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1.  5-HT1A Receptor Binding is Increased After Recovery from Bulimia Nervosa Compared to Control Women and is Associated with Behavioral Inhibition in Both Groups 
Objective
Because altered serotonin (5-HT) function appears to persist after recovery from bulimia nervosa (RBN), we investigated the 5-HT1A receptor, which could contribute to regulation of appetite, mood, impulse control, or the response to antidepressants.
Method
Thirteen RBN individuals were compared to 21 healthy control women (CW) using positron emission tomography and [carbonyl-11C]WAY100635 ([11C]WAY).
Results
RBN had a 23–34% elevation of [11C]WAY binding potential (BP)P in subgenual cingulate, mesial temporal, and parietal regions after adjustments for multiple comparisons. For CW, [11C]WAY BPP was related negatively to novelty seeking, whereas for RBN, [11C]WAY BPP was related positively to harm avoidance and negatively related to sensation seeking.
Discussion
Alterations of 5-HT1A receptor function may provide new insight into efficacy of 5-HT medication in BN, as well as symptoms such as the ability to inhibit or self-control the expression of behaviors related to stimulus seeking, aggression, and impulsivity.
doi:10.1002/eat.20843
PMCID: PMC4286242  PMID: 20872754
bulimia nervosa; 5-HT1A receptor; positron emission tomography; behavioral inhibition; subgenual cingulate; mesial temporal cortex
2.  Altered Striatal Response to Reward in Bulimia Nervosa After Recovery 
Objective
It is possible that disturbances of systems modulating reward may contribute to a vulnerability to develop an eating disorder.
Method
This hypothesis was tested by assessing functional magnetic resonance brain imaging response to a monetary reward task known to activate the anterior ventral striatum (AVS), a region implicated in motivational aspects toward stimuli. To avoid the confounding effects of malnutrition, 10 women who had recovered from bulimia nervosa (BN) were compared with 10 healthy comparison women (CW).
Results
For the AVS, CW distinguished positive and negative feedback, whereas recovered BN women had similar responses to both conditions. In addition, these groups had similar patterns of findings for the dorsal caudate.
Discussion
We have previously shown that individuals recovered from anorexia nervosa (AN) also had altered striatal responses and difficulties in differentiating positive and negative feedback. Thus BN and AN individuals may share a difficulty in discriminating the emotional significance of a stimulus.
doi:10.1002/eat.20699
PMCID: PMC4286149  PMID: 19434606
bulimia nervosa; magnetic resonance imaging; reward; recovery; striatum
3.  Altered brain response to reward and punishment in adolescents with Anorexia Nervosa 
Psychiatry research  2013;214(3):10.1016/j.pscychresns.2013.07.004.
Adults recovered from anorexia nervosa (AN) have altered reward modulation within striatal limbic regions associated with the emotional significance of stimuli, and executive regions concerned with planning and consequences. We hypothesized that adolescents with AN would show similar disturbed reward modulation within the striatum and the anterior cingulate cortex, a region connected to the striatum and involved in reward-guided action selection. Using functional magnetic resonance imaging, twenty-two adolescent females (10 restricting-type AN, 12 healthy volunteers) performed a monetary guessing task. Time series data associated with monetary wins and losses within striatal and cingulate regions of interest were subjected to a linear mixed effects analysis. All participants responded more strongly to wins versus losses in limbic and anterior executive striatal territories. However, AN participants exhibited an exaggerated response to losses compared to wins in posterior executive and sensorimotor striatal regions, suggesting altered function in circuitry responsible for coding the affective context of stimuli and action selection based upon these valuations. As AN individuals are particularly sensitive to criticism, failure, and making mistakes, these findings may reflect the neural processes responsible for a bias in those with AN to exaggerate negative consequences.
doi:10.1016/j.pscychresns.2013.07.004
PMCID: PMC3880152  PMID: 24148909
Anorexia Nervosa; functional magnetic resonance imaging; reward; striatum; cingulate
4.  High-fat taste challenge reveals altered striatal response in women recovered from bulimia nervosa: A pilot study 
Objectives
Individuals with anorexia nervosa (AN) and bulimia nervosa (BN) tend to have disordered thinking and eating behaviours in regards to fat containing foods. This is the first study to investigate neuronal pathways that may contribute to altered fat consumption in eating disordered patients.
