Longitudinal developmental fMRI studies just recently began to focus on within-subject reliability using the intraclass coefficient (ICC). It remains largely unclear which degree of reliability can be achieved in developmental studies and whether this depends on the type of task used. Therefore, we aimed to systematically investigate the reliability of three well-classified tasks: an emotional attention, a cognitive control, and an intertemporal choice paradigm. We hypothesized to find higher reliability in the cognitive task than in the emotional or reward-related task. 104 healthy mid-adolescents were scanned at age 14 and again at age 16 within M = 1.8 years using the same paradigms, scanner, and scanning protocols. Overall, we found both variability and stability (i.e. poor to excellent ICCs) depending largely on the region of interest (ROI) and task. Contrary to our hypothesis, whole brain reliability was fair for the cognitive control task but good for the emotional attention and intertemporal choice task. Subcortical ROIs (ventral striatum, amygdala) resulted in lower ICCs than visual ROIs. Current results add to the yet sparse overall ICC literature in both developing samples and adults. This study shows that analyses of stability, i.e. reliability, are helpful benchmarks for longitudinal studies and their implications for adolescent development.

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Physical health can be measured in several ways both based on subjective experiences and with objective tools. However, mental health can only be measured through subjective experiences and sensations, which can be biased. Therefore, researchers adopted the notion of an objective tool to assess well-being as a complement to existing self-reported scales and suggested that heart rate variability (HRV) might be an indicator of well-being. Hence, this thesis investigates the relationship between subjective well-being (SWB) and HRV, particularly high frequency-HRV (HF-HRV). Three hypotheses, which included different forms of well-being, were developed to test the relationship. And the hypotheses were: Cognitive well-being correlates positively with HF-HRV. Positive affect correlates positively with HF-HRV, and negative affect correlates negatively with HF-HRV. A total of 19 healthy Swedish females aged from 20-35 participated and answered questionnaires measuring SWB. After they completed the SWB-scales, their heart rate was measured and then converted into HF-HRV data. The findings revealed no correlations between the cognitive SWB and HF-HRV, neither to affective SWB.

Aging and Alzheimer’s disease (AD), are associated with disabling sleep and cognitive deficits. Specifically, aging and Alzheimer’s disease is associated with reduced quantity and quality of the deepest stage of sleep, called slow-wave-sleep (SWS). Interestingly, SWS has been implicated in hippocampus-dependent memory in mice. More importantly, sleep deprivation, aging, and AD are all associated with deficits in memory. Therefore, I hypothesize that, in aging and AD, the sleep deficits are, at least in part, responsible for memory impairments and increasing the quantity and quality of SWS will reverse these memory deficits. I first developed mouse models of SWS enhancement in aging and AD. Chemogenetic activation of the parafacial zone GABAergic neurons enhances SWS in aged mice as previously described in adult mice. Similarly, in AD mice, SWS enhancement is as effective as in littermate wild-type controls. Then, I used these mouse models to characterize the role of SWS in memory using novel gain-of-sleep experiments. I found that acute SWS enhancement: 1) reduce spatial memory in adult mice and 2) failed to improve spatial memory in aged mice. In a preliminary study, acute SWS enhancement seems to improve contextual memory in AD mice. Collectively, my work provides a novel mouse model of SWS enhancement in aging and AD, offering a pivotal tool to study the role of SWS in physiological functions and neurodegenerative diseases. Furthermore, my results suggest that acute SWS enhancement does not benefit the behavioral manifestation of memory consolidation in adult mice and aged mice.

In adults, sex and steroid hormone differences have been observed in several cognitive domains, most notably in the domains of spatial processing, language, and manual dexterity. Age-related cognitive differences have also been observed throughout the lifespan, with many improvements occurring during childhood. While cognition improves with age, other factors (i.e., sex, pubertal status, and steroid hormone levels) may also influence development. The present study compared performance on a visuo-spatial working memory (VSWM) task and three simple articulation (ART) tasks. Pubertal status and hormone levels, at time of testing, were measured. Sex, pubertal status, and hormone differences were observed. This study is one of the first to provide evidence of such differences in typically developing adolescents.

