Theses and Dissertations

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Open Access
1 month effect of breaking up sedentary activity on insulin sensitivity and glucose homeostasis in free-living overweight/obese adults
(Colorado State University. Libraries, 2019) Schreck, Laura M., author; Hickey, Matthew, advisor; Bergouignan, Audrey, advisor; Broussard, Josiane, committee member; Melby, Christopher, committee member
Sedentary behavior (SB) triggers an inability to adjust substrate use to substrate availability (low metabolic flexibility, MF), which may precede glucose intolerance in the pathogenesis of insulin resistance. We and others have shown that frequent interruptions in SB leads to improved glycemic control, however the underlying role of MF in this process is unknown. This study examined the effects of breaking up SB on MF and glucose metabolism in free-living overweight and obese adults. To distinguish effects of breaking up SB from being physically active, we also studied a group where participants performed a single energy matched continuous bout of exercise. Physically inactive, adults (12F/9M, mean±SD, age: 33±8 yr, BMI: 29.5±3.3 kg/m2) were randomly assigned to a 4 week intervention consisting of brisk walking for 5 min each hour for 10h, 5 d/wk (MICRO, n=10), or 4 weeks of an intervention consisting of one continuous 45 min bout of exercise per day, 5d/wk (ONE, n=9). Outcomes assessed at baseline and after each intervention included: MF (waking respiratory quotient, RQ, minus sleeping RQ as measured in a whole room calorimeter), insulin sensitivity (SI, IVGTT), 24h glycemia (continuous glucose monitor), 24h glucose oxidation (U13C glucose tracer), SB, time spent standing, time spent stepping (ActivPAL) and TEE (double labeled water). Groups were similar on all outcome variables at baseline. Linear mixed models evaluated intervention and intervention-by-group effects. MICRO and ONE decreased time sitting and increased time stepping with no significant changes in TEE. Compared to ONE, MICRO decreased 24h glycemic variability (p=0.06), improved the acute whole body insulin sensitivity (p=0.08) and acute insulin response to glucose (AIRg) (p=0.02) , maintained exogenous glucose oxidation (p<0.03) and improved MF (p=0.02). Independent of time sitting and stepping, breaking up SB improves glucose homeostasis and MF. The effects of such an intervention in persons with type 2 diabetes warrants further study.
Open Access
A case study of a wheat-free diet on autoimmune disease progression
(Colorado State University. Libraries, 2014) Connor, Trevor, author; Cordain, Loren, advisor; Hickey, Matthew, committee member; Ryan, Elizabeth, committee member; Schenkel, Alan, committee member
Background and Aims: Autoimmune disease encompasses a broad range of over 80 conditions for which only three have an identified environmental trigger. Gliadin is the trigger in celiac disease, a condition that has been linked to other autoimmune conditions including Crohn's disease and type I diabetes (T1D). The purpose of this study was to investigate case studies of autoimmune patients who employed a wheat-free or Paleo-style diet (WFP) to manage their conditions. Methods: A descriptive case study was performed that utilized questionnaires administered online and medical records from autoimmune disease patients who had consumed a WFP diet. Results: Fifty-seven patients were evaluated in the study (mean age 37.3 yrs., SD 10.1), including 23 males and 34 females, 24 of whom provided medical records. Thirty of the 57 volunteers demonstrated signs of disease improvement while consuming a WFP. The rates varied across conditions with eight of eight Crohn's disease patients experiencing remission, while three of four T1D patients exhibited signs of improvement. Five of 15 patients with ankylosing spondylitis, rheumatoid arthritis, or undifferentiated and multiple connective tissue disorders worsened while on the diet. Conclusions: Patients with single organ autoimmune diseases previously linked to increased intestinal permeability showed the greatest improvement after consuming a WFP. The results of these case studies warrant further controlled research examining the effects of wheat consumption on Crohn's disease and T1D.
