The search for effective treatment facilitating recovery from concussive injury, as well as reducing risk for recurrent concussion is an ongoing challenge. This study aimed to determine: a) ...feasibility of selective brain cooling to facilitate clinical symptoms resolution, and b) biological functions of the brain within athletes in acute phase of sports-related concussion. Selective brain cooling for 30 minutes using WElkins sideline cooling system was administered to student-athletes suffering concussive injury (n=12; tested within 5±3 days) and those without history of concussion (n=12). fMRI and ASL sequences were obtained before and immediately after cooling to better understanding the mechanism by which cooling affects neurovascular coupling. Concussed subjects self-reported temporary relief from physical symptoms after cooling. There were no differences in the number or strength of functional connections within Default Mode Network (DMN) between groups prior to cooling. However, we observed a reduction in the strength and number of connections of the DMN with other ROIs in both groups after cooling. Unexpectedly, we observed a significant increase in cerebral blood flow (CBF) assessed by ASL after selective cooling in the concussed subjects compared to the normal controls. We suggest that compromised neurovascular coupling in acute phase of injury may be temporarily restored by cooling to match CBF with surges in the metabolic demands of the brain. Upon further validation, selective brain cooling could be a potential clinical tool in the minimization of symptoms and pathological changes after concussion.
Involvement in sport has been an integral part of American culture, both as a social entity as well as a developmental one. However, despite the ever-growing popularity of sport, major concern has ...been raised recently regarding the safety of contact sports. By nature, contact sports often involve exposure of the head to potentially damaging forces. Sports-related concussion and repetitive exposure to impacts have become areas of growing public concern, especially given their potential link to long-term neurodegenerative damage. While this area of study has been burgeoning more recently, much is still unknown about these injuries and their long-term effects. More specifically, there have been questions raised regarding why, in individuals exposed to the same sport over the same periods of time, some individuals are functionally and clinically resilient to deficits while other individuals are susceptible to functional and structural damage from head injuries. Therefore, the overall goal of this dissertation was to examine, using multiple modalities, why some individuals may be more susceptible and some more resilient to brain changes after sports-related concussion or to repetitive exposure of head acceleration events. Individually, Chapter 2 was a systematic examination of the current literature regarding clinical/cognitive, imaging, and biomarker outcomes over the course of a single season of participation in contact sports focusing on athletes’ college-aged and younger. Chapter 3 examined the influence of an individual athlete’s genetics on past history of sport-related concussion. Chapter 4 examined various clinical and cognitive outcomes over the course of a single season of football participation and, in addition, compared reproducibility between two seasons and how governing body rule changes might indirectly affect outcome. Chapter 5 examined the role of the cervical spinal cord in exposure to repetitive head acceleration events using diffusion tensor imaging. Jointly, these chapters serve to further the understanding of 1) how different modalities can be used to study head injuries in an efficient, yet clinically and functionally relevant way, and 2) how to begin to identify and distinguish factors that may differentiate individuals in regard to their susceptibility or resiliency to injury. The concept of susceptibility versus resiliency requires further study before concrete answers are determined, but this dissertation contributes to the growing body of work on the topic and how individual factors can be examined to best protect athletes and keep sports safe.
Context
In collision sports, particularly American football, athletes can accumulate thousands of subconcussive impacts, or head acceleration events (HAEs), across a single season; however, the ...short-term consequences of these impacts are not well understood.
Objective
To investigate the effects of the accumulation of impacts during practices on cognitive functions over a single football season.
Design
Prospective observational study.
Setting
Athletic training room and University laboratory.
Participants
Twenty-three NCAA Football Bowl Subdivision players.
Main outcome measures
Helmet accelerometers during practices and virtual reality testing (VR; balance, reaction time, spatial memory) before and after the season.
Results
Preseason had the majority of ≥80 G impacts while during the season had the majority of ≥25 G to <80 G impacts and positional differences showed that linemen had the majority of both types. Virtual reality analysis revealed that scores significantly decreased after the season for spatial navigation (p < 0.05) but not for balance or reaction time. Significant correlations (p < 0.05) were found between cognitive measures and player demographic variables.
Conclusions
Even in the absence of clinical symptoms and concussion diagnosis, repetitive impacts may cause cognitive alterations. Documenting the distribution of impact quantity and intensity as a function of time and position may be considered by coaches and clinicians to reduce the accumulation of impacts in athletes exposed in contact sports.
