Nancy L. Zucker - US grants

DESCRIPTION (provided by candidate): This mentored K23 award in patient-oriented research for Dr. Nancy Zucker, sponsored by Dr. Cynthia Bulik, describes a rigorous five year training program in the area of treatment development for eating disorders, initially for anorexia nervosa. Anorexia nervosa continues to have one of the highest mortality rates among psychiatric disorders, yet the most efficacious manner in which to treat this disorder continues to be debated. Completion of this training program will allow Dr. Zucker to adapt treatment models that have been effective in the management of other childhood disorders to adolescents with eating disorders and their families. She will receive further advanced training in child and adolescent cognitive development, child and family treatment approaches, and research design. She will use this advanced instruction to further develop and pilot a group parent training program for the management of anorexia nervosa. The specific aims of this proposal are: 1) to examine the preliminary efficacy of a group parent-training program on adolescent eating disorder symptoms; 2) to examine changes in parent variables that have been reported to impact treatment outcome, 3) to examine changes in family functioning, and 4) to examine the treatment acceptability of the intervention. The intervention combines skills in behavior modification and dialectical behavior therapy while targeting parent variables that have been reported in families of adolescents with anorexia nervosa. Dr. Zucker will conduct a two-stage research design. Phase 1 will consist of focus groups comprised of members of parent training groups that Dr. Zucker has previously conducted. Results from Phase I will be used to improve the intervention. She will then subject the improved intervention to a pilot, pre-post, randomized design to assess preliminary efficacy in Phase 2. This initial trial will lead to further enhancements of the program, will define the populations most suited to a group parent-training model, will permit exploration of potential mechanisms of action, and will highlight additional participant needs for further treatment development. Pilot data from this proposal will place her in a position to apply for funding via the R01 mechanism to subject the intervention to more systematic study. Thus, the coursework, training workshops, and mentored research experiences will allow Dr. Zucker to combine effective approaches for alternative childhood disorders with advanced training in cognitive development to design approaches for the treatment of adolescent eating disorders.

[unreadable] DESCRIPTION (provided by applicant): Death by suicide occurs in a disproportionate percentage of individuals with anorexia nervosa (AN), with a standardized mortality ratio indicating a 57 fold greater risk of death from suicide relative to an age-matched cohort. These shocking statistics speak to the incapacitating, perplexing, and isolating nature of AN, a severe psychiatric illness that negatively impacts the biological, emotional, and psychosocial functioning of both the affected individual and her or his family. Longitudinal studies indicate impaired social functioning increases risk for fatal outcomes. Social impairment persists and affects quality of life even after recovery. Despite this knowledge, very little is known about social information processing in AN. Careful study of social cognition in AN may elucidate impaired processes that may influence outcome and therapeutic efficacy: difficulty forming therapeutic alliances, disturbances in body image, impaired empathy, and dearth of secure attachments. Symptoms of autistic spectrum disorders (ASD), particularly in cognitive domains that impact social cognition, are overrepresented in individuals with chronic AN and persist after recovery. In contrast, eating disturbances in ASD are widely acknowledged, but are seldom the topic of systematic inquiry. Relative to AN, social information processing in ASD is well characterized and may help to inform the characterization of these domains in AN. The goals of this investigation are: 1) to provide a detailed characterization of the behavioral, visual, and neurocognitive processes that subserve social information processing in AN; 2) to differentiate the contribution of low weight status on these deficits by characterizing changes over the course of illness, 3) to compare the neurocircuitry of social cognition in relation to females with high functioning autism; and 4) to develop a new paradigm for assessing social information processing during parent and child interactions across emotionally valanced conditions. We will achieve these goals using a battery of neuropsychological and social cognitive measures, fMRI while viewing dynamic facial affective stimuli, and eye-tracking while viewing social information processing tasks. Sophisticated methodologies that characterize the cognitive processes that underlie social information processing deficits and map onto functional neurocircuits may greatly enhance our knowledge of the pathophysiology of AN and may open new avenues for effective treatment development. