Mild Traumatic Brain injury (mTBI) is one of the most common forms of acquired neurological damage. However, the term 'mild' TBI is misleading because the physical, cognitive and emotional impairments that can follow from mTBI can be significant. In order to provide objective, prognostic measures for diagnosing the severity of mTBI and identifying individuals who may be at risk for poor outcomes a battery of neuropsychological measures for detecting cognitive impairment was evaluated. The Rapid Screen of Concussion (RSC) is a collection of tests assessing verbal recall, orientation, processing speed and speed of language comprehension. Previous studies have demonstrated that the RSC has acceptable reliability, validity and sensitivity to cognitive impairment that arises during the acute stages of injury. However, no studies have investigated the predictive validity of this instrument. Moreover it is unclear what additional patient or post injury variables could assist in identifying those individuals who may be at risk of poor neuropsychological outcomes following mTBI. These were among the main issues that were addressed across the five empirical studies in this thesis. A pragmatic, prospective, longitudinal and cross-sectional study of the sequelae of mTBI in patients presenting to the Department of Emergency Medicine of the Royal Brisbane and Women's hospital was the basis of this project. The first empirical chapter (chapter 2), examined the psychometric properties of two measures of verbal learning and memory and investigated their potential for discriminating between mTBI and orthopaedic controls. The performance of 93 patients with mTBI and 68 participants with orthopaedic injuries was analysed to identify the number of individuals who performed at ceiling on the Hopkins Verbal Learning test (HVLT-R) versus a 5-word test of immediate and delayed recall. While both of these verbal recall measures were effective in separating the mTBI and orthopaedic groups, overall, the HVLT-R was shown to be a more suitable measure for screening for deficits in verbal learning and memory after mTBI. Given the superiority of the HVLT-R as a measure of verbal learning and memory, chapter 3 aimed to examine whether inclusion of this test could improve the sensitivity of the RSC in mTBI compared to orthopaedic and uninjured control samples. Results were generally within the direction predicted. Significant differences were found between groups on the majority of cognitive indices assessed. Both the orthopaedic and mTBI group performed more poorly than the uninjured group on all measures except the Hopkins delayed recognition. Additional performance decrements shown by the mTBI group compared to the orthopaedic group illustrate that factors beyond the general effects of trauma influence performance and may be related to cognitive impairment specific to sustaining mTBI. Overall it was concluded that the revised RSC is a sensitive instrument deserving investigation in assessing the more long term cognitive effects following mTBI. Chapter 4 applied this sensitive battery for investigation of group and individual recovery of neuropsychological test performance and post-concussive symptom reporting up to 3-months after mTBI. A sample of 30 mTBI participants and 30 uninjured controls were serially assessed on cognitive measures and symptom report scales immediately after injury and after 1-week, 1-month and 3-months. Symptom reporting on the Rivermead post-concussive inventory separated the mTBI and control groups after 1-week but diagnostic accuracy was no greater than chance at 1 and 3-months. In contrast the mTBI group performed more poorly than controls on measures on neuropsychological measures acutely, at 1-week and 1-month, with group differences still evident after 3-months. Nonethless, a trend of progressive recovery over time was seen in the mTBI group. In chapter 5, criteria utilising the concepts of reliable and statistically significant change were applied to the data. Overall, 73% of mTBI patients were impaired on one or more tests acutely. Significant recovery was demonstrated by 20% of mTBI participants by 3-months; however recovery remained incomplete for half of the mTBI participants by 3-months. These results highlighted the importance of an individual approach to the assessment of mTBI and support the notion that a proportion of mTBI cases may have protracted difficulties. Chapter 6 extended these findings by showing that the RSC has prognostic ability. It was found that acute neuropsychological performance on the RSC was a significant predictor of performance on an extended battery at 3-months. The final chapter provides a general discussion and synthesis of the findings. In summary, the present dissertation demonstrated that inclusion of a sensitive measure of verbal recall led to improved diagnostic validity of the RSC. Neuropsychological measures rather than symptom reporting were sensitive in detecting cognitive impairment at 3-months. Analysis of individuals showed that up to 50% of the group had failed to – demonstrate reliable recovery – that is, make improvements over and above practice effects after 3-months. Finally, acute neuropsychological performance was predictive of long term performance. Overall, the present thesis has identified a short battery of tests that is suitable for assessment of mTBI within 24 hours and may assist in identifying individuals at risk of poor cognitive outcomes after mTBI.

