Neuroimaging of structural pathology and connectomics in traumatic brain injury: Toward personalized outcome prediction.

Recent contributions to the body of knowledge on traumatic brain injury (TBI) favor the view that multimodal neuroimaging using structural and functional magnetic resonance imaging (MRI and fMRI, respectively) as well as diffusion tensor imaging (DTI) has excellent potential to identify novel biomarkers and predictors of TBI outcome. This is particularly the case when such methods are appropriately combined with volumetric/morphometric analysis of brain structures and with the exploration of TBI-related changes in brain network properties at the level of the connectome. In this context, our present review summarizes recent developments on the roles of these two techniques in the search for novel structural neuroimaging biomarkers that have TBI outcome prognostication value. The themes being explored cover notable trends in this area of research, including (1) the role of advanced MRI processing methods in the analysis of structural pathology, (2) the use of brain connectomics and network analysis to identify outcome biomarkers, and (3) the application of multivariate statistics to predict outcome using neuroimaging metrics. The goal of the review is to draw the community's attention to these recent advances on TBI outcome prediction methods and to encourage the development of new methodologies whereby structural neuroimaging can be used to identify biomarkers of TBI outcome

White matter integrity related to functional working memory networks in traumatic brain injury

Objective: This study explores the functional and structural patterns of connectivity underlying working memory impairment after severe traumatic axonal injury. Methods: We performed an fMRI n-back task and acquired diffusion tensor images (DTI) in a group of 19 chronic-stage patients with severe traumatic brain injury (TBI) and evidence of traumatic axonal injury and 19 matched healthy controls. We performed image analyses with FSL software and fMRI data were analyzed using probabilistic independent component analysis. Fractional anisotropy (FA) maps from DTI images were analyzed with FMRIB's Diffusion Toolbox. Results: We identified working memory and default mode networks. Global FA values correlated with both networks and FA whole-brain analysis revealed correlations in several tracts associated with the functional activation. Furthermore, working memory performance in the patient group correlated with the functional activation patterns and with the FA values of the associative fasciculi. Conclusion: Combining structural and functional neuroimaging data, we were able to describe structural white matter changes related to functional network alterations and to lower performance in working memory in chronic TBI

Pivotal Role of Anterior Cingulate Cortex in Working Memory after Traumatic Brain Injury in Youth

In this fMRI study, the functions of the anterior cingulate cortex (ACC) were studied in a group of adolescents who had sustained a moderate to severe traumatic brain injury (TBI). A spatial working memory task with varying working memory loads, representing experimental conditions of increasing difficulty, was administered. In a cross-sectional comparison between the patients and a matched control group, patients performed worse than Controls, showing longer reaction times and lower response accuracy on the spatial working memory task. Brain imaging findings suggest a possible double-dissociation: activity of the ACC in the TBI group, but not in the Control group, was associated with task difficulty; conversely, activity of the left sensorimotor cortex (lSMC) in the Control group, but not in the TBI group, was correlated with task difficulty. In addition to the main cross-sectional study, a longitudinal study of a group of adolescent patients with moderate to severe TBI was done using fMRI and the same spatial working memory task. The patient group was studied at two time-points: one time-point during the post-acute phase and one time-point 12 months later, during the chronic phase. Results indicated that patients’ behavioral performance improved over time, suggesting cognitive recovery. Brain imaging findings suggest that, over this 12-month period, patients recruited less of the ACC and more of the lSMC in response to increasing task difficulty. The role of ACC in executive functions following a moderate to severe brain injury in adolescence is discussed within the context of conflicting models of the ACC functions in the existing literature

Methylphenidate-mediated motor control network enhancement in patients with traumatic brain injury.

PRIMARY OBJECTIVE: To investigate functional improvement late (>6 months) after traumatic brain injury (TBI). To this end, we conducted a double-blind, placebo-controlled experimental medicine study to test the hypothesis that a widely used cognitive enhancer would benefit patients with TBI. RESEARCH DESIGN: We focused on motor control function using a sequential finger opposition fMRI paradigm in both patients and age-matched controls. METHODS AND PROCEDURES: Patients' fMRI and DTI scans were obtained after randomised administration of methylphenidate or placebo. Controls were scanned without intervention. To assess differences in motor speed, we compared reaction times from the baseline condition of a sustained attention task. MAIN OUTCOMES AND RESULTS: Patients' reaction times correlated with wide-spread motor-related white matter abnormalities. Administration of methylphenidate resulted in faster reaction times in patients, which were not significantly different from those achieved by controls. This was also reflected in the fMRI findings in that patients on methylphenidate activated the left inferior frontal gyrus significantly more than when on placebo. Furthermore, stronger functional connections between pre-/post-central cortices and cerebellum were noted for patients on methylphenidate. CONCLUSIONS: Our findings suggest that residual functionality in patients with TBI may be enhanced by a single dose of methylphenidate.The study was funded by the Evelyn Trust- grant number 06/20. C.D. was funded by the Clinical Academic Research Awards organized by the East of England Multi Professional Deanery. B.J.S. consults for Cambridge Cognition, Otsuka, Servier and Lundbeck. She holds a grant from Janssen/J&J and has share options in Cambridge Cognition. D.K.M. is supported by the Neuroscience Theme of the NIHR Cambridge Biomedical Research Centre and NIHR Senior Investigator awards, and by Framework Program 7 funding from the European Commission (TBIcare). He has received lecture and consultancy fees and support for research from Glaxo SmithKline, Solvay and Linde. E.A.S. is funded by the Stephen Erskine Fellowship, Queens' College, Cambridge, UK