Open Access
A novel approach to real-time monitoring of erythrocyte ATP release as a function of hypoxia
(Colorado State University. Libraries, 2020) Smith, Meghan E., author; Dinenno, Frank, advisor; Lark, Daniel, committee member; Amberg, Gregory, committee member
Background: Matching blood flow to tissue oxygen demand is essential for maintaining metabolic homeostasis and sustaining human life. Recent studies suggest that red blood cells (RBCs) play a role in local vasodilatory signaling by releasing ATP in response to hypoxia. RBC ATP release and overall function are impaired with age and disease. Until now, luciferin/luciferase bioluminescence is the only method described to quantify ATP release from RBCs. Here, we describe a novel approach where ATP release is measured as a function of hypoxia continuously and in real time using an Oroboros Oxygraph O2K respirometer. Purpose: This report describes the development and application of this new approach. Methods: We obtained blood samples from 10 healthy, young adults (18-35y) via venipuncture. Washed RBCs were diluted to 5% hematocrit and added to the glass chamber of a calibrated Oxyfluorimeter along with 5μM Mg-G. Nitrogen gas was constantly injected into the chamber at 1 ml/min to decrease PO2. An LED-based fluorescence detection device monitored Mg-G fluorescence, which was used to calculate extracellular [ATP]. Results: When 5% HCT RBCs were exposed to 30 minutes of hypoxia, Mg-G fluorescence (V) continuously increased. During 30 minutes of progressive hypoxia, PO2 in the chamber decreased from 121.9 ± 1.3 to 9.8 ± 0.8 mmHg, and D extracellular [ATP] from normoxia (μM) increases from 0 to 6,985.0 ± 793.6 μM. Extracellular [ATP] accumulates markedly when PO2 in the chamber reaches 50.60 ± 1.52 mmHg. Conclusion: Using this novel method, we identified a PO2 threshold at which extracellular ATP accumulates rapidly, which is consistent with the range of PO2 that elicits Hb desaturation in RBCs. This approach may allow for detailed mechanistic studies into the relationship between hypoxia, Hb desaturation, and RBC ATP release.
Open Access
A single high-altitude training bout improves high-altitude aerobic performance following one week of low altitude training
(Colorado State University. Libraries, 2011) Andersen, Brady Dean, author; Chicco, Adam J., advisor; Hickey, Matthew Sean, committee member; Gotshall, Robert William, 1945-, committee member; Turk, Daniel E. (Daniel Ernest), 1961-, committee member
Consecutive bouts of aerobic exercise at high-altitude are known to improve subsequent aerobic exercise performance at high altitude due to a variety of acute and chronic adaptations referred to as altitude acclimatization. However, it is unclear whether these benefits can be elicited by a single bout of high-altitude exercise followed by several days of training at lower altitude. PURPOSE: We investigated whether a single bout of hill running exercise performed at high-altitude improves running performance, arterial oxygen saturation (SaO2), hematocrit (HCT) and perceived exertion (RPE) during a strenuous timed run at high-altitude performed 1 week following the training stimulus. METHODS: Participants were well-trained competitive runners (VO2 max 52 ± 5 ml/kg/min, aged 42 ± 14 yrs, n = 8) living in Fort Collins, CO (5,003 ft) that were naïve to higher altitudes for at least 8 weeks. All were training regularly (66 ± 3 miles/wk) and refrained from any non-prescribed altitude exposure for the duration of the study. Baseline testing consisted of a timed run on the Mt. Evans Scenic Byway in Colorado (11.5 miles at 11,500-14,100 ft) followed by one week of training in Fort Collins. Runners were then randomized to perform a 12 mile hill running workout in Fort Collins (LOW; 5,550-7,170 ft, n = 4) or Mt. Evans (HIGH; 12,750-14,100 ft, n = 4). All runners then engaged in 1 week of routine training in Fort Collins followed by a post-test run at Mt. Evans that was identical to the baseline test. RESULTS: There were no significant differences in run-time from pre to post-test for either group. Pre-run (11,500 ft) percent change in SaO2 was significantly different between groups (+3.70 ± 2.95% in High; -3.95 ± 1.62% in Low, P = 0.029). The high group experienced a 4.01 ± 2.72% mean increase in exercising SaO2 from pre to post-test, while the Low group decreased 1.21 ± 1.41% from pre to post-test (P = 0.029). In addition, the High group experience a 8.45 ± 8.13% increase in recovery SaO2 from pre to post-test at an elevation of 14,100 feet, while the Low group had a 2.21 ± 2.82% decrease in recovery SaO2 from pre to post-test at an elevation of 14,100 feet (P = 0.057) . HCT increased from pre post-test to post post-test in the Low group only (43.55 ± 1.04% & 45.67 ± 0.79% respectively; P = 0.68). There were no differences in HR or RPE within or between High and Low groups. CONCLUSION: A single high-altitude training bout prior to 1 week of low-altitude training improves subsequent aerobic performance and arterial O2 saturation at high-altitude, while a single bout performed 2 weeks prior to testing is ineffective.
