Theses and Dissertations

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Open Access
Novel transcriptomic mechanisms of brain aging
(Colorado State University. Libraries, 2023) Cavalier, Alyssa Nicole, author; LaRocca, Thomas, advisor; Lark, Daniel, committee member; Hamilton, Karyn, committee member; Weir, Tiffany, committee member
As the world ages, the incidence of age-related diseases like dementia is expected to increase. Brain aging is characterized by declines in cognitive function that may develop into mild cognitive impairment, which increases the risk for dementia. In fact, age is the primary risk factor for late-onset Alzheimer's disease, which is the most common age-related dementia. The adverse cellular and molecular processes that underlie cognitive decline with aging in the brain are known collectively as the "hallmarks of brain aging." Advances in next-generation sequencing (e.g., transcriptomics/RNA-seq) have made it possible to investigate age- and disease-related changes in the brain at the broad gene expression level, and to identify potential therapeutic targets. With the support of my committee and mentoring team, I completed three studies using transcriptomics that characterize novel mechanisms that underlie brain aging. My findings include: (1) doxorubicin chemotherapy accelerates brain aging at the gene expression level, (2) apigenin nutraceutical supplementation targets age-related inflammation in the brain and rescues cognitive impairment in old mice, and (3) epigenetic dysregulation of transposable elements (remnants of viral infection in the genome) with aging contributes to age-related inflammation in Alzheimer's disease. Together, my work provides insight into transcripts and cellular/molecular pathways that are modifiable and may be therapeutic targets to delay or prevent consequences of brain aging.
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Effect of a videoconference-delivered physical activity intervention on quality of life in colorectal cancer survivors
(Colorado State University. Libraries, 2023) Prien, Lydia, author; Leach, Heather, advisor; Schmid, Arlene A., committee member; Zimmaro, Lauren A., committee member
INTRODUCTION: Colorectal cancer is the fourth most common cancer diagnosed in both men and women in the United States. For every 100 people diagnosed with colon cancer, 64 are expected to live five or more years after diagnosis. With this growing number of colorectal cancer survivors, quality of life (QOL) becomes an important patient reported outcome within this population. QOL is multidimensional and includes various dimensions of wellbeing (e.g., physical, emotional, social) that can be improved with physical activity. Previous research has established that face-to-face supervised physical activity (PA) interventions can improve QOL among colorectal cancer survivors (CRC) (Mishra et al., 2012). However, these interventions require a lot of resources, and may be difficult to access. Thus, researchers have turned to distance-based physical activity (PA) interventions (digital health tools, text messaging, prerecorded home-based workouts etc.) to increase access and scalability of PA interventions for CRC survivors. Previous studies that have examined the effect of distance-based PA interventions for improving QOL in CRC survivors did not find improvements in QOL. For example, Kim et al. (2019) found no significant improvements in QOL following an unsupervised, homebased, DVD exercise program, and Chan et al. (2022) found no significant changes in QOL, following a text messaging intervention. These finding suggest that distance-based PA interventions may not be as effective as face-to-face for improving QOL in CRC survivors and may be due to a lack of contact with other survivors and/or diminished PA adherence/compliance due to lack of supervision and instruction from an exercise professional. Since the COVID-19 pandemic, videoconference PA interventions have grown in popularity, and may be able to overcome some of the limitations of both face-to-face and distance-based PA interventions for improving QOL in CRC survivors. However, to date there are no previous studies that have examined the effect of a videoconference intervention on QOL in CRC survivors. This study will examine changes in QOL in colorectal cancer survivors following a 12-week, videoconference, PA intervention. This study will be a secondary data analysis of participants enrolled in Testing Group Activity CorrelaTes In Colorectal Cancer Survivors (TACTICS), a pilot randomized controlled trial with the primary aims of determining feasibility, and preliminary effects on physical activity. METHODS: TACTICS is a 12-week pilot randomized controlled trial where the intervention group received group-based exercise sessions 2x/week, and five behavior change discussion sessions delivered via Zoom. The control group received standard physical activity recommendations. QOL was measured at baseline and 12-weeks using the Functional Assessment of Cancer Therapy–Colorectal (FACT-C). Mean change, standard deviation, and effect size were reported to measure improvements in QOL. Established minimal clinically important differences (MCID) are a Δ5 points for total and a Δ2 points for QOL subscales. The proportion achieving MCID's in intervention vs. control were compared using Fisher's Exact tests, and independent t-tests or chi square tests explored differences in participant characteristics between those did vs. did not achieve MCID. RESULTS: Participants (n= 13 intervention, n=12 control) were mostly 56% female and M=61.2±11.7 years old. Among intervention participants, proportion who achieved MCID was 23.1% total, 15.4% physical, 38.5% functional, 23.1% social, and 15.4 % emotional, compared to 41.7% total, 33.3% physical, 25.0% functional, 41.7% social wellbeing, and 16.7% emotional among control. None of these proportions differed between groups (p>.05). For the physical QOL subscale, BMI was higher [t(11)=2.92, p=.014] and baseline scores were lower [t(7)=-2.34, p=.052] among those who achieved MCID. CONCLUSION: We observed small improvements in QOL within CRC survivors. There were no statistically significant differences in achieving clinically relevant improvements in QOL between intervention and control group participants. Larger randomized studies are needed to definitively determine if a videoconference exercise intervention can elicit clinically relevant improvements in QOL compared to a control group.
