This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.ABSTRACTWe propose three aims to study the neurobehavioral effects of mild traumatic brain injury (MTBI) over six months relative to orthopedic injury (OI) in adolescents and young adults on: (1) change in integrity of cerebral white matter as measured by diffusion tensor imaging (DTI) at baseline and six months postinjury; (2) change in brain region volumes of white matter and gray matter based on analysis of magnetic resonance imaging (MRI) at baseline and six months; (3) change in episodic memory, information processing speed, and executive function at baseline, three, and six months post-injury; (4) change in postconcussion symptoms and emotional status at baseline, three, and six months postinjury; and, (5) the relation of brain imaging measures to acute injury variables and the outcome domains. This project also involves investigation of biomarkers to determine whether they are sensitive to the neural injury associated with MTBI. A blood sample would be taken in the pilot study and in the actual project and the serum would be used for analysis of biomarkers. We would evaluate the moderating effects of family environment (socioeconomic level, stressors and social resources) and control for the effects of preinjury trauma exposure, posttraumatic stress, and depressive symptoms. In the pilot study children age 15-21 years (as defined by the NIH) and adults 22-24 years who sustain a mild TBI (n=10) or OI (n=10) would be studied at baseline (within 1 week post-injury). Although this pilot study is limited to collection of data at baseline, in the actual project we propose to follow-up the patients at 1, 3, and 6 months post-injury, including repeat brain imaging at 6 months. Cognitive control tasks include the Flanker (interference and no-go), Sternberg Item Recognition (interference and working memory), stop signal (stopping a response), selective learning (selectivity in learning items belonging to highly rewarded categories), a complex working memory task (Keeping Track), and a peg board measure of motor speed. Post-concussion symptoms would be measured by a checklist completed by the patient. Functional limitations and general emotional status would be measured by self-report forms and a brief interview. Pre-injury psychiatric status would be evaluated by a structured psychiatric interview. Brain white matter integrity will be evaluated by voxel based and region of interest (ROI) analyses of the DTI data. The ROIs to be analyzed will be normal appearing white matter in areas known to be particularly vulnerable to DAI, including (1) splenium, and genu of corpus callosum; (2) superior limb of the internal capsule; and, (3) centrum semiovale. Brain regional volumes would be measured by manual tracing and segmentation of gray and white matter for: (1) corpus callosum regions including the splenium, and genu; (2) superior limb of the internal capsule; (3) centrum semiovale; (4) ventrolateral and ventromedial prefrontal cortex; (5) superior medial and lateral prefrontal cortex; (6) superior temporal gyrus; and, (7) whole brain. Interrater reliability for the DTI ROI and brain region volumetric analyses will be confirmed prior to analyzing the group data. Statistical analysis of the hypotheses would use general linear mixed models. Based on analysis of the pilot data, we will calculate sample size estimates for the proposed NIH submission.HYPOTHESIS Hypothesis 1. At one week and at six months following MTBI, adolescents and young adults exhibit DAI on DTI and loss of brain region volumes on MRI relative to patients with orthopedic injury (OI) with disproportionate axonal injury in areas known to be susceptible to shearing effects of rotational acceleration, including (1) corpus callosum regions including the splenium, and genu; (2) superior limb of the internal capsule; and, (3) centrum semiovale).Hypothesis 2. Adolescents and young adults with Glasgow Coma Scale (GCS) scores of 13-14 have more severe axonal injury than those with GCS scores of 15 on DTI performed at baseline and at six months post-injury. As a corollary, (a) patients with confirmed unconsciousness immediately after mild TBI have more severe axonal injury on DTI at baseline and at six months post-injury than those without confirmed unconsciousness; and (b) duration of posttraumatic amnesia (PTA) is directly related to the extent of axonal injury and loss of brain region volumes.Hypothesis 3. Extent of axonal injury and loss of brain region volumes detected at six months is greater than at baseline as measured by repeated DTI and volumetric analysis of MRI. Hypothesis 4. More extensive axonal injury measured by DTI is directly related to loss of brain region volumes of white matter on MRI. Hypothesis 5. Recovery of information processing speed, cognitive control, and episodic memory is related to the extent of axonal injury seen on DTI. More extensive axonal injury is predictive of slower recovery in all three cognitive domains. As a corollary, greater loss of brain region volumes is inversely related to rate of recovery in three cognitive domains.Hypothesis 6. Recovery of information processing speed, cognitive control, and episodic memory are related to both return and adjustment to school and work.Hypothesis 7. Cognitive symptoms such as poor concentration, reduced memory efficiency, and attention problems following mild TBI are related to extent of axonal injury seen on DTI and to brain region volume loss measured from MRI.Hypothesis 8. Emotional symptoms such as anxiety, depression, and general distress following mild TBI are not related to extent of axonal injury measured by DTI or brain region volume changes. Hypothesis 9: Cognitive and emotional symptoms are related to functional outcome, including return and adjustment to school and work.Hypothesis 10: Biomarkers of neural proteins can differentiate MTBI from OI and are related to extent of axonal injury.
SPECIFIC AIMS Specific Aim 1: (Injury Variables and Imaging): Investigate acute injury variables in relation to diffusion tensor imaging (DTI) and volumetric analysis of magnetic resonance imaging (MRI) in adolescents and young adults who undergo brain imaging within one week and at six months after sustaining mild traumatic brain injury (TBI).
Specific Aim 2 : (Cognitive Recovery): Investigate cognitive recovery from mild TBI in adolescents and young adults in relation to axonal injury and loss of brain region volumes.
Specific Aim 3 : (Post-concussion Symptoms): Investigate changes in post-concussion symptoms and their relation to axonal injury.
Specific Aim 4 : (Biomarkers): Investigate the specificity and sensitivity of biomarkers for MTBI relative to OI.
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