Aberrant Brain Activation During a Response Inhibition Task in Adolescent Eating Disorder Subtypes

Article

Am J Psychiatry 168:1, January 2011 ajp.psychiatryonline.org 55

individuals. For example, relative to healthy comparison subjects, individuals with bulimia nervosa who used laxa-tives were observed to make more errors of commission on a go/no-go task and endorse higher ratings for impul-sive behaviors on a self-report assessment (4). Similarly, cognitive research in inhibitory processing using a motor stop-signal paradigm and a motor Stroop task found that patients with restricting type anorexia displayed supe-rior response inhibition overall, with fewer impulsive errors, than patients with the binge eating/purging type (8). Anorexia nervosa patients with binge eating/purging behaviors also made more response errors on a modifi ed version of the Hayling sentence completion task relative to patients with the restricting subtype (8, 9). Thus, because of the evidence suggesting similarities in impulsive cogni-tive styles between anorexia nervosa, binge eating/purg-ing type, and bulimia nervosa, we grouped both disorders together as a single category of binge eating/purging-type eating disorders in order to compare these patients with individuals in a restricting type anorexia group and a healthy comparison group for this study of cognitive inhibitory control.

Behavior and personality characteristics differ among patients with eating disorders, depending on subtype. Patients with binge eating or purging behaviors, such as anorexia nervosa, binge eating/purging type, and/or buli-mia nervosa, often display impulsive and disinhibited per-sonality characteristics. In contrast, those with anorexia nervosa, restricting type (1–3), often show a restrictive and overly controlled behavioral style.

Disinhibition and impulsivity related to eating behav-iors are hallmarks of bulimia nervosa (4, 5). In recognition of this core feature of the disorder, the DSM-IV diagnostic description of bulimia nervosa incorporates the require-ment that binge eating episodes include this disinhibited (out of control) characteristic (6). Impulsivity may extend into other areas of life in addition to binge eating or purg-ing (2). For example, individuals with bulimia nervosa often report alcohol and drug abuse, self-harm, sexual disinhibition, and shoplifting (5). Some data suggest that the basis of cognitive and behavioral disinhibition in buli-mia nervosa may be related to serotonin dysregulation (7), while neuropsychological studies have found evi-dence of disinhibition at a neurocognitive level in affected

(Am J Psychiatry 2011; 168:55–64)

James Lock, M.D., Ph.D.

Amy Garrett, Ph.D.

Judy Beenhakker, M.S.

Allan L. Reiss, M.D.

Objective: Behavioral and personality characteristics associated with excessive inhibition and disinhibition are observed in patients with eating disorders, but neu-ral correlates of inhibitory control have not been examined in adolescents with these disorders.

Method: Thirteen female adolescents with binge eating and purging behaviors (i.e., bulimia nervosa or anorexia ner-vosa, binge eating/purging type);14 with anorexia nervosa, restricting type; and 13 healthy comparison subjects performed a rapid, jittered event-related go/no-go task. Functional magnetic resonance im-ages were collected using a 3 Tesla GE scanner and a spiral pulse sequence. A whole-brain three-group analysis of vari-ance in SPM5 was used to identify signifi -cant activation associated with the main effect of group for the comparison of cor-rect no-go versus go trials. The mean acti-vation in these clusters was extracted for further comparisons in SPSS.

Results: The binge eating/purging group showed signifi cantly greater ac-tivation than the healthy comparison group in the bilateral precentral gyri, an-terior cingulate cortex, and middle and superior temporal gyri as well as greater activation relative to both comparison and restricting type anorexia subjects in the hypothalamus and right dorso-lateral prefrontal cortex. Within-group analysis found that only the restricting type anorexia group showed a positive correlation between the percent correct on no-go trials and activation in poste-rior visual and inferior parietal cortex regions.

Conclusions: The present study pro-vides preliminary evidence that during adolescence, eating disorder subtypes may be distinguishable in terms of neu-ral correlates of inhibitory control. This distinction is consistent with differences in behavioral impulsivity in these patient groups.

