The Triple A study (Adolescents with Anorexia and Autism): A search for biomarkers

Anorexia Nervosa (AN) is a complex eating disorder, associated with a high physical and psychological risks, it has the highest death rate amongst psychiatric disorders. Treatment resistance is a huge challenge for clinicians and researchers, as approximately 50% of individuals diagnosed with AN do not respond to treatment and go on to develop a more severe and chronic form of the disorder. Research exploring thinking styles and the emotional profile of individuals with AN have demonstrated differences in thinking processes between those with AN and those who have never had an eating disorder. These include tendencies towards an inflexible thinking style, becoming stuck in details and difficulty with social functions such as recognising and expressing emotions and interacting with others. Brain imaging studies have also highlighted different patterns of brain function during these processes in individuals with AN. These difficulties are suggested to be a major contributing factor to the development and maintenance of the disorder.
These characteristics are also defining symptoms of Autism Spectrum Disorder (ASD), which has led to research focussing on the overlap between AN and ASD. Although ASD and AN are associated with opposite gender ratios (ASD being more common in males, AN more common in females), recent findings demonstrate that a proportion of adult females with severe and chronic AN have elevated levels of autistic symptoms. Such elevated ASD traits are also associated with poorer treatment outcomes.
There is little work focussing on this illness profile at the early stages of the disorder, and research is urgently need to examine both the cognitive and neurobiological profile of young people with AN when they first present with the disorder, also considering the potential role of ASD symptoms in their recovery.
Research examining brain activity during thinking and emotional processing has largely been conducted within an adult AN population, and further research is required to explore if there are similar abnormalities and differences in the brain activation of young people with AN, and how this may change as the illness progresses or when weight is restored. Exploring the impact on the brain at first presentation, during the illness and after recovery in young people will help define risk and maintaining factors and help predict treatment outcome. Overall, this work is likely to help develop treatment targeted at early illness stages, disrupt illness progression and reduce the percentage of individual going on to develop a more severe and enduring form of the disorder.
This study is the first of its kind to integrate innovative neuroimaging methods, neuro-cognitive measures and to develop profiles of the brain of adolescent AN patients with combined ASD symptoms when they are first presenting for treatment. This will allow for the study of the interaction between clinical features, thinking and social functioning styles. At baseline assessment adolescent patients with AN, those that have recovered from the disorder and age-matched healthy individuals will be asked to complete clinical and neuropsychological assessments, an MRI scan and questionnaires. Participants with current AN and recovered AN will then be asked to repeat these measures six months later (following treatment) to identify any differences in that may help predict treatment response or relapse.
We will use this data to build a database of critical factors influencing AN, including cognitive, emotional, brain imaging markers. This research and future larger scale investigations based on this study will help identify the most vulnerable patients at an earlier stage and those individuals unlikely to respond to current interventions. These findings may then be applied to create a more individualised support and treatment strategies.

Current research suggests that cognitive and emotion processing difficulties along with autistic symptoms contribute to the maintenance and development of anorexia nervosa (AN). However, these findings are based on work conducted largely in adults with AN and despite the fact that the illness typically develops during adolescence and that illness duration is likely to moderate treatment resistance in AN due to the presence of neuroprogressive changes. Thus, further work is needed to document the neurocognitive profile of AN during the early stage of their illness.
The proposed study aims to investigate neurobiological factors that may contribute to the development and maintenance of AN in children and adolescents first presenting for treatment using behavioural assessments and functional magnetic resonance imaging (fMRI). To achieve this aim we will investigate differences in the neural correlates of cognitive and emotional processing between three groups of young people aged 12-18 years, namely 40 patients with AN, 20 young people who have recovered from AN (recAN), and 40 age matched healthy controls (HC). Specifically, we will investigate differences in BOLD signal change during central coherence and emotional processing tasks using a 3T fMRI scanner. We will also explore correlates between resting state BOLD signal and performance on cognitive tasks assessing central coherence and cognitive flexibility conducted outside of the scanner. We will then examine how these differences in BOLD signal change correlate with presence of ASD symptoms as measured during a diagnostic interview in the AN and recAN groups. Finally, we will use supervised machine learning techniques to investigate BOLD signal patterns that predict the state of psychopathology as measured with a battery of self-report questionnaires and interviews at 6-month follow-up in the AN and recAN groups.

Anorexia nervosa (AN) has devastating consequences including not only on the individual due to lasting effects of starvation on the brain leading to treatment resistance, and ultimately death, but also on families' and carers' wellbeing. AN also has substantial financial impact on societal level costing UK economy approximately £1.25 billion per annum. Current research suggests that treatments should target the cognitive and emotion processing difficulties along with autistic symptoms that contribute to the maintenance and development of AN. However, because these findings are based on work conducted largely in adults with AN, there is pressing need for better understanding of the aetiology of AN during the early stages of illness to improve treatment outcome and reduce the devastating impact of the illness. We propose that improved understanding of the impact of autistic symptoms and the neural mechanisms that underlie difficulties in cognitive and emotional processes during early stages of illness has many practical implications.
Better understanding of the underlying neural mechanisms of AN during the early stages of illness, would allow for the development of new neurobiological models of AN that shifts focus from solely external influences, such as social and family, to include internal influences that integrate genetic and neurobiological contributions, across the age span. These findings and models would highlight the neurobiological bases of the illness, which can help lift some of the shame and stigma associated with the diagnosis. Stigma and shame have negative impact on agency in help-seeking, which further contribute to long duration of illness and treatment resistance due to denial.
Identification of neural inefficiencies present in young people with AN, allows for better understanding of the illness-related underlying mechanisms that contribute to the development of AN as well as the neuroprogressive changes that occur as a consequence of the illness. These findings could improve understanding of what mechanisms behavioural or non-invasive neurobiological treatments (e.g. TMS) should be targeting during the early stages of illness. The tasks used also easily lend themselves to a test battery that could be used to examine the effectiveness of new or currently available treatments. The findings can also shed light on the mechanisms through which the treatments work to allow further understanding of their effectiveness and their further improvement.
Finally, the findings from the study will also shed light on early diagnostic and neurobiological markers present at admission that predict good or poor response to currently available eating disorder treatments. These findings allow identification of predictors of potential chronicity early on and identify differences between treatment responders and non-responders. Treatments could then be developed to specifically target the non-responders who do not benefit from currently available treatments.
Therefore, the findings from the proposed study have substantial practical clinical implications and will help further understanding of the aetiology of AN as well as make contributions to evidence based medicine to target chronicity and treatment resistance.