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): (03) Biomarker Discovery and Validation general challenge Area and the 03-MH-101 Biomarkers in mental disorders specific challenge topic. Anorexia nervosa (AN) is a terrifying and perplexing disorder. Eating disorders, in general, rank among the top ten causes for disability among women, while AN has the highest mortality rate of any psychiatric disorder with a 57 fold increased risk of death due to suicide relative to an age- matched cohort. Despite these sobering statistics, one of the greatest mysteries of AN is that the ill state is prized by the individuals afflicted with this disorder. They report 'feeling better'while starved. In contrast, prior to the ill state, the majority with AN are diagnosed with an anxiety disorder and experience elevated levels of gastrointestinal symptoms, - conditions associated with increased visceral sensitivity. Notably, the severe starvation of AN principally onsets during adolescence, a vulnerable period of neural maturation and modification. Indeed, the course of AN is notable for a 'critical period'of intervention. The likelihood of improvement in symptoms of AN diminishes markedly if aggressive treatment is not undertaken during the vulnerable developmental window of early to middle adolescence. This body of evidence suggests that sensitivity to change in the internal state of the body (i.e. interoceptive sensitivity) exists premorbidly in those with AN, that biological alterations during adolescence may potentiate somatic sensitivity, that starvation during this period may dampen somatic experience, and that critical alterations in brain neural circuitry during this period may be crucial in shaping disorder course. In a sample of 75 adolescents (25 in the acute state of malnourishment of anorexia nervosa, 25 weight-restored from anorexia nervosa, and 25 typically developing controls), we will complete the following aims. We will: 1) characterize differences in interoceptive signaling from the upper GI tract and the interoceptive cortex, 2) characterize the differences in prefrontal cortical modulation of interoceptive cortex, and 3) characterize differences in the role of orbitofrontal cortex on modulation of cortical activity and connectivity with interoceptive cortex. By studying patterns of neural activation and psychophysical response that alter as a function of starvation and are associated with interoceptive sensitivity, we can formulate novel hypotheses on biological changes associated with starvation that are reinforcing for this group and derive novel treatment targets. PUBLIC HEALTH RELEVANCE STATEMENT: Anorexia nervosa (AN) is a terrifying and perplexing disorder. Eating disorders, in general, rank among the top ten causes for disability among women, while AN has the highest mortality rate of any psychiatric disorder with a 57 fold increased risk of death due to suicide relative to an age-matched cohort. Despite these sobering statistics, one of the greatest mysteries of AN is that the ill state is prized by the individuals afflicted with this disorder. They report 'feeling better'while starved. In contrast, prior to the ill state, the majority with AN are diagnosed with an anxiety disorder and experience elevated levels of gastrointestinal symptoms, - conditions associated with increased sensitivity to body changes (e.g. sensing the pit in your gut when you have done something wrong or the butterflies in your gut when you are worried about something). In fact, sensitivity to these internal sensations (called interoceptive sensitivity) has profound implications well beyond anorexia nervosa. Interoceptive sensitivity is associated with the strength of emotional memories, the depth with which we can understand others, and may be associated with the strength of emotional learning. As adolescence is a time of profound brain and body change, this developmental period may be a key window to study how individuals differ in this sensitivity and the boundaries that define pathological development. In fact, the severe starvation of AN principally begins during adolescence. Thus, malnourishment during this period may have particularly profound negative effects. In fact, the course of AN is notable for a 'critical period'of intervention. The likelihood of improvement in symptoms of AN diminishes markedly if aggressive treatment is not undertaken during the vulnerable developmental window of early to middle adolescence. Using functional neuroimaging we will examine neural circuits in the brain that may help us to identify brain regions that may contribute to difficulties with sensitivity to internal bodily states in those with anorexia nervosa and how these differ from typically developing adolescents. By studying patterns of neural activation and psychophysical response that alter as a function of starvation and are associated with interoceptive sensitivity, we can formulate novel hypotheses on biological changes associated with starvation that are reinforcing for this group and derive novel treatment targets for those with anorexia nervosa and better understand the transitioning mind-body connection of adolescence.

