Clinical and Neurobehavioral Changes With Weight Loss Drug Discontinuation and Reinitiation

Change From On-Treatment to Discontinuation and Re-Initiation in Food Cue-Evoked BOLD Response in Reward and Salience Brain Regions

Time frame · Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation

This outcome measures within-participant change in blood-oxygen-level-dependent (BOLD) signal during a food cue reactivity task, assessed using functional magnetic resonance imaging (fMRI). BOLD response will be quantified as the mean percent signal change in predefined reward- and salience-related regions of interest (including the ventral striatum and insula) during food image presentation relative to non-food control images. Higher BOLD values indicate greater neural responsivity to food cues.

Change From Baseline in Resting-State Functional Connectivity Within Salience and Executive Control Networks

Time frame · Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation

This outcome measures within-participant change in resting-state functional connectivity, assessed using fMRI. Connectivity strength will be calculated using correlation coefficients between predefined brain regions within salience and executive control networks. Higher values indicate stronger functional connectivity.

Change From Baseline in Brain Glutamate Levels

Time frame · Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation

This outcome measures within-participant change in neurochemical and dopaminergic markers associated with reward processing. Glutamate levels will be measured in the medial prefrontal cortex using magnetic resonance spectroscopy (MRS). Higher values indicate greater metabolite concentration or signal intensity.

Change From Baseline in State Food Craving Severity

Time frame · Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation

This outcome measure assesses within-participant change in momentary food craving severity. Food cravings will be measured using the Food Cravings Questionnaire-State (FCQ-S), a self-report instrument assessing current craving intensity. Scores range from 15 to 75, with higher scores indicating greater food craving severity.

Change From Baseline in Blood-Brain Permeability Levels

Time frame · Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation

This outcome measures within-participant change in neurovascular properties of the blood-brain barrier. Blood-brain barrier permeability to water will be measured using phase-contrast arterial spin tagging (WEPCAST). Higher values indicate greater blood-brain barrier permeability.

Change From Baseline in Trait Food Craving Severity.

Time frame · Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation

This outcome measure assesses within-participant change in habitual food craving frequency and intensity. Trait-level food cravings will be assessed using the Food Cravings Questionnaire-Trait, a self-report questionnaire. Scores range from 21 to 126, with higher scores indicating more frequent and intense food cravings.

Change From Baseline in Addictive-Like Eating Symptoms.

Time frame · Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation

This outcome measure assesses within-participant change in addictive-like eating behaviors. Addictive-like eating symptoms will be assessed using the Yale Food Addiction Scale 2.0, a self-report measure of addictive-like eating based on diagnostic criteria. Symptom counts range from 0 to 11, with higher scores indicating greater severity of addictive-like eating behavior.

Change From Baseline in Intrusive Food-Related Thoughts.

Time frame · Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation

This outcome measure assesses within-participant change in the frequency of intrusive food-related thoughts. Intrusive food-related cognitions will be assessed using the Food Noise Questionnaire, a self-report measure consisting of five items assessing persistent and intrusive thoughts about food. Total scores range from 0 to 20, with higher scores indicating greater food noise and more frequent intrusive food-related thoughts.

Change From Baseline in Dietary Pattern Quality.

Time frame · Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation

This outcome measure assesses within-participant change in dietary behaviors and overall eating patterns. Dietary patterns will be assessed using the Rapid Eating Assessment for Participants - Shortened Version, a self-report questionnaire evaluating habitual dietary behaviors. Total scores range from 13 to 39, with higher scores indicating healthier dietary patterns.

Change From Baseline in Perceived Loss of Control Over Eating.

Time frame · Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation

This outcome measure assesses within-participant change in perceived loss of control over eating behavior. Perceived loss of control will be assessed using the Loss of Control Over Eating Scale-Short Form, a self-report questionnaire assessing the subjective experience of being unable to control eating. Total scores range from 7 to 35, with higher scores indicating greater perceived loss of control over eating.

Change From Baseline in Psychological Responsiveness to Food Availability.

Time frame · Baseline (on tirzepatide), 3-4 weeks of discontinuation, and 6-8 weeks of re-initiation

This outcome measure assesses within-participant change in psychological responsiveness to the food environment. Responsiveness to food availability will be assessed using the Power of Food Scale, a self-report questionnaire measuring the psychological impact of food availability independent of actual consumption. Scores are calculated as a mean item score ranging from 1 to 5, with higher scores indicating greater psychological impact of food availability.