The overall aim of this thesis is to contribute to the development and implementation of evidence-based physical activity promotion strategies for people with acquired brain injury (ABI). A randomized controlled trial (RCT) will furnish the highest level of evidence regarding the efficacy of a given intervention, but the immaturity of this area of research means that, currently, an RCT is not an appropriate research design. Therefore the purpose of the program of research presented in this thesis was to strategically contribute to the evidence base required to justify the conduct of a well designed RCT of an intervention promoting physical activity for people with ABI. By increasing participation in free-living, moderate intensity walking, people with ABI may reduce the oxygen cost of walking, thereby improving everyday functioning. The first study (presented in Chapter 3) evaluated a novel over-ground walking protocol in which a third party assists participants with ABI to reproduce previously self-selected comfortable and brisk walking speeds. Such a protocol could be used in conjunction with a portable indirect calorimetry to evaluate changes in oxygen cost of self-selected walking speeds over time. Thirteen people with ABI and related gait pattern impairment (age 31 + 8 yrs) completed two familiarization and two testing sessions. The first testing session used a self-paced (SP) protocol in which participants walked for 6 minutes at two self-selected speeds – comfortable and brisk paces. The second, conducted one week later, used an externally-paced (EP) protocol in which participants were instructed to walk at the pace indicated by the test administrator, who verbally and visually guided the participant to walk at their previous self-selected comfortable and brisk paces. In each testing session participants wore a portable indirect calorimeter (Cosmed K4b2). Measures obtained were oxygen cost of walking (l.min-1) and distance walked (m). Analysis demonstrated that the EP protocol reproduced distances walked at comfortable and brisk speeds with a high degree of accuracy and that agreement between measures of oxygen cost obtained during the SP and EP protocols were acceptable. Steady-state oxygen uptake is characteristic of a constant workload and was elicited during both EP walking trials, indicating that walking speeds were constant throughout the walk trials. It was concluded that the EP protocol described is a valid means of assisting people with ABI to reproduce overground walking speeds and that the protocol would be useful for evaluating changes in the oxygen cost of those walking speeds that may occur over the course of an intervention. The purpose of the second study (presented in Chapter 4) was to evaluate the validity of a uniaxial accelerometer (MTI Actigraph) for measuring physical activity in people with acquired brain injury (ABI) using portable indirect calorimetry (Cosmed K4b2) as a criterion measure. Fourteen people with ABI and related gait pattern impairment (age 32 + 8 years), wore an MTI Actigraph that measured activity (counts.min-1) and a Cosmed K4b2 that measured oxygen consumption (ml.kg-1.min-1) during four activities – quiet sitting (QS), comfortable paced (CP), brisk paced (BP) and fast paced (FP) walking. MET levels were predicted from Actigraph counts using a published equation and compared with Cosmed measures. Predicted METs for each of the 56 activity bouts (14 participants x four bouts) were classified (light, moderate, vigorous or very vigorous intensity) and compared with Cosmed-based classifications. Results indicated that Actigraph counts provide a valid index of activity across the intensities investigated in this study. For light to moderate activity, Actigraph-based estimates of METs are acceptable for group-level analysis and are a valid means of classifying activity intensity. The Actigraph significantly underestimated higher intensity activity although, in practice, this limitation will have minimal impact on activity measurement of most community-dwelling people with ABI as higher intensity activity is likely to be rare in this group. In the third study (presented in Chapter 5), 18 community-dwelling adults with acquired brain injury and a related gait pattern impairment (32.3 + 7.5 yrs) participated in an 8-week intervention promoting