Open Access
Exploring cancer survivors' preferences for a physical activity maintenance program
(Colorado State University. Libraries, 2023) Anderson, Hadalyn, author; Leach, Heather, advisor; Fruhauf, Christine, committee member; Faro, Jamie, committee member
Purpose: Physical activity (PA) offers long-term health benefits for cancer survivors (CS), if sustained. Community-based exercise programs have shown short-term effectiveness in increasing PA among cancer survivors, but evidence of their effect on long-term PA engagement (i.e., PA maintenance) is lacking. This study (1) quantitatively explored cancer survivors' preferences for a PA maintenance program and whether preferences were impacted by PA levels, and (2) qualitatively explored participants' preferences of a PA maintenance program and PA-related barriers. Methods: CS who completed one of three original cancer-specific community-based exercise programs participated in a pilot PA maintenance program (i.e., two exercise and discussion sessions). (1) Participants completed questionnaires via REDCap database to assess interest in a PA maintenance program (i.e., likelihood of attending, perceived helpfulness and enjoyment, and preferences of frequency, duration, and time until maintenance program commencement) and PA levels. Participants reported current PA levels compared to when they finished the original program (greater or same vs. lower PA levels) and completed the Godin Leisure-Time Exercise Questionnaire to determine whether they were currently meeting PA guidelines (≥150 mins/week of moderate aerobic PA + 2 days of strength training). (2) Participants also completed semi-structured focus groups via Zoom that aimed to answer the following questions regarding participants': (i) maintenance program experience, (ii) suggestions for future maintenance program implementation, (iii) perceived elements of the original program that were helpful in maintaining PA, and (iv) barriers experienced following the original program. Frequencies from (1) were calculated, and Fisher's exact tests were used to compare proportions between maintenance program preferences and participants' PA levels. Qualitative data from (2) were transcribed verbatim, coded inductively, and analyzed using thematic analysis. Themes and frequencies of references (%) were calculated. Results: (1) Participants (N=20) were M=60±13 years old, non-Hispanic White (95%), female (95%), and diagnosed with breast (50%), ovarian (20%), or other (30%) cancer. Average time since program completion was M=26.2 ± 35.7 (1-110) months. Most participants (65%) reported exercising more or the same amount since original program completion, and 35% met PA guidelines. The majority were likely to attend maintenance exercise (90%) and discussion (80%) sessions. All (100%) participants thought maintenance exercise sessions would be helpful and most (85%) for discussion sessions. There were no differences in responses based on PA levels (all p>.05). (2) Themes identified for (i) were Accountability (36%), Shared Cancer Survivor Experience (26%), Individualized Exercise Prescription (30%), and Discussion Session Content (8%); (ii) were Accountability (8.929%), Discussion Session Content (26.79%), and Discussion (19.64%) and Exercise (44.64%) Session Delivery; (iii) were Accountability (39.39%), Individualized Exercise Prescription (30.3%), and Discussion Session Content (30.3%); and (iv) were Psychological (41.38%), Physical (27.59%), and Environmental (31.03%). Conclusion: Participants had positive perceptions of the maintenance program. Future studies should measure effectiveness of a maintenance program to support PA maintenance and encompass program leader perspectives to work towards achieving pragmatic solutions to maintain PA maintenance programs within community-based settings.
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How are driving licensure status, delay in driving licensure, and driving exposure associated with alcohol and drug use, parental monitoring knowledge, peer alcohol and drug use, and health, education, and employment of emerging adults?
(Colorado State University. Libraries, 2023) Gao, Xiang, author; Li, Kaigang, advisor; Vaca, Federico E., committee member; Sharp, Julia, committee member; DeYoung, Wendy, committee member
Independence and mobility facilitated by driving privileges could have a major impact on alcohol and drug use, parental monitoring knowledge, peer alcohol and drug use, and health, education, and employment of emerging adults. Driving privileges may provide emerging adults with the ability to move more freely, and that mobility may affect their access to drugs and alcohol. It may also mean that emerging adults with driving privileges were more likely to be in environments where alcohol and drugs were available. Parents of emerging adults with driving privileges may be more involved in monitoring their child's driving activities, resulting in higher levels of parental monitoring knowledge. Emerging adults with driving privileges were more likely to report a higher level of peer alcohol and drug use because having access to a car allowed them to spend more time with their peers and engage in alcohol and drug use. On the other hand, driving privileges may have positive impacts on the health, education, and employment of emerging adults. Having the ability to travel to places of employment and educational institutions may open more opportunities and allow for greater access to resources. This could lead to improved academic and professional outcomes. Overall, driving privileges may have both positive and negative impacts on alcohol and drug use, parental monitoring knowledge, peer alcohol and drug use, and health, education, and employment of emerging adults. It was important to consider these trade-off impacts when considering how to best support emerging adults in their development. My dissertation explored how were driving licensure status, delay in driving licensure, and driving exposure associated with alcohol and drug use, parental monitoring knowledge, peer alcohol and drug use, and health, education, and employment of emerging adults. Data was collected from a nationally representative sample of U.S. emerging adults starting at grade 10th for a seven-year longitudinal assessment. Having driving licensure in high school, no delay in driving licensure, and higher driving exposure were associated with higher levels of alcohol and drug use, higher levels of parental monitoring knowledge, higher levels of peer alcohol and drug use, better health, higher levels of education attainment, and more working hours in emerging adulthood. My dissertation could inform policymakers and practitioners on the importance of driving privileges in promoting the well-being of emerging adults.
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Identifying novel molecular mechanisms of healthspan using multi-omics
(Colorado State University. Libraries, 2023) Smith, Meghan Elizabeth, author; LaRocca, Tom, advisor; Hamilton, Karyn, committee member; Broussard, Josiane, committee member; Ehrhart, Nicole, committee member
An important goal in research on aging is to extend healthspan, the period of life spent healthy and disease-free. Next-generation sequencing and other emerging bioinformatics technologies (e.g., RNA-seq/transcriptomics, epigenetic profiling, and proteomics) have made it possible to broadly profile potential molecular mediators of aging, and perhaps identify therapeutic targets. The studies in this dissertation focus on using transcriptomics and complementary "multi-omics" strategies to characterize novel cellular mechanisms of aging, and to determine their relevance to systemic/functional health in humans. With the guidance of my mentoring team, I completed three studies in which I identified novel mediators of healthspan-related exercise training responsiveness, age-related inflammation, and cognitive/motor function decline in middle-aged and older adults. One particularly novel focus among these studies was the role of non-coding repetitive RNAs (derived from transposable elements) in healthspan. Transposable elements have been linked to known mechanisms of aging, and this topic is reviewed at the start of this dissertation to provide perspective on their role in the context of research on aging biology. Collectively, my findings represent new ideas for targetable genes and proteins that may influence human healthspan.
