The Impact of the Physiological Response to Sugar on Brain Activity and Behavior

Study Overview
=================
Brief Summary
-----------------
The goal of this pilot study is to test the feasibility of assessing how biological factors and chemical properties of sugars may influence metabolism and food reward in humans. The main questions it aims to answer are: Can differences in appetitive responses and neural activations to sucrose (table sugar) and its chemical components (glucose and fructose) be measured and quantified? Are there detectable differences in how combinations of sugars and non-nutritive sweeteners commonly found in our food supply influence appetitive responses and neural activation? This study is a crossover design, meaning every participant will complete every condition. Participants will consume beverages containing sucrose, glucose, or fructose, which are each novelly flavored, 6 times within a week. During one of the consumption times, energy expenditure, carbohydrate oxidation, and blood glucose will be measured in the lab before and for 2 hours after consumption. After participants have consumed each condition, they will undergo a tasting task in the MRI scanner, neural responses to receipt of the beverages are measured. Another group of participants will undergo the same study design but with sucrose, high fructose corn syrup, or sucrose + non-nutritive sweetener as the conditions.

Detailed Description
-----------------
Prior studies in humans indicate that while energy expenditure response is similar after consumption of equal amounts of fructose, glucose, and sucrose (a dimer of glucose + fructose), carbohydrate oxidation and blood glucose responses differ. Elevated carbohydrate oxidation responses appear to be driven by the presence of fructose, and elevated blood glucose responses appear to be driven by the presence of glucose. Prior work also suggests that post-ingestive signals of glucose availability, measure specifically as blood glucose levels, intestinal glucose transporter activity, and carbohydrate oxidation rate, are all associated with elevated brain response to calorie-predictive flavor cues and reward learning of these flavor cues. However, in animal models, glucose has been shown to repeatedly and reliably condition these calorie-predictive learning responses, but fructose does not. Human work has indicated that oxidation of glucose is critical for these responses. Thus, it is unclear what roles fructose and glucose each play in conditioning reward responses and flavor-calorie learning. We hypothesize that fructose plays a synergistic role in enhancing flavor-calorie learning without itself conditioning the reward response.

Official Title
-----------------
The Impact of the Physiological Response to Sugar on Brain Activity and Behavior

