Emotional Regulation, Cognition, Impulsivity and Reward System in Obesity: A Prospective Study of Bariatric Surgery

This research investigates obesity and associated psychiatric symptoms and disorders in a wide range of perspectives, to demonstrate the effects of obesity on the brain. The 1st aim is to assess the psychiatric symptom profiles in the group of obese patients applying for bariatric surgery and to determine the associated environmental stress factors. While, it is known that eating disorders, mood disorders and psychiatric drugs can cause obesity, obesity can also cause many psychiatric complications such as depression and cognitive disorders. There are no multi-centered studies that are conducted in this respect, and the guidelines on pre-evaluation and follow-up of patients are also lacking. The 2nd aim is to evaluate and monitor cognitive characteristics before and after bariatric surgery in obese patients. Obese people are at increased risk of dementia and are more likely to have cognitive deficits, especially executive function problems, that can affect everyday life. For this reason, obese individuals should be examined and monitored in more detail in terms of their cognitive characteristics and the change of cognitive functions during the weight loss process. The 3rd aim is to examine the relationship between obesity, bariatric surgery and reward processing system. Studies have been limited in determining whether addiction in these people is due to a search of a continuous substance as a cognitive feature or whether it is difficult to terminate it as an impulsive behavior when encountered with a pleasurable substance, even though there is no reward seeking or reward dependence. The 4th aim is the determination of the neuroanatomical and molecular components of cognitive changes observed after bariatric surgery. During the dynamic process following bariatric surgery, a variety of metabolites, chemokines, and microbiota changes may also affect the brain health and cognition. The 5th aim is to determine factors of eating, emotional regulation, reward system, addiction and impulsivity, and other psychopathologies that cause suboptimal weight loss or weight gain after bariatric surgery. Understanding the psychological and neurobiological factors involved in these processes can improve surgical interventions and significantly increase the quality of life for patients.

Aim 1: To assess the psychiatric symptom profiles in the group of obese patient candidates applying for bariatric surgery and to determine the associated environmental stress factors.

Patients will be evaluated with psychosocial scales as part of their pre-surgery assessments. The first psychosocial evaluation of the patients will be performed by a structured clinical interview (SCID) by Dr. Hale Yapici Eser, Dr. Özge Kılıç and then, the participants will be asked to fill in the self-assessment scales and they will be applied some computer based cognitive tests via the assistance of Candan Yasemin Eren.

Scales used to model environmental factors:

1. Sociodemographic Data Form
2. Childhood Trauma Questionnaire
3. Chronic Stress Scale
4. Perceived Stress Scale
5. Distress Thermometer
6. Multidimensional Scale of Perceived Social Support

   Scales used to evaluate psychiatric symptom profile:
7. Beck Depression Scale
8. Beck Anxiety Scale
9. Barratt Impulsivity Scale
10. Cognitive Failures Questionnaire
11. Mood Disorder Questionnaire
12. Yale Food Addiction Scale
13. Relationship Scales Questionnaire
14. Difficulties in Emotion Regulation Scale
15. Snaith-Hamilton Pleasure Scale

Patients will fill these measurements using Qualtrics. The findings of the structured interview and results of the scale scores will be analyzed by SPSS. From these scales, evaluations other than scales 2 and 13 will be re-administered at the 3rd month and 12th months after bariatric surgery. Scale scores will be used for follow-up of patients.

Aim 2: To evaluate and monitor cognitive characteristics before and after bariatric surgery in obese patients.

The cognitive functions of the patients will be assessed, pre and post operationally (3rd and 12th months), by the Penn-CNP neuropsychological test battery and the 'Cognitive Failures Questionnaire' indicated as the 10th item above. 'Cognitive Failures Questionnaire' is a self-administered scale, which is aimed at questioning the different areas of cognition such as attention, memory and perception. Penn-CNP is a neuropsychological test battery developed by Prof. Dr. Rachel Gur at the University of Pennsylvania and already in use on large sampled and multi centered researches. The required tasks of this battery is translated into Turkish by establishing a connection between Dr. Hale Yapici Eser and these research centers.