Aberrant Brain Activation During a Response Inhibition Task in Adolescent Eating Disorder Subtypes

ABERRANT BRAIN ACTIVATION IN ADOLESCENT EATING DISORDER SUBTYPES

56 ajp.psychiatryonline.org Am J Psychiatry 168:1, January 2011

Neural differences in executive functioning related to inhibitory control may be associated with the cognitive and clinical symptoms in bulimia nervosa (10–12). How-ever, only limited functional imaging studies have exam-ined inhibition and disinhibition in bulimia nervosa to date. A recent study conducted by Mars h et al. (11) exam-ined response inhibition in adult patients with bulimia nervosa. These authors found that adult subjects with bulimia nervosa responded more impulsively and made more errors on a response inhibition task (Simon task [13]) relative to healthy comparison subjects, and patients with the most severe symptoms made the most errors. During correct responding on incongruent trials, patients failed to activate frontostriatal circuits to the same degree as healthy comparison subjects, including the bilateral inferior frontal gyrus, lenticular and caudate nuclei, and the anterior cingulate cortex. Marsh et al. concluded that diminished activity in these regions may contribute to the loss of control in the eating behavior of patients with bulimia nervosa. In contrast to patients with bulimia ner-vosa, clinical reports document perseverative, obsessive, and rigid thinking styles in patients with anorexia nervosa. Patients with anorexia nervosa are frequently perfection-istic and report obsessive-compulsive personality traits and obsessive-compulsive disorder (OCD) in childhood (1). Studies have also found that those who have recov-ered from anorexia nervosa continue to exhibit anxiety, perfectionism, infl exible thinking, and overconcern with symmetry, exactness, and order (14, 15). Neuropsycholog-ical research provides additional evidence of reduced cog-nitive fl exibility (set shifting) and an excessively detailed information processing style (weak central coherence), with a neglect of the overall picture (gestalt), in adults with anorexia nervosa (9, 12, 16, 17). Limited neuroimag-ing data in adults with anorexia nervosa support this idea as well. For example, Zastrow et al. (12) found decreased activation in the anterior cingulate cortex and striatum associated with impaired cognitive behavioral fl exibility.

Adolescents with eating disorders have rarely been examined in structural or functional neuroimaging stud-ies (18). It is well known that brain development undergoes signifi cant alteration in adolescence (19), and devel-opment of executive functioning skills is a particularly dynamic process during this period (20), associated with increasing abilities pertaining to decision making, social processing, and inhibitory control. These refi nements lead to what has been called the collaborative brain (21), wherein improved connections allow the prefrontal cortex to modulate critical interconnected subcortical structures (e.g., the basal ganglia and amygdala). The lateral prefron-tal cortex has a distinct architectonic “trend” within the frontal lobe (22). The lateral aspect develops later than other regions, both in ontogeny and in phylogeny, and is important for making inhibitory processes more effi cient.

In summary, phenomenological, clinical, neuropsycho-logical, neuroimaging, and neurodevelopmental fi ndings

support the likely importance of examining inhibition/disinhibition in adolescents with eating disorders. Fur-ther, evidence suggests that aberrant functioning of the inferior frontal and anterior cingulate gyri is likely to be associated with impulsivity and disinhibition in anorexia nervosa patients who binge eat and purge but not in those with the restricting subtype (11). Examination of response inhibition using functional magnetic resonance imaging (fMRI) in adolescents with eating disorders, specifi cally comparing those with restricting type anorexia with those who have bulimia nervosa or anorexia nervosa, binge eating/purging type, provides an opportunity to explore these processes in the developing brain and to distin-guish patients with these subtypes from each other on a neural basis as well as from healthy comparison subjects. Examining neural correlates of inhibitory control in an adolescent population that is not severely emaciated and not chronically ill may help to distinguish these features associated with the onset of eating disorders as opposed to the secondary effects associated with starvation and prolonged disease.

This preliminary study is the fi rst, to our knowledge, to examine brain activation associated with response inhibi-tion in adolescents with eating disorders and, further, to compare patients with binge eating/purging behaviors with patients with a restrictive subtype of anorexia nervosa and with a healthy comparison group. We hypothesized that brain activation associated with inhibitory control during a go/no-go task would differ in adolescents with eating disorders relative to a healthy comparison group. We predicted that those with binge eating/purging behav-iors would have abnormal activation in frontostriatal regions typically associated with response inhibition rela-tive to healthy comparison subjects as well as to patients with anorexia nervosa, restricting type. We also predicted that we would fi nd evidence of excessive inhibition in the restricting type anorexia group relative to both healthy comparison subjects and patients with binge eating/purg-ing behaviors.

