Boredom is a common human experience, yet little is known about its underlying neural mechanisms. This thesis first set out to investigate the construct of boredom and more closely examined its relationship to phenomenologically similar mood states of depression, apathy and anhedonia. Next, deficits in sustained attention, and novelty seeking were examined in patients with traumatic brain injury (TBI), who are characterized by atypically high levels of boredom. Study 1 established that although related to varying degrees to apathy, anhedonia, and depression, boredom is indeed a distinct emotional experience. Furthermore, two boredom proneness subtypes - agitated and apathetic - were identified which varied in their relationships to depression. The relationship between boredom and depression was found to be high only in the agitated boredom prone subtype, which is characterised by a high degree of motivation to engage in meaningful, stimulating activities despite the fact that all attempts to do so fail to satisfy. In Study 2, the relationship between boredom proneness and depression was found to be greater in TBI patients than in healthy controls. Using a behavioral measure of sustained attention (SART; Robertson et al., 1997), Study 3 demonstrated a relationship between boredom proneness and sustained attention in healthy controls, such that RTs were faster and commission errors more prevalent in the agitated boredom prone subtype. No relationship between boredom proneness and sustained attention was found in TBI patients. So while attention and boredom show a clear relationship in the healthy brain, this relationship may be disrupted in TBI patients. Finally, Study 4 demonstrated an association between agitated boredom proneness and a preference for novel stimuli across participant groups. In addition, patients had a poorer ability to discriminate between similar and dissimilar stimuli than controls, which was more evident in the agitated boredom prone group. It may be the case then that agitated boredom prone individuals fail to satisfy their desire to engage in stimulating activities in part because they fail to accurately identify when something is indeed novel. Taken together, these results highlight important distinctions between apathetic and agitated boredom proneness, and the way in which these subtypes relate to depression, attention, and novelty seeking, in brain injured patients and healthy controls. More work is needed to determine the role played by boredom in TBI, particularly as this evolves from acute to chronic stages of the illness. Importantly, identifying boredom as a key element in depressive mood disorders, attention deficits (e.g., attention deficit hyperactivity disorder), and novelty seeking behaviour, facilitates the design and implementation of appropriate intervention strategies. For example, it will become increasingly important to deal with boredom as a significant component of depression. Thus, the work presented here represents a novel and important contribution to the study of boredom in that it brings the field one step closer to understanding and treating the experience. Further investigation with greater numbers of patients is necessary to fully explicate the relationship between boredom and depression, attention, and novelty seeking in TBI.

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abstract: Traumatic brain injury (TBI) is a leading cause of disability worldwide with 1.7 million TBIs reported annually in the United States. Broadly, TBI can be classified into focal injury, associated with cerebral contusion, and diffuse injury, a widespread injury pathology. TBI results in a host of pathological alterations and may lead to a transient blood-brain-barrier (BBB) breakdown. Although the BBB dysfunction after TBI may provide a window for therapeutic delivery, the current drug delivery approaches remains largely inefficient due to rapid clearance, inactivation and degradation. One potential strategy to address the current therapeutic limitations is to employ nanoparticle (NP)-based technology to archive greater efficacy and reduced clearance compared to standard drug administration. However, NP application for TBI is challenging not only due to the transient temporal resolution of the BBB breakdown, but also due to the heterogeneous (focal/diffuse) aspect of the disease itself. Furthermore, recent literature suggests sex of the animal influences neuroinflammation/outcome after TBI; yet, the influence of sex on BBB integrity following TBI and subsequent NP delivery has not been previously investigated. The overarching hypothesis for this thesis is that TBI-induced compromised BBB and leaky vasculature will enable delivery of systemically injected NPs to the injury penumbra. This study specifically explored the feasibility and the temporal accumulation of NPs in preclinical mouse models of focal and diffuse TBI. Key findings from these studies include the following. (1) After focal TBI, NPs ranging from 20-500nm exhibited peak accumulation within the injury penumbra acutely (1h) post-injury. (2) A smaller delayed peak of NP accumulation (40nm) was observed sub-acutely (3d) after focal brain injury. (3) Mild diffuse TBI simulated with a mild closed head injury model did not display any measurable NP accumulation after 1h post-injury. (4) In contrast, a moderate diffuse model (fluid percussion injury) demonstrated peak accumulation at 3h post-injury with up to 500 nm size NPs accumulating in cortical tissue. (5) Robust NP accumulation (40nm) was found in female mice compared to the males at 24h and 3d following focal brain injury. Taken together, these results demonstrate the potential for NP delivery at acute and sub-acute time points after TBI by exploiting the compromised BBB. Results also reveal a potential sex dependent component of BBB disruption leading to altered NP accumulation. The applications of this research are far-reaching ranging from theranostic delivery to personalized NP delivery for effective therapeutic outcome. / Dissertation/Thesis / Doctoral Dissertation Biomedical Engineering 2018

