American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2010
We performed association studies with 5,151 SNPs that were judged as likely candidate genetic var... more We performed association studies with 5,151 SNPs that were judged as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN) based on location under reported linkage peaks, previous results in the literature (182 candidate genes), brain expression, biological plausibility, and estrogen responsivity. We employed a case-control design that tested each SNP individually as well as haplotypes derived from these SNPs in 1,085 case individuals with AN diagnoses and 677 control individuals. We also performed separate association analyses using three increasingly restrictive case definitions for AN: all individuals with any subtype of AN (All AN: n = 1,085); individuals with AN with no binge eating behavior (AN with No Binge Eating: n = 687); and individuals with the restricting subtype of AN (Restricting AN: n = 421). After accounting for multiple comparisons, there were no statistically significant associations for any individual SNP or haplotype block with any definition of illness. These results underscore the importance of large samples to yield appropriate power to detect genotypic differences in individuals with AN and also motivate complementary approaches involving Genome-Wide Association (GWA) studies, Copy Number Variation (CNV) analyses, sequencing-based rare variant discovery assays, and pathwaybased analysis in order to make up for deficiencies in traditional candidate gene approaches to AN.
was on the SAB of Expression Analysis (Durham, NC). Cynthia Bulik was a consultant for Shire Phar... more was on the SAB of Expression Analysis (Durham, NC). Cynthia Bulik was a consultant for Shire Pharmaceuticals at the time the manuscript was written. Federica Tozzi was full time employee of GSK at the time when the study was performed. David A. Collier was employed by Eli Lilly UK for a portion of the time that this study was performed. James L. Kennedy has received honoraria from Eli Lilly and Roche. Robert D. Levitan has received honorarium from Astra-Zeneca.
Individuals with bulimia nervosa (BN) cycle between periods of binge-eating and compensatory beha... more Individuals with bulimia nervosa (BN) cycle between periods of binge-eating and compensatory behavior and periods of dietary restraint, suggesting extremes of under and overcontrol that may be metabolic-state related. This study examined the influence of hunger and satiety on impulsivity and neural responding during decision-making. Twenty-three women remitted from BN (RBN) and 20 healthy comparison women (CW) performed a delay discounting task after a 16-hr fast and following a standardized meal during functional neuroimaging. A dual-systems approach examined reward valuation (decision trials where the early reward option was available immediately) and cognitive control (all decision trials). Interactions of Group × Visit (Hungry, Fed) for immediate reward revealed that CW had greater activation when hungry versus fed in the ventral striatum and dorsal caudate, whereas RBN had greater response when fed versus hungry in the dorsal caudate. Compared to CW, RBN showed decreased response when hungry within the left dorsal caudate and ventral striatum and increased response when fed in bilateral dorsal caudate. No differences were found within cognitive control regions or with choice behavior. Reward sensitivity is normally increased when hungry and decreased when fed; our findings in CW provide further support of hunger-based reward sensitivity within the striatum. However, RBN showed no differences for hunger and satiety in the ventral striatum and greater activation in the dorsal caudate when fed compared to hungry. This suggests RBN may be less sensitive to reward when hungry but do not devalue reward when satiated, indicating altered metabolic modulation of self-regulatory control. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Background and objectives: Intolerance of uncertainty (IU) is a transdiagnostic process contribut... more Background and objectives: Intolerance of uncertainty (IU) is a transdiagnostic process contributing to the maintenance of anxiety disorders, and is a potential target for treatment. Recent literature has investigated IU as a cognitive process underpinning pathological fear and anxiety in Anorexia Nervosa (AN). The current study was designed to examine trait and state IU, and their relationship to restrictive eating disorder symptoms, anxiety, worry, cognitive rigidity and eating behaviour. Methods: A sample of undergraduate women (N = 85) completed measures of eating disorder symptoms, IU, cognitive rigidity and worry. Participants were randomised to complete an eating task under one of two conditions: the "certain" condition received a high-calorie meal and nutritional information, while the "uncertain" condition received the meal alone. During the meal, state IU and state anxiety were examined at three time-points (baseline, pre-eating, post-eating). Results: Trait IU was correlated with cognitive rigidity, worry, global eating disorder symptoms, and, in particular, dietary restraint. No differences emerged between conditions with respect to eating-related anxiety, or amount of food eaten. Controlling for condition and eating disorder symptoms, state IU predicted pre-eating anxiety. Beyond the contribution of condition, BMI and eating disorder symptoms, state IU predicted consumption, specifically greater dietary restriction. Limitations: The study employed a non-clinical sample. Conclusions: IU may be implicated in a rigid cognitive style, the anxiety response to energy-dense food, and restrictive eating behaviour. Should these findings be replicated in a clinical sample, then IU might emerge as an adjunctive treatment target for AN.
Interoception, or the sensing and integration of bodily state signals, has been implicated in ano... more Interoception, or the sensing and integration of bodily state signals, has been implicated in anorexia nervosa (AN), given that the hallmark symptoms involve food restriction and body image disturbance. Here we focus on brain response to the anticipation and experience of affective interoceptive stimuli. Women remitted from AN (RAN; N = 18) and healthy comparison women (CW; N = 26) underwent a pleasant affective touch paradigm consisting of gentle strokes with a soft brush administered to the forearm or palm during functional neuroimaging. RAN had a lower brain response relative to CW during anticipation of touch, but a greater response when experiencing touch in the right ventral mid-insula. In RAN, this reduced anticipatory response was associated with higher levels of harm avoidance. Exploratory analyses in RAN also suggested that lower response during touch anticipation was associated with greater body dissatisfaction and higher perceived touch intensity ratings. This reduced responsivity to the anticipation of pleasant affective interoceptive stimuli in association with higher harm avoidance, along with an elevated response to the experience of touch, suggests an impaired ability in AN to predict and interpret incoming physiological stimuli. Impaired interoception may thus impact one's sense of self, thereby supporting observations of disturbed body image and avoidance of affective and social stimuli. Therapeutic approaches that help AN to better anticipate and interpret salient affective stimuli or improve tolerance of interoceptive experiences may be an important addition to current interventions.
occipital fasciculus (left>right). TD children had more asymmetry in the corticospinal tract (lef... more occipital fasciculus (left>right). TD children had more asymmetry in the corticospinal tract (left>right). Post-hoc analyses identified underlying unilateral between-group differences in these regions (p<0.001). Conclusions: We identified hemispheric asymmetries in white matter integrity in children with WS, which may contribute to the clinical phenotype of the syndrome. Future work will explore the impact of this asymmetry on cognition and behavior.