Open Access
A smart-device based motor function battery
(Colorado State University. Libraries, 2018) Monaghan, Patrick G., author; Tracy, Brian L., advisor; Fling, Brett W., committee member; Stephens, Jaclyn, committee member
Growth in the older population will increase the overall impact of age-related neurological disorders. Aging and neurological conditions share features such as impaired motor function and physical dysfunction including reduced muscle strength and power, slowness of movement, increased movement variability and balance dysfunction. Successful performance of daily activities and maintenance of mobility is key to independence and quality of life. Therefore, tracking changes in physical function is critical in gauging quality of life. However truly quantitative measures of physical capacity often require the use of expensive, lab-based equipment. Smart devices contain sensitive tri-axial accelerometers and gyroscopes that measure acceleration and rotation and offer a more cost-effective, portable yet still quantitative means of physical assessment. The purpose is to describe an iPod Touch-instrumented test battery designed to assess features of physical and motor function often shared by normal aging and age-related movement disorders. We have been assessing the correlation between measures taken from expensive lab devices and the iPod Touch smart device for a variety of movements. We developed and tested a multi-item smart device-based battery of motor tasks that addresses motor variability, slowness and postural instability across a range of young, healthy college students. By changing the location of the device we can assess upper and lower limb movement speed and power, hand tremor, or postural control. We have also used previously validated lab devices concurrently with the smart device, which allows us to correlate the results between devices to assess the extent of the association between devices. Outcomes such as peak acceleration and variability of movements can be obtained. Generally, the smart device demonstrated strong correlations with the lab grade sensors for all motor tasks. Furthermore, the smart device was also correlated with the accelerometer across a large range of speed and variability. Strong correlations were seen in ballistic arm and leg tasks, tremor, and postural control assessments. This finding suggests that the smart device can sufficiently assess a broad range of functional capacity. This battery can then be used to study populations exhibiting motor impairment, ranging from older adults, to neurological patients. Using the sensors on the smart device, this testing can be administered remotely and inexpensively by non-experts, providing cost-effective, mobile, user- and patient-friendly physical function testing. More importantly, accessibility of testing is increased while retaining quantitative precision. This should aid in quantifying disease progression and response to pharmacological or exercise/rehabilitative intervention, with the goal of improved function and quality of life in those with impairment.
Open Access
Accuracy of walking metabolic prediction equations using a large diverse data set
(Colorado State University. Libraries, 2014) Woods, Rachel M., author; Browning, Raymond C., advisor; Hickey, Mathew, committee member; Melby, Christopher, committee member
Walking metabolic rate prediction equations are commonly used to estimate oxygen consumption, exercise intensity and energy expenditure across a wide range of ages and anthropometrics. Despite their widespread use, independent validations of these equations using metabolic data from a large number of individuals are uncommon. PURPOSE: To assess the accuracy of the commonly used ACSM and Pandolf walking metabolic rate prediction equations, along with two new walking metabolic rate predictions equations developed by Weyand et al. and Browning et al., using data from a large number of adults. METHODS: We used demographic, anthropometric, walking speed, and oxygen consumption data from several laboratories (N = 450 (164 Males, 286 females), 18-85 years old, 16.5-44 kg/m2). We estimated oxygen consumption using each prediction equation in 1,078 walking trials ranging from 0.55-2.18 m/s, and 0.5-12% grade. Comparisons between predictive methods were made for all walking trials, as well as among normal weight participants during level and gradient walking, and overweight and obese participants during level and gradient walking. We computed the mean prediction difference (MPD) as the difference between predicted vs. measured rates of oxygen consumption (ml/kg/min) for each trial, and examined the relationship between the MPD and measured oxygen consumption (ml/kg/min) using modified Bland-Altman plots. Linear regression was used to determine the intercept (fixed bias) and slope (proportional bias) for each equation. The absolute value of the mean prediction difference, and Root Mean Square Error (RMSE) values were also calculated for each equation and population. RESULTS: For level walking, all prediction equations had mean prediction differences that were statistically different from zero (P ≤ 0.05) except for the Browning et al., equation when applied to normal weight individuals and the Pandolf equation when applied to overweight and obese individuals. Most importantly, all prediction equations had significant (P ≤ 0.05) fixed and proportional bias, and demonstrated large RMSE (7.8-23.5% of mean measured metabolic rate) that were similar across equations and population. In addition, prediction error increased as measured metabolic rate increased for all equations. CONCLUSION: The metabolic prediction equations evaluated here each had considerable error when compared to measured values, regardless of the population in which the equation was created and/or validated. Improvements in prediction equations may require using approaches that aim to minimize RMSE and/or developing population/intensity specific equations.