The field of cognitive neuroscience has benefited greatly from multimodal investigations of the human brain, which integrate various tools and neuroimaging data to understand brain functions and guide treatments for brain disorders. In this dissertation, we present a series of studies that illustrate the use of multimodal approaches to investigate brain structure and function, brain connectivity, and neuromodulation effects. Firstly, we propose a novel landmark-guided region-based spatial normalization technique to accurately quantify brain morphology, which can improve the sensitivity and specificity of functional imaging studies. Subsequently, we shift the investigation to the characteristics of functional brain activity due to visual stimulations. Our findings reveal that the task-evoked positive blood-oxygen-level dependent (BOLD) response is accompanied by sustained negative BOLD responses in the visual cortex. These negative BOLD responses are likely generated through subcortical neuromodulatory systems with distributed ascending projections to the cortex. To further explore the cortico-subcortical relationship, we conduct a multimodal investigation that involves simultaneous data acquisition of pupillometry, electroencephalography (EEG), and functional magnetic resonance imaging (fMRI). This investigation aims to examine the connectivity of brain circuits involved in the cognitive processes of salient stimuli. Using pupillary response as a surrogate measure of activity in the locus coeruleus-norepinephrine system, we find that the pupillary response is associated with the reorganization of functional brain networks during salience processing. In addition, we propose a cortico-subcortical integrated network reorganization model with potential implications for understanding attentional processing and network switching. Lastly, we employ a multimodal investigation that involves concurrent transcranial magnetic stimulation (TMS), EEG, and fMRI to explore network perturbations and measurements of the propagation effects. In a preliminary exploration on brain-state dependency of TMS-induced effects, we find that the propagation of left dorsolateral prefrontal cortex TMS to regions in the lateral frontoparietal network might depend on the brain-state, as indexed by the EEG prefrontal alpha phase. Overall, the studies in this dissertation contribute to the understanding of the structural and functional characteristics of brain network systems, and may inform future investigations that use multimodal methodological approaches, such as pupillometry, brain connectivity, and neuromodulation tools. The work presented in this dissertation has potential implications for the development of efficient and personalized treatments for major depressive disorder, attention deficit hyperactivity disorder, and Alzheimer's disease.

Indiana University-Purdue University Indianapolis (IUPUI) / Alcohol related problems and abuse continue to be serious problems in the U.S. today affecting nearly 17.6 million Americans. Understanding of the specific genes and related behaviors associated with alcohol use may provide substantial preventative measures for those who are at an increased risk. Genetically selected lines such as the high-alcohol preferring (HAP) and low-alcohol preferring (LAP) mice have been created to examine which endophenotypes co-segregate with alcohol preference. One behavioral trait that has been commonly associated with alcohol related problems is impulsivity. Impulsivity is the inability to withhold a response (motor impulsivity) or to act without forethought (cognitive impulsivity). The latter comprises much of the research and literature today using delay discounting models to tease out differences in subject’s wiliness to discount larger reinforcers for smaller immediate reinforcers. This study utilized relatively two newer paradigms associated with motor impulsivity in attempt to test differences in response disinhibition between two independent replicate HAP and LAP lines. It is hypothesized that the genes responsible for alcohol preference would be genetically correlated with motor impulsivity as HAP mice would display a greater degree of response disinhibition. Two independent replicates consisting of 48 mice (24 HAP II and 24 LAP II, representing the 37th generation; 24 HAP III and 24 LAP III, representing the 13th generation) were tested in two separate identical experiments. Each experiment was comprised of three phases. Phase I utilized a fixed interval (FI) 120s procedure for 30 days. After the 30 days of FI exposure mice were immediately moved to phase II for 10 days which implored a differential reinforcement of low rate procedure (DRL) at a time interval of 20s. Phase III used the same procedures as Phase II except the DRL was increased to 32s. As hypothesized, there was a moderate genetic correlation between alcohol preference and impulsivity as the HAP II mice displayed greater response disinhibition throughout all three phases compared to the LAP II mice. No differences were observed amongst the replicate III mice in any of the three phases. The findings from this study provide additional support that a genetic correlation between alcohol preference and impulsivity exists as seen in the delay discounting literature. Though this was observed in only one of the two replicates, interpretations must be taken at caution as the replicate III mice are still in the early stages of selection. It is possible at this stage in the selection process that increases in alcohol over successive generations are associated with selecting for taste until a threshold is met where selection shifts to pharmacologic drinking relevance. Until later generations of replicate III mice are studied where pharmacologic drinking occurs, conclusions from this study provide a moderate genetic correlation between alcohol preference and impulsivity.