Methods
We used functional magnetic resonance imaging (fMRI) to compare responses to a high-fat cream stimulus, water, and a non-caloric viscous stimulus (CMC) to control for response to viscosity in individuals recovered from AN (N = 15), BN (N = 14) and a healthy control sample (CW, N = 18).
Results
An interaction analysis (ANOVAR) comparing the three groups (AN, BN, CW) and the three conditions (cream, CMC, water) revealed significant differences in the left anterior ventral striatum (AVS). A post hoc analysis displayed a higher magnitude of response for the contrast cream/water in BN compared to AN or CW and for the contrast CMC/water in BN compared to AN.
Conclusions
BN showed an exaggerated AVS response for the cream/water contrast in comparison to AN or CW. Moreover, BN showed an exaggerated AVS response for the CMC/water contrast in comparison to AN. These findings support the possibility that BN have an altered hedonic and/or motivational drive to consume fats.
doi:10.3109/15622975.2012.671958
PMCID: PMC4301574  PMID: 22540408
Anorexia nervosa; bulimia nervosa; fMRI; striatum; fat
5.  Altered 5-HT2A Receptor Binding after Recovery from Bulimia-Type Anorexia Nervosa: Relationships to Harm Avoidance and Drive for Thinness 
Several lines of evidence suggest that a disturbance of serotonin neuronal pathways may contribute to the pathogenesis of anorexia nervosa (AN) and bulimia nervosa (BN). This study applied positron emission tomography (PET) to investigate the brain serotonin 2A (5-HT2A) receptor, which could contribute to disturbances of appetite and behavior in AN and BN. To avoid the confounding effects of malnutrition, we studied 10 women recovered from bulimia-type AN (REC AN–BN, >1 year normal weight, regular menstrual cycles, no binging, or purging) compared with 16 healthy control women (CW) using PET imaging and a specific 5-HT2A receptor antagonist, [18F]altanserin. REC AN–BN women had significantly reduced [18F]altanserin binding potential relative to CW in the left subgenual cingulate, the left parietal cortex, and the right occipital cortex. [18F]altanserin binding potential was positively related to harm avoidance and negatively related to novelty seeking in cingulate and temporal regions only in REC AN–BN subjects. In addition, REC AN–BN had negative relationships between [18F]altanserin binding potential and drive for thinness in several cortical regions. In conclusion, this study extends research suggesting that altered 5-HT neuronal system activity persists after recovery from bulimia-type AN, particularly in subgenual cingulate regions. Altered 5-HT neurotransmission after recovery also supports the possibility that this may be a trait-related disturbance that contributes to the pathophysiology of eating disorders. It is possible that subgenual cingulate findings are not specific for AN–BN, but may be related to the high incidence of lifetime major depressive disorder diagnosis in these subjects.
doi:10.1038/sj.npp.1300430
PMCID: PMC4301578  PMID: 15054474
anorexia nervosa; bulimia nervosa; serotonin; receptor; cingulate cortex; positron emission tomography
6.  Primary Amenorrhea in Anorexia Nervosa: Impact on Characteristic Masculine and Feminine Traits 
Animal studies indicate gonadal hormones at puberty have an effect on the development of masculine and feminine traits. However, it is unknown whether similar processes occur in humans. We examined whether women with anorexia nervosa (AN), who often experience primary amenorrhea, exhibit attenuated feminization in their psychological characteristics in adulthood due to the decrease/absence of gonadal hormones at puberty. Women with AN were compared on a number of psychological characteristics using General Linear Models based on the presence/absence of primary amenorrhea. Although women with primary amenorrhea exhibited lower anxiety scores than those without primary amenorrhea, in general, results did not provide evidence of attenuated feminization in women with AN with primary amenorrhea. Future research should utilize novel techniques and direct hormone measurement to explore the effects of pubertal gonadal hormones on masculine and feminine traits.
doi:10.1002/erv.2263
PMCID: PMC4266542  PMID: 24123541
Organizational effects; sex differences; amenorrhea; pubertal timing; anorexia nervosa
7.  Interaction between serotonin transporter and dopamine D2/D3 receptor radioligand measures is associated with harm avoidant symptoms in anorexia and bulimia nervosa 
Psychiatry research  2012;211(2):10.1016/j.pscychresns.2012.06.010.
Rationale
Individuals with anorexia nervosa (AN) and bulimia nervosa (BN) have alterations of measures of serotonin (5-HT) and dopamine (DA) function, which persist after long-term recovery and are associated with elevated harm avoidance (HA), a measure of anxiety and behavioral inhibition.