Context
After concussion, many different symptoms can occur and persist that can affect daily functioning. Many of these symptoms could have implications in an athlete’s ability to return to ...academics. Unlike return to play, return to academics is less studied and less regulated. There is little research examining the effects of concussion on grade point average (GPA) and results have been inconsistent.
Objective
To examine the effects of concussion on college GPA.
Design
Retrospective observational study
Setting
University laboratory
Participants
Division I athletes after their first concussion (n = 26) and Division I athletes without a history of concussion (n = 30).
Main Outcome Measures
GPA and demographic information was obtained for the semester before injury, the semester of injury, and the semester after injury.
Results
Statistical analysis using generalized linear mixed model analysis revealed a significant interaction (p < 0.05) of group (concussion vs. control) by time, with the concussed group having a significant decrease in GPA from semester before injury to semester of injury, and a significant main effect for sex (p < 0.05) with females having higher GPAs than males.
Conclusions
Since the cognitive demands of academics can potentially exacerbate symptomology of concussion, the identification of students at risk for difficulties is critical.
Abstract
Purpose: Reovirus (Respiratory Enteric Orphan virus) Serotype 3 – Dearing Strain is a naturally occurring, ubiquitous, non-enveloped human virus. Reovirus has been shown to replicate ...specifically in, and be cytopathic to, transformed cells possessing an activated Ras signaling pathway. We conducted a Phase I trial of Reolysin, a manufactured, purified reovirus, in children with relapsed or refractory extracranial solid tumors to define a maximum tolerated or recommended phase 2 dose (PP2D), as well as its toxicities and pharmacokinetic properties.
Experimental Design: Reovirus was administered intravenously, daily for 5 consecutive days every 28 days for up to 12 cycles. Using a 3+3 design, two planned dose levels were evaluated: 3 x 108 TCID50/kg (∼60% of the adult dose) and 5 x 108 TCID50/kg. The cohort was expanded at the RP2D to obtain additional single agent safety and viral clearance data. Additionally, a 3rd cohort received the RP2D ( 5 x 108 TCID50/kg Reolysin) plus oral cyclophosphamide (50 mg/m2/day x 21 days). Twice weekly quantitative real time PCR of reovirus genomic RNA from serum, stool and saliva, and antiviral immune response by ELISA was evaluated after the first two courses.
Results: Twenty-nine patients were enrolled, one was subsequently found to be ineligible. Of the 28 eligible patients, 5 are not evaluable (one is still on study) for dose-limiting toxicity (DLT). Six evaluable patients were enrolled on dose level 1; one with extensive pulmonary metastases experienced grade 5 respiratory failure attributed to their underlying disease. Given the severity of the event, the cohort was expanded to six without further DLTs. None of the six evaluable patients enrolled on dose levels 2 and 3, respectively, had a DLT. One patient in the single agent expansion cohort experienced a grade 5 thromboembolic event, grade 4 hypokalemia, grade 3 hypocalcemia, grade 4 hypophosphatemia, grade 3 hyponatremia, and grade 3 hypoalbuminemia possibly attributed to the Reolysin. With twice weekly monitoring by quantitative real time PCR, the median time to a clear the reovirus viremia was 6.5 days. Seven patients were viremic beyond the five days of therapy. No patient had detectable virus in their serum beyond day 17. Only one patient had detectable viral RNA in saliva or stool (day 6 in saliva). Four patients receiving the RP2D had stable disease at the end of one cycle, all others had progressive disease. All patients developed an anti-reovirus antibody during the first cycle of treatment. In three patients receiving a second cycle of reovirus, peak viral levels were reduced relative to cycle 1. There were no objective responses.
Conclusions: Reovirus at a dose of 5 x 108 TCID50/kg daily for 5 days is well tolerated alone and in combination with oral cyclophosphamide. Virus is cleared rapidly from the serum of most patients, even when given with cyclophosphamide, and shedding in stool and saliva is not seen.
Citation Format: Edward A. Kolb, Valerie B. Sampson, Deborah Stabley, Alexa Walter, Timothy P. Cripe, Pooja Hingorani, Charlotte Hsieh Ahern, Ashish M. Ingle, Brenda J. Weigel, Susan B. Blaney. A phase I trial and viral clearance study of reovirus (Reolysin) in children with relapsed or refractory extra-cranial solid tumors: A Children's Oncology Group phase I consortium report. abstract. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B74.