lifestyle physical activity. The aims were threefold: to evaluate the physical and psychosocial effects of the intervention; to assess whether the intervention increased the physical activity of participants; and to qualitatively evaluate the perceived effectiveness and acceptability of the intervention. Data were collected at six time points over 28 weeks: three pre-intervention, one each at 12 weeks prior (T1), 11 weeks prior (T2) and immediately pre-intervention (T3); and three post-intervention at immediately after (T4), four weeks after (T5) and eight weeks after (T6) the intervention. Physical outcomes measured were oxygen cost of comfortable and brisk-paced walking and maximum distance walked in three minutes. Psychosocial outcomes measured were SF-36, Depression Anxiety and Stress Scales (DASS), Rosenberg Self-Esteem Scale (RSES), Satisfaction with Life Scale (SWLS) and the Barriers to Health Activities for Disabled Persons (BHADP). Physical activity was sampled 6 days at T3, T4 and T6 and two measures were obtained – Actigraph counts per day and total minutes of activity greater than or equal to moderate intensity. Semi-structured interviews were used to evaluate the perceived effectiveness and acceptability of the intervention. The intervention comprised weekly, home-based, interactive problem-solving sessions designed to identify and overcome barriers to activity and to promote walking, together with facilitation of a community based leisure activity of the participant’s choice. Results indicated that the intervention improved important aspects of physical and psychosocial health for community-dwelling people with ABI. Compared with mean baseline measures, improvements in oxygen cost of brisk walking and self-esteem occurred that were both clinically and statistically significant at T6 (p < 0.01). Significant changes in two subscales of the SF-36 and the SWLS also occurred, although they were not sustained at T6. Measures of physical activity increased but not to an extent that was statistically significant. Qualitative data were principally positive, with 100% of participants and their significant others indicating they would recommend the program to another person with ABI. Given the particularly low levels of physical activity in the ABI population, and the correspondingly large individual and community benefits of that will be accrued if their physically active behavior can be increased, the promising results from this program of research indicate that there is a strong justification for allocating the resources necessary to conduct a sufficiently powered, randomized controlled trial of a lifestyle physical activity intervention for people with ABI.

Thesis (M.A.)--Miami University, Dept. of Speech Pathology and Audiology, 2006. / Title from first page of PDF document. Includes bibliographical references (p. 44-50).

Η ετερότοπη οστεοποίηση είναι ένα όχι σπάνιο φαινόμενο που οδηγεί σε δημιουργία οστικών δομών σε σημεία που φυσιολογικά υπάρχουν μαλακά μόρια. Ετερότοπη οστεοποίηση μπορεί να προκληθεί κατόπιν τοπικού τραύματος, κατόπιν νευρολογικού τραύματος, ύστερα από χειρουργική επέμβαση σε περιοχές όπως τα ισχία και οι αγκώνες, λόγω γενετικού υποστρώματος σε ασθενείς πολύ μικρών ηλικιών και τέλος αντιδραστικές ετερότοπες οστεοοποιήσεις άνω ή κάτω άκρων. Στην παρούσα διατριβή προσεγγίστηκε η νευρογενούς αιτιολογίας ετερότοπη οστεοποίηση, κυρίως κατόπιν ΚΕΚ. Ο παθοφυσιολογικός μηχανισμός του φαινομένου είναι εν πολλοίς άγνωστος και αυτό που θεωρείται δεδομένο είναι η διαταραχή του ισοζυγίου οστεοβλαστικής – οστεοκλαστικής δραστικότητας κατόπιν της δράσης του επαγωγικού παράγοντα. Ύστερα από τη δράση του επαγωγικού παράγοντα –στη συγκεκριμένη περίπτωση της ΚΕΚ – αυξάνεται η οστεοβλαστική δραστηριότητα τοπικά. Κατά το σχηματισμό του οστού λοιπόν, παράγονται και εκκρίνονται πρωτεογλυκάνες στις αλυσίδες των οποίων προσκολλώνται οι γλυκοζαμινογλυκάνες. Πρωτεογλυκάνες και γλυκοζαμινογλυκάνες συναποτελούν μαζί με τις κολλαγονικές και μη κολλαγονικές πρωτεΐνες, τα τρία κύρια είδη μακρομορίων του εξωκυττάριου δικτύου του οστού. Σκοπός της μελέτης μας ήταν αφενός η μελέτη των πρωτεογλυκανών και γλυκοζαμινογλυκανών στο ετερότοπο οστό σε αντιδιαστολή με φυσιολογικό-ορθότοπο οστό προκειμένου να διερευνηθεί ο ρόλος τους στην δημιουργία του φαινομένου της ετρότοπης οστεοποίησης. Αφετέρου για