DESCRIPTION (provided by applicant): This application, Feelings and Body Investigators (FBI): Interoceptive Exposure for Child Abdominal Pain is in response to PA-11-177, Translational Research for the Development of Novel Interventions for Mental Disorders (R21/R33). We propose development and pilot-testing of an acceptance- based behavioral treatment for young children (5-8 years old) with functional abdominal pain (FAP; R21, n=26, R33, n=100). FAP is one of the most frequent somatic syndromes in young children, causes significant impairment, and is predictive of psychiatric and pain disorders later in childhood and in adulthood. No treatments exist for very young children with FAP. Research supports that FAP is influenced by: (1) early pain on the neurodevelopment of the gut-brain axis and (2) maladaptive interactions with the social environment that inadvertently increase somatic fear. These vulnerabilities provide targets for early intervention. OBJECTIVE: To develop and pilot an intervention for FAP based on fundamental neuroscience research on the aberrant neurodevelopment of the gut-brain axis and subsequent modification by the social environment. Our treatment 1) links intervention strategies to unique patterns of neural circuit maturation associated with early visceral pain on the gut-brain axis, 2) adapts acceptance-based behavioral strategies used to address psychopathology in older children to younger children, and 3) incorporates caregivers as role models and facilitators based on attachment research. METHODS: Our ten session intervention trains children to be Feeling and Body Investigators. Half of the sessions will be done in clinic and half at home via web-camera to facilitate generalization. During the treatment child/caregiver dyads will 1) gather body clues (Learn), 2) investigate (Experience: perform interoceptive mystery missions to explore a body sensation), 3) organize body clues (Contextualize: recall other contexts that evoke similar sensations), and 4) go on increasingly daring missions (Challenge: decrease avoidance and safety behaviors). In the R21 phase we will develop and refine the FBI intervention in 26 child- caregiver dyads. In the R33 phase we will randomize 100 children with FAP to FBI or an active control (parent education with standard medical care) to conduct a pilot-test of the feasibility, acceptability, an clinical significance of FBI compared with an active control treatment. We will use epidemiological methods to screen all eligible children attending primary care practices so that our sample will be representative of young children with FAP, not simply a convenience sample. If we are successful, young children with FAP who complete our FBI early intervention will learn to experience changes in the viscera as fun and fascinating, rather than scary, and will develop new capacities for pain management, adaptive functioning, and emotion regulation. The success of our early intervention for FAP in young children will also have broad implications for the treatment and prevention of mental illness and chronic abdominal pain.

