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.