The Penn-CNP neuropsychological test battery can assess cognitive features such as emotion recognition and discrimination, working memory, visual-spatial perception and memory, motor praxis, impulsivity and attention. Some of these tests are aimed at evaluating the effect of reaction time and motor capacity on test responses, while others investigate emotion recognition processes with different aspects of cognition such as attention, working and long-term memory, executive functions and visual-spatial perception.For each test applied with this battery, the test results are automatically calculated by the system and the response time, correct and incorrect answers for each response are also presented in an analytical data format. The program also does unbiased arithmetic calculations on important data for further analysis.

Test result tables of the battery can be reviewed in detail from the following link:

https://penncnp.med.upenn.edu/doc.pl?section=pi\&content=factsheets/penncnp_test_descriptions-v1.00.pdf

Cognitive scales will be repeated at 0, 3 and 12 months post-operation. These follow-ups have important implications. Findings obtained for each test will be monitored in terms of changes between pre and post operation. Also, the effects of the variables mentioned in method 4 will be analyzed on the scores obtained on each cognitive test by the SPSS program. In addition, test results will be compared in terms of the changes made in the measurements in the control group mentioned in method 4.

Aim 3: To examine the relationship between obesity, bariatric surgery and reward processing system.

The cognitive functions of the patients will be assessed with the "Probabilistic Reward Task (PRT)" pre and 3rd and 12th months after bariatric surgery to examine the changes in the reward learning systems after bariatric surgery.PRT is a signal detection task used for measuring hedonic capacity and reward learning based on monetary reward enhancement. Developed by Diego Pizzagalli in 2005, PRT is an objective assessment of the participants' tendency to modulate their behavior in relation to the prize. At each trial, subjects are asked to choose between two very similar stimuli. The stimuli consist of simple cartoon faces presented at the center of the monitor. Subjects are instructed to press on the appropriate button to determine whether the stimulus is presented with long (11 mm) or short (10 mm) mouth. One of the stimuli (the "rich stimulus") is awarded three times more often than the other ("lean") but the subjects do not know about it. The reward is presented with: "True! You have earned 25 cents". In healthy controls, this reinforcement method leads to response bias, and more frequent rewarding stimuli are preferred. The response bias towards the more frequently rewarded stimuli will be used to operationalize reward sensitivity. Due to participation and validity of the test participants will be given 20 TL independently from their performance. Mentioned evaluations will be repeated at 0, 3 and 12 months. Findings obtained for each test will be monitored in terms of changes between pre and post operation. Also, the effects of the variables mentioned in method 4 will be analyzed on the scores obtained on each cognitive test by the SPSS program.

Aim 4: Determination of the neuroanatomical and molecular components of cognitive changes observed after bariatric surgery.

In this part of the study, brain imaging and biochemical measurements will be conducted. Patients who have completed Method 1 will be evaluated on psychiatric examination and scale scores to be able to be eligible for this stage. During the preliminary evaluations, people with conditions that might affect their cognition and cause brain damage will not be included. Patients who meet the criteria will be exposed to the following measurements at pre-operative, 3 and 12 months. A second group of healthy volunteers with normal body mass index, paired with age, gender, education status and psychiatric assessment scale scores, with normal BMI, will be formed.

Imaging studies: Structural and functional changes in the brain will be evaluated by magnetic resonance imaging (MRI). Thin-section T1-weighted images for evaluation of gray matter changes, resting functional magnetic resonance images for evaluation of functional changes will be obtained. For resting fMRI, patients will be asked to rest eyes closed for 6 minutes without thinking anything. MRI examination will be repeated both for the obese patient group and concurrently healthy controls before surgery (0 months) and after surgery at 3 and 12 months. Imaging will take approximately 30 minutes.

