This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Trauma is the leading cause of morbidity and mortality in children, and traumatic brain injury (TBI) is the most important determinant of the degree of severity. Consequently, research into TBI recovery and outcome is a high priority. Coma is a poorly understood condition, especially in cases of traumatic brain injury (TBI). This stems from TBI being attributed to diffuse damage of multiple brain regions through a variety of different Recovery from coma is a gradual continuum of return of consciousness, a process that is often confusing to families and staff. During the early recovery in those with very severe injuries, it can be difficult to distinguish those who will remain in a persistent vegetative state from those whose recovery will continue. In addition, it is difficult to assess who will have a more complete recovery of neurological function. This inability to adequately assess these patients stems from a lack of understanding the basic brain mechanisms involved in recovery from coma. Availability of objective evidence concerning brain activity during recovery would not only lead to a better understanding of these recovery mechanisms but could lead to improved ability to assess long-term outcome, provide focussed rehabilitation, choose appropriate medical, and improve appropriate utilization of long-term resources. The advent of sophisticated imaging techniques now allows us to observe the structural (e.g., MRI), metabolic (MRS), and functional (fMRI) activity of the brain noninvasively in a manner that previously was not possible. While the scope of our investigations appear comprehensive, we have designed the studies to be performed all in one scanning session for each evaluation. We are interested in using these three techniques to serially explore the evolution of structural brain injuries following TBI; the metabolic changes post-injury through the recovery process by obtaining regional assessments of neural metabolism with longitudinal spectroscopic measures of metabolic brain activity including NAA and lactate; as well as serial fMRI studies to evaluate the activation of the brain by functional activities during and after the recovery from coma. These studies will consist of auditory and visual stimuli, administered to determine levels of conscious recognition throughout the recovery process. We hypothesize that emergence from coma in children is based on the achievement of functional reconnections among a distributed set of neuronal circuits in the brain. We plan to be able to monitor the functional reconnection process through fMRI by assessing patients longitudinally before and after the emergence from coma, a process that for most of our patients is completed within days to weeks. In shock-trauma units and rehabilitation programs, emergence from coma is defined functionally as the ability of a patient to follow a simple verbal command. Therefore we will focus on brain responses to sounds and words (neutral and positively rewarding) and compare them to responses to visual and other sensory stimulation. We expect that comparison of networks of activated cortical and subcortical regions before and after emergence from coma in a series of patients will reveal critical networks that provide an essential substrate for consciousness. Since we are not aware of any similar work in humans, it is hard to predict what the results will be. However we expect that both vertical caudal-to-rostral hierarchies and horizontal transcortical network connections will be essential for emergence from coma. For example, we expect that activation of a combination of brainstem, thalamic and cortical pathways rather than simply brainstem structures alone will be essential for emergence. However, we expect that activation of lower levels plus a single cortical area alone will not be enough. Animal studies suggest that coincident recruitment of multiple, bilateral cortical association areas beyond primary cortical sensory representations is essential for emergence of consciousness. We expect to be able to understand this critical mass of connections and their topographic architecture. This work is likely to have considerable practical therapeutic as well as fundamental neuroscientific value. From a practical standpoint, families and the treatment team are both anxious to have objective information about what is going on in the brain. fMRI provides a new window on the working brain that should help the watching and waiting process. In addition, we hope that the technique will help with prognosis and with evaluating objective responses to rehabilitative interventions. From a fundamental standpoint, we expect that the diversity of traumatic lesions leading to unconsciousness will allow us to approach the consciousness problem from multiple directions. By comparing network properties of coma versus emergence in patients with multiple scattered lesions, we may be able to distill the critical network links that make consciousness possible. In addition, some patients are left with noticeable residual deficits following emergence from coma. Assessment of cortical and subcortical circuits through the coma recovery process may provide useful insights as to why full recovery occurs in some cases and not others, and how this may lead to focussing of treatment options and the timing of administration of those treatments.
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