The ENIGMA - Eating Disorders Initiative: A Global Neuroimaging Study of Anorexia and Factors Affecting Clinical Outcomes

ABSTRACT Anorexia nervosa (AN) has one of the highest mortality rates of all psychiatric conditions due to long-term physical complications and a suicide rate over 50 times higher than the general population. The mortality rate encompasses a combination of the medical sequelae of underweight and death by suicide – and increases by around 5% with each decade of illness. Around one-third of people with AN develop a chronic disorder. If AN is not treated, serious complications such as heart conditions and kidney failure can arise and eventually lead to death. Despite the severity of AN, the neurobiological mechanisms that influence risk and treatment outcomes in AN are poorly understood; AN is severely understudied compared to other psychiatric conditions. Little is known about the alterations in brain circuitry and function in AN, and which brain changes predict future remission or relapse. Findings to date often raise questions related to the acute state: What are the acute and lasting effects of starvation? Which brain differences are related to the illness rather than undernutrition, and which are reversible with treatment? Which clinical measures, risk factors, and brain abnormalities are most important in understanding risk for AN and longer-term illness courses? To address these knowledge gaps, we launch the ENIGMA Eating Disorders Initiative – a global alliance to bring together clinical and neuroimaging experts in eating disorders worldwide to address pressing questions in AN research. This new international initiative is a coordinated data analysis platform to determine multimodal neuroimaging signatures of AN from 31 diverse datasets worldwide. We build on our promising pilot data that shows 1) one of the largest effects on brain structure ever observed among psychiatric conditions, and 2) some of the brain anomalies in AN are reversible after weight restoration treatment in a subset of patients. Identifying circuits and functions that can be restored, and in which patient subgroups, is critical. In the largest and most diverse worldwide dataset ever analyzed (n~1,600 cases and ~1,700 HCs), we will identify multimodal brain biomarkers of AN, its driving mechanisms, which brain abnormalities can be reversed, and in which patients. To boost statistical rigor, reproducibility and power, our coordinated international alliance will pool diverse brain and clinical data internationally using harmonized analytic workflows. We build on the successful launch of our ENIGMA Eating Disorders working group, which published the most highly powered neuroimaging study of AN. Our Specific Aims are to: (1) identify multimodal brain signatures of AN, with the power and diversity of data to understand which brain signatures are reproducible in patients across the world; (2) disentangle undernutrition effects on the brain from the aberrant brain circuitry that drives the condition and increases risk of relapse; and (3) longitudinally assess relapse and recovery, to better predict remission and risk for AN. Our Precision Medicine approach responds to NIMH’s mission to seek more reproducible, objective biomarkers of disease for individual monitoring and management, to assist prognosis, and discover factors that influence relapse, suicidality, or recovery.