The purpose of the current study was to determine if the Nova Multilingual Neuropsychological Battery (NMNB) can detect neurological deficits in the traumatic brained injured (TBI) Hispanic sample by comparing subtest mean scores to the normal group mean scores. The NMNB is comprised of 39 subtests and was developed to account for language and cultural factors thought to influence neuropsychological test results. It was hypothesized that significant differences would be found in NMNB measures sensitive to brain damage. A sample size of 100 English-Spanish speaking bilinguals (50 TBI and 50 cognitively intact participants) was tested in Spanish in order to compare cognitive performance across the various NMNB measures. Due to the number of comparisons, the alpha level for this study was set to .01 to reduce Type I error. Results of the ANCOVA's partially supported the hypothesis after controlling for age and education. Findings show that the NMNB measures were able to successfully detect the TBI Spanish group from the normal Spanish group. Significant differences were displayed in the tests measuring nonverbal abilities, memory and learning, visual spatial skills, and executive functioning. More specifically, no significant differences were displayed in the tests measuring crystallized premorbid abilities, while tests measuring more fluid abilities detected problems with abstract thinking and information processing in the TBI sample. A similar deficit pattern was displayed across all measures of higher functioning systems. Deficits were detected in the nonverbal measures that involved complex attention (selective, divided, and alternating forms of attention) and concentration for visuospatial tasks, pattern synthesis and manipulation, but not for simple visuospatial attentional activities. Significant differences were found in motor speed, but not in the number of errors. These findings support previous research indicating that Hispanics tend to favor accuracy over speed. Additionally, results reveal significant differences across all memory measures. Using Cohen's d, large effect sizes were displayed between the groups ranging from 1.5 to 2.3 in the verbal and visual memory measures. Similar effect sizes were also displayed in tests of executive functioning. Preliminary data of this study suggests that the NMNB may be a sound assessment tool for detecting neurological impairments in TBIs. Collectively, the NMNB displayed significant differences in motor and processing speed, memory, visuospatial tasks, and executive functioning commonly documented in non-Hispanic TBIs. This study concluded that culturally sensitive neuropsychological tests that also control for demographic variables such as age and education can provide accurate results for Hispanics with TBI. However, these results should be interpreted with caution as this study was limited to a small sample size with an unequal proportion of TBI severity levels and educational experiences beyond educational levels. Future studies should focus on obtaining larger samples with varying TBI severity levels. Samples should also include bilingual Hispanics tested in English as well as monolingual Spanish speakers in order to develop profiles that may be useful in differential diagnosis.

Traumatic brain injury (TBI) constitutes a major health problem and is a leading cause of long-term disability and death. Patients with severe traumatic brain injury, S-TBI, comprise a heterogeneous group with varying complexity and prognosis. The primary aim of this thesis was to increase knowledge about clinical course and outcome with regard to prognostic factors. Papers I, II and III were based on data from a prospective multicentre observational study from six neurotrauma centers (NCs) in Sweden and Iceland of patients (n=103-114), 18-65 years with S-TBI requiring neurosurgical intensive care or collaborative care with a neurosurgeon (the “PROBRAIN” study).  Paper IV and V were performed on a regional subset (n=37). In Paper I, patients with posttraumatic disorders of consciousness (DOC) were assessed as regards relationship between conscious state at 3 weeks and outcomes at 1 year. The number of patients who emerged from minimally conscious state (EMCS) 1 year after injury according to status at 3 weeks were: coma (0/6), unresponsive wakeful syndrome (UWS) (9/17), minimally conscious state (MCS) (13/13), anaesthetized (9/11). Outcome at 1 year was good (Glasgow Outcome Scale Extended (GOSE>4) in half of the patients in MCS (or anaesthetized) at 3 weeks, but not for any of the patients in coma or UWS.    In Paper II, the relationships between clinical care descriptors and outcome at 1 year were assessed. A longer length of stay in intensive care, and longer time between discharge from intensive care and admission to inpatient rehabilitation, were both associated with a worse outcome on the GOSE. The number of intervening care units between intensive care and rehabilitation, was not significantly associated with outcome at 1 year.  In Paper III, the clinical course of cognitive and emotional impairments as reflected in the Barrow Neurological Institute Screen for Higher Cerebral Functions (BNIS) and the Hospital Anxiety and Depression Scale (HADS) were assessed from 3 weeks to 1 year together with associations with outcomes GOSE and Rancho Los Amigos Cognitive Scale-Revised (RLAS-R) at 1 year. Cognition improved over time and appeared to be stable from 3 months to 1 year.  In Paper IV, clinical parameters, the clinical pathways from injury to 3 months after discharge from the NC in relation to outcomes 3 months post-injury. Ratings on the RLAS-R improved significantly over time. Eight patients had both “superior cognitive functioning” on the RLAS-R and “favourable outcome” on the GOSE. Acute transfers to the one regional NC was direct and swift, transfers for postacute rehabilitation scattered patients to many hospitals/hospital departments, not seldom by several transitional stages.  In Paper V, an initial computerized tomography of the brain (CTi) and a further posttraumatic brain CT after 24 hours (CT24) were evaluated according to protocols for standardized assessment, the Marshall and Rotterdam classifications. The CT scores only correlated with clinical outcome measures (GOSE and RLAS-R) at 3 months, but failed to yield prognostic information regarding outcome at 1 year. A prognostic model was also implemented, based on acute data (CRASH model). This model predicted unfavourable outcomes for 81% of patients with bad outcome and for 85% of patients with favourable outcome according to GOSE at 1 year. When assessing outcomes per se, both GOSE and RLAS-R improved significantly from 3 months to 1 year.  The papers in this study point both to the generally favourable outcomes that result from active and aggressive management of S-TBI, while also underscore our current lack of reliable instruments for outcome prediction. In the absence of an ability to select patients based on prognostication, the overall favourable prognosis lends support for providing active rehabilitation to all patients with S-TBI. The results of these studies should be considered in conjunction with the prognosis of long-term outcomes and the planning of rehabilitation and care pathways. The results demonstrate the importance of a combination of active, acute neurotrauma care and intensive specialized neurorehabilitation with follow-up for these severely injured patients.