Open Access
Acute ascorbic acid administration improves exercise hyperemia during rhythmic but not single contractions in aging humans
(Colorado State University. Libraries, 2009) Simpson, Carrie Beth, author; Dinenno, Frank A., advisor; Earley, Scott, committee member; Bell, Christopher, committee member
Age-related increases in oxidative stress are known to impair endothelium dependent vasodilation in older healthy humans. As a result, many researchers have speculated that endothelial dysfunction contributes to impaired muscle blood flow and vascular control during exercise. Further, elevations in oxidative stress and subsequent endothelial dysfunction could possibly explain our recent observations of impaired contraction-induced rapid vasodilation in older adults. Therefore, we directly tested the hypothesis that acute ascorbic acid administration would augment (1) rapid vasodilation in response to single muscle contractions as well as (2) the hyperemic response to sustained rhythmic contractions in older healthy humans, and that this would be due to improved endothelium-dependent vasodilation. In 14 young (22±1 yrs) and 14 healthy older men and women (65±2 yrs), we measured forearm blood flow (FBF; Doppler ultrasound) and calculated vascular conductance (FVC) responses to single, 1 second dynamic contractions at 10, 20, and 40% maximum voluntary contraction (MVC) before and after intra-arterial administration of ascorbic acid (AA). We also measured these variables during rhythmic handgrip exercise at 10% maximum voluntary contraction. After 5 minutes of steady-state exercise with saline, ascorbic acid (AA) was infused via brachial artery catheter for 10 minutes during continued exercise. For single contractions, prior to AA peak vasodilator responses to all contraction intensities were impaired ~35-50% in older adults (P<0.05), as were the immediate (1st cardiac cycle post contraction) vasodilator responses at 20 and 40% MVC (~50%; P<0.05). In contrast to our hypothesis, AA did not influence contraction-induced rapid vasodilation in either group (all NS). Regarding rhythmic handgrip exercise, FBF (~28%) and FVC (~31%) were lower in older vs young adults (P=0.06 and P<0.05) prior to AA. In young adults, AA administration did not significantly influence FBF and FVC, whereas FBF and FVC increased 30±4% in older adults at end exercise (P<0.05). AA did not influence vasodilator responses to sodium nitroprusside in either group, but significantly improved vasodilation to acetylcholine in older adults only (P<0.05). We conclude that endothelial dysfunction is not the primary mechanism underlying impaired contraction-induced rapid vasodilation with human aging; however acute AA administration increases muscle blood flow during dynamic exercise in older adults, which is likely due to an improvement in endothelium dependent vasodilation.
Open Access
Acute beet juice ingestion improves estimates of insulin sensitivity in obese adults
(Colorado State University. Libraries, 2014) Beals, Joseph William, author; Bell, Christopher, advisor; Hickey, Matthew, committee member; Gentile, Christopher, committee member
Poor glucose regulation is strongly associated with low nitric oxide (NO) bioavailability; a characteristic that may be improved with stimulation of NO generating pathways. For example, endothelial nitric oxide synthase null mice demonstrate improved glucose metabolism following sodium nitrate ingestion. Dietary nitrates are sequentially reduced in the oral and gastric cavities to NO, a process that is attenuated by rinsing with an antibacterial mouthwash. We hypothesized that acute dietary nitrate consumption will improve glucose tolerance. 9 sedentary, healthy, obese adults (2 male; body mass index: 33.7 ± 4.0 kg/m2: age: 45±7 years; mean ± SE) were studied. Using a randomized crossover design, four oral glucose tolerance tests were performed (equal carbohydrate load). To assess the influence of dietary nitrate, subjects consumed either 500mL of beet juice + 25g glucose, or 500mL of water + 75g glucose, with and without prior antibacterial mouthwash use. Beet juice was selected because it is rich in nitrate. Venous blood samples were collected for the determination of glucose and insulin concentrations. Neither the circulating glucose nor insulin responses were influenced by beet juice and/or mouthwash (P>0.05). However, the Matsuda Index, an estimate of insulin sensitivity, was greater for beet juice compared with beet juice preceded by mouthwash (104.6 ± 11.7 vs. 83.5 ± 11.1; P<0.05). These preliminary data suggest that acute dietary nitrate ingestion may promote insulin sensitivity in obese adults.
Open Access
Adjusting attitudes about altitude: novel approaches to promote human performance in high-altitude
(Colorado State University. Libraries, 2014) Scalzo, Rebecca Lynn, author; Bell, Christopher, advisor; Hamilton, Karyn L., advisor; Miller, Benjamin F., committee member; Kanatous, Shane B., committee member
Military personnel frequently operate in environmental extremes, such as high-altitude, without adequate time for acclimatization. Altitude mediated decrements in human physiological function jeopardize mission success and personal safety. The following dissertation describes three experiments directed at the identification of non-traditional, military specific approaches to promote human functional performance in high-altitude. The specific aims of the following experiments were: 1) to compare the difference in time trial performance in normoxia and hypoxia following oral administration of a placebo, a non-specific phosphodiesterase inhibitor/adenosine receptor antagonist (Aminophylline), a carbonic anhydrase inhibitor (Neptazane), or the combination of Aminophylline and Neptazane; 2) to assess endurance exercise performance in hypoxia following an intravenous infusion of glucose with and without prior sympathetic nervous system inhibition (clonidine); and 3) to determine endurance exercise performance in hypoxia following a high-carbohydrate meal with and without prior/concurrent administration of an oral insulin sensitizer (metformin) and to compare hypoxic endurance exercise performance with endurance exercise performance in normoxia following the same meal. When compared with normoxia, hypoxia attenuated endurance exercise performance in these experiments. In experiment 1, we found that concomitant administration of Aminophylline and Neptazane attenuated the hypoxia-mediated deficit in endurance exercise performance compared with placebo. Neither Aminophylline nor Neptazane alone ameliorated this decrement. In experiment 2, prior clonidine administration attenuated the cardiovascular response to hypoxia assessed by heart rate and blood pressure responses at rest but did not deleteriously impact endurance exercise performance in hypoxia. Finally, the preliminary data from experiment 3 suggest metformin improved the metabolic response to a high-carbohydrate meal in hypoxia, and potentially augmented skeletal muscle glycogen synthesis. Endurance exercise performance was unaffected in hypoxia following metformin administration. Collectively, the data from these experiments suggest these pharmacological treatments, compatible with military specific demands, effectively promote human physiological function in high-altitude.