Eating and Weight Disorders-studies on Anorexia Bulimia and Obesity, Feb 14, 2022
Research and clinical experience suggest that individuals with anorexia nervosa (AN) have deficit... more Research and clinical experience suggest that individuals with anorexia nervosa (AN) have deficits in gastric interoception, which has been hypothesized to maintain restrictive eating. Behavioral water load tasks (WLTs) have the capability to noninvasively assess gastric interoception; however, to date, no studies have examined WLTs in AN. Thus, the present proof-of-concept pilot study explored the preliminary validity of a WLT in individuals with AN. Participants were n = 10 individuals with AN and n = 10 matched-control women (CW). Participants completed self-report questionnaires before and after a WLT, in which participants were asked to drink water until “completely full”. Participants with AN drank significantly less water than CW (AN = 240(109.14) milliliters (ml), CW = 398.00(149.21) ml, p = 0.02, Cohen’s d = 1.21), but reported greater increases in negative affect pre- to-post-WLT (p = 0.04, partial eta2 = 0.21). Correlations between WLT performance and interoceptive sensibility in AN and CW participants supported the convergent validity of the WLT. Preliminary results support the potential utility of the WLT as a behavioral measure of gastric interoception in patients with AN. Future research should examine how response to the WLT changes over the course of intervention and how results are related to treatment outcome. Level IV: Evidence obtained from multiple time series analysis such as case studies. (NB: Dramatic results in uncontrolled trials might also be regarded as this type of evidence).
Background-The neural mechanisms of anorexia nervosa (AN), a severe and chronic psychiatric illne... more Background-The neural mechanisms of anorexia nervosa (AN), a severe and chronic psychiatric illness, are still poorly understood. Altered body state processing, or interoception, has been documented in AN, and disturbances in aversive interoception may contribute to distorted body perception, extreme dietary restriction, and anxiety. As prior data implicate a potential mismatch between interoceptive expectation and experience in AN, we examined whether AN is associated with altered brain activation before, during, and after an unpleasant interoceptive state change. Methods-Adult women remitted from AN (RAN; n = 17) and healthy control women (CW; n = 25) underwent functional magnetic resonance imaging during an inspiratory breathing load paradigm. Results-During stimulus anticipation, the RAN group, relative to CW, showed reduced activation in right mid-insula. In contrast, during the aversive breathing load, the RAN group showed increased activation compared with CW in striatum and cingulate and prefrontal cortices. The RAN group also showed increased activation in prefrontal cortices, bilateral insula, striatum, and amygdala after stimulus offset. Time course analyses indicated that RAN responses in interoceptive processing regions during breathing load increased more steeply than those of CW. Exploratory analyses revealed that hyperactivation during and after breathing load was associated with markers of past AN severity. Conclusions-Anticipatory deactivation with a subsequent exaggerated brain response during and after an aversive body state may contribute to difficulty predicting and adapting to internal
The neurocomputational processes underlying bulimia nervosa and its primary symptoms, out-of-cont... more The neurocomputational processes underlying bulimia nervosa and its primary symptoms, out-of-control overeating and purging, are poorly understood. Research suggests that the brains of healthy individuals form a dynamic internal model to predict whether control is needed in each moment. This study tested the hypothesis that this computational process of inhibitory control is abnormally affected by metabolic state (being fasted or fed) in bulimia nervosa. A Bayesian ideal observer model was fit to behavioral data acquired from 22 women remitted from bulimia nervosa and 20 group-matched controls who completed a stopsignal task during two counterbalanced functional MRI sessions, one after a 16 h fast and one after a meal. This model estimates participants' trial-by-trial updating of the probability of a stop signal based on their experienced trial history. Neural analyses focused on control-related Bayesian prediction errors, which quantify the direction and degree of "surprise" an individual experiences on any given trial. Regardless of group, metabolic state did not affect behavioral performance on the task. However, metabolic state modulated group differences in neural activation. In the fed state, women remitted from bulimia nervosa had attenuated prediction-error-dependent activation in the left dorsal caudate. This fed-state activation was lower among women with more frequent past binge eating and self-induced vomiting. When they are in a fed state, individuals with bulimia nervosa may not effectively process unexpected information needed to engage inhibitory control. This may explain the difficulties these individuals have stopping eating after it begins.
International Journal of Eating Disorders, Mar 30, 2022
ObjectivePrevious research examining family functioning in eating disorder (ED) treatment has foc... more ObjectivePrevious research examining family functioning in eating disorder (ED) treatment has focused primarily on outpatient settings. However, few studies have examined this aspect in partial hospitalization programs. To address this gap, this study examined family functioning over the course of an ED partial hospitalization program (PHP) in adolescent females (M(SD) age = 15.66 (1.50)).MethodParticipants (n = 105) completed the Family Assessment Device and Eating Disorder Examination Questionnaire at treatment admission, 1‐month post‐admission, and discharge.ResultsResults from repeated measures analysis of variance indicated adolescents perceived an improvement in family functioning regarding Communication, Affective Responsiveness, and Behavioral Control through 1‐year follow‐up (p values &lt; .05). Neither family functioning at admission nor change in family functioning in the first month correlated with any outcomes (weight, ED symptoms, and remission).DiscussionResults support that family functioning does not contribute to ED severity, and that treatment can improve adolescent perception of family functioning. Given the importance of involving the family in ED treatment, identifying mediators of treatment outcomes is critical to improve treatment efficacy.Public SignificanceAdolescents in a partial hospital program (PHP) for eating disorders (EDs) perceived improvements in their family communication, behavior, and ability to process appropriate emotions from admission to 1‐year post‐treatment, although these aspects did not significantly predict treatment outcomes. The findings provide helpful information for future research on adolescents with EDs in higher levels of care and underscore the importance of exploring mechanisms of family‐based treatment in PHP.