να διερευνηθεί καλύτερα ο παθοφυσιολογικός μηχανισμός του φαινομένου, μελετήθηκαν κυτταρικοί πληθυσμοί με οστεοβλαστική δραστηριότητα στο περιφερικό αίμα ασθενών που είχαν υποστεί ΚΕΚ και νοσηλεύονταν στη ΜΕΘ, καθώς και πειραματοζώων κατόπιν τεχνητής επαγωγής Κρανιοεγκεφαλικής Βλάβης. Η θειική χονδροϊτίνη και το υαλουρονικό οξύ είναι οι μοναδικοί τύποι γλυκοζαμινογλυκανών στο εξωκυττάριο δίκτυο ετερότοπου οστού όπως και στο φυσιολογικό. Εντούτοις, το ολικό ποσό τους είναι κατά 70% μικρότερο σε σύγκριση με αυτό του φυσιολογικού οστού. Διαφορετική είναι και η εκατοστιαία αναλογία αυτών των μακρομορίων. Η επικρατούσα μορφή δισακχαρίτη θειικής χονδροϊτίνης είναι η θειωμένη στην θέση 6. Ωστόσο η ποσοτική διαφοροποίηση από το φυσιολογικό οστό τόσο στους 4 θειωμένους όσο και στους μη θειωμένους δισακχαρίτες είναι υπαρκτή σε όλα τα ετερότοπα δείγματα. Από πλευράς πρωτεογλυκανών η αγγρικάνη και η διακοσμητίνη είναι ποιοτικά παρούσες στο εξωκυττάριο δίκτυο οστίτη ιστού. Επομένως, ποσοτικές διαφοροποιήσεις στο ετερότοπο οστό σε αντιδιαστολή με το φυσιολογικό είναι υπαρκτές και αυτή η διαφοροποίηση πιθανώς αντικατοπτρίζει διαφορετικές ενζυμικές δραστηριότητες στο φαινόμενο της ετερότοπης οστεοποίησης. Στη μελέτη των κυτταρικών πληθυσμών με οστεοβλαστική δραστηριότητα στο περιφερικό αίμα διαπιστώνονται τα ακόλουθα: Αυξημένη οστεοβλαστική δραστηριότητα στους πληθυσμούς CD-63(+) η οποία εμφανίζει κορυφή στις 6-10 ημέρες μετά την ΚΕΚ. Αυξανόμενη οστεοβλαστική δραστηριότητα πληθυσμών κυττάρων osteocalcin (+) σε όλες τις μετρήσεις μετά την ΚΕΚ. Το σύστημα οστεοπροτεγερίνης – sRANKL εμφανίζει τα εξής χαρακτηριστικά: η osteoprotegerin είναι μετρήσιμη και αυξάνει προς το τέλος των μετρήσεων. Το sRANKL απεναντίας δεν είναι μετρήσιμο σε καμία χρονική στιγμή κατόπιν της ΚΕΚ. Τα παραπάνω συνεπάγονται ότι η ΚΕΚ είναι παράγων επαγωγής οστεοβλαστικής δραστηριότητας όχι μόνο τοπικά αλλά και συστηματικά. Η εκτροπή της οστεοβλαστικής δραστηριότητας προς δημιουργία ετερότοπης οστεοποίησης χρήζει μελέτης μεγαλυτέρου δείγματος ασθενών και πιθανότατα και σε επίπεδα γονιδιακής έκφρασης κυτταρικών καλλιεργειών ασθενών κατόπιν ΚΕΚ. / Ηeterotopic ossification is a relatively frequent phenomenon that leads to the formation of heterotopic osseous structures at points where soft molecules normally do exist. Heterotopic ossification can be induced after local lesion, neurological lesion, after surgical intervention in regions as the hips and the elbows, due to genetic causes in patients of very small ages and, finally, the phenomenon has been observed as distinct, reactive cases in upper or lower limbs. In this Thesis, pathophysiology and mechanisms of neurogenic heterotopic ossification were studied. Pathways of the phenomenon still unknown to date. What is thaught to be the case in the formation of HO, is the disturbance of balance of osteoblastic to osteoclastic activities, after the induction-Head injury in this situation. After Traumatic Brain Injury, osteoblastic activity is induced locally. During bone formation proteoglycans are produced and secreted. Glucozaminoglycans are attached on the side chains of Proteoglycans. Proteoglycans and Glycozaminoglycans constitute along with collageneous and non-collageneous proteins the major macromolecules of extracellular matrix. The purpose of our study was the characterization of proteoglycans and glycozaminoglycans of the heterotopic bone versus the normotopic bone towards the elucidation of their role in the heterotopic bone formation. On the other hand, a more detailed approach to the pathophysiology of the phenomenon requires cellular populations expressing osteoblastic activities to be observed and studied. This is done in peripheral blood of patients that had sustained traumatic brain injuries and being hospitalized within IC units. Same studies on cellular populations have been conducted in a rabbit animal model of traumatic brain injury. Chondroitin-Sulfate and Hyaluronate are the only glycozaminoglycans that have been observed in extracellular matrix of heterotopic bone as well as in normotopic one. Quantitative analyses, however, revealed that their total amount is 70% less compared to normotopic bone. The commonest form of dissacharites of chondroitin-sulfate is the one sulfated at 6-O. However, there is a significant quantitative difference between normotopic and heterotopic