Objective
Based on theories that 5-HT is an aversive motivational system that may oppose a DA-related appetitive system, we explored interactions of positron emission tomography (PET) radioligand measures that reflect portions of these systems.
Methods
Twenty-seven individuals recovered (REC) from eating disorders (EDs) (7 AN-BN, 11 AN, 9 BN) and 9 control women (CW) were analyzed for correlations between [11C]McN5652 and [11C]raclopride binding.
Results
There was a positive correlation between [11C]McN5652 binding potential BPnon displaceable(ND)) and [11C]raclopride BPND for the dorsal caudate (r(27) = .62; p < .001), antero-ventral striatum (r(27) = .55, p = .003), middle caudate (r(27) = .68; p < .001), ventral (r(27) = .64; p < .001) and dorsal putamen (r(27) = .42; p = .03). No significant correlations were found in CW. [11C]raclopride BPND, but not [11C]McN5652 BPND, was significantly related to HA in REC EDs. A linear regression analysis showed that the interaction between [11C]McN5652 BPND and [11C]raclopride BPND in the dorsal putamen significantly (b = 140.04; t (22) = 2.21; p = .04) predicted HA.
Conclusions
This is the first study using PET and the radioligands [11C]McN5652 and [11C]raclopride to show a direct relationship between 5-HT transporter and striatal DA D2/D3 receptor binding in humans, supporting the possibility that 5-HT and DA interactions contribute to HA behaviors in EDs.
doi:10.1016/j.pscychresns.2012.06.010
PMCID: PMC3880148  PMID: 23154100
anorexia nervosa; bulimia nervosa; positron emission tomography; dopamine; serotonin; harm avoidance
8.  Are Extremes of Consumption in Eating Disorders Related to an Altered Balance between Reward and Inhibition? 
The primary defining characteristic of a diagnosis of an eating disorder (ED) is the “disturbance of eating or eating-related behavior that results in the altered consumption or absorption of food” (DSM V; American Psychiatric Association, 2013). There is a spectrum, ranging from those who severely restrict eating and become emaciated on one end to those who binge and overconsume, usually accompanied by some form of compensatory behaviors, on the other. How can we understand reasons for such extremes of food consummatory behaviors? Recent work on obesity and substance use disorders has identified behaviors and neural pathways that play a powerful role in human consummatory behaviors. That is, corticostriatal limbic and dorsal cognitive neural circuitry can make drugs and food rewarding, but also engage self-control mechanisms that may inhibit their use. Importantly, there is considerable evidence that alterations of these systems also occur in ED. This paper explores the hypothesis that an altered balance of reward and inhibition contributes to altered extremes of response to salient stimuli, such as food. We will review recent studies that show altered sensitivity to reward and punishment in ED, with evidence of altered activity in corticostriatal and insula processes with respect to monetary gains or losses, and tastes of palatable foods. We will also discuss evidence for a spectrum of extremes of inhibition and dysregulation behaviors in ED supported by studies suggesting that this is related to top-down self-control mechanisms. The lack of a mechanistic understanding of ED has thwarted efforts for evidence-based approaches to develop interventions. Understanding how ED behavior is encoded in neural circuits would provide a foundation for developing more specific and effective treatment approaches.
doi:10.3389/fnbeh.2014.00410
PMCID: PMC4260511  PMID: 25538579
anorexia nervosa; bulimia nervosa; eating disorders; reward processing; inhibition; cognitive control; gustatory processing
9.  Current Status of Functional Imaging in Eating Disorders 
The International journal of eating disorders  2012;45(6):10.1002/eat.22016.
Eating Disorders are complex psychiatric problems that involve biologic and psychological factors. Brain imaging studies provide insights how functionally connected brain networks may contribute to disturbed eating behavior, resulting in food refusal and altered body weight, but also body preoccupations and heightened anxiety. In this article we review the current state of brain imaging in eating disorders, and how such techniques may help identify pathways that could be important in the treatment of those often detrimental disorders.
doi:10.1002/eat.22016
PMCID: PMC3872533  PMID: 22532388
10.  Alterations in white matter microstructure in women recovered from anorexia nervosa 
The International journal of eating disorders  2013;46(7):10.1002/eat.22154.
Objective
A recent study of ill individuals with anorexia nervosa (AN) reported microstructural alterations in white matter integrity including lower fractional anisotropy and higher mean diffusivity. The present study was designed to determine whether such alterations exist in longterm recovered AN individuals and to examine potential associations with underlying AN traits.