ObjectiveAlexithymia is proposed as a prominent clinical feature of eating disorders (EDs). Howev... more ObjectiveAlexithymia is proposed as a prominent clinical feature of eating disorders (EDs). However, despite theoretical reason to believe that alexithymia could interfere with the success of treatments, few studies have tested whether alexithymia changes over the course of treatment. The goals of the current study were to evaluate (a) changes in alexithymia over the course of intensive Dialectical Behaviour Therapy (DBT) for EDs, and (b) associations between alexithymia and ED symptoms over time.MethodA mixed‐diagnostic group of patients with EDs (N = 894) completed the Eating Disorders Examination—Questionnaire (EDE‐Q) and the Toronto Alexithymia Scale (TAS‐20) throughout intensive treatment and at various lengths of follow‐up (6, 12, 24 months).ResultsResults suggested that even after controlling for relevant covariates, there were significant decreases in alexithymia from intake to discharge and discharge to follow‐up. Models exploring changes in self‐reported ED symptoms indicated that TAS‐20 scores significantly related to ED symptoms across timepoints, such that greater alexithymia was associated with greater severity of symptoms.ConclusionsAltogether, findings support an association between alexithymia and ED symptoms over treatment and suggest that emotion‐focussed therapies like DBT may result in decreases in alexithymia. Future research should explore whether this effect is consistent across therapies without an emotional focus.
International Journal of Eating Disorders, Dec 31, 2018
Identifying processes that may interfere with corrective learning during treatments for anorexia ... more Identifying processes that may interfere with corrective learning during treatments for anorexia nervosa (AN) may help to improve the effectiveness of existing interventions. We propose that certain cognitive processes characteristic of the AN temperament may help explain previous findings in AN suggesting difficulty updating previously learned associations and learning from feedback. Specifically, we hypothesize that engagement in repetitive negative thinking (RNT), including worry and rumination, could interfere with corrective learning that is critical to the success of behavioral treatments. In doing so, we draw from existing work in anxiety and mood disorders linking RNT to the maintenance of symptoms and poorer response to cognitivebehavioral treatments. Next, we outline hypothesized mechanisms through which engagement in RNT before, during, and after exposure to aversive stimuli could interfere with learning in AN. We then provide recommendations for how these hypothesized associations could be tested in future research. Although prior work has suggested that RNT processes are common among individuals with AN, this work has been primarily descriptive in nature. We propose that extending this work through direct examination of the impact of active engagement in RNT on corrective learning could aid in identifying AN maintenance processes that could be explicitly targeted in treatment.
Individuals with bulimia nervosa (BN) engage in episodes of binge eating, marked by loss of contr... more Individuals with bulimia nervosa (BN) engage in episodes of binge eating, marked by loss of control and eating despite fullness. Does altered reward and metabolic state contribute to BN pathophysiology? Normally, hunger increases (and satiety decreases) reward salience to regulate eating. We investigated whether BN is associated with an abnormal response in a neural circuit involved in translating taste signals into motivated behavior, when hungry and fed. Twenty-six women remitted from BN (RBN) and 22 control women (CW) were administered water and sucrose during two counterbalanced fMRI visits, following a 16-hour fast or a standardized breakfast. Significant Group x Condition interactions were found in the left putamen, insula, and amygdala. Post-hoc analyses revealed CW were significantly more responsive to taste stimuli when hungry versus fed in the left putamen and amygdala. In contrast, RBN response did not differ between conditions. Further, RBN had greater activation in the left amygdala compared to CW when fed. Findings suggest that RBN neural response to rewarding stimuli may not be modulated by metabolic state. Data raise the possibility that disinhibited eating in BN could result from a failure to devalue food reward when fed, resulting in an exaggerated response.
The general transcription factor IIE (TFIIE) is essential for transcription initiation by RNA pol... more The general transcription factor IIE (TFIIE) is essential for transcription initiation by RNA polymerase II (RNA pol II) via direct interaction with the basal transcription/DNA repair factor IIH (TFIIH). TFIIH harbors mutations in two rare genetic disorders, the cancer-prone xeroderma pigmentosum (XP) and the cancer-free, multisystem developmental disorder trichothiodystrophy (TTD). The phenotypic complexity resulting from mutations affecting TFIIH has been attributed to the nucleotide excision repair (NER) defect as well as to impaired transcription. Here, we report two unrelated children showing clinical features typical of TTD who harbor different homozygous missense mutations in GTF2E2 (c.448G>C [p.Ala150Pro] and c.559G>T [p.Asp187Tyr]) encoding the beta subunit of transcription factor IIE (TFIIEb). Repair of ultraviolet-induced DNA damage was normal in the GTF2E2 mutated cells, indicating that TFIIE was not involved in NER. We found decreased protein levels of the two TFIIE subunits (TFIIEa and TFIIEb) as well as decreased phosphorylation of TFIIEa in cells from both children. Interestingly, decreased phosphorylation of TFIIEa was also seen in TTD cells with mutations in ERCC2, which encodes the XPD subunit of TFIIH, but not in XP cells with ERCC2 mutations. Our findings support the theory that TTD is caused by transcriptional impairments that are distinct from the NER disorder XP.