Open Access
The transcallosal highway: the ipsilateral silent period as a neural biomarker for impaired corpus callosum communication and gait asymmetry in people with multiple sclerosis
(Colorado State University. Libraries, 2023) Acosta, Jordan, author; Fling, Brett, advisor; Rudolph, Alan, committee member; Miravalle, Augusto, committee member; Schmid, Arlene, committee member
Multiple sclerosis is a neurodegenerative disease that damages the myelin sheath within the central nervous system. Axonal demyelination, particularly in the corpus callosum, impacts communication between the brain's hemispheres in persons with multiple sclerosis (PwMS). Changes in transcallosal communication impairs the coordination of gait which requires constant communication across the corpus callosum to excite and inhibit specific muscle groups. To further evaluate the functional role of transcallosal communication in gait and mobility, this study assessed the ipsilateral silent period (iSP), an indirect marker of transcallosal inhibition in PwMS. This study utilizes transcranial magnetic stimulation (TMS) to assess the inhibitory capacity between the brain's hemispheres. There is a lack of research analyzing directionality data between the more and less affected hemisphere in PwMS. Therefore, we evaluated outcome metrics dependent upon the individual's more affected hemisphere calculated from the subject's more affected limb observed during walking assessments and self-report. We hypothesize that the iSP may serve as a neural biomarker for transcallosal impairments evaluated by directionality differences between the hemispheres and highlight transcallosal inhibition as an underlying neural mechanism for gait asymmetries in PwMS. From twenty-nine PwMS, metrics such as depth iSP% average, duration, depth iSP% max, and onset latency were collected. No statistically significant differences were found between the two hemispheres. This suggests that PwMS may be able to preserve their interhemispheric inhibitory capacity irrespective of their more affected hemisphere. Additionally, another component of the study investigated gait coordination utilizing a split-belt treadmill training paradigm. Limb excursion asymmetry (LEA) measures, pre and post-training, were analyzed for spatial coordination and as a measurement of locomotor adaptability in PwMS. The relationship between LEA change and dSP% average highlighted a significant correlation (r=0.46, p= 0.02). Thus, showing that less interhemispheric inhibition corresponds with more spatial adaptability leading to a more symmetric gait. These findings may help determine the potential of iSPs as a neural biomarker to address gait asymmetries and stratify participants into mobility rehabilitation protocols.
Open Access
The effects of sleep extension on physical and cognitive performance in AROTC cadets
(Colorado State University. Libraries, 2023) Wedderburn, J'Michael, author; Broussard, Josiane, advisor; Lipsey, Tiffany, committee member; Eakman, Aaron, committee member; Brager, Allison, committee member
College students and military personnel have limited sleep opportunities; Reserve Officer Training Corps (ROTC) cadets belong to both groups. Thus, cadets are at a heightened risk of insufficient sleep. Sleep loss can have deleterious effects on physical and cognitive health (Halson et al., 2014). In military professions, these impairments have potentially fatal consequences, as decreased performance will result in diminished operational readiness. Recent evidence suggests that sleep extension is a valid intervention to increase sleep duration (Bonnar et al., 2018). Thus, we aim to identify if sleep extension improves performance in chronically sleep-deprived ROTC cadets. This study examines the impact of 1-week of sleep extension on physical and cognitive performance in Army ROTC cadets. We recruited 16 healthy, active male and female participants aged 18-35 from Colorado State University's ROTC program. Participants were equipped with Actiwatches and completed daily sleep questionnaires and diaries during the habitual and sleep extension periods. Sleep extension was achieved by asking participants to spend 10 hours in bed to increase sleep by at least 1 hour per night. Cadets then completed a series of physical and cognitive tests to measure performance on tactically relevant tasks. The physical testing consisted of a vertical jump, 3-repetition maximal hexagon deadlift, 300-meter shuttle, and a 1-mile run; and cognitive test consisted of a psychomotor vigilance test, the Purdue pegboard test Tiffin (1948), the STROOP color-word test Jensen (1965), and a simulated shooting exercise. Wilcoxon Signed rank-test and two samples paired t-test statistical analysis compared baseline, physical, and cognitive testing data to post-intervention testing data. Cognitive and physical testing occurred after 1-week of habitual sleep and 1-week of sleep extension. The mean objective Total Sleep Time (TST) was 6.07 ± 0.15 hours during the baseline period and 7.03 ± 0.17 hours during the sleep extension period (P=<0.0001). The mean Epworth Sleepiness Scale (ESS) rating was outside of normal limits at 10.47 ± 1.16 during the habitual sleep period; it decreased to fall within the normal limits during the sleep extension period at 7.10 ± 0.79 (P <0.005) (Shattuck & Matsangas. 2014). There were statistically significant differences found on 2 of the 4 Purdue pegboard tests and deadlift performance from habitual sleep to the sleep extension period. The mean hands and assembly scores significantly improved (P = 0.038 and P=0.003, respectively). Performance on the 3-repetition maximal hexagon deadlift increased significantly during the habitual sleep period and sleep extension period (p = .007). The limited sleep opportunities ROTC cadets encounter have negative implications on physical and cognitive performance; based on our findings in the current study, it is plausible that sleep was not extended to an adequate duration to elicit cognitive and physical performance improvements in all of the tested cognitive and physical measure. Thus, more research is needed to investigate the relationship between sleep duration and sleep quality and their effect on cognitive and physical performance in tactical population.
Open Access
The effect of circadian regulation and sleep disruption on metabolic homeostasis
(Colorado State University. Libraries, 2022) Morton, Sarah J., author; Broussard, Josiane L., advisor; Hickey, Matthew S., committee member; Dinenno, Frank A., committee member; Bergman, Bryan C., committee member; Prenni, Jessica E., committee member
Sleep and circadian disruption are ubiquitous in modern society. While the National Sleep Foundation recommends adults sleep 7-9 hours per night, the average sleep duration of American adults has decreased from ~8.8 hours to ~6.8 hours over the last century, with 1 in 3 people report sleeping fewer than 6.5 hours per night during the work week. People who sleep fewer than 6 hours per night have a three-fold risk of impaired fasting glucose than those sleeping at least 8 hours per night. Laboratory studies report that as little as one night of insufficient sleep impairs insulin sensitivity, which is a common risk factor for obesity and diabetes. Circadian misalignment is common in people who work non-standard hours, including evening, night, or rotating shifts, and is associated with increased fasting glucose and insulin concentrations, as well as impaired insulin sensitivity. Moreover, circadian misalignment can also occur as a consequence of insufficient sleep. With more than 35% of adults reporting insufficient amounts of sleep, chronic and acute circadian misalignment are likely even more prevalent than commonly recognized. Sleep and circadian disruption are associated with increased mortality rates and health problems, including obesity and diabetes. However, the molecular mechanisms by which these impairments occur are not known. Thus, the overall goal of this dissertation was to determine the circadian rhythms of substrate oxidation and hormonal regulators of energy balance as well as to identify molecular alterations associated with insufficient sleep, including skeletal muscle lipid accumulation and altered gene expression, and their relation with insulin sensitivity. The primary findings are that in healthy, young, lean participants 1) carbohydrate and lipid oxidation as well as ghrelin and peptide YY have circadian rhythms as identified by a constant routine protocol and 2) insufficient sleep induces skeletal muscle lipid accumulation and altered gene expression as well as impaired insulin sensitivity. Together, these studies indicate that sleep and circadian disruption may impair insulin sensitivity via dysregulated lipid metabolism.
