Thesis (Ed.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Problem The purpose of this study was to investigate the relation of anxiety to learning in brain injured adults, and to determine how their performance was affected by reassurance instructions, additional practice, and variations in task content and difficulty. Scope The study involved forty patients with brain injury of cerebrovascular origin who were admitted to the neurological service of a hospital in the Massachusetts Public Health system. The patients ranged in age from fifty to sixty six, and in intelligence quotient from eighty to one hundred and twelve. They were evenly divided on sex, but the lateral distribution of lesion favored the right cerebral hemisphere with seventy per cent of the patients having damage on that side, and thirty per cent on the contralateral side. None of the patients had dysphasic language disorders or visual disorders, and at the time of participation in the study all were scheduled to commence therapy within a period of two weeks. Procedure Patients scoring in the upper and lower forty per cent of the distribution of anxiety scores on both the Buss Anxiety Rating Scale, and the Manifest Anxiety Scale were matched in respect to age, intelligence, sex, and the lateral location of cerebral lesion. They were then assigned to either an additional practice or a reassurance instructions treatment category on the basis of a table of random numbers. [TRUNCATED] / 2999-01-01

Yes / Klüver-Bucy syndrome (KBS) is a rare clinical presentation following traumatic brain injury (TBI). Symptoms include visual agnosia, placidity, hyperorality, sexual hyperactivity, changes in dietary behavior, and hypermetamorphosis. The purpose of this article was to identify and synthesize the available evidence from case reports and case series on the treatment profile of KBS among adolescents and adults after TBI. Four bibliographic databases (MEDLINE OVID, EMBASE, PsycINFO, and SCOPUS) were searched for relevant literature. No date or language restrictions were applied. All case reports containing original data on KBS following TBI among adolescents and adults were included. Articles were evaluated, and data were extracted according to predefined criteria. The literature search identified 24 case reports of KBS post-TBI published between 1968 and 2017. Most case subjects were male (70.1%), and the mean age at injury was 25.1 years (range, 13–67 years). Injury to one or both temporal lobes occurred in most cases. Inappropriate sexual hyperactivity was the most common KBS symptom, followed by a change in dietary behavior and hyperorality. Visual agnosia was the least reported. In 50% of cases, the patient fully recovered from KBS. One-half of all participants described pharmacological management; the most common medication prescribed was carbamazepine. Overall, there was a lack of data available on pharmacotherapy initiation and duration. The complex presentation of KBS presents challenges in terms of treatment options. Although overall individuals who were prescribed carbamazepine had positive outcomes, given the reliance on case reports, it is difficult to make a definitive recommendation to guide clinical practice. / Institute for Safety, Compensation and Recovery Research, Monash University, Bionomics,Eli Lilly, Lundbeck, Novartis, Servier

Concussion is the most common form of brain injury, comprising over 80% of traumatic brain injuries (TBIs) occurring in the United States and around the world. While many individuals are able to fully recover in the weeks following a concussion, an estimated 50% of patients go on to suffer from persistent symptoms that may range from months to years in duration. Among the most common complaints of those with persistent symptoms is sadness or depression, and significantly elevated rates of suicide have been reported in this population. Females are more likely to develop persistent symptoms and have reported higher rates of neuropsychiatric symptoms than males following injury. Altered glutamatergic neurotransmission has been implicated as a possible cause of depression following concussion due to similarities in glutamatergic changes that occur following concussion and during depression, independently of brain injury. Excitotoxicity is known to occur following TBI, resulting in neuronal death, and dysfunction in the cells that survive. Glutamatergic dysfunction occurring in regions such as the hippocampus, prefrontal cortex or amygdala, may be a driver of depressed mood or major depressive disorder (MDD) in concussed individuals as these regions, among others, have previously been linked to MDD. There are currently no approved pharmacological treatments for TBI symptoms. Therefore, gaining insight into chronic pathophysiology