We propose a translational approach to the study of anorexia nervosa (AN) based on our human subj... more We propose a translational approach to the study of anorexia nervosa (AN) based on our human subject studies where there are characteristic elevations in 5-HT(1A) receptor binding, associated harm avoidance behaviors, reduced impulsivity, and comorbid anxiety disorders. Towards this goal, the hyponeophagia assay was implemented whereby food-deprived mice show increased latency to begin feeding in a novel, anxiogenic environment. The non-selective serotonin agonist, 5-MeODMT, potentiates feeding inhibition compared to the inhibition generated by the anxiogenic environment in a drug-by-environment interaction. Thus, using hyponeophagia in mice, it was possible to study the following key components of AN: anxiety; feeding inhibition; and a modulatory role of the serotonergic system. A major prediction of the proposed AN model is that 5-HT(1A) receptor activation is necessary for feeding inhibition. In support of this model, the 5-HT(1A) receptor antagonist, WAY100635, reverses the 5-Me...
Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric c... more Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric conditions with likely rare and common genetic and environmental determinants. To identify genetic variants associated with AN, we pursued a series of sequencing and genotyping studies focusing on the coding regions and upstream sequence of 152 candidate genes in a total of 1205 AN cases and 1948 controls. We identified individual variant associations in the Estrogen Receptor-(ESR2) gene, as well as a set of rare and common variants in the Epoxide Hydrolase 2 (EPHX2) gene, in an initial sequencing study of 261 early-onset severe AN cases and 73 controls (P ¼ 0.0004). The association of EPHX2 variants was further delineated in: (1) a pooling-based replication study involving an additional 500 AN patients and 500 controls (replication set P ¼ 0.00000016); (2) single-locus studies in a cohort of 386 previously genotyped broadly defined AN cases and 295 female population controls from the Bogalusa Heart Study (BHS) and a cohort of 58 individuals with self-reported eating disturbances and 851 controls (combined smallest single locus Po0.01). As EPHX2 is known to influence cholesterol metabolism, and AN is often associated with elevated cholesterol levels, we also investigated the association of EPHX2 variants and longitudinal body mass index (BMI) and cholesterol in BHS female and male subjects (N ¼ 229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (Po0.01). These findings suggest a novel association of gene variants within EPHX2 to susceptibility to AN and provide a foundation for future study of this important yet poorly understood condition.
Objective: Anorexia nervosa (AN) has the highest mortality rate of any psychiatric condition, yet... more Objective: Anorexia nervosa (AN) has the highest mortality rate of any psychiatric condition, yet the pathophysiology of this disorder and its primary symptom-extreme dietary restrictionremains poorly understood. In states of hunger relative to satiety, the rewarding value of food stimuli normally increases to promote eating, yet individuals with AN avoid food despite emaciation. This study aimed to examine potential neural insensitivity to these effects of hunger in AN. Method: At two counterbalanced visits, one after a 16-hour fast and one after a standardized meal, 26 women remitted from AN (RAN; to avoid the confounding effects of malnutrition) and 22 matched control women (CW) received tastes of sucrose and water while functional MRI data were acquired. Within a network-of-interest responsible for food valuation and transforming taste signals into motivation to eat, we compared groups across conditions on blood-oxygen-leveldependent (BOLD) signal and task-based functional connectivity. Results: Subjects had similar BOLD responses to sucrose and water tastants. A Group x Condition interaction in the ventral caudal putamen indicated that hunger had opposite effects on tastant response in CW and RAN participants: CW showed an increase, and RAN showed a decrease, in BOLD response when hungry. Hunger had a similar opposite effect on insula-toventral caudal putamen functional connectivity in RAN compared with CW. Exploratory analyses indicated that lower caudate response to tastants when hungry was associated with higher harm avoidance among RAN participants.
The conceptual framework regarding the aetiology of eating disorders (EDs) has changed dramatical... more The conceptual framework regarding the aetiology of eating disorders (EDs) has changed dramatically in recent decades. Cutting-edge neuroimaging techniques have led to advancements in understanding the underlying neurobiology of anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). Techniques such as magnetic resonance imaging (MRI), positron emission tomography (PET), and diffusion tensor imaging (DTI) allow the opportunity to examine not only structural, but also functional, abnormalities that contribute to extreme eating behaviours characteristic of these life-threatening disorders. Furthermore, research using imaging paradigms suggests that variations in neurobiology are associated with traits that persist after recovery. This chapter will provide insights regarding neural pathways involved in the processing of appetite, reward, mood, body perception, and cognitive inhibition as they pertain to EDs. Findings relevant to feeding disorders will also be discussed. Conclusions will include considerations of treatment applications and directions for future research.
Despite initial data suggesting positive treatment outcomes for adolescent eating disorder day-ho... more Despite initial data suggesting positive treatment outcomes for adolescent eating disorder day-hospital programmes (DHPs), existing studies have included limited follow-up, small samples, and a focus on restricting-type eating disorders. To address these gaps, we explored naturalistic outcomes for an adolescent eating disorders DHP. Adolescent participants (N = 265) completed measurements at treatment admission, discharge (n = 170), and various lengths of follow-up (n = 126; M follow up = 278.87 days). Results from multilevel models indicated significant increases in body weight for the anorexia nervosa group throughout treatment and maintenance of increased body weight from discharge to follow-up. In bulimic spectrum disorders, binge eating and purging significantly decreased from intake to discharge and did not change from discharge to follow-up. Across the entire sample, eating disorder symptoms decreased from intake to discharge and did not change from discharge to follow-up. Further, anxiety and depression decreased over the course of treatment and continued to decrease over the follow-up period. The current investigation represents the first study to explore longitudinal DHP outcomes within adolescent bulimic spectrum eating disorders. Our findings also highlight many challenges inherent in conducting naturalistic research; it is critical that the field continue to develop solutions to the barriers inherent in conducting longitudinal research on eating disorder treatment.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2010
We performed association studies with 5,151 SNPs that were judged as likely candidate genetic var... more We performed association studies with 5,151 SNPs that were judged as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN) based on location under reported linkage peaks, previous results in the literature (182 candidate genes), brain expression, biological plausibility, and estrogen responsivity. We employed a case-control design that tested each SNP individually as well as haplotypes derived from these SNPs in 1,085 case individuals with AN diagnoses and 677 control individuals. We also performed separate association analyses using three increasingly restrictive case definitions for AN: all individuals with any subtype of AN (All AN: n = 1,085); individuals with AN with no binge eating behavior (AN with No Binge Eating: n = 687); and individuals with the restricting subtype of AN (Restricting AN: n = 421). After accounting for multiple comparisons, there were no statistically significant associations for any individual SNP or haplotype block with any definition of illness. These results underscore the importance of large samples to yield appropriate power to detect genotypic differences in individuals with AN and also motivate complementary approaches involving Genome-Wide Association (GWA) studies, Copy Number Variation (CNV) analyses, sequencing-based rare variant discovery assays, and pathwaybased analysis in order to make up for deficiencies in traditional candidate gene approaches to AN.