Open Access
Short-term metabolic effects of breaking up sedentary behaviors
(Colorado State University. Libraries, 2022) De Jong, Nathan Paul, author; Hickey, Matthew S., advisor; Bergouignan, Audrey, committee member; Braun, Barry, committee member; Melby, Christopher L., committee member
"Sit Less, Move More" has become a widespread public health message due in part to the recognition that sedentary behaviors (i.e., sitting) are associated with all-cause mortality and increased risk for obesity, diabetes, cardiovascular diseases and some cancers, even when accounting for time spent in moderate-to-vigorous physical activity. Recent epidemiological and experimental evidence from acute and short-term studies indicate that reducing and breaking up sedentary behaviors (i.e., sitting) may be a useful strategy for glucose control. Acute experimental trials (5-12 hr exposure) demonstrate that breaking up sedentary time with short-frequent bouts of physical activity is associated with lower postprandial glucose and insulin concentrations while a time-matched single-continuous bout is associated with lower postprandial triglyceride concentrations in response to standardized meals. This suggests differential substrate oxidation may be responsible for the changes in postprandial metabolites. However, what is unknown is (1) whether breaking up sedentary behaviors with short-frequent bouts of physical activity is a strategy that can be implemented in the daily life of sedentary, physically inactive adults; (2) whether the acute metabolic benefits previously observed are sustained or diluted beyond the acute exposure period (> 5-12 hr); (3) whether the effects are due to the active breaks per se or to increases in total energy expenditure and/or total active time and (2) the characterization of potential underlying physiological, cellular, and molecular mechanisms. The primary objective of this dissertation is to investigate the feasibility of implementing short-frequent bouts of physical activity to break up sedentary behaviors into daily life over the short-term (4-day) in those who are habitually inactive and the effect on nutrient metabolism when energy expenditure and balance are matched. We hypothesized that breaking up sedentary behaviors with short-frequent bouts of physical activity is a feasible lifestyle intervention to increase physical activity which will be associated with attenuated glycemia by an increase in postprandial carbohydrate oxidation. In a randomized cross-over study, we compared the short-term effects (4-day) of breaking up sedentary behaviors with short-frequent bouts of moderate intensity physical activity (MICRO: 5-min walk bout every hour for 9 consecutive hours per day) to a time-matched single-continuous bout of moderate intensity physical activity (ONE: 45-min continuous walking bout per day), and a sedentary control (SED: habitual sedentary behaviors and physical inactivity each day) in inactive male and female adults with overweight or obesity. To reach our overall objective, three independent specific aims were pursued: 1) to determine the feasibility of implementing MICRO compared to ONE on daily time spent sitting and physically active over the short-term; 2) to determine the effect of MICRO compared to ONE on nutrient metabolism and insulin sensitivity; 3) to characterize the short-term effect of MICRO compared to ONE on permeabilized skeletal muscle fiber respiration and gene expression of proteins involved in the regulation of metabolic pathways. Results from this dissertation demonstrate that 1) MICRO is a feasible intervention to promote physical activity both on workdays and non-working days in those who are at high risk for metabolic disease; (2) At the same energy expenditure and balance, MICRO resulted in a greater reliance on carbohydrate as fuel during the waking period when the bouts were performed and over 24 hr. In contrast, a single isoenergetic continuous bout of moderate intensity walking increased 24 hr total and dietary fat oxidation. Both physical activity interventions lowered postprandial insulin and improved fasting indexes of insulin sensitivity compared to SED; 3) While no changes were observed after MICRO in mitochondrial oxidative capacity, MICRO is a sufficient stimulus to promote adaptations in skeletal muscle augmenting pathways associated with substrate oxidation. Independent of detectable differences in insulin sensitivity, total active time, and energy expenditure, breaking up sedentary behaviors with short-frequent bouts of physical activity spread throughout the day is a viable lifestyle intervention for glucose control compared to the same amount of physical performed as a single continuous bout with the rest of the day spent sedentary. This evidence can be used to refine future physical activity guidelines to prevent and treat metabolic diseases, not in terms of intensity of exercise per day per week but in terms of avoidance of sedentary activities through short bouts of physical activity.
