Preliminary novel research findings indicate that a subset of individuals with moderate to severe traumatic brain injury show bilateral hippocampal atrophy progressing beyond the acute stage post-injury. The present study proposes a novel, integrated model of neuroprotection against subacute hippocampal atrophy (i.e., atrophy occurring beyond the initial 3 months post-injury) via environmental enrichment, drawing on theoretical models and research findings from the fields of environmental enrichment, brain and cognitive reserve, and neuroplastic models of functional recovery from brain injury. Objectives: (a) to examine the relationship between environmental enrichment factors and subacute hippocampal atrophy and (b) to examine the relationship between subacute hippocampal atrophy and return to productivity. Design: Retrospective observational within-subjects. Participants: Patients (N=21) with moderate to severe TBI. Measures: Primary predictors: Self-report ratings of environmental enrichment factors (i.e., hours of cognitive, physical, and social activities, meditation/prayer, and therapy). Primary outcome: hippocampal volume change between 5 months and 24+ months post-injury based on initial and follow-up MRI scans; Brain Injury Community Rehabilitation Outcome Scales-39 (BICRO-39). Results: Generalized environmental enrichment (i.e., an aggregate of cognitive, physical, and social activity) was significantly negatively correlated with subacute bilateral hippocampal atrophy (p<.05). Cognitive activity was the environmental enrichment element that accounted for the greatest degree of variance (32%) in subacute bilateral hippocampal atrophy (p<.01). Frequency of meditation/prayer was significantly negatively correlated with right hippocampal subacute atrophy (<.05) after controlling for socioeconomic status and generalized environmental enrichment. Level of education and pre-injury occupational attainment did not correlate with subacute hippocampal atrophy. Conclusion: Findings suggest that a fixed degree of neural reserve at the time of brain injury may not confer neuroprotection against structural pathology in the manner suggested by the present study’s proposed model of neuroprotection via environmental enrichment. Instead, findings suggest that in order for environmental enrichment to positively modulate susceptibility to subacute hippocampal atrophy post-TBI, environmental enrichment exposure must occur during the subacute phase post-injury rather than prior to injury.

Preliminary novel research findings indicate that a subset of individuals with moderate to severe traumatic brain injury show bilateral hippocampal atrophy progressing beyond the acute stage post-injury. The present study proposes a novel, integrated model of neuroprotection against subacute hippocampal atrophy (i.e., atrophy occurring beyond the initial 3 months post-injury) via environmental enrichment, drawing on theoretical models and research findings from the fields of environmental enrichment, brain and cognitive reserve, and neuroplastic models of functional recovery from brain injury. Objectives: (a) to examine the relationship between environmental enrichment factors and subacute hippocampal atrophy and (b) to examine the relationship between subacute hippocampal atrophy and return to productivity. Design: Retrospective observational within-subjects. Participants: Patients (N=21) with moderate to severe TBI. Measures: Primary predictors: Self-report ratings of environmental enrichment factors (i.e., hours of cognitive, physical, and social activities, meditation/prayer, and therapy). Primary outcome: hippocampal volume change between 5 months and 24+ months post-injury based on initial and follow-up MRI scans; Brain Injury Community Rehabilitation Outcome Scales-39 (BICRO-39). Results: Generalized environmental enrichment (i.e., an aggregate of cognitive, physical, and social activity) was significantly negatively correlated with subacute bilateral hippocampal atrophy (p<.05). Cognitive activity was the environmental enrichment element that accounted for the greatest degree of variance (32%) in subacute bilateral hippocampal atrophy (p<.01). Frequency of meditation/prayer was significantly negatively correlated with right hippocampal subacute atrophy (<.05) after controlling for socioeconomic status and generalized environmental enrichment. Level of education and pre-injury occupational attainment did not correlate with subacute hippocampal atrophy. Conclusion: Findings suggest that a fixed degree of neural reserve at the time of brain injury may not confer neuroprotection against structural pathology in the manner suggested by the present study’s proposed model of neuroprotection via environmental enrichment. Instead, findings suggest that in order for environmental enrichment to positively modulate susceptibility to subacute hippocampal atrophy post-TBI, environmental enrichment exposure must occur during the subacute phase post-injury rather than prior to injury.

In this thesis, we look at evidence accumulated on the prefrontal cortical and hippocampal regions of the brain and review theories about the possible roles each structure has on human memory and behaviour. Aspects of these theories are tested via a self-reinforcing computational network model. We propose this model may simulate the underlying mechanisms or processes of the prefrontal-hippocampal interaction during performance of memory tasks that require intact prefrontal and hippocampal structures. / Thesis / Master of Science (MSc)

Temporal context memory is a type of episodic memory that refers to memory for the timing of events. Temporal context includes environmental cues that provide information about the time point at which an event happened. The purpose of the present studies is to investigate the brain mechanisms underlying temporal context processing by using both fMRI and ERP techniques. The fMRI study investigated whether hippocampal representations in CA1 and DG/CA3 subfields were sensitive to the flow of physical time, and if so, whether the number of events that occur during a time period influences the temporal representation of a target event. Results showed that both CA1 and DG/CA3 were sensitive to the flow of physical time, which was indicated by higher representational similarity between two pictures that occurred closer in time than those that occurred more distant in time. However, the variety of preceding events did not influence temporal representation, which was demonstrated by the lack of a significant representational similarity difference between two pictures that were interleaved with variable events as opposed to similar events. The ERP study compared the ERP correlates of temporal to spatial context. Results showed that temporal and spatial contexts had overlapping ERP effects except that the ERP effects of temporal context were more frontally distributed than spatial context. Both the fMRI and ERP studies indicate that temporal context is associated with similar neural correlates to other types of context in episodic memory. / Ph. D.