was on the SAB of Expression Analysis (Durham, NC). Cynthia Bulik was a consultant for Shire Phar... more was on the SAB of Expression Analysis (Durham, NC). Cynthia Bulik was a consultant for Shire Pharmaceuticals at the time the manuscript was written. Federica Tozzi was full time employee of GSK at the time when the study was performed. David A. Collier was employed by Eli Lilly UK for a portion of the time that this study was performed. James L. Kennedy has received honoraria from Eli Lilly and Roche. Robert D. Levitan has received honorarium from Astra-Zeneca.
Individuals with bulimia nervosa (BN) cycle between periods of binge-eating and compensatory beha... more Individuals with bulimia nervosa (BN) cycle between periods of binge-eating and compensatory behavior and periods of dietary restraint, suggesting extremes of under and overcontrol that may be metabolic-state related. This study examined the influence of hunger and satiety on impulsivity and neural responding during decision-making. Twenty-three women remitted from BN (RBN) and 20 healthy comparison women (CW) performed a delay discounting task after a 16-hr fast and following a standardized meal during functional neuroimaging. A dual-systems approach examined reward valuation (decision trials where the early reward option was available immediately) and cognitive control (all decision trials). Interactions of Group × Visit (Hungry, Fed) for immediate reward revealed that CW had greater activation when hungry versus fed in the ventral striatum and dorsal caudate, whereas RBN had greater response when fed versus hungry in the dorsal caudate. Compared to CW, RBN showed decreased response when hungry within the left dorsal caudate and ventral striatum and increased response when fed in bilateral dorsal caudate. No differences were found within cognitive control regions or with choice behavior. Reward sensitivity is normally increased when hungry and decreased when fed; our findings in CW provide further support of hunger-based reward sensitivity within the striatum. However, RBN showed no differences for hunger and satiety in the ventral striatum and greater activation in the dorsal caudate when fed compared to hungry. This suggests RBN may be less sensitive to reward when hungry but do not devalue reward when satiated, indicating altered metabolic modulation of self-regulatory control. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Background and objectives: Intolerance of uncertainty (IU) is a transdiagnostic process contribut... more Background and objectives: Intolerance of uncertainty (IU) is a transdiagnostic process contributing to the maintenance of anxiety disorders, and is a potential target for treatment. Recent literature has investigated IU as a cognitive process underpinning pathological fear and anxiety in Anorexia Nervosa (AN). The current study was designed to examine trait and state IU, and their relationship to restrictive eating disorder symptoms, anxiety, worry, cognitive rigidity and eating behaviour. Methods: A sample of undergraduate women (N = 85) completed measures of eating disorder symptoms, IU, cognitive rigidity and worry. Participants were randomised to complete an eating task under one of two conditions: the "certain" condition received a high-calorie meal and nutritional information, while the "uncertain" condition received the meal alone. During the meal, state IU and state anxiety were examined at three time-points (baseline, pre-eating, post-eating). Results: Trait IU was correlated with cognitive rigidity, worry, global eating disorder symptoms, and, in particular, dietary restraint. No differences emerged between conditions with respect to eating-related anxiety, or amount of food eaten. Controlling for condition and eating disorder symptoms, state IU predicted pre-eating anxiety. Beyond the contribution of condition, BMI and eating disorder symptoms, state IU predicted consumption, specifically greater dietary restriction. Limitations: The study employed a non-clinical sample. Conclusions: IU may be implicated in a rigid cognitive style, the anxiety response to energy-dense food, and restrictive eating behaviour. Should these findings be replicated in a clinical sample, then IU might emerge as an adjunctive treatment target for AN.
Interoception, or the sensing and integration of bodily state signals, has been implicated in ano... more Interoception, or the sensing and integration of bodily state signals, has been implicated in anorexia nervosa (AN), given that the hallmark symptoms involve food restriction and body image disturbance. Here we focus on brain response to the anticipation and experience of affective interoceptive stimuli. Women remitted from AN (RAN; N = 18) and healthy comparison women (CW; N = 26) underwent a pleasant affective touch paradigm consisting of gentle strokes with a soft brush administered to the forearm or palm during functional neuroimaging. RAN had a lower brain response relative to CW during anticipation of touch, but a greater response when experiencing touch in the right ventral mid-insula. In RAN, this reduced anticipatory response was associated with higher levels of harm avoidance. Exploratory analyses in RAN also suggested that lower response during touch anticipation was associated with greater body dissatisfaction and higher perceived touch intensity ratings. This reduced responsivity to the anticipation of pleasant affective interoceptive stimuli in association with higher harm avoidance, along with an elevated response to the experience of touch, suggests an impaired ability in AN to predict and interpret incoming physiological stimuli. Impaired interoception may thus impact one's sense of self, thereby supporting observations of disturbed body image and avoidance of affective and social stimuli. Therapeutic approaches that help AN to better anticipate and interpret salient affective stimuli or improve tolerance of interoceptive experiences may be an important addition to current interventions.
occipital fasciculus (left>right). TD children had more asymmetry in the corticospinal tract (lef... more occipital fasciculus (left>right). TD children had more asymmetry in the corticospinal tract (left>right). Post-hoc analyses identified underlying unilateral between-group differences in these regions (p<0.001). Conclusions: We identified hemispheric asymmetries in white matter integrity in children with WS, which may contribute to the clinical phenotype of the syndrome. Future work will explore the impact of this asymmetry on cognition and behavior.