Rats were administered nicotine (0.3 mg/kg) for 11 consecutive days before and after an electrolytic medial frontal cortex lesion. Behavioral testing was arranged so that the rats were tested on the RAM 1 day after drug administration followed by behavioral testing on the MWT 19 days after drug treatment, or tested on the MWT 1 day after drug administration followed by testing on the RAM4 days after drug treatment. Results of MWT testing showed that regardless of the drug/behavioral testing interval, lesioned rats given nicotine demonstrated enhancement relative to saline-treated animals. Results of RAM testing showed that nicotine improved performance in non-lesioned rats compared to non-lesioned rats given saline. Four days after drug administration, nicotine improved performance in lesioned rats to levels of non-lesioned rats regardless of drug treatment. A second experiment was implemented to determine if the previous training on the MWT affected performance on the RAM.

Depression and related disorders are characterized by motivational dysfunctions, including deficits in behavioral activation and exertion of effort. Animal models of relevance to depression represent a critical starting point in elucidating the neurobiological mechanisms underlying motivational dysfunctions. The present study explored the use of the Wistar-Kyoto (WKY) animal model of depression to examine effort-related functions as measured by voluntary wheel running and performance on a mixed fixed ratio 5/progressive ratio (FR5/PR) operant task. Given the known link between activational aspects of motivation and the mesocorticolimbic dopamine (DA) system, the behavioral effects of d-amphetamine (0.5 and 1.0 mg/kg, IP), a psychostimulant that increases DA release, were evaluated in WKY and control Sprague-Dawley (SD) male and female rats responding on a mixed FR5/PR task. An additional experiment assessed intracellular content of monoamine neurotransmitters and their metabolites in relevant mesocorticolimbic brain regions, including the medial prefrontal cortex, the nucleus accumbens and the ventrolateral striatum using HPLC-ED. WKY rats demonstrated initial effort-related deficits in FR5/PR responding compared to SD controls, which ameliorated with training. Amphetamine significantly decreased FR5 work output, but increased responding on the PR phase in both SD and WKY rats. This effect was more pronounced in SD rats compare to WKY rats. In addition, sex differences were evident both in FR5/PR performance and in the behavioral response to amphetamine treatment. Moreover, females demonstrated higher levels of voluntary wheel-running than males. Finally, tissue concentrations of dopamine were lower in the NA and VLS of WKY compared to SD rats. Taken together, results suggest dysfunctions in mesolimbic DA neurotransmission in the WKY strain, likely underlying the depressive phenotype. The present study represents an important initial step in validating the WKY strain as a rat model of effort-related dysfunctions relevant to depression and other neuropsychiatric disorders.

Background: Traumatic brain injury (TBI) still remains a difficult disorder to treat. TBI has been associated to chronic neuroinflammation and a high risk for neurodegenerative disorders. Since 2001 between ten to twenty percent of all deployed military members have suffered a combat-related TBI. Nearly twenty to thirty percent of those will experience chronic cognitive, behavioral and somatic symptoms after suffering a TBI. Methods: The objective of this review is to evaluate current literature examining vitamin D as a neurosteroid with protective properties and its clinical relevance after traumatic brain injury. Vitamin D is known to participate in neurobiological processes and genomic regulation in the brain. Clinical and laboratory findings support that vitamin D modulates the immune responses to trauma, diminishes oxidative and toxic damage, and inhibiting activation and progression of the neuroinflammation. Inadequate levels of vitamin D have been identified as a common risk factor for many neurological disorders and have been linked to poorer recovery. Results: This review found compelling evidence to support that the pathology of TBI is closely associated with neuroprotective mechanisms of vitamin D. Low vitamin D levels are common among US active duty military and veterans. The findings strongly suggest that optimizing vitamin D prior to injury could improve the recovery for military members after experiencing a TBI. Vitamin D ameliorates brain damage by modulating neuroinflammation, improving cell survival and down-regulating mechanisms involved in the progression of cell damage following a TBI. However, further studies are needed to evaluate the effects of vitamin D optimization in TBI outcomes.