underlying TBI symptoms, including depression, is essential to support the development of therapeutic approaches for patients. The glutamate system represents a promising avenue of investigation in the context of chronic TBI pathophysiology. Using a clinically-relevant rodent model of concussion, this work sought to elucidate chronic glutamatergic changes occurring in the brain in association with the development of depression-like behavior following injury. Delayed-onset deficits in social and self-care behaviors were observed in association with region-specific changes in N-methyl-D-aspartate (NMDA) receptor and glutamate transporter expression in injured male animals. Females responded differently to injury, showing disinhibition and compulsive behaviors in conjunction with upregulation of glutamatergic signaling proteins. Further, this work aimed to investigate chronic sex-specific responses to TBI. Direct comparisons of behavioral changes in injured males and females demonstrated differences in both the emergence and nature of behavioral deficits. Examinations of hippocampal subregions showed deeper specificity in expressional changes in glutamatergic markers with both region- and sex-specific alterations observed at a chronic time point. Additionally, proteomic analysis was employed to evaluate widespread protein-level changes in the injured frontal cortex, and results revealed significant dysregulation in pathways involved in excitatory neurotransmission and calcium signaling. However, the dysregulated proteins within these pathways differed in a sex-dependent manner, indicating a sexual dimorphism in chronic TBI pathophysiology. Potential drug targets were also identified for investigation in future studies. The fundamental work presented in these studies provides strong evidence of dynamic, sex-specific modifications in the glutamate system in association with chronic TBI deficits in a translational model, ultimately providing a foundation for future development of therapeutic options to improve the lives of patients suffering with persistent symptoms. / Doctor of Philosophy / Concussion is the most common form of brain injury, comprising over 80% of traumatic brain injuries (TBIs) occurring in the United States and around the world. While many individuals are able to fully recover in the weeks following a concussion, an estimated 50% of patients go on to suffer from persistent symptoms that may range from months to years in duration. Among the most common complaints of those with persistent symptoms is sadness or depression, and significantly elevated rates of suicide have been reported in this population. Females are also more likely to develop persistent concussion symptoms and tend to experience more severe symptoms than males, but the reasons for this are not known. Changes in important signaling proteins, which allow neurons to properly communicate with one another, have been observed in the brains of concussed patients. Changes in the same proteins have been reported in depressed patients, leading to the belief that these signaling proteins may be involved in the development of depression after a brain injury. These proteins are involved in glutamate signaling, and glutamate is the main excitatory neurotransmitter in the brain. Excitatory neurotransmission is responsible for activating receptors which can lead to the firing of neurons, hence its importance in neuron communication. There are currently no approved treatments for TBI symptoms. Therefore, gaining insight into the chronic biological changes underlying TBI symptoms, including depression, is essential to support the development of therapies for patients. Using a rodent model of concussion, this work identified long-term changes in important glutamate signaling proteins in injured animals which were observed alongside depression-like behaviors. Injured male rodents were less social and were less motivated to take care of themselves, similar to humans with major depressive disorder (MDD). Female rodents showed different changes in depression-like behaviors and also developed behaviors similar to humans with obsessive compulsive disorder (OCD). This work demonstrated the development of sex-specific symptoms in injured animals, and these were accompanied by different changes in key glutamate signaling proteins, which suggests problems in neuron communication due to injury. These protein changes were detected in regions of the brain linked to MDD. The fundamental work presented in these studies provides strong evidence of dynamic, sex-specific modifications in the glutamate system in association with chronic TBI symptoms, ultimately providing a foundation for future development of therapeutic options to improve the lives of patients suffering with persistent symptoms.