Embargo
Determinants of driving performance following stroke
(Colorado State University. Libraries, 2022) Pollet, Aviva Katherine, author; Lodha, Neha, advisor; Li, Kaigang, committee member; Schmid, Arlene A., committee member
Overall introduction: Individuals with stroke experience motor and cognitive deficits both of which can impact driving performance. Using two separate studies, we evaluated the influence of motor and cognitive factors on driving performance in stroke survivors. In the first study, we evaluated how driving impairments in stroke survivors is influenced by the use of either the paretic or non-paretic leg for pedal control. Methods 1: Twenty-two individuals with chronic stroke were recruited in two groups depending on their lower-limb choice for pedal control 1) paretic leg drivers, individuals using their paretic leg to control the car pedals (N = 11, 68.4 ± 7.8 years) and 2) non-paretic leg drivers, individuals using their non-paretic leg to control the car pedals (N = 11, 61.1 ± 13.7 years). Both groups performed a car following task in a driving simulator. The task required participants to follow a lead car by controlling the gas pedal accurately and respond to brake lights by pressing the brake pedal as fast as possible. We quantified gas pedal error using root mean square error (RMSE). We measured brake response time as the time from the onset of the brake lights of the lead car to the application of the brake pedal. We also dissociated the brake response time into pre-motor and motor response times. We used the Driving Habits Questionnaire (DHQ) to measure self-reported on-road driving behavior. Additionally, using surface electromyography (EMG), we analyzed neuromuscular activation using burst duration and amplitude, and coordination using overlap and coactivation of the tibialis anterior (TA) and medial gastrocnemius (MG) during the braking portion of the car following task. Results 1: The paretic leg drivers showed greater gas pedal RMSE than the non-paretic leg drivers (p ≤ 0.01). The paretic leg drivers had a slower brake response time than the non-paretic leg drivers (p < 0.05). Premotor response time was not different between the two groups (p = 0.71), however, the paretic leg drivers had a significantly slower motor response time relative to the non-paretic leg drivers (p < 0.05). The paretic leg drivers had lower DHQ scores than the non-paretic leg drivers (p ≤ 0.01). DHQ and brake response time were negatively correlated (r = - 0.42, p ≤ 0.05). Additionally, paretic leg drivers showed longer TA EMG burst duration (p <0.05) and more TA-MG overlap (p <0.05). TA EMG burst duration was positively correlated to brake response time (r = 0.51, p < 0.05) and motor response time (r = 0.61, p < 0.05). TA-MG overlap was positively correlated to brake response time (r = 0.76, p = 0.001). In the second study, we evaluated how cognitive load influenced driving impairments in stroke survivors. Methods 2: Ten individuals with chronic stroke participated in the current study (N = 10, 65.6 ± 14.9 years). The participants performed simulated driving without (single-task) and with (dual-task) a cognitive load. The single-task driving required participants to drive along a rural road and brake as quickly as possible when an unexpected hazard, such as wildlife crossing into the driving lane, was encountered. The dual-task driving required participants to drive in the same driving scenario while performing a secondary cognitive task. The cognitive task involved mental arithmetic to induce higher cognitive load while driving. Specifically, participants were asked to subtract 4 and add 3 to a random number and do so repeatedly until the end of the driving task. We measured lane departures as the number of times the edge of the participant's vehicle left the designated driving lane. We measured speed compliance as the percent of total time the individual was within +/- 5 MPH of the speed limit between events. Additionally, we measured brake response time as the time from the appearance of the hazard stimulus to the application of the brake pedal. Results 2: Individuals with stroke show more lane departures throughout the entire drive during dual-task driving than single-task driving (p < 0.05). Additionally, individuals with stroke show worse speed compliance during dual-task driving than single-task driving (p < 0.05). There was no difference in brake response time between the single-task and dual-task driving (p = 0.18). Overall conclusion: Driving performance in stroke survivors is influenced by limb selection for pedal control and cognitive load. The current studies demonstrate the need to assess and train motor and cognitive deficits that contribute to driving performance in individuals with stroke. Motor deficits in pedal control and brake response time contribute to unsafe driving in individuals with stroke. Cognitive deficits in lane departures and speed compliance in driving with cognitive load also contribute to unsafe driving in individuals with stroke. To address these deficits, stroke driving rehabilitation programs should focus on driving leg and cognitive environment of driving.
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Brain protein synthesis rates and energy sensing in sulfur-amino acid restricted mice
(Colorado State University. Libraries, 2022) Martinez, Wenceslao, author; Hamilton, Karyn, advisor; LaRocca, Thomas, committee member; Moreno, Julie, committee member
Protein homeostasis (proteostasis) is the maintenance of the cellular proteome through protein synthesis, folding, trafficking, and degradation. Loss of proteostasis is considered one of the hallmarks of aging and is a driver for age-related neurodegenerative diseases. Dietary sulfur amino acid restriction (SAAR), a life-/healthspan extending treatment, activates mechanisms that maintain proteostasis in the liver. However, it is unknown if dietary SAAR activates mechanisms promoting proteostatic maintenance in the brain. To address this knowledge gap, wild-type male C57Bl/B6 mice were fed one of two levels of SAAR (expressed as % kcal); 0.18% methionine and 0% cysteine (Low SAAR) or 0.12% methionine and 0% cysteine (High SAAR), or a matched control diet sufficient (0.85-0.88%) in methionine. Deuterium enriched water was used to measure rates of newly synthesized proteins and DNA (as a marker of cellular proliferation). Brains were collected at days 1, 3, 7, 14, 21, and 35 of treatment. Mitochondrial, cytosolic, and mixed fractions of frontal cortex were analyzed for rates of protein synthesis and cell proliferation using GC/MS. A one phase association was used to determine the rate of the rise of newly synthesized protein and DNA to capture the kinetic parameter k (1/d). Phosphorylated and total protein content for AMP-protein kinase (AMPK), ribosomal Protein S6 (RPS6) and eukaryotic Initiation Factor 2 (eIF2) were measured at day 1 (acute) and day 35 (long-term) via western blot. Mitochondrial protein synthesis rates were significantly greater in the Low SAAR diet compared to the matched control diet, but did not differ in the cytosolic and mixed fractions. Protein synthesis rates in all fractions of the High SAAR diet were not different from control. There was no significant difference in cell proliferation rates between the SAAR diets and their control matched diets. However, in the High SAAR diet, as reflected by greater protein synthesis to DNA synthesis ratios, more newly synthesized proteins were allocated toward mitochondrial proteome maintenance rather than cell proliferation compared to control. At day 1, eIF2 activation tended to greater (p=0.0922) in the Low SAAR diet compared to control, but was not different at day 35 in the Low SAAR or High SAAR diets. AMPK activation did not differ in the Low SAAR or High SAAR diet compared to their controls at day 1 and day 35. RPS6 activation was not significantly different at day 1 or day 35 in either SAAR diet compared to their controls. This is the first study to simultaneously assess rates of protein synthesis and cell proliferation in the frontal cortex during dietary SAAR, as well as assess activation of key energy sensing proteins. The results from this study show that despite restriction of the sulfur amino acids, rates of protein synthesis were maintained in the cytosolic and mixed fractions with Low SAAR, while the rate of mitochondrial protein synthesis was greater than the control group with Low SAAR but not High SAAR. Dietary SAAR also promoted allocation of more newly synthesized proteins towards maintenance of the existing proteome, with less for new cell proliferation.