Method
Twelve adult women recovered from restricting-type AN and 10 control women were studied using diffusion tensor imaging.
Results
Overall, there was no significant fractional anisotropy alteration in recovered AN, in contrast to a prior study reporting lower fractional anisotropy in ill AN. Further, recovered AN showed lower mean diffusivity in frontal, parietal and cingulum white matter relative to control women, contrary to elevated mean diffusivity previously reported in ill AN. Lower longitudinal diffusivity in recovered AN was associated with higher harm avoidance. However, more severe illness history was associated with worse white matter integrity after recovery in the same direction as reported in prior work.
Discussion
Our findings suggest that fractional anisotropy in recovered AN is not different from controls, however, a novel pattern of lower mean diffusivity was evidenced in recovered AN, and this alteration was associated with harm avoidance. Notably, severity of illness history may have long-term consequences, emphasizing the importance of aggressive treatment.
doi:10.1002/eat.22154
PMCID: PMC3812403  PMID: 23818167
eating disorders; anorexia nervosa; white matter; diffusion tensor imaging; harm avoidance; anxiety
11.  Differential weight restoration on olanzapine versus fluoxetine in identical twins with anorexia nervosa 
Objective
No studies have compared the response to selective serotonin reuptake inhibitors and atypical antipsychotics in anorexia nervosa. This case study examines such a comparison.
Method
This report describes a case of 12-year-old identical twins with anorexia nervosa, one of whom was treated with olanzapine and the other with fluoxetine, while undergoing family therapy.
Results
Twin A treated with fluoxetine went from 75% to 84.4% ideal body weight, while Twin B treated with olanzapine went from 72% to 99.9% ideal body weight over the course of 9 months.
Discussion
This case supports the need for adequately powered, controlled clinical trials to test the efficacy of olanzapine in adolescents presenting with anorexia nervosa.
doi:10.1002/eat.20917
PMCID: PMC3579522  PMID: 21344468
12.  Factors Associated With Recovery from Anorexia Nervosa 
Journal of psychiatric research  2013;47(7):972-979.
Previous studies of prognostic factors of anorexia nervosa (AN) course and recovery have followed clinical populations after treatment discharge. This retrospective study examined the association between prognostic factors—eating disorder features, personality traits, and psychiatric comorbidity—and likelihood of recovery in a large sample of women with AN participating in a multi-site genetic study. The study included 680 women with AN. Recovery was defined as the offset of AN symptoms if the participant experienced at least one year without any eating disorder symptoms of low weight, dieting, binge eating, and inappropriate compensatory behaviors. Participants completed a structured interview about eating disorders features, psychiatric comorbidity, and self-report measures of personality. Survival analysis was applied to model time to recovery from AN. Cox regression models were used to fit associations between predictors and the probability of recovery. In the final model, likelihood of recovery was significantly predicted by the following prognostic factors: vomiting, impulsivity, and trait anxiety. Self-induced vomiting and greater trait anxiety were negative prognostic factors and predicted lower likelihood of recovery. Greater impulsivity was a positive prognostic factor and predicted greater likelihood of recovery. There was a significant interaction between impulsivity and time; the association between impulsivity and likelihood of recovery decreased as duration of AN increased. The anxiolytic function of some AN behaviors may impede recovery for individuals with greater trait anxiety.
doi:10.1016/j.jpsychires.2013.02.011
PMCID: PMC3682792  PMID: 23535032
Eating disorders; anorexia nervosa; recovery; prognostic factors; personality; comorbidity
13.  Does a shared neurobiology for foods and drugs of abuse contribute to extremes of food ingestion in anorexia and bulimia nervosa? 
Biological psychiatry  2013;73(9):836-842.
Is starvation in anorexia nervosa (AN) or overeating in bulimia nervosa (BN) a form of addiction? Alternatively, why are individuals with BN more vulnerable and AN protected from substance abuse? Such questions have been generated by recent studies that suggest that there are overlapping neural circuits for foods and drugs of abuse.
In order to determine whether a shared neurobiology contributes to eating disorders (EDs) and substance abuse, this review focused on imaging studies that investigated response to tastes of food and tasks designed to characterize reward and behavioral inhibition in AN and BN.
