Cognitive Control Function and Moderate-to-Severe Traumatic Brain Injury: Functional and Structural Brain Correlates

Abstract

Clinical signs of traumatic brain injury (TBI) such as altered- or complete loss of consciousness, other neurological signs, and findings based on conventional neuroimaging, represents important information for initial treatment and further follow-up of TBI survivors. However, not all real-life problems after TBI are easily detected by conventional imaging methods or neurological exams. This is particularly evident when trying to assess the more subtle effects of TBI, such as cognitive and emotional problems, that are often experienced in the chronic stage, after the initial recovery period has passed. The main aim for this thesis was to extend current knowledge on functional and structural changes in the brain after moderate-to-severe TBI by means of advanced neuroimaging methods, and to relate these findings to injury-related variables and functional measures known to be important for outcome. A particular focus was on investigating cognitive control function, as this has been demonstrated to play an especially important role for functional outcome after TBI. In order to reach this aim, several studies with different but related perspectives were performed, and four papers (Paper I – IV) based on these studies are included in this thesis. In Paper I, a large group of healthy participants was included in a study in order to validate a clinically relevant task protocol that could measure both adaptive and stable cognitive control processes in the brain by means of blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI). Results from this study gave further support for a core network of cognitive control, with overlapping activations for both stable and adaptive processes, comprised by brain regions bilaterally in the insula (and adjacent cortices) and dorsal medial frontal cortex. It was also established that in this particular task, adaptive cognitive control processes by and large were distributed in more anterior regions of the prefrontal cortex as compared to stable cognitive control processes. Another novel and important finding, was that only stable cognitive control processes were affected by time on task (TOT), indicating that this contrast might be particularly sensitive for detecting adaptive changes in the brain. In Paper II, it was demonstrated that executive, emotional and behavioral problems were more frequently reported in chronic moderate-to-severe TBI survivors as compared to healthy controls. The results also indicated that identification of traumatic axonal injury (TAI) and symptoms of depression in an earlier phase after injury, might give a warning of later problems. Furthermore, self-report measures of cognitive control seemed to extend the information obtained from performance-based measures. In Paper III, it was shown that neuronal correlates of adaptive and stable cognitive control processes were differently affected by moderate-to severe TBI. Moreover, TBI survivors exhibited increased TOT related BOLD activation related to stable cognitive control processes in the right inferior parietal lobe and right prefrontal cortex. Increases in BOLD activations had a dose-dependent relationship with injury severity, with increased activation with more severe injury. Interestingly, increased BOLD activations after TBI were related to better self-reported cognitive control function in everyday-life situations, indicating a compensatory role for these activations. In paper IV, it was shown that more severe injury based on clinical signs, and findings on conventional MRI evaluations, was related to more pronounced alterations of white matter microstructure in a wide range of tracts as measured with diffusion tensor imaging (DTI). Reduced white matter integrity in TBI survivors was also associated with worse global outcome, and poorer cognitive control function as measured by performance-based measures. No association was found between any of the DTI measures and self-reported cognitive control function. The findings presented in this thesis demonstrated that a broad assessment is warranted in order to optimize our understanding and follow-up of TBI patients. Also, it was shown that subtle changes in brain structure and function, not necessarily detectable with conventional imaging tools, might still have an important impact on how TBI survivors are able to cope with every-day life. A particularly interesting finding with possible clinical implications was that performance-based cognitive control function in chronic TBI was related to subtle structural changes in the brain as measured with DTI, whereas selfreported problems were exclusively related to functional adaptations as measured with fMRI. In general, knowing that self-reported cognitive control function in chronic moderate- to-severe TBI survivors is associated with functional changes in the brain, gives an important perspective when seeing patients where such problems are not easily explained by conventional neuropsychological measures. More than that, as these functional changes were shown to play a potential compensatory role, this might indicate a potential target for neuro-rehabilitation.