Open Access
Anthropometric indicators of obesity and their link to lifestyle and cardiovascular risk in Colorado firefighters
(Colorado State University. Libraries, 2011) O'Toole, Lorin, author; Nelson, Tracy, advisor; Lipsey, Tiffany, committee member; Peel, Jennifer, committee member
Cardiovascular disease (CVD) is the leading cause of death in firefighters as it is in the general population. Despite data promoting Colorado as the leanest state in the nation and the image of firefighters as healthy and physically fit, obesity is evident in Colorado firefighters and continues to be an important CVD risk factor. PURPOSE: To determine obesity prevalence, depending on measurement and classification, and its association with lifestyle factors and cardiovascular (CV) risk in a cohort of Colorado firefighters. METHODS: Analysis was conducted on data from 466 Colorado firefighters (41 females; 425 males). Using standard classification cut-points, prevalence of obesity was determined using body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR), sagittal abdominal diameter (SAD), and percent body fat (%BF) from skin fold (SF) and hydrodensitometry (H) measurements. Lifestyle factors used in the analysis included diet, physical activity, sleep, tension and depression. Lipids, C-reactive protein (CRP) levels, predicted maximal oxygen consumption and fitness measures were also included. CV risk was assessed using the Cooper Risk Profile. Correlation statistics were run for each anthropometric measure with the above variables. RESULTS: Obesity prevalence varied by measurement: BMI=9.8% females, 19.1% males; WC=19.5% females, 18.9% males; WHR=19.5% females, 8.0% males; SAD=31.6% females, 43.5% males; %BF(SF)=17.1% females (7.3% for >35%BF), 15.1% males; %BF(H)=23.7% females (13.2% for >35%BF), 28.6% males. In both sexes, all anthropometric measures were positively correlated with triglycerides and CRP and inversely associated with high-density lipoprotein cholesterol (except BMI in females), the sit and reach test and estimated maximal oxygen consumption (except BMI in females) (p≤0.05). All anthropometric measures were significantly correlated with CV risk (p≤0.05) except WHR in females. The strongest link to CV risk was %BF(SF) in females and WHR in males. CONCLUSIONS: The prevalence of obesity in Colorado firefighters varies depending on the measure used. There are significant associations between obesity and lifestyle factors that should be further explored. Percent BF(SF) and WHR may be appropriate in assessing CV risk in populations of female and male firefighters, respectively, of similar demographics.
Embargo
Association between youth involvement in home/community gardening and health behaviors
(Colorado State University. Libraries, 2024) Perrault, Ashley, author; Li, Kaigang, advisor; Butki, Brian, committee member; Braungart-Rieker, Julia, committee member
American youth are developing risk factors for historically "adult diseases" at increasingly high rates. These risk factors, such as obesity, elevated blood lipid, blood pressure and insulin resistance, put children at a high risk for developing chronic disease early in life, including before reaching adulthood. School gardening programs are effective at improving dietary intake, physical activity levels and BMI of youth. Despite the success of such programs, there is a need for interventions that effectively target child behaviors while at home. Family-based home and/or community gardens may promote child health behaviors similar to those that occur in school-based gardening programs. A home and/or community garden has the added benefit of parental involvement, which has been shown to be essential for effective child health interventions. The current study examined the relationship between youth involvement in a home and/or community garden and various health behaviors. A convenience sample of 124 adults participated in a cross-sectional survey from June – October 2023. Participants answered questions about family and child involvement in a home/community garden, child health behaviors and parent health behaviors. Health behaviors assessed were physical activity minutes, sedentary behavior, frequency of fruit and vegetable intake and mental health symptoms. Independent sample t-tests indicated that gardening youth had lower sedentary time (t(112) = -1.95, p = 0.03), as well as higher frequency of fruit (t(110) = 2.14, p = 0.02) and vegetable intake (t(109) = 2.67, p = 0.004). Parent fruit intake had a positive linear association with child fruit intake (β = 0.51, p = <0.001), as did parent gardening belief (β = 4.04, p = 0.01). Mediation analysis indicated a positive association between path a (gardening status and parent fruit intake: β=3.06, 95% CI: 0.08, 6.03, p = 0.04) and path b (parent fruit intake and child fruit intake: β = 0.48, 95% CI: 0.30, 0.65, p = <0.001). Gardening status was no longer associated with child fruit intake after the inclusion of parent intake (c': β = 1.64, 95% CI: -1.06, 4.35, p = 0.23), suggesting that parental fruit intake fully mediated the relationship between gardening status and child fruit intake. Gardening status had a positive linear association with child vegetable intake (β = 3.4, p = 0.02), as did parent vegetable intake (β = 0.21, p = 0.004). These findings indicate that youth involvement in a family-based home and/or community garden may be associated with positive health outcomes, especially regarding dietary intake. Parental influence was also associated with positive youth health outcomes. Our findings suggest that home and/or community gardens may provide an effective technique for child health interventions.