BN and those with substance abuse disorders may share dopamine D2 receptor related vulnerabilities, and opposite findings may contribute to “protection” from substance abuse in AN. Moreover, imaging studies provide insights into executive cortico-striatal processes related to extraordinary inhibition and self-control in AN and diminished inhibitory self-control in BN that may influence the rewarding aspect of palatable foods and likely other consummatory behaviors.
AN and BN tend to have premorbid traits, such as perfectionism and anxiety that make them vulnerable to employing extremes of food ingestion which serve to reduce negative mood states. Dysregulation within and/or between limbic and executive cortio-striatal circuits contributes to such symptoms. Limited data support the hypothesis that reward and inhibitory processes may contribute to symptoms in ED and addictive disorders, but little is known about the molecular biology of such mechanisms in terms of shared or independent processes.
doi:10.1016/j.biopsych.2013.01.002
PMCID: PMC3755487  PMID: 23380716
imaging; eating disorders; anorexia nervosa; bulimia nervosa; PET; fMRI; addictive Disorders
14.  Altered insula response to sweet taste processing after recovery from anorexia and bulimia nervosa 
The American journal of psychiatry  2013;170(10):1143-1151.
Objective
Recent studies suggest that altered function of higher-order appetitive neural circuitry may contribute to restricted eating in anorexia nervosa and overeating in bulimia nervosa. This study used sweet tastes to interrogate gustatory neurocircuitry involving the anterior insula and related regions that modulate sensory-interoceptive-reward signals in response to palatable foods.
Method
Subjects recovered from anorexia and bulimia were studied to avoid confounding effects of altered nutritional state. Functional magnetic resonance imaging measured brain response to repeated tastes of sucrose and sucralose to disentangle neural processing of caloric and non-caloric sweet tastes. Whole-brain functional analysis was constrained to anatomical regions of interest.
Results
Compared to matched control women (n=14), women recovered from anorexia (n=14) had diminished (F(1,27)=7.79, p=0.01) and women recovered from bulimia (n=14) had exaggerated (F(1,27)=6.12, p=0.02) right anterior insula hemodynamic response to tastes of sucrose. Furthermore, anterior insula responses to sucrose compared to sucralose was exaggerated in recovered subjects (lower in women recovered from anorexia and higher in women recovered from bulimia).
Conclusions
The anterior insula integrates sensory/reward aspects of taste in the service of nutritional homeostasis. For example, one possibility is that restricted eating and weight loss occur in anorexia nervosa because of a failure to accurately recognize hunger signals, whereas overeating in bulimia nervosa could represent an exaggerated perception of hunger signals. This response may reflect the altered calibration of signals related to sweet taste and the caloric content of food and may offer a pathway to novel and more effective treatments.
doi:10.1176/appi.ajp.2013.11111745
PMCID: PMC3971875  PMID: 23732817
15.  Altered BOLD Response during Inhibitory and Error Processing in Adolescents with Anorexia Nervosa 
PLoS ONE  2014;9(3):e92017.
Background
Individuals with anorexia nervosa (AN) are often cognitively rigid and behaviorally over-controlled. We previously showed that adult females recovered from AN relative to healthy comparison females had less prefrontal activation during an inhibition task, which suggested a functional brain correlate of altered inhibitory processing in individuals recovered from AN. However, the degree to which these functional brain alterations are related to disease state and whether error processing is altered in AN individuals is unknown.
Methodology/Principal Findings
In the current study, ill adolescent AN females (n = 11) and matched healthy comparison adolescents (CA) with no history of an eating disorder (n = 12) performed a validated stop signal task (SST) during functional magnetic resonance imaging (fMRI) to explore differences in error and inhibitory processing. The groups did not differ on sociodemographic variables or on SST performance. During inhibitory processing, a significant group x difficulty (hard, easy) interaction was detected in the right dorsal anterior cingulate cortex (ACC), right middle frontal gyrus (MFG), and left posterior cingulate cortex (PCC), which was characterized by less activation in AN compared to CA participants during hard trials. During error processing, a significant group x accuracy (successful inhibit, failed inhibit) interaction in bilateral MFG and right PCC was observed, which was characterized by less activation in AN compared to CA participants during error (i.e., failed inhibit) trials.