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Rapporten innehåller analysen av 26 olika situationer inom ishockey. Situationerna är hårda tacklingar från olika matchar och ligor. Analyserade tacklingar resulterade INTE i hjärnskakning, likadana situationer kan ge upphov till hjärnskakning. Målet med projektet är bland annat skapa en kontrollgrupp för studierna i hjärnskakning inom ishockey. Tidigare studier utfördes för situationer som resulterar i hjärnskakningar. Rapporten pekar kort på huvudet och nackens anatomi d.v.s. skalp, hjärnan och skallben. Begreppet hjärnskakning med dess symptom förklarades också. I valda video sekvenserna analyserades huvudets kinematik och kollisionssekvenser mellan huvud och den andra parten som kan vara en annans axel, huvud, arm eller is eller glasvägg(plexiglas). Resultatet ska komma överens med tidigare gjorda arbete. / The report includes analysis of 15 different situations in Ice-hockey. The situations are hard tackles from different matches and leagues. The analyzed tackles did Not resulted to concussion, but similar situations can be concussions. The goal of the project includes creating a control group for the studies of concussions in ice-hockey. Previous or parallel studies have been down to situations that result to concussions. The report indicates short to head and neck anatomy that is scalp, brain and skull. The concept of concussion with its symptoms explained in this report. The selected video sequences were analyzed head kinematics and collision sequences between the head and the other part that may be another person's shoulder, head, arm or ice or glass wall. When the video sequences were analyzed attempted to controll the head speed, head acceleration and the tackles angle. The results should agree with previous works.

Mammalian brain is challenging to study due to its heterogeneity and complexity. However, recent advances in molecular imaging, genomics and proteomics have contributed significantly to achieve insights into molecular basis of brain function and pathogenesis of neurological disorders. Efficient sample preparation is an integral part of a successful mass spectrometry (MS)-based proteomics. Apart from the identification, quantification of proteins is needed to investigate the alterations between proteome profiles from different sample sets. Therefore, this thesis investigates optimizing and application of the MS compatible sample preparation techniques for the identification and quantification of proteins from brain tissue. The central objective of this thesis was (i) to improve the extraction of proteins as well as membrane proteins (MPs) from the brain tissue and (ii) to apply the optimized method along with the stable isotope dimethyl labeling (DML) and label-free (LF) MS approaches for the relative quantification of the brain proteome profiles during neurological conditions such as Alzheimer’s disease (AD) and traumatic brain injury (TBI).  First study described in this thesis is focused on the qualitative aspects for the brain tissue sample preparation. The optimized extraction buffers from first study containing n-octyl-β-glucopyranside or triton X-114 were used in the further quantitative studies to extract the proteins from patient (AD or TBI) and control human brain samples. Triton X-114 has additional advantage of separating MPs into a micellar phase. Therefore we also investigated the possibility to apply this in combination with DML quantitation approach for enrichment of low abundant MPs from AD brains. AD and TBI causes severe socio-economic burden on the society and therefore there is a need to develop diagnostic markers to detect the early changes in the pathology of the disease. Analytical tools and techniques applied and discussed in this thesis for neuroproteomics applications proved to be powerful and reliable for analyzing complex biological samples to generate high-throughput screening and unbiased identification and quantitation of disease-specific proteins that are of great importance in understanding the disease pathology.

BACKGROUND:Diffuse axonal injury is a common consequence of traumatic brain injury (TBI) and often co-occurs with hypoxia, resulting in poor neurological outcome for which there is no current therapy. Here, we investigate the ability of the multifunctional compound erythropoietin (EPO) to provide neuroprotection when administered to rats after diffuse TBI alone or with post-traumatic hypoxia.METHODS:Sprague-Dawley rats were subjected to diffuse traumatic axonal injury (TAI) followed by 30minutes of hypoxic (Hx, 12% O2) or normoxic ventilation, and were administered recombinant human EPO-alpha (5000IU/kg) or saline at 1 and 24hours post-injury. The parameters examined included: 1) behavioural and cognitive deficit using the Rotarod, open field and novel object recognition tests / 2) axonal pathology (NF-200) / 3) callosal degradation (hematoxylin and eosin stain) / 3) dendritic loss (MAP2) / 4) expression and localisation of the EPO receptor (EpoR) / 5) activation/infiltration of microglia/macrophages (CD68) and production of IL-1beta.RESULTS:EPO significantly improved sensorimotor and cognitive recovery when administered to TAI rats with hypoxia (TAI+Hx). A single dose of EPO at 1hour reduced axonal damage in the white matter of TAI+Hx rats at 1day by 60% compared to vehicle. MAP2 was decreased in the lateral septal nucleus of TAI+Hx rats / however, EPO prevented this loss, and maintained MAP2 density over time. EPO administration elicited an early enhanced expression of EpoR 1day after TAI+Hx compared with a 7-day peak in vehicle controls. Furthermore, EPO reduced IL-1beta to sham levels 2hours after TAI+Hx, concomitant to a decrease in CD68 positive cells at 7 and 14days.CONCLUSIONS:When administered EPO, TAI+Hx rats had improved behavioural and cognitive performance, attenuated white matter damage, resolution of neuronal damage spanning from the axon to the dendrite, and suppressed neuroinflammation, alongside enhanced expression of EpoR. These data provide compelling evidence of EPO's neuroprotective capability. Few benefits were observed when EPO was administered to TAI rats without hypoxia, indicating that EPO's neuroprotective capacity is bolstered under hypoxic conditions, which may be an important consideration when EPO is employed for neuroprotection in the clinic.