Abstract
Transcriptomics, regional cerebral blood flow (rCBF), and a virtual reality-based spatial motor task were integrated using mediation analysis in a novel demonstration of “imaging omics.” ...Data collected in National Collegiate Athletic Association (NCAA) Division I football athletes cleared for play before in-season training showed significant relationships in 1) elevated levels of miR-30d and miR-92a to elevated putamen rCBF, 2) elevated putamen rCBF to compromised Balance scores, and 3) compromised Balance scores to elevated microRNA (miRNA) levels. rCBF acted as a consistent mediator variable (Sobel’s test P < 0.05) between abnormal miRNA levels and compromised Balance scores. Given the involvement of these miRNAs in inflammation and immune function and that vascular perfusion is a component of the inflammatory response, these findings support a chronic inflammatory model in these athletes with 11 years of average football exposure. rCBF, a systems biology measure, was necessary for miRNA to affect behavior.
Owing to the increasing publicity that comes with professional and collegiate NCAA sports, concussion has become a major concern for players and spectators of sport. With concussion, many symptoms ...and physiological changes occur affecting both the short‐term and long‐term functioning of the patient. Many facets of daily activity including cognitive, executive, affective, and vestibular functioning may be affected after this injury. This chapter presents the signs and symptoms of concussion, the current diagnostic practices, and the assessment and management tools. The most common “treatment” for concussion is physical and cognitive rest, especially in the early stages of injury. The chapter discusses the psychological effects of concussive injury. Concussive injury can follow persistent cognitive difficulties in executive functioning, learning and memory, attention, speed processing, and language function in both children and adults. Sex, age, and previous concussive history greatly affect susceptibility to injury and post‐injury outcomes.
The trajectory of an individual's recovery after traumatic brain injury (TBI) is heterogeneous, with complete recovery in some cases but persistent disability in others. We hypothesized that changes ...in structural brain network abnormalities guide the trajectory of an individual's recovery post-injury. Our objective was to characterize the variability in recovery post-TBI by identifying a putative neuroimaging biomarker of traumatic axonal injury (TAI) in individuals with mild TBI. We analyzed 70 T1-weighted and diffusion MRIs longitudinally collected from 35 individuals during the subacute and chronic post-injury periods. Each individual underwent longitudinal blood work to characterize blood protein biomarkers of axonal and glial injury and assessment of post-injury recovery in the subacute and chronic periods. By comparing the MRI data of individual cases with 35 controls, we estimated the longitudinal change in structural brain network abnormalities. We validated this proxy measure of TAI with independent measures of acute intracranial injury estimated from head CT and blood protein biomarkers. Post-injury structural network abnormality was significantly higher than controls in both subacute and chronic periods, associated with an acute CT lesion and subacute blood levels of glial fibrillary acid protein (r=0.5, p=0.008) and neurofilament light (r=0.41, p=0.02). Longitudinal change in abnormality associated with change in functional outcome status (r=-0.51, p=0.003) and post-concussive symptoms (BSI: r=0.46, p=0.03; RPQ:r = 0.46, p=0.02). Brain regions that most closely mapped onto symptom change over time corresponded to structural network hubs or areas susceptible to neurotrauma. Structural network abnormalities might be a biomarker of TAI. Assessing changes in brain network abnormality might enable better patient stratification for monitoring recovery after neurotrauma.
Traumatic brain injury is a global public health problem associated with chronic neurological complications and long-term disability. Biomarkers that map onto the underlying brain pathology driving ...these complications are urgently needed to identify individuals at risk for poor recovery and to inform design of clinical trials of neuroprotective therapies. Neuroinflammation and neurodegeneration are two endophenotypes associated with increases in brain extracellular water content after trauma. The objective of this study was to describe the relationship between a neuroimaging biomarker of extracellular free water content and the clinical features of patients with traumatic brain injury. We analyzed a cohort of 64 adult patients requiring hospitalization for non-penetrating traumatic brain injury of all severities as well as 32 healthy controls. Patients underwent brain MRI and clinical neuropsychological assessment in the subacute (2-weeks) and chronic (6-months) post-injury period, and controls underwent a single MRI. For each subject, we derived a summary score representing deviations in whole brain white matter (1) extracellular free water volume fraction (VF) and (2) free water-corrected fractional anisotropy (fw-FA). The summary specific anomaly score (SAS) for VF was significantly higher in TBI patients in the subacute and chronic post-injury period relative to controls. SAS for VF significantly correlated with neuropsychological functioning in the subacute, but not chronic post-injury period. These findings indicate abnormalities in whole brain white matter extracellular water fraction in patients with TBI and are an important step toward identifying and validating noninvasive biomarkers that map onto the pathology driving disability after TBI.
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