Eating and Weight Disorders-studies on Anorexia Bulimia and Obesity, Feb 14, 2022
Research and clinical experience suggest that individuals with anorexia nervosa (AN) have deficit... more Research and clinical experience suggest that individuals with anorexia nervosa (AN) have deficits in gastric interoception, which has been hypothesized to maintain restrictive eating. Behavioral water load tasks (WLTs) have the capability to noninvasively assess gastric interoception; however, to date, no studies have examined WLTs in AN. Thus, the present proof-of-concept pilot study explored the preliminary validity of a WLT in individuals with AN. Participants were n = 10 individuals with AN and n = 10 matched-control women (CW). Participants completed self-report questionnaires before and after a WLT, in which participants were asked to drink water until “completely full”. Participants with AN drank significantly less water than CW (AN = 240(109.14) milliliters (ml), CW = 398.00(149.21) ml, p = 0.02, Cohen’s d = 1.21), but reported greater increases in negative affect pre- to-post-WLT (p = 0.04, partial eta2 = 0.21). Correlations between WLT performance and interoceptive sensibility in AN and CW participants supported the convergent validity of the WLT. Preliminary results support the potential utility of the WLT as a behavioral measure of gastric interoception in patients with AN. Future research should examine how response to the WLT changes over the course of intervention and how results are related to treatment outcome. Level IV: Evidence obtained from multiple time series analysis such as case studies. (NB: Dramatic results in uncontrolled trials might also be regarded as this type of evidence).
Background-The neural mechanisms of anorexia nervosa (AN), a severe and chronic psychiatric illne... more Background-The neural mechanisms of anorexia nervosa (AN), a severe and chronic psychiatric illness, are still poorly understood. Altered body state processing, or interoception, has been documented in AN, and disturbances in aversive interoception may contribute to distorted body perception, extreme dietary restriction, and anxiety. As prior data implicate a potential mismatch between interoceptive expectation and experience in AN, we examined whether AN is associated with altered brain activation before, during, and after an unpleasant interoceptive state change. Methods-Adult women remitted from AN (RAN; n = 17) and healthy control women (CW; n = 25) underwent functional magnetic resonance imaging during an inspiratory breathing load paradigm. Results-During stimulus anticipation, the RAN group, relative to CW, showed reduced activation in right mid-insula. In contrast, during the aversive breathing load, the RAN group showed increased activation compared with CW in striatum and cingulate and prefrontal cortices. The RAN group also showed increased activation in prefrontal cortices, bilateral insula, striatum, and amygdala after stimulus offset. Time course analyses indicated that RAN responses in interoceptive processing regions during breathing load increased more steeply than those of CW. Exploratory analyses revealed that hyperactivation during and after breathing load was associated with markers of past AN severity. Conclusions-Anticipatory deactivation with a subsequent exaggerated brain response during and after an aversive body state may contribute to difficulty predicting and adapting to internal
The neurocomputational processes underlying bulimia nervosa and its primary symptoms, out-of-cont... more The neurocomputational processes underlying bulimia nervosa and its primary symptoms, out-of-control overeating and purging, are poorly understood. Research suggests that the brains of healthy individuals form a dynamic internal model to predict whether control is needed in each moment. This study tested the hypothesis that this computational process of inhibitory control is abnormally affected by metabolic state (being fasted or fed) in bulimia nervosa. A Bayesian ideal observer model was fit to behavioral data acquired from 22 women remitted from bulimia nervosa and 20 group-matched controls who completed a stopsignal task during two counterbalanced functional MRI sessions, one after a 16 h fast and one after a meal. This model estimates participants' trial-by-trial updating of the probability of a stop signal based on their experienced trial history. Neural analyses focused on control-related Bayesian prediction errors, which quantify the direction and degree of "surprise" an individual experiences on any given trial. Regardless of group, metabolic state did not affect behavioral performance on the task. However, metabolic state modulated group differences in neural activation. In the fed state, women remitted from bulimia nervosa had attenuated prediction-error-dependent activation in the left dorsal caudate. This fed-state activation was lower among women with more frequent past binge eating and self-induced vomiting. When they are in a fed state, individuals with bulimia nervosa may not effectively process unexpected information needed to engage inhibitory control. This may explain the difficulties these individuals have stopping eating after it begins.
International Journal of Eating Disorders, Mar 30, 2022
ObjectivePrevious research examining family functioning in eating disorder (ED) treatment has foc... more ObjectivePrevious research examining family functioning in eating disorder (ED) treatment has focused primarily on outpatient settings. However, few studies have examined this aspect in partial hospitalization programs. To address this gap, this study examined family functioning over the course of an ED partial hospitalization program (PHP) in adolescent females (M(SD) age = 15.66 (1.50)).MethodParticipants (n = 105) completed the Family Assessment Device and Eating Disorder Examination Questionnaire at treatment admission, 1‐month post‐admission, and discharge.ResultsResults from repeated measures analysis of variance indicated adolescents perceived an improvement in family functioning regarding Communication, Affective Responsiveness, and Behavioral Control through 1‐year follow‐up (p values &lt; .05). Neither family functioning at admission nor change in family functioning in the first month correlated with any outcomes (weight, ED symptoms, and remission).DiscussionResults support that family functioning does not contribute to ED severity, and that treatment can improve adolescent perception of family functioning. Given the importance of involving the family in ED treatment, identifying mediators of treatment outcomes is critical to improve treatment efficacy.Public SignificanceAdolescents in a partial hospital program (PHP) for eating disorders (EDs) perceived improvements in their family communication, behavior, and ability to process appropriate emotions from admission to 1‐year post‐treatment, although these aspects did not significantly predict treatment outcomes. The findings provide helpful information for future research on adolescents with EDs in higher levels of care and underscore the importance of exploring mechanisms of family‐based treatment in PHP.