MethodThis study was approved by the Stanford University Internal

Review Board, and all volunteers signed informed consent (signed by parents for participants <18 years old) and/or assent (for par-ticipants <18 years old) forms before participation. Eating disorder subjects were current outpatients recruited from the Stanford Uni-versity Child and Adolescent Psychiatry Clinic. Diagnoses of eating disorders and comorbid psychiatric disorders were made by clini-cians with expertise in eating disorders in children and adolescents, and diagnoses were confi rmed by the Eating Disorder Examination (23), which was administered independently by trained interview-ers. Participants with eating disorders were required to meet full DSM-IV criteria for their respective diagnosis within 3 months of study participation. Subjects with eating disorders also completed other diagnostic and clinical assessments (Table 1). Volunteers were 16 female subjects with anorexia nervosa, restricting type; 15 with binge eating/purging behaviors (11 with bulimia nervosa and four with anorexia nervosa, binge eating/purging type); and

LOCK, GARRETT, BEENHAKKER, ET AL.


provides optimal signal-to-noise while minimizing susceptibility effects (24). Thirty axial slices (3 mm thick, 1 mm skip) parallel to the anterior commissure-posterior commissure line and cover-ing the whole brain were imaged (TR=2,000 msec; TE=30 msec; fl ip angle=90°; 1 interleave; fi eld of view=22 cm2; matrix=64×64; in-plane spatial resolution=3.125 mm). The task was presented using E-Prime software (Psychology Software Tools, Pittsburgh), which also triggered the initiation of the scan. Visual stimuli were projected from the foot of the scanner onto a screen attached to the head coil and viewed via a mirror.

Subjects performed a rapid, jittered event-related go/no-go task featuring a series of letters. They pushed a button in response to all letters, except for the infrequent letter X. This task is a classic test of executive function, requiring effortful inhibition of a pre-potent response (25). The task lasted 16 minutes and displayed 300 go stimuli and 75 no-go stimuli (1:4 ratio). The intertrial inter-val was jittered from 2 to 12 seconds.

16 healthy comparison subjects. None of the subjects with bulimia nervosa had a history of anorexia nervosa, and none of the subjects with restricting type anorexia had a history of bulimia nervosa. Healthy comparison subjects were recruited through advertise-ments in local newspapers. For all three groups, eligible partici-pants had no contraindications for magnetic resonance imaging (MRI) and no coexisting major neurological problems (e.g., seizure disorder, traumatic brain injury with loss of consciousness, mul-tiple sclerosis) or psychotic disorders.

MRI Acquisition

Imaging data were acquired on a 3.0 Tesla GE Signa Excite mag-net (General Electric Co., Milwaukee), housed in the Lucas Imag-ing Center of Stanford University, using a custom-built whole head coil providing a 35% advantage in signal-to-noise ratio over that of the standard GE coil. Following a three-plane localizer scan, fMRI data were collected using a spiral-in/-out sequence, which

TABLE 1. Clinical and Demographic Characteristics of Patients With Eating Disorders and Healthy Comparison Subjects

Variable

Group

Between-Group Comparisons

1. Anorexia Nervosa, Restricting Type

(N=14)

2. Binge Eating/Purging Behaviors

(N=13)

3. Healthy Comparison (N=13)

Mean SD Mean SD Mean SDAge (years) 15.02 1.74 17.26 1.23 15.93 1.39 2>3, p=0.016; 2>1, p=0.002Duration of illness (months) 32.07 19.91 28.92 18.03Binge eating episodes

(28 days)0 0 16.61 19.11 0.23 0.83 2>3, p=0.005; 2>1, p=0.003

Purging episodes (28 days) 0.21 0.80 16.15a 23.02 0.00 0.00 2>3, p=0.018; 2>1, p=0.016Eating Disorder Examination

total score1.19 1.47 3.08 1.09 0.29 0.34 2>3, p<0.001; 2>1, p=0.001

Multidimensional Anxiety Scale for Children total score

45.07 11.63 47.54 9.78 39.62 8.56 2>3, p=0.038

Beck Depression Inventory total score

14.07 12.75 23.62 13.42 4.92 5.35 2>3, p<0.001; 1>3, p=0.024

Barratt Impulsiveness Scale, Version 11, total score

53.66 6.27 68.84 9.46 57.02 8.14 2>3, p=0.002; 2>1, p<0.001

Weight (lbs) 92.4 11.85 126.12 29.24 127.63 17.3 3>1, p<0.001; 2>1, p=0.001Percent of ideal body

weight (lbs)b88.3 9.76 100.96 20.07 105.67 13.72 3>1, p=0.001

N % N % N %Weight <86% of ideal body

weight (lbs)6 42.86 2 15.38

Current psychotropic medicationc

10 7.14 1 7.69

Comorbid diagnosisd 3 21.43 3 23.08Regular menstruation

(3 months)e10 7.14 8 61.54 13 100 2>1, p<0.001; 3>1, p<0.001

EthnicityCaucasian 12 85.70 9 69.23 10 76.9Asian 10 7.14 2 15.38 2 15.38Mixed 10 7.14 2 15.38 1 7.69