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Attention impairment is one of the most common complaints following Traumatic Brain Injury (TBI). Multiple studies have shown that performance on neuropsychological tests of attention is affected by many factors, including injury severity and effort. The aim of this study was to determine the effect of injury severity on neuropsychological tests across different domains of attention while controlling for effort. The domains of focused attention, selective attention, divided attention, sustained attention, and working memory were assessed by performance on the Digit Span Forward subtest, the Stroop Color Word Test, the Trail Making Test, the Conners' Continuous Performance Test - II, and Digit Span Backwards subtest, respectively. Effort was determined according to performance on the Portland Digit Recognition Test and the Test of Memory Malingering. Effort was found to have a greater effect on test performance (.79) than injury severity (.47). Clinical implications of the findings are discussed.

Traumatic brain injury (TBI) is a devastating disease causing disability and death, and currently there are no effective treatments available. Therefore, there is an utmost need to improve our understanding of the pathophysiology of TBI and to identify potential therapies that can provide neuroprotection after injury. The aims of this thesis were to develop an in vivo and in vitro model of TBI, in which to assess the potential neuroprotective effects of an omega-3 polyunsaturated fatty acid (PUFAs), docosahexaenoic acid (DHA). Method The controlled cortical impact (CCI) in vivo model of TBI was optimized and performed in mice. Both a behavioural (Morris water maze (MWM) for cognitive deficits) and histological endpoints (astrogliosis, lesion size and activated microglia) were used to assess severity and neuroprotective effects of DHA. An in vitro model of mechanical TBI was also set up and optimized. This model employed 3D astrocyte cultures obtained from GFP positive rat pups. The CCI impactor from the in vivo studies was used to damage the cultures, and at 24 hours, 5 days and 10 days the astrogliosis and cell number was measured. Results The optimization of the in vivo studies demonstrated that at impaction depth of 2.2 mm produced an injury that was significantly different to the sham injury, in MWM performance and increased astrogliosis. Interestingly, there was an increase in the amount of astrogliosis on the contralateral side of the brain. A second study performed using the 2.2 mm injury parameters was performed, where an injection of DHA was administered via the tail vein 30 min after injury. The DHA-treated group did not demonstrate any neuroprotection compared to the injury-only group. However, there was an increase in the amount of astrogliosis in the contralateral hippocampus of the DHA-treat group. In the fat-1 studies it was shown that older male mice performed worse in the MWM, that the fat-1 gene did not confer neuroprotection but did lead to increased astrogliosis. The in vitro study revealed that astrocytes in the lesioned gels demonstrated an increase in astrogliosis, there was also an increase in the number of cell in the cultures following the lesion. Conclusion In conclusion, the in vivo model of CCI replicated components of the human TBI including a behavioural deficit and pathophysiological changes. Omega-3 PUFAs failed to demonstrate functional neuroprotection in this model, but histologically, promoted an increase in reactive astrogliosis. The development of a novel in vitro model of focal injury in a 3D culture system, that elicits reactive astrogliosis, could be used to support further studies of the astrocytic responses to mechanical injury.