Conclusion/Significance
Consistent with our prior findings in recovered AN, ill AN adolescents, relative to CA, showed less inhibition-related activation within the dorsal ACC, MFG and PCC as inhibitory demand increased. In addition, ill AN adolescents, relative to CA, also showed reduced activation to errors in the bilateral MFG and left PCC. These findings suggest that altered prefrontal and cingulate activation during inhibitory and error processing may represent a behavioral characteristic in AN that is independent of the state of recovery.
doi:10.1371/journal.pone.0092017
PMCID: PMC3961291  PMID: 24651705
16.  Temporal Sequence of Comorbid Alcohol Use Disorder and Anorexia Nervosa 
Addictive behaviors  2012;38(3):1704-1709.
Women with eating disorders have a significantly higher prevalence of substance use disorders than the general population. The goal of the current study was to assess the temporal pattern of comorbid anorexia nervosa (AN) and alcohol use disorder (AUD) and the impact this ordering has on symptomatology and associated features. Women were placed into one of three groups based on the presence or absence of comorbid AUD and the order of AN and AUD onset in those with both disorders: (1) AN Only, (2) AN First, and (3) AUD First. The groups were compared on psychological symptoms and personality characteristics often associated with AN, AUD, or both using general linear models. Twenty-one percent of women (n = 161) with AN reported a history of AUD with 115 reporting AN onset first and 35 reporting AUD onset first. Women with binge-eating and/or purging type AN were significantly more likely to have AUD. In general, differences were found only between women with AN Only and women with AN and AUD regardless of order of emergence. Women with AN and AUD had higher impulsivity scores and higher prevalence of depression and borderline personality disorder than women with AN Only. Women with AN First scored higher on traits commonly associated with AN, whereas women with comorbid AN and AUD displayed elevations in traits more commonly associated with AUD. Results do not indicate a distinct pattern of symptomatology in comorbid AN and AUD based on the temporal sequence of the disorders.
doi:10.1016/j.addbeh.2012.10.005
PMCID: PMC3558554  PMID: 23254222
anorexia nervosa; alcohol use disorder; comorbidity; age of onset
17.  Nothing Tastes as Good as Skinny Feels: The Neurobiology of Anorexia Nervosa 
Trends in neurosciences  2013;36(2):10.1016/j.tins.2013.01.003.
Individuals with anorexia nervosa (AN) engage in relentless, restrictive eating and often become severely emaciated. Because there are no proven treatments, AN has high rates of relapse, chronicity, and death. Those with AN tend to have childhood temperament and personality traits, such as anxiety, obsessions, and perfectionism, which may reflect neurobiological risk factors for developing AN. Restricted eating may be a means of reducing negative mood caused by skewed interactions between serotonin aversive or inhibitory and dopamine reward systems. Brain imaging studies suggest altered eating is a consequence of dysregulated reward, and/or awareness of homeostatic needs, perhaps related to enhanced executive ability to inhibit incentive motivational drives. Understanding the neurobiology of this disorder is likely to be important for developing more effective treatments.
doi:10.1016/j.tins.2013.01.003
PMCID: PMC3880159  PMID: 23333342
anorexia nervosa; eating disorders; dopamine; serotonin; fMRI; PET brain imaging
18.  ALTERED INSULA ACTIVATION DURING PAIN ANTICIPATION IN INDIVIDUALS RECOVERED FROM ANOREXIA NERVOSA: EVIDENCE OF INTEROCEPTIVE DYSREGULATION 
Background
Recent evidence raises the possibility that symptoms of anorexia nervosa (AN) could be related to impaired interoception. Pain is an interoceptive process with well-characterized neuroanatomical pathways that may overlap to a large degree with neural systems that may be dysregulated in AN individuals, such as the insula.
Methods
Functional Magnetic Resonance Imaging (fMRI) was used to assess neural substrates of pain anticipation and processing in ten healthy control women (CW) and 12 individuals recovered from AN (REC AN) in order to avoid the confounding effects of malnutrition. Painful heat stimuli were applied while different colors signaled the intensity of the upcoming stimuli.
Results
REC AN compared to CW showed greater activation within right anterior insula (rAI), dorsolateral prefrontal cortex (dlPFC) and cingulate during pain anticipation, and greater activation within dlPFC and decreased activation within posterior insula during painful stimulation. Greater anticipatory rAI activation correlated positively with alexithymic feelings in REC AN subjects.