Conditions
-----------------
Food Preferences, Appetitive Behavior

Intervention / Treatment
-----------------
* Other: Conditioned Stimulus: Sucrose (aim 1)
* Other: Conditioned Stimulus: Glucose (aim 1)
* Other: Conditioned Stimulus: Fructose (aim 1)
* Other: Conditioned Stimulus: Sucrose (aim 2)
* Other: Conditioned Stimulus: High Fructose Corn Syrup (aim 2)
* Other: Conditioned Stimulus: Sucrose + Non-nutritive Sweetener (aim 2)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: BMI between 18.5-25 kg/m2 Not pregnant or planning to become pregnant during study participation Residing in the Roanoke area and/or willing/able to attend sessions at the Fralin Biomedical Research Institute (FBRI) at Virginia Tech Carilion Weigh at least 110 lbs Exclusion Criteria: Current inhaled nicotine use History of alcohol dependence. Current or past diagnosis of cardiometabolic disease or problems, including diabetes, endocrine, heart, or thyroid problems, that may influence study outcomes Hemoglobin A1C >5.7% Taking medications known to influence study measures (including attention-deficit/hyperactivity disorder (ADHD), allergy, antidepressant, antipsychotic, anxiolytic, birth control, blood pressure, blood glucose, cholesterol, thyroid, sleep, or weight loss medications) Active medical or neurologic disorder, including cardiometabolic conditions or gastrointestinal conditions that may influence study outcomes Recent change in body weight (gain or loss of > 5 lbs within the past 3 months) Current shift work (typical pattern of work/activity overnight) Previous weight loss surgery Adherence to a special diet within the past 3 months (e.g., low-carb or ketogenic diet, exclusion of food groups/specific macronutrients, intermittent fasting, etc.) Allergy to any food or ingredient included in the study diets, meals, or beverages Currently pregnant or planning to become pregnant during study participation Claustrophobia Contraindications for MRI, including pacemaker, aneurysm clips, neurostimulators, cochlear or other implants, metal in eyes, regular work with steel, etc. (Note: This is an fMRI-specific exclusion criterion. Participants may be allowed to participate in all other study sessions and measures that do not involve fMRI.) Contraindications for bioelectrical impedance analysis, specifically implanted devices Use of substances (or combinations of substances) in doses and frequencies that could influence neural outcomes of study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Conditioned Stimulus: Sucrose (aim 1)<br>Participants will undergo exposure sessions with flavored beverage solutions containing sucrose. | Other: Conditioned Stimulus: Sucrose (aim 1)<br>* Participants will consume flavored beverage solutions containing 110 calories of sucrose in 6 exposure sessions within 1 week. One exposure session will include pre- and post-consumption blood draws and indirect calorimetry measurements inside a metabolic chamber over a 2-hour period. The other 5 exposure sessions will occur at specified times outside the laboratory sessions. Subjective ratings of internal state (i.e., hunger, fullness, and thirst) will be collected throughout each exposure. Subjective ratings of liking and wanting of each beverage will also be assessed.<br>* Other names: Flavored beverage solution with 110 calories of sucrose;|
| Experimental: Conditioned Stimulus: Glucose (aim 1)<br>Participants will undergo exposure sessions with flavored beverage solutions containing glucose. | Other: Conditioned Stimulus: Glucose (aim 1)<br>* Participants will consume flavored beverage solutions containing 110 calories of glucose in 6 exposure sessions within 1 week. One exposure session will include pre- and post-consumption blood draws and indirect calorimetry measurements inside a metabolic chamber over a 2-hour period. The other 5 exposure sessions will occur at specified times outside the laboratory sessions. Subjective ratings of internal state (i.e., hunger, fullness, and thirst) will be collected throughout each exposure. Subjective ratings of liking and wanting of each beverage will also be assessed.<br>* Other names: Flavored beverage solution with 110 calories of glucose;|
| Experimental: Conditioned Stimulus: Fructose (aim 1)<br>Participants will undergo exposure sessions with flavored beverage solutions containing fructose. | Other: Conditioned Stimulus: Fructose (aim 1)<br>* Participants will consume flavored beverage solutions containing 110 calories of fructose in 6 exposure sessions within 1 week. One exposure session will include pre- and post-consumption blood draws and indirect calorimetry measurements inside a metabolic chamber over a 2-hour period. The other 5 exposure sessions will occur at specified times outside the laboratory sessions. Subjective ratings of internal state (i.e., hunger, fullness, and thirst) will be collected throughout each exposure. Subjective ratings of liking and wanting of each beverage will also be assessed.<br>* Other names: Flavored beverage solution with 110 calories of fructose;|