Neuroimaging of structural pathology and connectomics in traumatic brain injury: Toward personalized outcome prediction☆

Recent contributions to the body of knowledge on traumatic brain injury (TBI) favor the view that multimodal neuroimaging using structural and functional magnetic resonance imaging (MRI and fMRI, respectively) as well as diffusion tensor imaging (DTI) has excellent potential to identify novel biomarkers and predictors of TBI outcome. This is particularly the case when such methods are appropriately combined with volumetric/morphometric analysis of brain structures and with the exploration of TBI-related changes in brain network properties at the level of the connectome. In this context, our present review summarizes recent developments on the roles of these two techniques in the search for novel structural neuroimaging biomarkers that have TBI outcome prognostication value. The themes being explored cover notable trends in this area of research, including (1) the role of advanced MRI processing methods in the analysis of structural pathology, (2) the use of brain connectomics and network analysis to identify outcome biomarkers, and (3) the application of multivariate statistics to predict outcome using neuroimaging metrics. The goal of the review is to draw the community's attention to these recent advances on TBI outcome prediction methods and to encourage the development of new methodologies whereby structural neuroimaging can be used to identify biomarkers of TBI outcome

Neuroimaging in repetitive brain trauma

Sports-related concussions are one of the major causes of mild traumatic brain injury. Although most patients recover completely within days to weeks, those who experience repetitive brain trauma (RBT) may be at risk for developing a condition known as chronic traumatic encephalopathy (CTE). While this condition is most commonly observed in athletes who experience repetitive concussive and/or subconcussive blows to the head, such as boxers, football players, or hockey players, CTE may also affect soldiers on active duty. Currently, the only means by which to diagnose CTE is by the presence of phosphorylated tau aggregations post-mortem. Non-invasive neuroimaging, however, may allow early diagnosis as well as improve our understanding of the underlying pathophysiology of RBT. The purpose of this article is to review advanced neuroimaging methods used to investigate RBT, including diffusion tensor imaging, magnetic resonance spectroscopy, functional magnetic resonance imaging, susceptibility weighted imaging, and positron emission tomography. While there is a considerable literature using these methods in brain injury in general, the focus of this review is on RBT and those subject populations currently known to be susceptible to RBT, namely athletes and soldiers. Further, while direct detection of CTE in vivo has not yet been achieved, all of the methods described in this review provide insight into RBT and will likely lead to a better characterization (diagnosis), in vivo, of CTE than measures of self-report

Functional Brain Hyperactivations Are Linked to an Electrophysiological Measure of Slow Interhemispheric Transfer Time after Pediatric Moderate/Severe Traumatic Brain Injury.

Increased task-related blood oxygen level dependent (BOLD) activation is commonly observed in functional magnetic resonance imaging (fMRI) studies of moderate/severe traumatic brain injury (msTBI), but the functional relevance of these hyperactivations and how they are linked to more direct measures of neuronal function remain largely unknown. Here, we investigated how working memory load (WML)-dependent BOLD activation was related to an electrophysiological measure of interhemispheric transfer time (IHTT) in a sample of 18 msTBI patients and 26 demographically matched controls from the UCLA RAPBI (Recovery after Pediatric Brain Injury) study. In the context of highly similar fMRI task performance, a subgroup of TBI patients with slow IHTT had greater BOLD activation with higher WML than both healthy control children and a subgroup of msTBI patients with normal IHTT. Slower IHTT treated as a continuous variable was also associated with BOLD hyperactivation in the full TBI sample and in controls. Higher WML-dependent BOLD activation was related to better performance on a clinical cognitive performance index, an association that was more pronounced within the patient group with slow IHTT. Our previous work has shown that a subgroup of children with slow IHTT after pediatric msTBI has increased risk for poor white matter organization, long-term neurodegeneration, and poor cognitive outcome. BOLD hyperactivations after msTBI may reflect neuronal compensatory processes supporting higher-order capacity demanding cognitive functions in the context of inefficient neuronal transfer of information. The link between BOLD hyperactivations and slow IHTT adds to the multi-modal validation of this electrophysiological measure as a promising biomarker

Neural correlates of motor deficits in young patients with traumatic brain injury

We discuss the changes in motor control as a result of traumatic brain injury (TBI) in children and adolescents. Besides behavioral/kinematic studies, the neural correlates of altered motor control, examined by means of functional magnetic resonance imaging and diffusion tensor imaging, will be presented. These studies show evidence for not only principal deficits in the control of movements in young TBI patients but also plastic changes in the brain to compensate for these deficits