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Caffeine augments the lactate and interleukin-6 response to moderate-intensity exercise in males but not females
(Colorado State University. Libraries, 2022) Abbotts, Kieran Shay Struebin, author; Bell, Christopher, advisor; Hamilton, Karyn, committee member; Melby, Christopher, committee member
The release of interleukin (IL)-6 from contracting skeletal muscle is thought to contribute to some of the health benefits bestowed by exercise. This IL-6 response appears proportional to exercise volume. Unfortunately, high volumes of exercise are not feasible for all people. Caffeine augments the magnitude of increase in circulating concentration of IL-6 in response to high-intensity and long-duration exercise, in males. Caffeine is also known to increase circulating concentrations of lactate during exercise. One of the mechanisms thought to contribute to IL-6 release from exercising skeletal muscle is lactate production. We hypothesized that caffeine, ingested prior to moderate-intensity exercise, would lead to greater circulating concentrations of lactate and IL-6 in a study population comprising both males and females. 15 healthy adults (9 males and 6 females, aged 26±7 years, (mean ± SD)) completed 30-minutes of moderate-intensity cycle ergometer exercise, equivalent to the ventilatory threshold, after ingesting either caffeine (6 mg/kg) or placebo. Arterialized-venous blood was collected throughout each of the exercise sessions. Compared with placebo, caffeine increased end-exercise circulating concentrations of lactate (5.72±3.95 vs. 7.14±4.66 mmol/L, P<0.001) but not end-exercise IL-6 (1.84±0.97 vs. 2.37±1.04 pg/mL, P=0.139). However, when females were excluded from the analysis, caffeine augmented (P=0.04) the magnitude of increase of end-exercise IL-6 concentration (1.80±0.86 vs. 2.57±1.21 pg/mL); this effect was further exaggerated after 30-minutes of inactive recovery (3.81±2.32 vs. 5.06±3.22 pg/mL). Noteworthy, caffeine evoked greater end-exercise lactate concentrations in data sets containing only males (P=0.02) and only females (P=0.002) but did not influence the IL-6 response in females (P=0.94). Our preliminary data imply that in males unable/unwilling to perform high-intensity and/or long-duration exercise, caffeine may potentially enhance the IL-6 mediated health benefits of relatively short, moderate-intensity exercise.
Open Access
Bayes'd and confused: novel applications of Bayesian inference to better understand sensorimotor uncertainty
(Colorado State University. Libraries, 2021) Whittier, Tyler Thorley, author; Fling, Brett W., advisor; Rhea, Christopher K., committee member; Seidler, Rachael D., committee member; Weller, Zachary D., committee member
Effective motor control relies on accurate sensory information. However, sensory information is inherently variable and clouded with uncertainty. Yet, humans perform motor skills with a high degree of proficiency and reliability. How the central nervous system (CNS) controls motor function amid the uncertainty of sensory signals is not known. Researchers in recent years have suggested that the brain may control movement in a way that can be explained by Bayesian inference. Bayesian inference posits that the most probable outcome is the product of both the currently available data (sensory information) as well as previously collected data (learned expectations). Applying Bayesian inference to a motor control context, we suggest that the CNS accounts for the uncertainty in sensory information by filling in the gaps of uncertainty with learned expectations when forming beliefs on where our body parts are in space. While initial findings on this topic are promising, they predominantly involve one-dimensional upper-body tasks. The purpose of this dissertation was to determine if Bayesian model of sensorimotor control is consistent in a full body stepping movement and if it can be further utilized to understand sensory function in various contexts. The first study in this dissertation was done to discover if the center of mass (CoM) position is estimated in a Bayesian way during stepping, like what has been shown in upper body movements. The second study sought to identify if Bayesian position estimations are beneficial to overall motor performance. In the third study, we applied what we have discovered about Bayesian inference in full body movements to understand the effects of transcutaneous electric nerve stimulation (TENS) on positional awareness during motor control. We hope to build on these findings to better understand how sensory information is utilized by the CNS to control movement.
Open Access
Novel modulators of blood pressure with age: a physiological and bioinformatics-based approach
(Colorado State University. Libraries, 2021) Bachman, Nate P., author; Braun, Barry, advisor; LaRocca, Thomas J., advisor; Chicco, Adam J., committee member; Gentile, Christopher L., committee member
Systolic blood pressure (SBP) increases with age and is a significant risk factor cardio- and cerebrovascular diseases. While the causes of high blood pressure (hypertension) have been extensively studied, the causes of the age-related rise in blood pressure independent of chronic disease remain unclear. Thus, the identification of novel mechanisms underlying age-related high blood pressure may lead to new strategies to reduce chronic disease risk in older adults. Therefore, the goal of this dissertation was to use both physiological and bioinformatics-based approaches to better elucidate contributors to elevated blood pressure in healthy older adults. The main findings are that 1) inhibition of Rho-kinase (an enzyme that participates in numerous cellular/regulatory pathways) lowers systemic blood pressure in healthy older adults concomitant with reduced vascular resistance but not improved endothelial function, 2) genes expression patterns in peripheral white blood cells differ in healthy older adults with elevated SBP compared to those with normal SBP and transcriptomic (RNA) changes relate to vascular and immune function, and 3) circulating chemokines and whole blood immune-related transcripts track with elevated SBP in healthy older adults. Taken together, this work shows that Rho-kinase, circulating RNA transcripts, and circulating chemokines may be novel therapeutic targets and/or biomarkers of elevated blood pressure in healthy older adults with untreated hypertension.
Open Access
Peripheral blood flow regulation in persons with multiple sclerosis
(Colorado State University. Libraries, 2021) Ketelhut, Nathaniel B., author; Fling, Brett W., advisor; Hickey, Matthew S., committee member; Chicco, Adam J., committee member; Myers, Brent, committee member
Multiple sclerosis (MS) is an inflammatory, degenerative disease of the central nervous system that is believed to be autoimmune in nature. The disease affects approximately one million people in the United States and results in a wide variety of symptoms including impaired physical function, reduced exercise capacity, and increased fatigability. Although considerable effort has been invested in improving our understanding of the neuromuscular contributions to these symptoms, no studies have investigated whether cardiovascular autonomic dysfunction compromises skeletal muscle blood flow in persons with MS (PwMS). Indeed, approximately 50% of PwMS have an abnormal response to tests of cardiovascular autonomic function, and skeletal muscle blood flow is positively associated with exercise capacity. Thus, the overall goal of this dissertation was to determine whether PwMS have impaired skeletal muscle blood flow responses to exercise relative to age- and sex-matched healthy controls. The primary findings are that 1) the local control of skeletal muscle blood flow during exercise is intact in PwMS, 2) skeletal muscle blood flow is likely reduced during exercise that engages the autonomic nervous system in MS, which may be due to increased α-adrenergic mediated vascular tone, and 3) that PwMS may experience hypersensitivity to α-adrenergic signaling as evidenced by levels of systemic vascular resistance relative to plasma concentrations of norepinephrine. Together, these studies indicate that compromised skeletal muscle blood flow during exercise may contribute to reduced exercise capacity and increased fatigability in PwMS.