Increased temperature is common after brain trauma and stroke, considered to be detrimental to outcome and usually treated with systemic cooling interventions. However, targeting cooling interventions at the head may be more logical. In addition to arterial blood, the human brain is cooled by heat loss through the skull and heat loss from the upper airways. It is these two mechanisms of heat loss which are the subject of this thesis. The initial research aim was to find out if restoring ‘normal’ airflow through the upper respiratory tracts of intubated, brain-injured patients could reduce brain temperature. Air at room temperature and humidity replicating normal resting minute volume was continuously administered nasally to 15 such patients. After a 30 minute baseline, they were randomised to receive airflow or no airflow for 6 hours and then crossed over for a further 6 hours. The airflow did not produce significant reductions in intracranial temperature (Mean -0.13 °C, SD 0.55 °C, 95% CI -0.43 to 0.17 °C). However, some evidence of heat loss through the skull was serendipitously observed. This was investigated formally in a randomised factorial trial, together with nasal airflow with enhancements (unhumidified air at twice minute volume with 20 ppm nitric oxide gas) intended to overcome some of the possible reasons for the neutral results with ‘normal’ airflow. After a 30 minute baseline, 12 intubated, brain-injured patients received enhanced nasal airflow, bilateral head fanning (8 m/s), both together and no intervention in randomised order. Each intervention was delivered for 30 minutes followed by 30 minutes washout. Mean brain temperature was reduced by 0.15 °C with nasal airflow (p=0.001, 95% CI 0.06 to 0.23 °C) and 0.26 °C with head fanning (p<0.001, 95% CI 0.17 to 0.34 °C). The estimate of the combined effect of airflow and fanning on brain temperature was 0.41 °C. Physiologically, this study demonstrated that heat loss through the upper airways and through the skull can reduce parenchymal brain temperature in brain-injured humans, that the effects are additive and the onset of temperature reduction is rapid. The most promising mechanism appeared to be heat loss through the skull and the final piece of research involved developing and initial (phase I) assessment of a convective head cooling device in healthy volunteers, with intracranial temperature measured non-invasively by magnetic resonance spectroscopy. After a 10 minute baseline, five healthy volunteers received 30 minutes head cooling followed by 30 minutes head and neck cooling via a hood and neck collar delivering 14.5 °C air at 42.5 L/s. The net brain temperature reduction with head cooling was 0.45 °C (SD 0.23 °C, p=0.01, 95% CI 0.17 to 0.74 °C) and with head and neck cooling 0.37 °C (SD 0.30 °C, p=0.049, 95% CI 0.00 to 0.74 °C). There was no significant reduction in cooling with progressive depth into the brain i.e. core brain was cooled. The main relevance of this research is physiological because it adds to knowledge and understanding of mechanisms of heat loss from the upper airways and through the skull in humans. Clinically, factors which enhance or inhibit these mechanisms may have an effect on brain temperature but the therapeutic relevance of head cooling by these methods requires further research.