BACKGROUND: Binge eating disorder (BED) is the worldwide most-prevalent eating disorder. It is associated with psychiatric comorbidities and obesity, a high impact in life functioning, and high morbidity and mortality. First symptoms appear frequently in youths, who most commonly present incomplete (subthreshold) criteria for BED (precursor forms, PREC-BED). While some subjects will evolve from PREC-BED to BED, there is no gold standard to identify the clinical evolution. Information from prior studies suggest early alterations in reward and inhibitory brain circuits in PREC-BED may predict increased vulnerability or resilience to develop BED. Tools based on MRI brain connectivity analyses (MRI-BC), built on robust and interpretable connectivity whole-brain models, have proven successful in diagnostic classification and predicting certain clinical outcomes. OBJECTIVES: To study MRI-BC diagnostic markers of PREC-BED and to explore prognosis at 1 year of follow-up in a sample of adolescents with obesity (12-17 years old). METHODS: A) Transversal analytical design: 3-group (n=34 per group) comparison of neuroimaging (MRI-BC), neurocognitive and clinical markers in adolescents with obesity and i) BED, ii) PREC-BED, iii) no BED nor PREC-BED (Healthy group, HC). B) Longitudinal analytical design, pilot, exploratory: adolescents with PREC-BED will be evaluated in clinical and neurocognitive variables at 1 year. Baseline brain neuroimaging variables (alone and in combination with clinical and neurocognitive variables) will be analyzed as predictors of clinical prognosis, including conversion to BED.

Background

Binge eating disorder (BED) has been a diagnosis on its own only since the last edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) in 2013. It is the most prevalent eating disorder worldwide, affecting more than 50 million subjects, world-wide. BED is characterized by binge eating episodes: eating a large amount of food in a discrete period and with a sense of lack of control. Two main peaks of onset have been identified: one is at mean age 14 and the second between 18-20 years old. BED is one of the primary chronic illnesses among adolescents and is commonly associated with psychiatric comorbidities (more than 60% of lifetime prevalence), but also with obesity and its physical consequences, showing a high impact in life functioning and a high morbi-mortality. BED prevalence in youth populations is between 1-3%, and up to 37% in adolescent population with obesity. These figures have raised in parallel with the high increase in obesity prevalence in this population. When considering subclinical presentations in the general population, which involve presenting some symptoms but not fulfilling all the diagnostic criteria for BED, the prevalence is 3%. Subclinical forms are described with terms such as emotional eating, disorganized eating, loss of control eating, among others. The latter is the only construct that has operationalized criteria. In some cases, but not all, individuals with these conditions might be diagnosed with specified or unspecified DSM-5 eating disorder categories ("other specified feeding or eating disorder" -OSFED-, or "eating disorder not otherwise specified" -EDNOS-).

The first symptoms of BED often appear in youths, who frequently exhibit incomplete criteria, which are associated with a future development of BED (i.e. subclinical forms or precursor forms, PREC-BED). These subclinical forms are more frequent in adolescents, in comparison to adults. The factors determining the conversion from PREC-BED to BED are unknown and to our knowledge, only one study evaluated the percentage of conversion to BED in a small sample of adolescents with PREC-BED, finding a 28% conversion rate. There is no gold standard for identifying the clinical progression of incomplete forms, which hinders prevention and personalized treatment.

The most kown underlying factor identified in BED is a dysfunction in emotional regulation, and neuroimaging studies have identified alterations in relevant brain circuits involved in these functions, such as reward response and response inhibition. These alterations are observed in BED and seem to be present in PREC-BED and could potentially predict a greater vulnerability or resilience to developing BED in the future. For example: Reward response: Subjects with BED present increased preference for immediate reward (as opposed to delayed), greater food-reward sensitivity and greater rash-spontaneous behaviour in the context of food. At the brain level, despite the scarce evidence, a large longitudinal study (i.e. Adolescent Brain Cognitive Development -ABCD- study) suggests that early brain structural differences during childhood of key reward regions (i.e. nucleus accumbens) might be a genetic predisposition for the development of obesity and possibly of an altered pattern of eating. In adult samples of BED, a few studies found structural or functional alterations in regions of the reward system. Inhibition: Evidences of poor impulse control or decreased inhibitory control come from adult samples, but also from the limited samples in youth, which are also limited. In adolescents with PREC-BED, some studies found hypoactivations during inhibitory processing regions, or during the inhibition of emotions in the the context of negative mood induction through a peer interaction paradigm. In another study, hyperactivations (as opposite to hypoactivations) of self-regulatory regions when receiving milkshake flavours during the neuroimaging session, were suggested as compensatory early mechanisms, representing an increased cognitive effort to regulate emotions under such restrictive conditions. Studies in BED were only found in adults.