Open Access
Associations between common variants in FTO and near MC4R genes on BMI, waist circumference, and type 2 diabetes prevalence among Hispanic and non-Hispanic White individuals: the San Luis Valley Diabetes Study
(Colorado State University. Libraries, 2011) Sayer, Richard Drew, author; Nelson, Tracy L., advisor; Hickey, Matthew S., committee member; Peel, Jennifer L., committee member; Hokanson, John, committee member
Introduction: The prevalence of obesity and type 2 diabetes (T2D) has risen sharply in the United States over the previous 40 years. Heritability estimates for obesity are generally high, and suggest that people may have genotypes that predisposes them to obesity when confronted with an obesogenic environment. Genetic variants in FTO and near MC4R genes have consistently been shown to be associated with risk of obesity. Methods: Utilizing data from the third examination of the San Luis Valley Diabetes Study (1997-1998, n = 837), we determined the minor allele frequency (MAF) and genotype distribution of single nucleotide polymorphisms (SNP)s rs8050136 and rs17782313 in a cohort of Hispanic and non-Hispanic white individuals. The associations between SNPs rs8050136 and rs17782313 and body mass index (BMI), waist circumference (WC), total energy intake, and T2D prevalence rates were determined. Results: MAFs and genotype distributions varied between Hispanics and non-Hispanic whites for both SNPs. Hispanics were less likely to be carriers of high-risk A allele at rs8050136 (MAF: 25% vs. 38.3%) and the high-risk T allele at rs17782313 (17% vs. 23.3%) than non-Hispanic whites. After controlling for age, there was a significant association between the rs8050136 SNP in FTO and BMI in all Hispanics (p = 0.0018) and Hispanic men (p = 0.0007), but the association was not significant in Hispanic women (p = 0.14). Among all Hispanics, homozygous carriers of the FTO high-risk A allele had an average BMI of 31.1 kg/m2 (95% CI: 29.0-33.1) compared to an average BMI of 27.1 kg/m2 (95% CI: 26.4-27.8) in homozygous carriers of the C allele. In Hispanic men, homozygous carriers of the high-risk A allele had an average BMI of 31,4 kg/m2 (95% CI: 28.5-34.3) compared to 25.9 kg/m2 (95% CI: 25.0-26.9) in homozygous carriers of the C allele. After controlling for age, there was also a significant association between the rs8050136 SNP and WC in Hispanic men (p = 0.0048), but not Hispanic women (p = 0.24). Hispanic male homozygous carriers of the A allele had an average WC of 104.2 cm (95% CI: 97.7-110.7) compared to an average WC of 94.1 cm (92.0-96.2) in homozygous carriers of the C allele. A high dietary fat intake was shown to modify the association between the FTO variant and BMI. No other significant associations were found between genetic variants in FTO or near MC4R on BMI, WC, total energy intake, or T2D prevalence. Discussion: Hispanics are less likely to be carriers of high-risk alleles in FTO (rs8050136) and near MC4R (rs17782313) than non-Hispanic whites. Our analysis demonstrates that the FTO variant is associated with BMI and WC in Hispanics and also that this relationship between the FTO variant and BMI is modified by dietary fat intake.
Open Access
Associations between gait coordination, variability and motor cortex inhibition in young and older adults
(Colorado State University. Libraries, 2018) Swanson, Clayton W., author; Fling, Brett W., advisor; Lodha, Neha, committee member; Burzynska, Agnieszka, committee member
Interlimb coordination and mobility (postural sway and turning) diminish with age, posing a risk for gait-related injuries. Further, levels of inhibition within the motor cortex are significantly associated with coordination of the upper extremities in healthy aging, however, it is unknown if this same association exists for lower extremity control. To investigate the relationship between gait coordination and cortical inhibition we measured gait coordination via the phase coordination index and motor cortex inhibition via the cortical silent period in 14 young and 15 older adults. Gait coordination was reduced in older adults across a variety of walking conditions, as was cortical inhibition, solely in the non-dominant motor cortex. Furthermore, young adults were better able to maintain lower extremity coordination and variability with reduced cortical inhibition, whereas older adults with increased cortical inhibition demonstrated better walking performance. These findings suggest a fundamental shift in the relationship between motor cortex inhibition and lower extremity control with age, similar to previous work demonstrating an age-related difference in the association between motor cortex inhibition with bimanual control.