Conclusions
REC AN showed a mismatch between anticipation and objective responses, suggesting altered integration and, possibly, disconnection between reported and actual interoceptive state. Alexithymia assessment provided additional evidence of an altered ability to accurately perceive bodily signals in women recovered from anorexia nervosa.
doi:10.1002/eat.22045
PMCID: PMC3507323  PMID: 22836447
Anorexia; insula; pain; anticipation; homeostasis; fmri; interoception; alexithymia; eating disorders; dorsolateral prefrontal
19.  Association Study of 182 Candidate Genes in Anorexia Nervosa 
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 pathway-based analysis in order to make up for deficiencies in traditional candidate gene approaches to AN.
doi:10.1002/ajmg.b.31082
PMCID: PMC2963154  PMID: 20468064
single nucleotide polymorphisms; probands; anorexia nervosa; bulimia nervosa
20.  Nutritional rehabilitation in anorexia nervosa: review of the literature and implications for treatment 
BMC Psychiatry  2013;13:290.
Restoration of weight and nutritional status are key elements in the treatment of anorexia nervosa (AN). This review aims to describe issues related to the caloric requirements needed to gain and maintain weight for short and long-term recovery for AN inpatients and outpatients.
We reviewed the literature in PubMed pertaining to nutritional restoration in AN between 1960–2012. Based on this search, several themes emerged: 1. AN eating behavior; 2. Weight restoration in AN; 3. Role of exercise and metabolism in resistance to weight gain; 3. Medical consequences of weight restoration; 4. Rate of weight gain; 5. Weight maintenance; and 6. Nutrient intake.
A fair amount is known about overall caloric requirements for weight restoration and maintenance for AN. For example, starting at 30–40 kilocalories per kilogram per day (kcal/kg/day) with increases up to 70–100 kcal/kg/day can achieve a weight gain of 1–1.5 kg/week for inpatients. However, little is known about the effects of nutritional deficits on weight gain, or how to meet nutrient requirements for restoration of nutritional status.
This review seeks to draw attention to the need for the development of a foundation of basic nutritional knowledge about AN so that future treatment can be evidenced-based.
doi:10.1186/1471-244X-13-290
PMCID: PMC3829207  PMID: 24200367
Anorexia nervosa; Treatment resistance; Nutritional rehabilitation; Refeeding; Weight restoration; Weight maintenance; Caloric requirements; Refeeding syndrome
21.  EARLY CHILDHOOD PEREFCTIONISM 
Objective
To examine childhood perfectionism in anorexia nervosa (AN) restricting (RAN), purging (PAN), and binge eating with or without purging (BAN) subtypes.
Method
The EATATE, a retrospective assessment of childhood perfectionism, and the Eating Disorder Inventory (EDI-2) were administered to 728 AN participants.
Results
EATATE responses revealed General Childhood Perfectionism, 22.3% of 333 with RAN, 29.2% of 220 with PAN, and 24.8% of 116 with BAN; School Work Perfectionism, 31.2% with RAN, 30.4% with PAN, and 24.8% with BAN; Childhood Order and Symmetry, 18.7% with RAN, 21.7% with PAN, and 17.8% with BAN; and Global Childhood Rigidity, 42.6% with RAN, 48.3% with PAN and 48.1% with BAN. Perfectionism preceded the onset of AN in all subtypes. Significant associations between EDI-2 Drive for Thinness and Body Dissatisfaction were present with four EATATE subscales.
Discussion
Global Childhood Rigidity was the predominate feature that preceded all AN subtypes. This may be a risk factor for AN.
doi:10.1002/eat.22019
PMCID: PMC3418385  PMID: 22488115
22.  Cognitive Set-Shifting in Anorexia Nervosa 
Objective
Adult anorexia nervosa (AN) is associated with inefficient cognitive flexibility and set-shifting. Whether such inefficiencies also characterize adolescent AN is an important area of research.
Method
Adolescents with AN and matched controls were administered a computerized task that required initial learning of an explicit rule using corrective feedback and learning of a new rule after a set number of trials. Adult patients with AN and controls were also examined.
Results
Adolescents with AN did not differ from matched controls with respect to set-shifting cost (decrease in performance after rule change), whereas adults with AN had significantly greater set-shifting cost compared with controls.
Discussion
This study suggests that set-shifting inefficiencies may not be a vulnerability factor for AN development in adolescents with AN, but might become an important aspect of the disorder at later age, and could point towards developmental neurobiologic brain changes that could affect AN at different ages.
doi:10.1002/erv.2172
PMCID: PMC3755493  PMID: 22492553
anorexia nervosa; neurobiology; childhood; set shifting; cognitive flexibility
23.  The Genetics of Anorexia Nervosa Collaborative Study: Methods and Sample Description 
Objective
Supported by National Institute of Mental Health (NIMH), this 12-site international collaboration seeks to identify genetic variants that affect risk for anorexia nervosa (AN).