Open Access
Reallocating time to physical activity and sleep: associations with quality of life and body mass index in cancer survivors
(Colorado State University. Libraries, 2021) Hidde, Mary, author; Leach, Heather, advisor; Broussard, Josiane, committee member; Lyden, Kate, committee member; Henry, Kim, committee member
Introduction: Quality of Life (QOL) and Body Mass Index (BMI) are important outcomes for cancer survivors due to their association with cancer-related morbidity and mortality. Lifestyle behaviors including physical activity (PA), sedentary time, and sleep are all potential intervention targets to improve QOL and BMI. The effect of these activities on QOL and BMI is most often studied in isolation despite the interdependent nature of these behaviors; time cannot be increased in one activity without decreasing time in another. Since these behaviors are often studied in isolation, it is difficult to assess if an improvement in QOL or BMI is attributed to increasing positive behaviors (i.e., PA or sleep), or decreasing negative behaviors (i.e., sedentary time). The growing interest around 24-hour activity patterns has increased researcher interest in objective measurement of PA and sleep using accelerometers. However, this currently requires researchers to utilize one device to measure sleep (i.e., Actiwatch) and one to measure waking behaviors (i.e., activPAL). This has led to high research costs and burden since the Actiwatch cannot measures waking behaviors and, until recently, the activPAL could not detect time in bed (TIB), limiting researcher's ability to objectively collect 24-hour activity data. In order to move the world of 24-hour activity forward and delineate the role time reallocations throughout the day affect pertinent cancer-related outcomes, additional research must be conducted to explore solutions to the high research costs and burden associated with 24-hour activity measurement. Therefore, the purpose of this dissertation is to (1) evaluate if the new activPAL algorithm designed to measure TIB can estimate TIB similarly to the valid and reliable Actiwatch and 2) evaluate, using an Isotemporal substitution model, the effects of reallocating time from one activity to another on QOL and BMI using accelerometry (Actiwatch and activPAL pending results of aim 1) to measure 24-hour activities. Methods: The activPAL algorithm's ability to measure TIB was evaluated using a cross-sectional analysis of participants (n=85) undergoing a time-restricted feeding study. Participants (for all studies) wore the activPAL accelerometer to measure waking behaviors and the Actiwatch to measure sleeping behaviors for 7 days, 24-hours per day. Repeated measures mixed effects models and Bland-Altman plots were used to compare the activPAL TIB estimates to the Actiwatch TIB estimate with type of device and day of wear as fixed effects and participant as a random effect. TIB results were then utilized in a cross-sectional analyses of cancer survivors (n=73) within 60 months of surgery, chemotherapy, and/or radiation. In addition to wearing the activPAL and Actiwatch, participants completed the Functional Assessment of Cancer Therapy-General (FACT-G) to measure QOL. Participants self-reported height and weight to calculate BMI. Demographics were calculated using mean ± standard deviation or frequencies (%). Isotemporal substitution models were used to evaluate the effects of reallocating 30 minutes of each activity to another. Statistical significance for all studies was set at p<.05. Results: The activPAL accelerometer does not estimate TIB similarly to the Actiwatch. Additionally, no significant interaction was observed for type of accelerometer and day of wear. There were no statistically significant reallocations for total QOL score or the included subscales. However for BMI, reallocating 30 minutes of sleep to sedentary time or moving 30 minutes of sedentary time to light PA did result in statistically significant changes in BMI. There were no statistically significant reallocations by moving moderate-vigorous PA to other activities of interest. Despite no statistical significance for QOL, reallocating time from sedentary time or light PA to MVPA resulted in clinically meaningful increases in QOL (>4 points). Conclusion: Estimates of TIB from the activPAL and Actiwatch accelerometers were not similar, suggesting that researchers who are interested in the 24-hour activity cycle will continue to require the use of both accelerometers to measure both sleep and active/waking behaviors. Results of reallocating time on QOL and BMI indicate that in addition to MVPA, sleep, and light PA are essential behaviors for cancer survivors. The work presented in this dissertation can provide a starting point for the development of 24-hour activity guidelines for improving BMI and QOL in cancer survivors; however, additional time reallocation studies using a larger sample size in order to include bouted and non-bouted activity time as well as more detailed measures of body composition (i.e., dual x-ray absorptiometry) are needed to further understand the role the 24-hour activity cycle has on BMI and QOL in cancer survivors.
Open Access
Feasibility, acceptability and preliminary effectiveness of a video conference delivered, group-based physical activity program for cancer survivors
(Colorado State University. Libraries, 2021) Howell, Matthew, author; Leach, Heather, advisor; Perry, Rick, committee member; Currin-McCulloch, Jen, committee member
Background: Although supervised cancer rehabilitation and exercise programs are effective for improving health outcomes among cancer survivors, widespread access is lacking, and the COVID-19 pandemic highlighted the need for innovative ways to reach and serve cancer survivors in their homes. Method: A single arm, pre-post study to assess feasibility, acceptability and preliminary effectiveness of Fitness for Cancer Therapy (Fit Cancer), an 8-week, group-based videoconference delivered exercise program. Feasibility and acceptability were captured by accrual, attendance and adherence rates and participant satisfaction and analyzed using descriptive statistics. Preliminary estimates of the effects of Fit Cancer on physical function, Quality of Life (QOL) and Exercise Self Efficacy (ESE) were measured at pre- and post-program and analyzed by percent change and one-tailed, paired sample t-tests. Results: A total of n = 39 participated in the study. Accrual (91%), retention (90%), adherence (88%) rates along with acceptability (94%) findings support feasibility. Physical activity measured by moderate-vigorous aerobic and resistance exercise had a percent change increase of 69.9% (p <0.05). Lower (10.4%, p <0.05) and upper body muscular endurance (22.4%, p <0.05) and single-leg balance (12.1%, p <0.05) all increased significantly. No changes were seen in QOL or BARSE and a reduction was seen in ESE (-8.1%, p <0.05). Conclusion: Results indicate that a videoconference delivered exercise program was feasible and acceptable and may help cancer survivors increase physical activity and muscular strength/endurance. A controlled trial is required to confirm these findings.
