Clinical and Neurobehavioral Changes With Weight Loss Drug Discontinuation and Reinitiation

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

This outcome measure assesses within-participant change in uncontrolled eating behavior. Uncontrolled eating will be assessed using the Uncontrolled Eating subscale of the Three-Factor Eating Questionnaire, a self-report measure of tendencies toward loss of control over eating. Subscale scores range from 3 to 36, with higher scores indicating poorer regulation of eating behavior.

This outcome measure assesses within-participant change in mood disturbance. Mood will be assessed using the Profile of Mood States-Short Form, a validated self-report questionnaire assessing multiple mood domains including tension, depression, anger, vigor, fatigue, and confusion. Mood disturbance will be quantified using the Total Mood Disturbance score, which ranges from -24 to 124, with higher scores indicating greater overall mood disturbance (reflecting higher negative mood and lower vigor).

This outcome measure assesses within-participant change in perceived psychological stress. Perceived stress will be measured using the Perceived Stress Scale (PSS), a self-report questionnaire assessing the degree to which situations in one's life are appraised as stressful over the past month. Scores range from 0 to 40, with higher scores indicating greater perceived stress.

This outcome measure assesses within-participant change in quality of life. Quality of life will be assessed using the World Health Organization Quality of Life-BREF, a 26-item self-report questionnaire assessing perceived quality of life across physical health, psychological health, social relationships, and environmental domains. Total scores range from 26 to 130, with higher scores indicating better overall quality of life.

This outcome measure assesses within-participant change in withdrawal-related psychological and behavioral distress during tirzepatide discontinuation. Withdrawal symptoms will be assessed using a Withdrawal Symptom Checklist, a self-report questionnaire assessing appetite and physiological symptoms, eating behavior and perceived control, restrictive dieting and compensatory behaviors, mood and emotional distress, and general physical and functional impairment associated with medication withdrawal. Items are rated on a 5-point scale ranging from 0 (not at all/never) to 4 (very severe/very often) and summed to create a total score. Total scores range from 0 to 128, with higher scores indicating greater withdrawal-related psychological and behavioral distress.

The Pittsburgh Sleep Quality Index (PSQI) is a 19-item self-report questionnaire assessing subjective sleep quality over the past month. Global scores range from 0 to 21, with higher scores indicating poorer sleep quality.

This outcome measure assesses within-participant change in addiction-related problem severity across multiple functional domains. Addiction-related severity will be assessed using the Addiction Severity Index, a standardized semi-structured interview administered by trained study personnel. The Addiction Severity Index evaluates seven domains: medical status, employment/support status, alcohol use, drug use, legal status, family/social functioning, and psychological status, based on both past 30-day functioning and lifetime history. Domain-specific composite scores range from 0 to 1, with higher scores indicating greater addiction-related problem severity.

This outcome measure assesses within-participant change in substance use behavior. Substance use frequency and quantity will be measured using the Timeline Follow-Back (TLFB) method, which captures the number of days and amount of alcohol, nicotine, and cannabis use over the past 30 days. Higher values indicate more frequent or greater substance use.

This outcome measure assesses within-participant change in engagement in risky, impulsive, and self-destructive behaviors. Behaviors will be assessed using the Risky, Impulsive, and Self-Destructive Behavior Questionnaire, a 38-item self-report measure. Frequency responses are binned and summed to create a total score ranging from 0 to 152, with higher scores indicating greater engagement in risky, impulsive, and self-destructive behaviors.

This outcome measure tests inhibitory control and attentional filtering, relevant to recovery-related changes in top-down regulation. This task takes around 3 minutes. This task contains one practice block, and 1-2 testing blocks. The first testing block contains 25 trails. If the participant passes, then participant will complete a second block as well (25 trials). The scoring will be divided into Accuracy and Reaction Time. Accuracy is scored on a scale of 0 - 5, and if the Accuracy score is greater then or equal to 80%, then the Reaction Time score will be considered. (If less then 80%, then Reaction Time Score will not be used). Reaction Time is scored on a scale of 0 - 5. The Final Score is equal to the Accuracy + Reaction Time. Higher scores indicate greater ability to filter out distracting stimuli and greater ability to focus.

This outcome measure tests mental flexibility, relevant to adaptive reorganization and reduced rigid maladaptive responding. This task takes around 4 minutes. This task contains one practice block and 3 testing blocks. The first two testing blocks contain 5 trials each, and the final block contains 50 trials (10 non-dominant and 40 dominant). If the participant fails to pass the first 2 testing blocks (score of 4/5), the task is over. The scoring will be divided into Accuracy and Reaction Time. Only 40 trials are used to score Accuracy, and is scaled from 0 - 5. If the Accuracy score is greater then or equal to 80%, then the Reaction Time score will be considered. (If less then 80%, then Reaction Time Score will not be used). Reaction Time is scored on a scale of 0 - 5. The Final Score is equal to the Accuracy + Reaction Time. Higher Scores indicate higher cognitive flexibility and attention.

This outcome measures within-participant changes in willingness to select high-effort/high-reward options in relation to medication status, assessed using computational models. A hierarchical drift diffusion model will estimate parameters reflecting decision dynamics, while a subjective value model will generate participant-level estimates of reward sensitivity, probability sensitivity, and effort cost. Increased effort expenditure after GLP1-RA discontinuation may reflect rebound increases in incentive salience and reward sensitivity.

This outcome measure provides a brief index of general cognitive efficiency and helps contextualize executive findings. This task takes around 4 minutes, and includes one continuous testing block. The testing block consists of two visual patterns where the participant had to choose "same" or "not the same". The scores is based off the amount of correct responses in 90 seconds (max is 130), and will be scaled based off participants age. The Mean will be 100, with a standard deviation of 15. Participants with scores greater then 100 will indicate greater cognitive efficiency then of similar age group.

This outcome measure captures emotional distress that may covary with neural markers of recovery, including anger, sadness, and fear. The 7 tasks included in this measure are: Anger, Anger/Hostility, Anger/Physical Aggression, Apathy, Fear/Anxiety, Fear/Somatic Arousal, and Sadness/Depression. Each task takes 2 minutes to complete and contains self reported emotional measures. Participants answer a series of questions, using a scale ranging from 1 ("Never") to 5 ("Always"). Scores are then combined and converted into a "T-score", with a mean of 50 and a standard deviation of 10. Higher T-scores indicate greater emotional distress.

This outcome measure indexes stress regulation, a clinically meaningful process linked to relapse vulnerability and functional recovery. This task takes 2 minutes and consists of self reported measures. Participants answer a series of questions using a scale ranging from 1 ("Never") to 5 ("Always"). Scores are then combined and converted into a "T-score", with a mean of 50 and a standard deviation of 10. Higher T-scores indicate greater perceived stress and reduced emotional regulation and coping.

This outcome measure captures positive psychological change and broader recovery-related adaptation. This task takes approximately 2 minutes, and uses a computer-adaptive test (CAT). Participants answer a series of questions using a scale ranging from 1 ("Never") to 5 ("Always"). Scores are then combined and converted into a "T-score", with a mean of 50 and a standard deviation of 10. Higher T-scores indicate greater sense of meaning and purpose, as well as greater feelings of optimism and hopefulness.