 mm, an overlapping slice thickness of 2.5 mm and 1-mm slice interval. We determined lesion location and volume from CT images using the Analysis of Brain Lesion (ABLe v.2.8b) software 7, 8 that is implemented within MEDx v.3.44 (Medical Numerics). We spatially normalized each CT image to a CT template brain image in Montreal Neurological Institute (MNI) space 9. We performed a spatial normalization with the automated image registration (AIR) algorithm 10, using a 12-parameter affine fit. We calculated lesion volume by manually tracing the lesion in all relevant slices of the CT image, and then summing the traced areas and multiplying by slice thickness. A trained neuropsychiatrist performed the manual tracing, which was then reviewed by an observer blind to the results of the clinical evaluation and neuropsychological assessment. A board certified neurologist experienced in reading brain scans has reviewed all the images and confirmed that no additional gray and white matter damage, stroke or additional injuries occurred post-injury.

3 VLSM analysis was performed on the spatially normalized CT scans and all results are in MNI space. At each voxel, either a one-tailed t-test (for Verbal Fluency) or a Mann- Whitney U test (for Trail Making and Twenty Questions) was performed in order to compare task performance between ptbi patients who had a lesion at that particular voxel and those that did not. We restricted all analyses to a minimum overlap of four ptbi patients with lesions in a given voxel to ensure adequate statistical power 11. Standardized test statistics were contrasted against a FDR (q=0.05) corrected threshold for multiple comparisons to detect voxels with a statistically significant lesion-deficit relationship. Only clusters with a minimum of 10 adjacent voxels were reported. Based on evidence from past studies (e.g., 12 ), we selected regions of interest (ROIs) expected to impact EF recovery, including the PFC, ACR and SLF. The ROIs were defined by selecting structures from the white matter atlas, and from the AAL atlas based on previously established criteria 13. Specifically, the PFC ROI was defined in the following regions: Superior frontal gyrus (orbital), middle frontal gyrus (orbital), inferior frontal gyrus (orbital), superior frontal gyrus (medial), anterior cingulate, olfactory cortex, gyrus rectus, MNI coordinates -20 x 20, z 1; Superior frontal gyrus (orbital), middle frontal gyrus (orbital), inferior frontal gyrus (orbital), olfactory cortex, MNI coordinates x 20 or x 20, z 1; Superior frontal gyrus (medial), anterior cingulate, median cingulate, MNI coordinates -10 x 10, z > 1; Superior frontal gyrus (dorsolateral), middle frontal gyrus (lateral), inferior frontal gyrus (triangular part), MNI coordinates x 10 or x 10, z > 1.

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5 12. Barbey AK, Colom R, Solomon J, Krueger F, Forbes C, Grafman J. An integrative architecture for general intelligence and executive function revealed by lesion mapping. Brain : a journal of neurology 2012;135: Krueger F, Pardini M, Huey ED, et al. The role of the Met66 brain-derived neurotrophic factor allele in the recovery of executive functioning after combat-related traumatic brain injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 2011;31: