Efficient behavior involves the coordinated activity of large-scale brain networks, but the way in which these networks interact is uncertain. One theory is that the salience network (SN)-which includes the anterior cingulate cortex, presupplementary motor area, and anterior insulae-regulates dynamic changes in other networks. If this is the case, then damage to the structural connectivity of the SN should disrupt the regulation of associated networks. To investigate this hypothesis, we studied a group of 57 patients with cognitive impairments following traumatic brain injury (TBI) and 25 control subjects using the stop-signal task. The pattern of brain activity associated with stop-signal task performance was studied by using functional MRI, and the structural integrity of network connections was quantified by using diffusion tensor imaging. Efficient inhibitory control was associated with rapid deactivation within parts of the default mode network (DMN), including the precuneus and posterior cingulate cortex. TBI patients showed a failure of DMN deactivation, which was associated with an impairment of inhibitory control. TBI frequently results in traumatic axonal injury, which can disconnect brain networks by damaging white matter tracts. The abnormality of DMN function was specifically predicted by the amount of white matter damage in the SN tract connecting the right anterior insulae to the presupplementary motor area and dorsal anterior cingulate cortex. The results provide evidence that structural integrity of the SN is necessary for the efficient regulation of activity in the DMN, and that a failure of this regulation leads to inefficient cognitive control. E fficient behavior involves the coordinated activity of largescale brain networks (1, 2). These networks can be identified by studying patterns of brain activity measured by functional MRI (fMRI) (3). A key question is whether-and in what waythe interactions between these networks control behavior. Regions on the medial wall of the frontal lobe, including the anterior cingulate cortex (ACC) and presupplementary motor area (preSMA), often show highly correlated brain activity with the anterior insula (AI) (4-6), and together they have been termed the salience network (SN) (4). In many situations, activity within this network appears to signal the need for behavioral change (7-9), and one proposal is that the SN may operate to dynamically control changes of activity in other networks (6).The role of the SN in mediating the function of other networks is likely to be most evident when a rapid change in behavior is required. We have previously studied this type of behavior in the context of motor control using the stop-signal task (SST) (10). The SST probes the ability to inhibit an action that has already been initiated. Stop trials require a switch from relatively automatic to highly controlled behavior. Parts of the right inferior frontal cortex, including the right AI (rAI), are important for the attentional processes involved in responding to an unexp...