Neuroimaging techniques using magnetic resonance imaging (MRI) allow for non-invasive study of live brain activity, which can be done during the participation of the subject in a task (for example, an inhibition task or a response processing task). This would allow the visualization of functional deficits evidenced during a cognitive demand; in the same manner the cardiologist may realize exercise tolerance test. Advanced MRI techniques nowadays offer unique insights into the anatomical and functional architecture of the brain. For example, advanced MRI brain connectivity (MRI-BC) techniques incorporate the modelling of brain dynamics between regions, which approximates to the inherent complexity of brain architecture and psychiatric disorders and open new perspective to investigate circuits and alterations involved in neurological and diseases. Such analysis can be conducted during a resting state in the MRI session, but also during specific task (for example, inhibition response task or reward-based task). One of the available whole-brain models of MRI-BC is called effective connectivity (EC), which provides information of the hierarchical or directional connectivity and/or activation between brain regions and networks. Our team (UPF team members) has developed a new technique to estimate EC, the MOU-EC generative model (Multivariate Ornstein-Uhlenbeck), which improves interpretability over other techniques and has been shown its relevance in predicting outcomes. Similar advanced techniques have proven useful in a few studies in eating disorders, including children with BED in one study and in EC in taste and food intake regulating circuits in anorexia and bulimia nervosa.

The development of prognostic markers in PREC-BED forms in the child and adolescent population would be highly relevant to increase the detection of these forms, prevent the development of BED, and enable early and personalized treatment. While neuroimaging markers alone and for diagnostic purposes have not yielded the expected results in other pathologies, it is possible that MRI-BC alone or in combination with other clinical and neuropsychological variables could constitute more sensitive and specific predictive models of risk, especially in pathologies with a bio-psychosocial origin like BED.

PROJECT'S AIM

The aim is to characterize regulation (reward and inhibition-based) processes in PREC-BED and BED in adolescents and to explore MRI-BC neurobiological markers of PREC-BED diagnosis and of prognosis at 1 year of follow-up.

FUNDING

Grant by the Instituto de Salud Carlos III (Ministerio de Ciencia, Innovación y Universades) and the private company Torrons Vicens.

Inclusion Criteria:

• Patients derived to the Endocrinology Department with obesity as the main criterion for consultation, measured as body mass index (BMI) z-score above 2 standard deviations.
• Age between 12-16 years old.
• Signed informed consent by parents or legal guardians of subjects, plus the signed consent by the adolescent when being 12 or older years/old.

Additional inclusion criteria for the BED and PREC-BED groups:

• The presence of DSM-5 criteria for BED in the BED group.
• Fulfilling the LOC (loss of control) criteria (related to the original Marcus&Kalarchian) in the PREC-BED group.

Exclusion Criteria:

• Intelligence quotient < 70 measured with the K-BIT.
• Any comorbid psychiatric disorder, except BED in the BED group or PREC-BED in the PREC-BED group. Tobacco use and the presence of an adaptative disorder or any mild anxiety disorder will be accepted in all groups.
• Traumatic brain injury or any neurological disorder.
• Use of dental braces (due to important artifact in MRI).
• MRI: Absolute contraindications (e.g.: metal objects), relative contraindications (claustrophobia). Anthropometric measures: Weight > 150Kg or shoulder to shoulder measurement > 70 cm.
• Any severe medical conditions (including Sleep apnea-hypopnea syndrome), except for obesity and metabolic syndrome.
• Not signing the informed consent.
• Pregnancy for females.

Adolescents with obesity (12-16 y/o) would be consecutively asked to participate when attending their visits at the Endocrinology Department at Hospital Sant Joan de Déu (HSJD).

All of the individual deidentified participant data may be provided to qualified researchers with academic interest in eating disorders. Data shared will be pseudonymised, with no Protected Health Information (PHI included).

Immediately following publication. No end date.

Proposals should be directed to the principal investigator. To gain access, data requestors will need to sign a data agreement with our institution, to comply with legal requirements and data protection rights. The study protocol and/or an amendment to the protocol will be reviewed by the corresponding Ethics Committees.