bone in 4-O sulfated as well as in non sulfated dissacharites. With regards to proteoglycans, aggrecan and decorin are present in extracellular matrix. Quantitative differences between normotopic and heterotopic bone do exist and reflect a possible alternative pathway of bone formation in the HO phenomenon. The studies on osteoblastic activities of peripheral blood after traumatic brain injury revealed that there is increased osteoblastic activity in CD-63 (+) population that peaks 6-10 days after the inciting event. Osteocalcin (+) population do excibit increased osteoblastic activity as well which increases along with time. The system osteoprotegerin - sRANKL presents the following characteristics: osteoprotegerin is measurable and increases towards the end of measurements. sRANKL on the contrary is not measurable at any time following traumatic brain injury. Consequently, Traumatic Brain Injury do induce osteoblastic activity not only locally but also systemically. The deviation of osteoblastic activity towards heterotopic ossification requires studies of bigger sample of patients, probably to the level of differential gene expression of cellular cultures derived from patients having sustained neurotrauma.

L’arrêt cardio circulatoire et le traumatisme crânien sont responsables de lésions cérébrales dont les conséquences médico économiques sont un réel enjeu de santé publique. Malgré des espoirs importants lors des travaux expérimentaux, la majorité des traitements neuroprotecteurs se sont révélés être des échecs lors du passage à la clinique humaine. Riche d’une expérience clinique vieille de plusieurs millénaires, la Médecine Chinoise Traditionnelle a démontré son efficacité en clinique sur des patients victimes d’accidents vasculaires cérébraux. Le MLC 601, et sa formule simplifiée le MLC901, produits issus de celle-ci, ont déjà été étudiés dans un travail expérimental réalisé sur un modèle d'ischémie focale dans le laboratoire d’accueil. L’effet pléiotrope du produit avait alors été souligné. L’objet de notre travail a été d’étudier les effets neuroprotecteurs et neurorégénérateurs du MLC901 sur 2 autres modèles expérimentaux de lésions cérébrales : l’ischémie globale, mimant les conséquences cérébrales d’un arrêt cardiaque et le traumatisme crânien par percussion liquidienne latérale. Nous insistons, dans ce travail, sur l’effet neuroprotecteur du produit agissant sur les mécanismes de nécrose, d’apoptose et de stress oxydant se mettant en place après la lésion initiale. Nous retrouvons également une action neurorégénérative avec une stimulation de la neurogenèse induite par la lésion. L’ensemble de ces mécanismes cellulaires mis en place est associé à une amélioration de la récupération des fonctions neurologiques des animaux mis en évidence par l'utilisation de tests comportementaux moteurs et cognitifs. Nous démontrons donc dans ce travail, l’effet neuroprotecteur et neurorégénérateur du MLC901 sur deux modèles expérimentaux de « cérébro lésion », l’un ischémique et l’autre traumatique. / Cardiac arrest and traumatic brain injury are a socio economic health problem. Despite lot of hopes on neuroprotective therapies, few confirmed promising experimental results in clinical studies. Traditional Chinese Medicine has been used for several centuries. Despite lot of clinical investigations, few data are available on mechanisms involved in their effects. Interesting results have been published in stroke patients, and experimental studies using MLC601 and MLC901 have been conducted in mouse focal ischemia models. The multiple mechanisms of action, neuroprotective and neuroregenerative, of these treatments have been highlighted. The purpose of our study was to analyse the neuroprotective and neuroregenerative actions of MLC901 on rat global ischemia and traumatic brain injury models. In these models, we confirmed the neuroprotective action on necrosis, apoptosis and oxidative stress and the neuroregenerative action by the way of neurogenesis activation. These cellular actions are associated with functional recovery in the two models. We confirmed in these two experimental models, the neuroprotective and neuroregenerative effects of MLC901 on post ischemic or post traumatic brain injuries. This approach is essential for Traditional Chinese Medicine to be accepted by occidental one.