Open Access
Associations between neuroanatomy and neurophysiology with turning performance in people with multiple sclerosis
(Colorado State University. Libraries, 2021) Swanson, Clayton Winford, author; Fling, Brett W., advisor; Leach, Heather J., committee member; Stephens, Jaclyn A., committee member; Mancini, Martina, committee member; Miravalle, Augusto A., committee member
Neurodegenerative diseases such as multiple sclerosis (MS) are associated with decreased mobility and a variety of changes affecting neural structure and function. Due to the cortical influence on various aspects of mobility, it is likely that these neural adaptations negatively affect mobility, and therefore, increase the potential for falls. Additionally, the progression of MS has been associated with cortical grey matter atrophy, and adaptions to neurophysiological activity. While previous research has demonstrated associations between levels of inhibition and a variety of turning characteristics in neurotypical young and older adults, it remains unclear if associations exist between cortical structure and function for dynamic lower limb control for daily tasks such as turning. Therefore, purpose of this project was to understand how sensorimotor cortical thickness and corticospinal excitation and inhibition contribute to turning performance in both people with MS (PwMS) and age-matched neurotypical control (HC) participants. Participants were asked to conduct a series of 360˚ in-place turns at two self-selected speeds and 180˚ turns during a self-selected pace two-minute walk test. Quantification of turning was assessed using wireless inertial sensors placed on each foot, around the waist, on the sternum, and on the forehead. Grey matter (GM) thickness of the sensorimotor cortex (i.e., pre-, para-, and postcentral gyri) was measured via magnetic resonance imaging (MRI) and processed using FreeSurfer 6.0.0 (http://surfer.nmr.mgh.harvard.edu/, Harvard University, Boston, MA, USA). To measure corticospinal excitation and inhibition single-pulse transcranial magnetic stimulation (TMS) was performed. The leg region of both motor cortices was identified by acquiring the resting motor threshold (RMT) of the tibialis anterior. To assess neurophysiology, participants sustained an isometric contraction in dorsiflexion at 15% of their maximal voluntary contraction for three-minutes. Simultaneously, a TMS stimulation was delivered at 120% of RMT every 7-10 seconds. This procedure was conducted for both cortical hemispheres. A total of forty-nine individuals (23 HC, 26 MS) participated in the study. PwMS demonstrated reduced turning performance for a variety of 360˚ turning variables, although only one variable was significant between groups for the 180˚ turns. GM thickness revealed significant cortical thinning of the pre- and paracentral gyri in the MS group, while the postcentral gyrus did not demonstrate between group differences. For TMS measures, PwMS demonstrated reductions in excitation and inhibitory capacity compared to neurotypical controls. All significant correlations were primarily observed in the MS group and demonstrated lateralization, such that they were limited to the left hemisphere. The current results showed that both cortical thickness and inhibitory activity were associated with turning performance in PwMS, but not in the HC group. The associations between inhibitory activity and turning performance were stronger than the associations between cortical thickness and turning performance. These results may indicate that inhibitory activity is more associated with dynamic lower limb movements compared to GM thickness. Furthermore, these results suggest that PwMS may rely on different neural resources to perform dynamic movements typically associated with fall risk.
Open Access
Associations between white matter microstructure of cerebellar connections and balance performance in people with multiple sclerosis
(Colorado State University. Libraries, 2020) Odom, Arianna D., author; Fling, Brett W., advisor; Mañago, Mark, committee member; Schmid, Arlene, committee member
Sensory reweighting, the ability to change the relative contribution of visual, vestibular and proprioceptive systems to balance in response to a changing environment, is critical to balance maintenance. The cerebellum contributes to sensory re-weighting through its white matter connections to the brainstem, the cerebellar peduncles. People with multiple sclerosis (PwMS) have impairments in both sensory reweighting and white matter microstructure of the cerebellar peduncles. The purpose of this study was to examine associations between the white matter microstructure of the cerebellar peduncles and balance performance during sensory-manipulated conditions to elucidate the extent of cerebellar-regulated balance in PwMS. We assessed cerebellar peduncle white matter microstructure with radial diffusivity and fractional anisotropy and standing balance performance with center of pressure-derived measures of path length, sway velocity and root mean square of sway during each sensory-manipulated condition of the Clinical Test of Sensory Integration on Balance in 24 PwMS and 21 neurotypical participants (HC). PwMS exhibited worse balance performance across all sensory-manipulated conditions and worse cerebellar peduncle white matter microstructure compared to HC. Notably, PwMS displayed differentially worse vestibular-based balance performance than HC which was associated with worse cerebellar peduncle white matter microstructure. In addition, PwMS demonstrated unique associations between cerebellar peduncle white matter microstructure and visual-based and proprioceptive-based balance performance that were not found in HC. Our findings suggest that PwMS may place a greater reliance on cerebellar-regulated proprioceptive- and visual-based balance control and demonstrate worse vestibular-based balance than HC, augmenting previous work indicating abnormal vestibular-based balance and a contribution of the ICP to proprioceptive-based balance performance in PwMS.