Method
Four hundred families will be ascertained with two or more individuals affected with AN. The assessment battery produces a rich set of phenotypes comprising eating disorder diagnoses and psychological and personality features known to be associated with vulnerability to eating disorders.
Results
We report attributes of the first 200 families, comprising 200 probands and 232 affected relatives.
Conclusion
These results provide context for the genotyping of the first 200 families by the Center for Inherited Disease Research. We will analyze our first 200 families for linkage, complete recruitment of roughly 400 families, and then perform final linkage analyses on the complete cohort. DNA, genotypes, and phenotypes will form a national eating disorder repository maintained by NIMH and available to qualified investigators.
doi:10.1002/eat.20509
PMCID: PMC3755506  PMID: 18236451
anorexia nervosa; eating disorders; bulimia nervosa; psychiatric disorders; genetics; linkage analysis; genomics
24.  The Significance of Repetitive Hair-Pulling Behaviors in Eating Disorders 
Journal of clinical psychology  2011;67(4):391-403.
We studied the relation between intrusive and repetitive hair-pulling, the defining feature of trichotillomania, and compulsive and impulsive features in 1453 individuals with anorexia nervosa and bulimia nervosa. We conducted a series of regression models examining the relative influence of compulsive features associated with obsessive compulsive disorder; compulsive features associated with eating disorders; trait features related to harm avoidance, perfectionism and novelty seeking; and self harm. A final model with a reduced sample (n=928) examined the additional contribution of impulsive attributes. One out of 20 individuals endorsed hair-pulling. Evidence of a positive association with endorsement of compulsive behavior of the obsessive compulsive spectrum emerged. Hair-pulling may be more consonant with ritualistic compulsions than impulsive urges in those with eating disorders.
doi:10.1002/jclp.20770
PMCID: PMC3664303  PMID: 21365638
eating disorders; trichotillomania; hair-pulling; anorexia nervosa; bulimia nervosa; impulsivity; compulsivity
25.  Postpartum and Depression Status are Associated With Lower [11C]raclopride BPND in Reproductive-Age Women 
Neuropsychopharmacology  2012;37(6):1422-1432.
The early postpartum period is associated with increased risk for affective and psychotic disorders. Because maternal dopaminergic reward system function is altered with perinatal status, dopaminergic system dysregulation may be an important mechanism of postpartum psychiatric disorders. Subjects included were non-postpartum healthy (n=13), postpartum healthy (n=13), non-postpartum unipolar depressed (n=10), non-postpartum bipolar depressed (n=7), postpartum unipolar (n=13), and postpartum bipolar depressed (n=7) women. Subjects underwent 60 min of [11C]raclopride–positron emission tomography imaging to determine the nondisplaceable striatal D2/3 receptor binding potential (BPND). Postpartum status and unipolar depression were associated with lower striatal D2/3 receptor BPND in the whole striatum (p=0.05 and p=0.02, respectively) that reached a maximum of 7–8% in anteroventral striatum for postpartum status (p=0.02). Unipolar depression showed a nonsignificant trend toward being associated with 5% lower BPND in dorsal striatum (p=0.06). D2/3 receptor BPND did not differ significantly between unipolar depressed and healthy postpartum women or between bipolar and healthy subjects; however, D2/3 receptor BPND was higher in dorsal striatal regions in bipolar relative to unipolar depressives (p=0.02). In conclusion, lower striatal D2/3 receptor BPND in postpartum and unipolar depressed women, primarily in ventral striatum, and higher dorsal striatal D2/3 receptor BPND in bipolar relative to unipolar depressives reveal a potential role for the dopamine (DA) system in the physiology of these states. Further studies delineating the mechanisms underlying these differences in D2/3 receptor BPND, including study of DA system responsivity to rewarding stimuli, and increasing power to assess unipolar vs bipolar-related differences, are needed to better understand the affective role of the DA system in postpartum and depressed women.
doi:10.1038/npp.2011.328
PMCID: PMC3327847  PMID: 22257897
D2/3 receptors; postpartum depression; PET; women; major depressive disorder; depression; unipolar; bipolar; imaging; clinical or preclinical; dopamine; psychiatry & behavioral sciences; D2/3 receptors; postpartum depression; positron emission tomography; women

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