We demonstrate that increased microglial activation can be present up to 17 years after TBI. This suggests that TBI triggers a chronic inflammatory response particularly in subcortical regions. This highlights the importance of considering the response to TBI as evolving over time and suggests interventions may be beneficial for longer intervals after trauma than previously assumed.

White matter disruption is an important determinant of cognitive impairment after brain injury, but conventional neuroimaging underestimates its extent. In contrast, diffusion tensor imaging provides a validated and sensitive way of identifying the impact of axonal injury. The relationship between cognitive impairment after traumatic brain injury and white matter damage is likely to be complex. We applied a flexible technique—tract-based spatial statistics—to explore whether damage to specific white matter tracts is associated with particular patterns of cognitive impairment. The commonly affected domains of memory, executive function and information processing speed were investigated in 28 patients in the post-acute/chronic phase following traumatic brain injury and in 26 age-matched controls. Analysis of fractional anisotropy and diffusivity maps revealed widespread differences in white matter integrity between the groups. Patients showed large areas of reduced fractional anisotropy, as well as increased mean and axial diffusivities, compared with controls, despite the small amounts of cortical and white matter damage visible on standard imaging. A stratified analysis based on the presence or absence of microbleeds (a marker of diffuse axonal injury) revealed diffusion tensor imaging to be more sensitive than gradient-echo imaging to white matter damage. The location of white matter abnormality predicted cognitive function to some extent. The structure of the fornices was correlated with associative learning and memory across both patient and control groups, whilst the structure of frontal lobe connections showed relationships with executive function that differed in the two groups. These results highlight the complexity of the relationships between white matter structure and cognition. Although widespread and, sometimes, chronic abnormalities of white matter are identifiable following traumatic brain injury, the impact of these changes on cognitive function is likely to depend on damage to key pathways that link nodes in the distributed brain networks supporting high-level cognitive functions.

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...

Traumatic brain injury often results in cognitive impairments that limit recovery. The underlying pathophysiology of these impairments is uncertain, which restricts clinical assessment and management. Here, we use magnetic resonance imaging to test the hypotheses that: (i) traumatic brain injury results in abnormalities of functional connectivity within key cognitive networks; (ii) these changes are correlated with cognitive performance; and (iii) functional connectivity within these networks is influenced by underlying changes in structural connectivity produced by diffuse axonal injury. We studied 20 patients in the chronic phase after traumatic brain injury compared with age-matched controls. Network function was investigated in detail using functional magnetic resonance imaging to analyse both regional brain activation, and the interaction of brain regions within a network (functional connectivity). We studied patients during performance of a simple choice-reaction task and at 'rest'. Since functional connectivity reflects underlying structural connectivity, diffusion tensor imaging was used to quantify axonal injury, and test whether structural damage correlated with functional change. The patient group showed typical impairments in information processing and attention, when compared with age-matched controls. Patients were able to perform the task accurately, but showed slow and variable responses. Brain regions activated by the task were similar between the groups, but patients showed greater deactivation within the default mode network, in keeping with an increased cognitive load. A multivariate analysis of 'resting' state functional magnetic resonance imaging was then used to investigate whether changes in network function were present in the absence of explicit task performance. Overall, default mode network functional connectivity was increased in the patient group. Patients with the highest functional connectivity had the least cognitive impairment. In addition, functional connectivity at rest also predicted patterns of brain activation during later performance of the task. As expected, patients showed widespread white matter damage compared with controls. Lower default mode network functional connectivity was seen in those patients with more evidence of diffuse axonal injury within the adjacent corpus callosum. Taken together, our results demonstrate altered patterns of functional connectivity in cognitive networks following injury. The results support a direct relationship between white matter organization within the brain's structural core, functional connectivity within the default mode network and cognitive function following brain injury. They can be explained by two related changes: a compensatory increase in functional connectivity within the default mode network; and a variable degree of structural disconnection that modulates this change in network function.

Traumatic brain injury (TBI) frequently produces impairments of attention in humans.These can result in a failure to maintain consistent goal-directed behavior. A predominantly right-lateralized frontoparietal network is often engaged during attentionally demanding tasks. However, lapses of attention have also been associated with increases in activation within the default mode network (DMN). Here, we study TBI patients with sustained attention impairment, defined on the basis of the consistency of their behavioral performance over time. We show that sustained attention impairments in patients are associated with an increase in DMN activation, particularly within the precuneus and posterior cingulate cortex. Furthermore, the interaction of the precuneus with the rest of the DMN at the start of the task, i.e., its functional connectivity, predicts which patients go on to show impairments of attention. Importantly, this predictive information is present before any behavioral evidence of sustained attention impairment, and the relationship is also found in a subgroup of patients without focal brain damage. TBI often results in diffuse axonal injury, which produces cognitive impairment by disconnecting nodes in distributed brain networks. Using diffusion tensor imaging, we demonstrate that structural disconnection within the DMN also correlates with the level of sustained attention. These results show that abnormalities in DMN function are a sensitive marker of impairments of attention and suggest that changes in connectivity within the DMN are central to the development of attentional impairment after TBI.