In this essay, changes in the human hippocampal volume and function induced by stress, depression and physical exercise are examined. Hippocampus is crucially involved in the acquisition and retrieval of episodic and spatial memory, and hippocampal volume correlates with episodic and spatial memory performance. Hippocampus has substantial plasticity and changes with age, but also in response to experiential factors across life. Stress and, under at least some circumstances, also depression have negative effects on hippocampal volume and memory function. The negative effects are believed to accelerate age-related decline in volume and function, mediated by exaggerated cortisol levels and dysfunction in the HPA-axis. Physical exercise is examined from two perspectives; aerobic and strength exercise. Aerobic exercise increases hippocampal volume across various ages and decelerates age-related hippocampal degeneration, whereas support for strength exercise-induced effects are mixed and need to be studied further. The positive effects are believed to be mediated by increased BDNF levels and regional cerebral blood volume. Although hippocampal volume normally correlates with hippocampus-dependent memory, studies on exercise-induced changes in human hippocampus-dependent memory have reported inconsistent results. Animal studies have observed both the negative and positive effects on hippocampal volume to relate to changes in neurogenesis, cell proliferation, and dendritic complexity. The negative and positive effects on hippocampal volume have been observed to be non-permanent, suggesting that physical exercise may prevent, attenuate and possibly reverse hippocampal degeneration induced by stress and depression. Further, more studies on sex and age differences, exercise intervention designs and functional values of physical exercise would be of value.

Transplants of fetal neural tissue survive and develop in lesion cavities produced in adult rats. The present experiment tested the effect of grafting fetal hippocampal or brainstem tissue on the ability of rats with hippocampal lesions to perform on a differential reinforcement of low response rate (DRL) operant schedule. The DRL interval was 20 s. Eighty-six percent of the hippocampal grafts and 69% of the brainstem grafts developed to maturity. Inspection of sections stained using a silver technique for axis cylinders or taken from rats in which the mature transplant had been injected with Fast blue, indicated that these grafts formed connections with the host brain. Consistent with previous reports, rats with hippocampal lesions were impaired in performance of the DRL task. Rats given fetal grafts of hippocampal tissue into the hippocampal lesion site on the day of lesion production were significantly better in performance of the DRL requirement than were lesion-only rats or rats receiving grafts of fetal brainstem tissue. The results of this study confirm that grafts of fetal brain tissue can both develop in a lesion site in an adult brain and ameliorate lesion-induced behavioral deficits.

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In the United States, 2.8 million people suffer a traumatic brain injury (TBI) annually. Between 25%-50% of TBI injuries happen under alcohol intoxication. It is not understood how alcohol impacts patient outcomes via secondary injury pathways. Secondary injury pathways offer a window for therapeutic interventions, but there has been little success finding effective medications. Slice cultures offer a way to study secondary injury mechanisms in a controlled manner. The transection injury can model excitotoxicy seen following TBI. The current studies examined the effect of alcohol intoxication and withdrawal at the time of injury, and the effect of a calpain inhibitor (MDL-28170) on cell death following a transection injury. Intoxication had no effect on cell death compared to the TBI condition. In the ethanol withdrawal (EWD) study, EWD did not increase cell death following the TBI except at 72 hours. There was no effect of MDL on cell death. The severity of the model may have caused a ceiling effect. Additionally, imaging points may not have been sufficient for proper characterization. Future studies should use a different injury mechanism and other imaging times should be considered.

This dissertation is a critical examination of the relationship between sleep problems and/or disorders, particularly Obstructive Sleep Apnea (OSA) and Alzheimer Disease (AD). First, I conducted an exhaustive systematic review of existing literature, and identified gaps in research that led to specific research aims. For the first aim, I conducted the first ever-published meta-analysis examining sleep, cognitive decline and AD, providing an aggregate effect of sleep on AD. Second, focusing on OSA, I conducted a study examining OSA’s effect on longitudinal changes on AD biomarkers in cognitive normal, MCI and AD subjects, using data from the Alzheimer Disease Neuroimaging Initiative (ADNI). Lastly, I conducted a review, integrating over 3 decades of research examining OSA and cognition; OSA and subsequent cognitive decline; and OSA and AD; with particular focus in appreciating the heterogeneity of OSA and its outcomes in distinct age groups. Results and implications from my research indicate that ample evidence exists linking sleep impairments and circadian regulating mechanisms directly to clinical symptoms in AD. Sleep problems and/or disorders increases your risk of cognitive decline and AD. OSA is associated with increased AD biomarker burden over time, and effects longitudinal changes in these biomarkers, such that OSA subjects progress faster than non-OSA subjects do. OSA may be age-dependent in older adults (60 – 70 years old) and the elderly (70 years and above) and is associated with neurodegenerative diseases particularly, cognitive decline and AD. Intermittent hypoxia and sleep fragmentation are two main processes by which OSA induces neurodegenerative changes. Therefore, clinical interventions aimed at OSA, such as treatment with CPAP or dental appliances, in cognitive normal and MCI patients, could possibly slow the progression of cognitive impairment to AD.