Open Access
Pharmacokinetic investigation of commercially available edible marijuana products in humans: potential influence of body composition and influence on glucose control
(Colorado State University. Libraries, 2021) Ewell, Taylor, author; Bell, Christopher, advisor; Hickey, Matthew, committee member; Hamilton, Karyn, committee member; Weir, Tiffany, committee member
Our investigation of five commercially available edible marijuana products containing 10mg of delta-9-tetrahydrocannabinol (THC) aimed to describe the pharmacokinetics of these products, investigate the potential influence of body composition on THC bioavailability, and, based on epidemiological research completed in the last decade, determine if acute marijuana ingestion influences glucose tolerance when compared to a THC-free gummy. We studied seven regular marijuana users. We utilized a single-blind randomized controlled crossover study design in which participants self-administered edible marijuana or a THC-free gummy. Thirty minutes following marijuana ingestion a standard oral glucose tolerance test was initiated via consumption of a 75g glucose drink. There was, at minimum, a four-day washout period between trials. Average time to peak plasma THC concentration ranged from 35 to 90 minutes, and average peak THC concentrations ranged from 3.2 to 5.5 ng/ml. Significant differences between products were identified twenty- and thirty-minutes post-ingestion. Several measures of body composition had significant correlations with plasma THC, although none of these correlations persisted across all products. There were no differences in indices of glycemic control between marijuana products or the THC-free gummy. Following acute edible marijuana ingestion in habitual users, significant differences in THC pharmacokinetics existed between similar products, possibly due to body composition, although glucose control was not impacted. In summary, these data may inform recreational users to the proper dose for marijuana ingestion to achieve the desired outcome and to avoid overdose.
Open Access
The interaction between cycling cadence and substrate utilization in trained cyclists
(Colorado State University. Libraries, 2021) Dippold, Victoria Mary Grace, author; Fahrner, Scott, advisor; Bell, Christopher, committee member; Hickey, Matthew, committee member; Orton, Christopher, committee member
Currently, the optimal pedaling rate for road cycling endurance performance is not very well understood. It is known that muscle fiber recruitment patterns vary between low and high cadence rates. However, it is unclear whether different muscle fiber recruitment patterns stimulate different substrate utilization patterns between low and high cycling cadences. PURPOSE: We investigated if pedaling at a higher cadence at a submaximal work level results in a higher proportion of fat oxidation compared to cycling at the same intensity at a low cadence. In addition, we aimed at studying the optimal cadence for endurance road cycling and why well-trained and professional cyclists tend to pedal at higher rates. METHODS: Participants were trained, competitive cyclists and/or triathletes (VO2 max 60.4 ± 7.1 ml/kg/min, aged 24 ± 2.5 years, n = 11) living in Fort Collins, CO. All were training at least 8 hours per week and had participated in a competitive event in the past two years. Baseline testing consisted of a maximal consumption test (VO2 max test) that started at a low work level (50 – 100 watts) and increased by 25 watts every three minutes until exhaustion after which a verification bout was performed. From the VO2 max test, the first ventilatory threshold (VT1) was determined for each participant and served as the power output used during the cadence protocol that followed on a separate day. The cadence protocol entailed seven stages each lasting six minutes in length with a four-minute recovery period in between. Work rate remained constant during the cadence protocol while a different cadence was assigned randomly to each stage (60, 70, 80, 90, 100, 110 and freely chosen cadence (FCC)). RESULTS: Cadence had a significant effect on HR (estimated slope = 0.2634, SE = 0.032, p < 0.001), VO2 (estimated slope = 0.098, SE = 0.012, p < 0.001), RER (estimated slope = 0.0007, SE = 0.0001, p < 0.001), as well as absolute (estimated slope = 0.012, SE = 0.001, p < 0.001) and relative percentage of CHO utilization (estimated slope = 0.2696, SE = 0.053, p < 0.001. Cadence did not have a significant effect on absolute fat utilization, but it did have a significant effect on the relative percentage of fat utilization (estimated slope = -0.2283, SE = 0.053, p < 0.001. VO2, HR, and VE were minimized at 70 rpm while carbohydrate utilization was minimized at 60 rpm. FCC was found to be 89.8 rpm. Pairwise comparisons with FCC showed significant mean differences with respect to HR and VO2 between FCC and 70, 100, and 110 rpms as well as significant mean differences with respect to CHO utilization between FCC and 110 rpms. CONCLUSION: The increase in energy expenditure at higher cadences is not counterbalanced by a significant increase in fat oxidation, thereby resulting in a carbohydrate penalty at higher cadences. FCC is not solely chosen to limit metabolic cost or optimize substrate utilization. An optimal pedaling cadence may be one that allows the cyclists to maintain the highest wattage desired without a considerable amount of muscular fatigue while minimizing the consequent increased metabolic cost and CHO penalty.
Open Access
Comparison of five oral cannabidiol preparations in adult humans: pharmacokinetics, body composition, and heart rate variability
(Colorado State University. Libraries, 2021) Williams, Natasha N. Bondareva, author; Bell, Christopher, advisor; Weir, Tiffany, committee member; LaRocca, Tom, committee member
Data supporting the physiological effects of cannabidiol (CBD) ingestion in humans are conflicting. Differences between CBD preparations and bioavailability may contribute to these discrepancies. Further, an influence of body composition on CBD bioavailability is feasible, but currently undocumented. The aims of this study were to: (1) compare the pharmacokinetics of five oral CBD preparations over 4 hours; (2) examine the relationship between body composition and CBD pharmacokinetics; and, (3) explore the influence of CBD on heart rate variability. In total, five preparations of CBD, standardized to 30 mg, were administered orally to 15 healthy men and women (21–62 years) in a randomized, crossover design. Prior to and 60 min following CBD ingestion, heart rate variability was determined. Body composition was assessed using dual energy X-ray absorptiometry. Peak circulating CBD concentration, time to peak concentration, and area under the curve was superior in a preparation comprising 5% CBD concentration liquid. Fat free mass was a significant predictor (R2 = 0.365, p = 0.017) of time to peak concentration for this preparation. Several heart rate variability parameters, including peak frequency of the high frequency band, were favorably, but modestly modified following CBD ingestion. These data confirm an influence of CBD preparation and body composition on CBD bioavailability, and suggest that acute CBD ingestion may have a modest influence on autonomic regulation of heart rate.