ObjectiveAlexithymia is proposed as a prominent clinical feature of eating disorders (EDs). Howev... more ObjectiveAlexithymia is proposed as a prominent clinical feature of eating disorders (EDs). However, despite theoretical reason to believe that alexithymia could interfere with the success of treatments, few studies have tested whether alexithymia changes over the course of treatment. The goals of the current study were to evaluate (a) changes in alexithymia over the course of intensive Dialectical Behaviour Therapy (DBT) for EDs, and (b) associations between alexithymia and ED symptoms over time.MethodA mixed‐diagnostic group of patients with EDs (N = 894) completed the Eating Disorders Examination—Questionnaire (EDE‐Q) and the Toronto Alexithymia Scale (TAS‐20) throughout intensive treatment and at various lengths of follow‐up (6, 12, 24 months).ResultsResults suggested that even after controlling for relevant covariates, there were significant decreases in alexithymia from intake to discharge and discharge to follow‐up. Models exploring changes in self‐reported ED symptoms indicated that TAS‐20 scores significantly related to ED symptoms across timepoints, such that greater alexithymia was associated with greater severity of symptoms.ConclusionsAltogether, findings support an association between alexithymia and ED symptoms over treatment and suggest that emotion‐focussed therapies like DBT may result in decreases in alexithymia. Future research should explore whether this effect is consistent across therapies without an emotional focus.
International Journal of Eating Disorders, Dec 31, 2018
Identifying processes that may interfere with corrective learning during treatments for anorexia ... more Identifying processes that may interfere with corrective learning during treatments for anorexia nervosa (AN) may help to improve the effectiveness of existing interventions. We propose that certain cognitive processes characteristic of the AN temperament may help explain previous findings in AN suggesting difficulty updating previously learned associations and learning from feedback. Specifically, we hypothesize that engagement in repetitive negative thinking (RNT), including worry and rumination, could interfere with corrective learning that is critical to the success of behavioral treatments. In doing so, we draw from existing work in anxiety and mood disorders linking RNT to the maintenance of symptoms and poorer response to cognitivebehavioral treatments. Next, we outline hypothesized mechanisms through which engagement in RNT before, during, and after exposure to aversive stimuli could interfere with learning in AN. We then provide recommendations for how these hypothesized associations could be tested in future research. Although prior work has suggested that RNT processes are common among individuals with AN, this work has been primarily descriptive in nature. We propose that extending this work through direct examination of the impact of active engagement in RNT on corrective learning could aid in identifying AN maintenance processes that could be explicitly targeted in treatment.
Individuals with bulimia nervosa (BN) engage in episodes of binge eating, marked by loss of contr... more Individuals with bulimia nervosa (BN) engage in episodes of binge eating, marked by loss of control and eating despite fullness. Does altered reward and metabolic state contribute to BN pathophysiology? Normally, hunger increases (and satiety decreases) reward salience to regulate eating. We investigated whether BN is associated with an abnormal response in a neural circuit involved in translating taste signals into motivated behavior, when hungry and fed. Twenty-six women remitted from BN (RBN) and 22 control women (CW) were administered water and sucrose during two counterbalanced fMRI visits, following a 16-hour fast or a standardized breakfast. Significant Group x Condition interactions were found in the left putamen, insula, and amygdala. Post-hoc analyses revealed CW were significantly more responsive to taste stimuli when hungry versus fed in the left putamen and amygdala. In contrast, RBN response did not differ between conditions. Further, RBN had greater activation in the left amygdala compared to CW when fed. Findings suggest that RBN neural response to rewarding stimuli may not be modulated by metabolic state. Data raise the possibility that disinhibited eating in BN could result from a failure to devalue food reward when fed, resulting in an exaggerated response.
The general transcription factor IIE (TFIIE) is essential for transcription initiation by RNA pol... more The general transcription factor IIE (TFIIE) is essential for transcription initiation by RNA polymerase II (RNA pol II) via direct interaction with the basal transcription/DNA repair factor IIH (TFIIH). TFIIH harbors mutations in two rare genetic disorders, the cancer-prone xeroderma pigmentosum (XP) and the cancer-free, multisystem developmental disorder trichothiodystrophy (TTD). The phenotypic complexity resulting from mutations affecting TFIIH has been attributed to the nucleotide excision repair (NER) defect as well as to impaired transcription. Here, we report two unrelated children showing clinical features typical of TTD who harbor different homozygous missense mutations in GTF2E2 (c.448G>C [p.Ala150Pro] and c.559G>T [p.Asp187Tyr]) encoding the beta subunit of transcription factor IIE (TFIIEb). Repair of ultraviolet-induced DNA damage was normal in the GTF2E2 mutated cells, indicating that TFIIE was not involved in NER. We found decreased protein levels of the two TFIIE subunits (TFIIEa and TFIIEb) as well as decreased phosphorylation of TFIIEa in cells from both children. Interestingly, decreased phosphorylation of TFIIEa was also seen in TTD cells with mutations in ERCC2, which encodes the XPD subunit of TFIIH, but not in XP cells with ERCC2 mutations. Our findings support the theory that TTD is caused by transcriptional impairments that are distinct from the NER disorder XP.