| Experimental: Conditioned Stimulus: Sucrose (aim 2)<br>Participants will undergo exposure sessions with flavored beverage solutions containing sucrose. | Other: Conditioned Stimulus: Sucrose (aim 2)<br>* Participants will consume flavored beverage solutions containing 110 calories of sucrose in 6 exposure sessions within 1 week. One exposure session will include pre- and post-consumption blood draws and indirect calorimetry measurements inside a metabolic chamber over a 2-hour period. The other 5 exposure sessions will occur at specified times outside the laboratory sessions. Subjective ratings of internal state (i.e., hunger, fullness, and thirst) will be collected throughout each exposure. Subjective ratings of liking and wanting of each beverage will also be assessed.<br>* Other names: Flavored beverage solution with 110 calories of sucrose;|
| Experimental: Conditioned Stimulus: High Fructose Corn Syrup (aim 2)<br>Participants will undergo exposure sessions with flavored beverage solutions containing high fructose corn syrup. | Other: Conditioned Stimulus: High Fructose Corn Syrup (aim 2)<br>* Participants will consume flavored beverage solutions containing 110 calories of high fructose corn syrup in 6 exposure sessions within 1 week. One exposure session will include pre- and post-consumption blood draws and indirect calorimetry measurements inside a metabolic chamber over a 2-hour period. The other 5 exposure sessions will occur at specified times outside the laboratory sessions. Subjective ratings of internal state (i.e., hunger, fullness, and thirst) will be collected throughout each exposure. Subjective ratings of liking and wanting of each beverage will also be assessed.<br>* Other names: Flavored beverage solution with 110 calories of high fructose corn syrup;|
| Experimental: Conditioned Stimulus: Sucrose + Non-nutritive Sweetener (aim 2)<br>Participants will undergo exposure sessions with flavored beverage solutions containing sucrose and a non-nutritive sweetener. | Other: Conditioned Stimulus: Sucrose + Non-nutritive Sweetener (aim 2)<br>* Participants will consume flavored beverage solutions containing a non-nutritive sweetener and 110 calories of sucrose in 6 exposure sessions within 1 week. One exposure session will include pre- and post-consumption blood draws and indirect calorimetry measurements inside a metabolic chamber over a 2-hour period. The other 5 exposure sessions will occur at specified times outside the laboratory sessions. Subjective ratings of internal state (i.e., hunger, fullness, and thirst) will be collected throughout each exposure. Subjective ratings of liking and wanting of each beverage will also be assessed.<br>* Other names: Flavored beverage solution with 110 calories of sucrose in addition to a non-nutritive sweetener;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in preference- liking | Subjective ratings of liking of flavors used in the intervention will be assessed at baseline and after the intervention. The generalized Labeled Magnitude Scale will be used. The scale is anchored by descriptors of Most Disliked Sensation Imaginable and Most Liked Sensation Imaginable at the lower and upper ends, respectively. The score is determined by the place on the scale participants select (range of scale is 0-100). An increase in score from baseline to post-intervention indicates an increase in liking. | Immediately after informed consent and in the post-test session approximately 5 weeks later | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-Test Measure of Preference- wanting | Subjective ratings of liking of flavors used in the intervention will be assessed at baseline and after the intervention. A Visual Analog Scale will be used. Participants select a place on the line that corresponds with their subjective rating, and the score is determined by the place selected (range of scores is 0-100). The line is anchored by polar opposite descriptors (Do not want at all and Want very much). An increase in score from baseline to post-intervention indicates and increase in wanting. | At the end of study; approximately 5 weeks after first session | 
| Post-Test Measure of Preference - wanting (ad libitum) | Ad libitum intake will be used as a measure of wanting in a post-test session. Participants will be provided each beverage used during the intervention and asked to drink as much or as little of them as they would like over a 30-minute period. | At the end of study; approximately 5 weeks after first session | 
| Post-Test Measure of Preference- wanting (forced choice) | Forced choice will be used as a measure of wanting in a post-test session. Participants will be provided each of the beverages used during the intervention and asked to choose 1 to take home with them. | At the end of study; approximately 5 weeks after first session | 
| Blood oxygen level-dependent (BOLD) response to beverages | In a post-test session, functional magnetic resonance imaging (fMRI) scans will be performed while beverages (without calories) used during the intervention are delivered through a custom manifold fitted to a head coil and connected to a pump system that allows precisely timed and measured delivery of liquids. | At the end of study; approximately 5 weeks after first session | 
| Blood glucose response to beverages | Blood glucose will be assessed at baseline and at set time points for 2 hours after consumption of intervention beverages in one exposure session. | Each week for 3 weeks during the study | 
| Energy expenditure in response to beverages | Indirect calorimetry will be used to determine energy expenditure at baseline and after consumption of intervention beverages in an exposure session. | Each week for 3 weeks during the study |