This study examined the efficacy of continuous nicotinamide (NAM) administration on recovery of function in rats following traumatic brain injury (TBI). TBI was induced via controlled cortical impact (CCI) bilaterally in the prefrontal cortex (+1.5, 0.0 relative to bregma) or sham surgeries were performed. Rats were then treated with either NAM (150 mg/kg/day) or vehicle (saline). Rats were tested behaviorally on the bilateral tactile adhesive removal task, locomotor placing task, novel exploratory behavior and the Morris water maze (MWM). Rats were also assessed histologically by looking at lesion size, GFAP expression (as a measure of active astroctyes) and MMP-9 expression (as a measure of inflammatory response) at time points of 24 and 48 hours and 30 days. The behavioral assessments showed significant improvements in the NAM-treated animals on the bilateral tactile adhesive removal, locomotor placing and MWM. The histological assessments showed significant lesion reduction at 30 days in the NAM-treated group. There were no differences between NAM-treated and vehicle groups on either GFAP or MMP-9 expression. These results indicate that NAM treatment after TBI can significantly improve recovery of function in rats.

It has been postulated that there could be a connection between traumatic brain injury (TBI) and motor neuron disease (MND), including amyotrophic lateral sclerosis (ALS). As chronic traumatic encephalopathy (CTE) is caused by repeated TBI and is a newly examined disease, there has been little evaluation of the potential relationship between CTE and ALS. It was proposed that CTE is a risk factor for not only MND, but also ALS. There is significant evidence that even a single TBI is a risk factor for Parkinson's disease (PD), thought to be invoked by the inflammatory process that the brain undergoes following a TBI. General rigorous physical activity with trauma to the trunk or extremities does not appear to be a risk factor for ALS. However, physical activity with associated head traumas, especially repeated head traumas, does seem to increase the likelihood of developing ALS. The biological mechanism for this is suspected to be increase in free radicals during exercise in individuals who are predisposed to decreased antioxidant function. Additionally, individuals who have suffered repeated head trauma, even amongst the general population in a non-athletic setting, has been shown to drastically increase the individual's chance of developing ALS. CTE, which is most common in athletes, is speculated to be caused by TAR DNA-binding protein 43 (TDP-43), tau neurofibrillary tangle (NFT), and beta-amyloid (A-Beta) protein inclusions in brain tissue following a multitude of TBI during high level sport activity. There are individuals who suffer initially CTE, followed by ALS, indicating CTE is clearly a risk factor for ALS. Anatomically, the TDP-43, NTF, and A-Beta; inclusions are present in the brain tissue of both individuals with CTE alone as well as the individuals with CTE and ALS. The anatomic difference between these two pathologies is the inclusion of these three proteins in the spinal cord of ALS patients as well. Unfortunately, there are indications that previous studies of professional athletes and their development of ALS have presented with significant issues including confounding factors of the subpopulation and sample sizing. Additionally, the anatomical cause of TBI leading to ALS is still unknown. Further evaluation on the relationship between head injury and ALS must be dedicated to investigating the mechanism involved in developed PD versus ALS following TBI. The biologic sequence following TBI that leads to ALS must be examined and compared to individuals whom develop ALS but did not suffer TBI. Moreover, an assessment must be made to determine what causes some individuals to develop protein inclusions solely in the brain tissue, leading to CTE, and some individuals to have an advancement of the protein inclusions into the spinal cord, leading additionally to CTE followed by ALS.

The understanding and treatment of brain disorders as well as the development of intelligent machines is hampered by the lack of knowledge of how the brain fundamentally functions. Over the past century, we have learned much about how individual neurons and neural networks behave, however new tools are critically needed to interrogate how neural networks give rise to complex brain processes and disease conditions. Recent innovations in molecular techniques, such as optogenetics, have enabled neuroscientists unprecedented precision to excite, inhibit and record defined neurons. The impressive sensitivity of currently available optogenetic sensors and actuators has now enabled the possibility of analyzing a large number of individual neurons in the brains of behaving animals. To promote the use of these optogenetic tools, this thesis integrates cutting edge optogenetic molecular sensors which is ultrasensitive for imaging neuronal activity with custom wide field optical microscope to analyze a large number of individual neurons in living brains. Wide-field microscopy provides a large field of view and better spatial resolution approaching the Abbe diffraction limit of fluorescent microscope. To demonstrate the advantages of this optical platform, we imaged a deep brain structure, the Hippocampus, and tracked hundreds of neurons over time while mouse was performing a memory task to investigate how those individual neurons related to behavior. In addition, we tested our optical platform in investigating transient neural network changes upon mechanical perturbation related to blast injuries. In this experiment, all blasted mice show a consistent change in neural network. A small portion of neurons showed a sustained calcium increase for an extended period of time, whereas the majority lost their activities. Finally, using optogenetic silencer to control selective motor cortex neurons, we examined their contributions to the network pathology of basal ganglia related to Parkinson’s disease. We found that inhibition of motor cortex does not alter exaggerated beta oscillations in the striatum that are associated with parkinsonianism. Together, these results demonstrate the potential of developing integrated optogenetic system to advance our understanding of the principles underlying neural network computation, which would have broad applications from advancing artificial intelligence to disease diagnosis and treatment.

