The Trail-Making Test (TMT) is a widely used neuropsychological measure that assesses visuomotor abilities and cognitive flexibility. For the TMT-A condition participants are required to locate and connect numbers (i.e. 1-2-3...) while in the TMT-B condition participants perform the set-shifting task of locating and connecting numbers and letters (i.e. 1-A-2-B...). The TMT-B condition has shown impairments in many clinical populations, particularly schizophrenia patients, but the neurobiological underpinning of the task can be difficult to discern given pragmatic obstacles in adapting the task for neuroimaging. In a behavioural testing experiment we demonstrated a close correspondence between performance on the standard TMT and a novel, computer programmed adaptation of the TMT (pcTMT). The pcTMT was designed for functional magnetic resonance imaging (fMRI) administration and neuroimaging data for this task were obtained in. A whole brain analysis revealed significantly greater activation during the pcTMT-B relative to the pcTMT-A in right inferior/middle frontal cortices, right precentral gyrus, left angular gyrus/left middle temporal gyrus. These results identify the regions that most likely underlie cognitive flexibility during the TMT and are candidate regions underlying the impairment of groups with poor set-shifting abilities. (Contains 8 figures and 1 table.)