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
Bone density in competitive cyclists: a longitudinal assessment across the cycling season
(Colorado State University. Libraries, 2015) Baker, Breanne S., author; Reiser, Raoul F., II, advisor; Browning, Raymond, committee member; Puttlitz, Christian, committee member
The purpose of this study was to investigate in a relatively large group of competitive cyclists how sex, competition level and type of racing influenced bone mineral density (BMD) and bone mineral content (BMC) at the beginning of the season and changes that occurred during the season. In total, 42 participants (22 males and 20 females) completed the study. Subjects were stratified by sex, USA Cycling Category and racing type. At the beginning of the season in February, participants were asked to complete a health history questionnaire, four day dietary log and a DXA scan. After a mean of 180 days participants completed another visit. At the beginning of the season significant differences were found between the groups. Pre-season sex differences were seen for height, Body Mass, Body Fat %, Lean Mass %, Lower Body (LB) BMCg, Upper Body (UB) BMCg, Shank BMD and estimated number of pre-season training (p≤0.015). Differences between Cat. 1 and Cat. 4 riders were observed for age and UB BMCg (p≤0.019). The number of years’ experience cycling and racing and the estimated number of races were significant pre-season difference between type of racing (p=0.019). BMD T Score was not significantly different between sexes, Cat. or type of racing and did not significantly increase over the season (p≥0.053). Further analysis shows a wide variety of positive and negative correlates of skeletal health that deserve further investigation such as age, body composition measures, diet and time spent cycling. This study suggests that cycling is not detrimental to BMD over a competitive season.
Open Access
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.
Open Access
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
Cannabis use in people with Multiple Sclerosis: the highway to lower disability?
(Colorado State University. Libraries, 2017) Kindred, John Harvey, author; Rudroff, Thorsten, advisor; Kalliokoski, Kari K., committee member; Kraft, Susan L., committee member; Tracy, Brian L., committee member
The following dissertation describes a series of investigations designed to identify possible effects of cannabis use in people with Multiple Sclerosis. The specific aims of the three projects were: 1) to determine the proportion of people with Parkinson's Disease and Multiple Sclerosis currently using cannabis and collect self-reported measures of disability, to include physical function, balance, and fatigue; 2) to determine if people with Multiple Sclerosis using cannabis perform better on functional tasks compared to individuals who are not using cannabis; 3) to determine if resting brain glucose uptake is altered in people with Multiple Sclerosis using cannabis compared to people not using cannabis. In Project 1 we found that a large portion of people with Parkinson's disease and Multiple Sclerosis responding to our survey are currently using cannabis. These individuals are also reporting lower levels of neurological disability, especially within the realms of mood, memory, and fatigue. A large majority of participants also reported reducing the amount of prescription medications since starting cannabis use. In project 2 we compared objective and subjective measurements of neurological disability between current cannabis users and data taken from a previous investigation investigating predictors/correlates of physical activity in people with Multiple Sclerosis. When we compared the users versus the non-users we found that users reported higher levels of fatigue as assessed by the fatigue severity scale questionnaire. We also found that people with Multiple Sclerosis using cannabis performed worse on the Paced Auditory Serial Addition Test, which is a measure of cognitive function. Project 3 utilized Positron Emission Tomography to measure brain glucose uptake with the glucose analog tracer [18F]-Fluorodeoxyglucose. Higher levels of glucose uptake were beneficially correlated with disability status, fatigue, and pain in our sample. These findings agree with previous studies and indicated that brain glucose uptake can be used as a biomarker in people with multiple sclerosis. When our sample was dichotomized into current cannabis users and non-users measures of disability were similar, except that cannabis users performed more poorly during cognitive function testing. Even though most measures of disability were similar between the groups, cannabis users were found to have greater glucose uptake throughout areas of the frontal and temporal lobes. This suggests that cannabis may provide beneficial effects in maintaining nervous system glucose uptake but may also be accompanied by negative effects on cognition in people with multiple sclerosis.