Intellectual Merit: This project will for the first time provide the fundamental tools to integrate unique multimodal data toward screening, diagnosis, and intervention in eating disorders, with an initial focus on children with ARFID and related developmental and health disorders. This work is critical for enriching the understanding of healthy development and for broadening the foundations of behavioral data science. ARFID ·motivates the development of new computer vision and data analysis tools critical for the analysis of multidimensional behavioral data. The main aims are: 1. Develop and user individualized and integrated continuous facial affect coding from videos to discern affective motivations for food avoidance, critical due to the unique sensory aspects of eating disorders, and resulting from active stimulation via friendly and carefully designed images/videos and real food presentation; 2. Use data analysis and machine learning to derive sensory profiles based on patterns of food consumption and preference from existing unique datasets of selective eaters; and 3. Translate the tools developed in Aims 1 and 2 into the clinic and home to assess the capacity of these tools to define a threshold of clinically significant food avoidance, to detect change in acceptability of food with repeated presentations, and to examine and modify the accuracy of our food suggestion algorithms. Broader Impacts: The impact of this application comprises two broad domains. First is the derivation of processes, tools, and strategies to analyze very disparate data across multiple levels of analysis and to codify those strategies to inform similar future work, in particular incorporating automatic behavioral coding. Second is the exploitation of these tools to address questions about the emergence of healthy/unhealthy food selectivity across the lifespan, including recommendation delivery via apps and at-home recordings. The health impact of even partial success in this project is very broad and significant. Undergraduate students will be involved in this project via the 6-weeks summer research program at the Information Initiative at Duke, a center dedicated to the fundamentals of data science and its applications; via the co-Pl's research lab devoted to eating disorders; and via the Pl's project dedicated to training undergraduate students to address eating disorders of their friends via an anonymous app. Outreach and dissemination will follow the broad use of the developed app, both in the clinic and the general population, including the Pl's connections with low-income and under-represented bi-lingual preK. RELEVANCE (See instructions): Eating disorders are potentially life-threatening mental illnesses affecting the general population; -90% of individuals never receive treatment, in part due to lack of awareness and access. Individuals with eating disorders experience a diminished quality of life, high mental and physical illness comorbidities, and an existence marked by profound loneliness and isolation. Combining expertise in eating disorders with computer vision and machine learning, we bring for the first time data science to this health challenge. PROJECT/PERFORMANCE S1TE(S) (If addItIonal space Is needed use Project/Performance Stte Format Page)

Avoidant Restrictive Food Intake Disorder (ARFID) is a newly articulated eating disorder in the DSM-5 in which individuals are not able to consume an adequate quantity or variety of food to sustain healthy growth and de- velopment. ARFID typically onsets in early childhood, yet identification of the disorder is poor. The end result is that children often have sustained inadequate nutrition with resulting severe physical consequences and threats to optimal social and emotional development. Early intervention is essential. However, there are no em- pirically validated treatments for young children with ARFID. Children with ARFID are known to be sensitive individuals: with a low threshold for noticing internal body sensations (e.g., gastrointestinal distress) and exter- nal sensory sensations (e.g., smells) and experiencing these sensations as uncomfortable/aversive. This sen- sitivity, and the associated negative emotional reactions (e.g., of disgust, fear, sadness), may encourage avoidance of activities that cause these sensory experiences, such as eating. An intervention that could change reactions to sensory and somatic sensations to one of playful curiosity may increase approach behav- ior and food consumption. We designed an acceptance-based interoceptive exposure treatment for children to achieve this goal. We teach children and caregivers to be ?FBI Agents,? individuals who view somatic and sen- sory sensations as clues to a mystery via the use of engaging illustrative cartoon characters (e.g., Gassy Gus), body investigations that provoke intense sensations and worksheets that map sensations to meanings and ac- tions. The goal is to make somatic and sensory experiences playful ? and to promote adaptive self-awareness and food approach. The overall objective of this study is to determine whether treatment results in reduced negative emotions to somatic and sensory sensations, including those associated with food and eating, and whether this, in turn, increases food approach. This will be accomplished by a randomized controlled trial (N = 140, 70 per cell) comparing The Feeling and Body Investigators (FBI) - ARFID Division treatment, a 20-session outpatient treatment, to a control group in children (5 to 9 years of age) with ARFID. The control treatment (FAD: Family-Assisted Diet) will provide family-supported exposure. Our proposed mediator of treatment re- sponse is negative affect: a child?s facial affect in response to food presentation as measured via smartphone videos. Outcomes include changes in anthropometric measurements, nutrition variety and adequacy, and psy- chosocial functioning. Medical and psychological measurements will be assessed pre- and post-treatment, at every session, and 3-month follow-up. Deliverables include an empirically validated treatment(s); medical guidelines for the early detection of insufficient nutrition; practical tools for assessing food acceptance in the home via smartphones; and guidance about the number of food presentations necessary to facilitate acceptance. Ultimately, we will evaluate this treatment and disseminate materials via primary care to provide tools to intervene early on food avoidance.