We propose a translational approach to the study of anorexia nervosa (AN) based on our human subj... more We propose a translational approach to the study of anorexia nervosa (AN) based on our human subject studies where there are characteristic elevations in 5-HT(1A) receptor binding, associated harm avoidance behaviors, reduced impulsivity, and comorbid anxiety disorders. Towards this goal, the hyponeophagia assay was implemented whereby food-deprived mice show increased latency to begin feeding in a novel, anxiogenic environment. The non-selective serotonin agonist, 5-MeODMT, potentiates feeding inhibition compared to the inhibition generated by the anxiogenic environment in a drug-by-environment interaction. Thus, using hyponeophagia in mice, it was possible to study the following key components of AN: anxiety; feeding inhibition; and a modulatory role of the serotonergic system. A major prediction of the proposed AN model is that 5-HT(1A) receptor activation is necessary for feeding inhibition. In support of this model, the 5-HT(1A) receptor antagonist, WAY100635, reverses the 5-Me...
Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric c... more Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric conditions with likely rare and common genetic and environmental determinants. To identify genetic variants associated with AN, we pursued a series of sequencing and genotyping studies focusing on the coding regions and upstream sequence of 152 candidate genes in a total of 1205 AN cases and 1948 controls. We identified individual variant associations in the Estrogen Receptor-(ESR2) gene, as well as a set of rare and common variants in the Epoxide Hydrolase 2 (EPHX2) gene, in an initial sequencing study of 261 early-onset severe AN cases and 73 controls (P ¼ 0.0004). The association of EPHX2 variants was further delineated in: (1) a pooling-based replication study involving an additional 500 AN patients and 500 controls (replication set P ¼ 0.00000016); (2) single-locus studies in a cohort of 386 previously genotyped broadly defined AN cases and 295 female population controls from the Bogalusa Heart Study (BHS) and a cohort of 58 individuals with self-reported eating disturbances and 851 controls (combined smallest single locus Po0.01). As EPHX2 is known to influence cholesterol metabolism, and AN is often associated with elevated cholesterol levels, we also investigated the association of EPHX2 variants and longitudinal body mass index (BMI) and cholesterol in BHS female and male subjects (N ¼ 229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (Po0.01). These findings suggest a novel association of gene variants within EPHX2 to susceptibility to AN and provide a foundation for future study of this important yet poorly understood condition.
Objective: Anorexia nervosa (AN) has the highest mortality rate of any psychiatric condition, yet... more Objective: Anorexia nervosa (AN) has the highest mortality rate of any psychiatric condition, yet the pathophysiology of this disorder and its primary symptom-extreme dietary restrictionremains poorly understood. In states of hunger relative to satiety, the rewarding value of food stimuli normally increases to promote eating, yet individuals with AN avoid food despite emaciation. This study aimed to examine potential neural insensitivity to these effects of hunger in AN. Method: At two counterbalanced visits, one after a 16-hour fast and one after a standardized meal, 26 women remitted from AN (RAN; to avoid the confounding effects of malnutrition) and 22 matched control women (CW) received tastes of sucrose and water while functional MRI data were acquired. Within a network-of-interest responsible for food valuation and transforming taste signals into motivation to eat, we compared groups across conditions on blood-oxygen-leveldependent (BOLD) signal and task-based functional connectivity. Results: Subjects had similar BOLD responses to sucrose and water tastants. A Group x Condition interaction in the ventral caudal putamen indicated that hunger had opposite effects on tastant response in CW and RAN participants: CW showed an increase, and RAN showed a decrease, in BOLD response when hungry. Hunger had a similar opposite effect on insula-toventral caudal putamen functional connectivity in RAN compared with CW. Exploratory analyses indicated that lower caudate response to tastants when hungry was associated with higher harm avoidance among RAN participants.
The conceptual framework regarding the aetiology of eating disorders (EDs) has changed dramatical... more The conceptual framework regarding the aetiology of eating disorders (EDs) has changed dramatically in recent decades. Cutting-edge neuroimaging techniques have led to advancements in understanding the underlying neurobiology of anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). Techniques such as magnetic resonance imaging (MRI), positron emission tomography (PET), and diffusion tensor imaging (DTI) allow the opportunity to examine not only structural, but also functional, abnormalities that contribute to extreme eating behaviours characteristic of these life-threatening disorders. Furthermore, research using imaging paradigms suggests that variations in neurobiology are associated with traits that persist after recovery. This chapter will provide insights regarding neural pathways involved in the processing of appetite, reward, mood, body perception, and cognitive inhibition as they pertain to EDs. Findings relevant to feeding disorders will also be discussed. Conclusions will include considerations of treatment applications and directions for future research.
Despite initial data suggesting positive treatment outcomes for adolescent eating disorder day-ho... more Despite initial data suggesting positive treatment outcomes for adolescent eating disorder day-hospital programmes (DHPs), existing studies have included limited follow-up, small samples, and a focus on restricting-type eating disorders. To address these gaps, we explored naturalistic outcomes for an adolescent eating disorders DHP. Adolescent participants (N = 265) completed measurements at treatment admission, discharge (n = 170), and various lengths of follow-up (n = 126; M follow up = 278.87 days). Results from multilevel models indicated significant increases in body weight for the anorexia nervosa group throughout treatment and maintenance of increased body weight from discharge to follow-up. In bulimic spectrum disorders, binge eating and purging significantly decreased from intake to discharge and did not change from discharge to follow-up. Across the entire sample, eating disorder symptoms decreased from intake to discharge and did not change from discharge to follow-up. Further, anxiety and depression decreased over the course of treatment and continued to decrease over the follow-up period. The current investigation represents the first study to explore longitudinal DHP outcomes within adolescent bulimic spectrum eating disorders. Our findings also highlight many challenges inherent in conducting naturalistic research; it is critical that the field continue to develop solutions to the barriers inherent in conducting longitudinal research on eating disorder treatment.
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