All brain group analyzes of the structural imaging data obtained at the pre-operative, baseline, time point of the obese patient group and the healthy control group will be performed and the brain regions in the obese patient group will be determined for the gray matter changes. The first stage analysis will focus on the brain areas where gray matter changes are observed, and these areas will be compared with the data obtained from the after bariatric surgery imaging sessions. For the evaluation of these changes, focus areas will be placed in the brain areas where obese individuals have gray matter changes, and detailed analysis will be made. Focused analysis and whole brain comparisons performed by placing the areas of interest as mentioned will be performed in comparison with longitudinal data (comparing baseline-3 and 12 months of obese individuals with each other) and normal healthy groups' 3 and 12 months data. In addition, structural changes in the brain will be analyzed in relation to cognitive functions, stress factors, and mood changes. For second stage analysis, interest areas will be placed to the prefrontal cortex, hippocampus, and temporal lobe and data of obese patient group and healthy controls will be compared at the baseline, 3rd and 12th months. In addition, a longitudinal analysis will be performed on the obese patient group (comparing 0-3 and 12 months of obese individuals with each other) to assess the effect of bariatric surgery on these brain areas.

In resting state fMRI, the focus now is to examine the functional connectivity changes in the ventral tegmental area as its activity correlates with reward learning and prefrontal cortex as the center for executive functions. Depending on the findings of the clinical data obtained from the study, different areas of interest will be identified and functional associations will be examined. Focused analyzes on areas of interest mentioned above will be performed both longitudinally (comparing 0-3 and 12 months of the obese individuals with each other) and 3 and 12 months comparisons between healthy controls and obese group. In addition, functional changes in the brain will be analyzed in relation to cognitive functions and mood changes.

Biological Analysis: Blood samples obtained will also be used to analyze peripheral biological markers that may be risk factors. Metabolic parameters, inflammatory markers, and GLP levels will be measured and recorded.

1. Serum cortisol levels
2. Serum GLP levels
3. Ghrelin, leptin
4. Calculation of HbA1C, glucose, insulin levels and HOMA IR
5. Thyroid stimulating hormone (TSH) levels
6. CRP levels
7. Inflammatory panel (IL-1, IL-6 and TNF-a levels)
8. B12, folic acid and ferritin levels
9. Serum lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride)
10. Liver function tests

In addition to neuroanatomical and other biomarkers, investigating physicians will monitor the general clinical status of the patients and changes such as hypertension and sleep apnea will be noted. Nutritionists will also follow diet compliance of the patients. Daily mobility and exercise levels will also be assessed. All of these obtained markers will be used both longitudinally (0-3 and 12 months of obese individuals compared to each other) and comparison to healthy controls at the 0, 3 and 12 months. During the collection of imaging and biomarkers data, the control group will be monitored for 12 months as well.

Aim 5: To determine factors of eating, emotional regulation, reward system, addiction and impulsivity, and other psychopathologies that cause suboptimal weight loss or weight gain after bariatric surgery.

Similar to the previous methods, patients will fill in the self-assessment scales and apply cognitive tests on the computer via the assistance of Candan Yasemin Eren. The tests to be applied in this section will be the scales used to evaluate the environmental and psychiatric profile described in method 1, the PENN-CNP battery described in method 2, and the PRT batteries in method 3.

Eligibility Criteria:
For obese patient group:

Inclusion Criteria:

1. Be between the ages of 18-65
2. To be able to give informed consent
3. Be a candidate for bariatric surgery.

Exclusion Criteria:

1. Dementia
2. Individuals with severe mental retardation and marked cognitive impairments
3. Psychotic disorders
4. Psychoactive substance addiction diagnosis

For healthy volunteers:

Inclusion criteria:

1. Be between the ages of 18-65
2. To be able to give informed consent
3. To be in normal range for BMI
4. To be observed as in the normal mental status examination

Exclusion criteria:

1. Dementia
2. Individuals with severe mental retardation and marked cognitive impairments
3. Psychotic disorders
4. Psychoactive substance addiction diagnosis