Chronic Traumatic Encephalopathy (CTE) has been linked to contact sports, most notably boxing and American football, due to their propensity for repetitive head impacts. Concerns in the community for the safety of athletes in all contact sports has driven a significant amount of research into concussions, their long term effects, and strategies for treatment and prevention. Knowledge of long term brain health in response to neurotrauma is limited, a gap especially noticeable in the literature on non-catastrophic brain injuries sustained as a child. Concussion is a common injury that is often self-resolving with no lasting neurologic or cognitive deficits. Although repetitive brain trauma is hypothesized to be necessary and sufficient to lead to CTE, no human or animal models have definitively demonstrated the pathophysiologic connection or confirmed the mechanism of symptoms. The research to date has been case based, lacking prospective cohorts, with data complicated by convenience sampling. These factors limit the generalizability of conclusions. CTE is neuropathologically defined with variable symptoms; however, it is only diagnosable at postmortem autopsy making the etiology and prevalence difficult to understand. As more research is published to understand if there is an association between a neurocognitive degenerative disease and contact sports, the concentration is on professional athletes. Yet professional athletes do not represent the overwhelming majority of all contact sport participants. The proposed study will compare adults who participated in youth football, but not beyond the high school level, to a control group of adults who did not play contact sports. Evaluating their cognitive function with an online assessment, the Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A), data will be analyzed for signs of clinical cognitive impairment. The objective is to measure adults who represent the high percentage of youth football players who do not continue to the advanced levels. Data obtained from this study will help communities make informed decisions, and create the foundation for future studies on long term benefits and risks of contact sports for children.

abstract: Development of post-traumatic epilepsy (PTE) after traumatic brain injury (TBI) is a major health concern (5% - 50% of TBI cases). A significant problem in TBI management is the inability to predict which patients will develop PTE. Such prediction, followed by timely treatment, could be highly beneficial to TBI patients. Six male Sprague-Dawley rats were subjected to a controlled cortical impact (CCI). A 6mm piston was pneumatically driven 3mm into the right parietal cortex with velocity of 5.5m/s. The rats were subsequently implanted with 6 intracranial electroencephalographic (EEG) electrodes. Long-term (14-week) continuous EEG recordings were conducted. Using linear (coherence) and non-linear (Lyapunov exponents) measures of EEG dynamics in conjunction with measures of network connectivity, we studied the evolution over time of the functional connectivity between brain sites in order to identify early precursors of development of epilepsy. Four of the six TBI rats developed PTE 6 to 10 weeks after the initial insult to the brain. Analysis of the continuous EEG from these rats showed a gradual increase of the connectivity between critical brain sites in terms of their EEG dynamics, starting at least 2 weeks prior to their first spontaneous seizure. In contrast, for the rats that did not develop epilepsy, connectivity levels did not change, or decreased during the whole course of the experiment across pairs of brain sites. Consistent behavior of functional connectivity changes between brain sites and the "focus" (site of impact) over time was demonstrated for coherence in three out of the four epileptic and in both non-epileptic rats, while for STLmax in all four epileptic and in both non-epileptic rats. This study provided us with the opportunity to quantitatively investigate several aspects of epileptogenesis following traumatic brain injury. Our results strongly support a network pathology that worsens with time. It is conceivable that the observed changes in spatiotemporal dynamics after an initial brain insult, and long before the development of epilepsy, could constitute a basis for predictors of epileptogenesis in TBI patients. / Dissertation/Thesis / M.S. Bioengineering 2012