Handedness (right) 14 100.00 11 84.62 11 84.62a One patient was omitted because of innumerable purging (specifi cally vomiting) episodes.b Patients had to meet criteria within the prior 3 months of the scan, and thus some were >85% of their ideal body weight (diagnostic crite-ria for anorexia nervosa: <85%).

c One patient in the binge eating/purging behaviors group was receiving fl uoxetine, and one patient in the restricting type anorexia group was receiving escitalopram.

d In the binge eating/purging behaviors group, one patient had major depressive disorder and generalized anxiety disorder, one had general-ized anxiety disorder, and one had obsessive-compulsive disorder (OCD); in the restricting type anorexia group, one patient had OCD, and two had major depressive disorder.

e Menstrual cycle data were collected for the prior 3 months. One restricting type anorexia patient met full anorexia nervosa criteria within the past 3 months, although she reported a current menstruation cycle at 78% of her ideal body weight.



purging behaviors, and 13 individuals in the healthy comparison group. Table 1 shows the demographic and clinical characteristics of each group. Handedness did not differ between groups. Age, scores on the Eating Dis-order Examination, and behavioral symptom reports are consistent with the clinical presentation of these disor-ders in adolescents. Therefore, participants with buli-mia nervosa and anorexia nervosa, binge eating/purging type, were at higher weights and were slightly older than participants with anorexia nervosa, restricting type (26). There was a signifi cant difference in age across the three groups, primarily associated with a low variance in age within each group (F=7.03, df=, 2, 37, p=0.003). Patients with binge eating/purging type were older than those with the restricting subtype and individuals in the healthy comparison group (binge eating/purging type: mean age=17.26 years [SD=1.18]; healthy comparison: mean age=15.93 years [SD=1.33]; anorexia nervosa, restricting type: mean age=15.02 years [SD=1.74]). Accordingly, we performed between-group comparisons of functional activation in SPSS with and without age as a covariate. Further analyses of the effects of age on brain activation are included in this report.

Behavioral Performance

All participants performed with high accuracy on the go trials and had a similar rate of false alarms on the no-go trials. The mean accuracy (percent correct) for go trials in the healthy comparison group was 94.64% (SD=9.96); in the binge eating/purging group it was 97.38% (SD=2.65); and in the restricting type anorexia group it was 97.71% (SD=3.31). The mean response time for go trials in the healthy comparison group was 386.49 msec (SD=55.88); in the binge eating/purging group it was 403.46 msec (SD=45.05); and in the restricting type anorexia group it was 356.54 msec (SD=90.68). The mean accuracy for no-go trials in the healthy comparison group was 73.74% (SD=14.54); in the binge eating/purging group it was 77.23% (SD=10.77); and in the restricting type anorexia group it was 70.86% (SD=12.11). The mean response time for false alarms in the healthy comparison group was 350.07 msec (SD=43.74); in the binge eating/purging group it was 333.09 msec (SD=29.23); and in the restrict-ing type anorexia group it was 341.62 msec (SD=25.13). There were no group differences in task accuracy for go or no-go trials. Additionally, there were no group differences in response time for go trials.

Correlations between age and task performance were not signifi cant across groups. Within groups, only one correlation was marginally signifi cant, which was within the restricting type anorexia group, where age was cor-related with response time for false alarms (r=0.54, p=0.047). Therefore, although older subjects took longer to make a false alarm on a no-go trial, the response time for false alarms was not signifi cantly different between groups.

Data Analysis

Functional data were analyzed using SPM5 (Wellcome Depart-ment of Imaging Neuroscience, London). Functional MRI data were corrected for slice timing, spatially realigned, motion repaired using the ArtRepair toolbox (http://cibsr.stanford.edu/tools/ArtRepair/ArtRepair.htm), normalized into an age-appro-priate stereotactic template from the Cincinnati Children’s Hos-pital Medical Center (https://irc.cchmc.org/software/pedbrain.php), smoothed with a 7-mm Gaussian fi lter, and high-pass fi l-tered. A fi xed-effects model compared correctly inhibited no-go trials with correct go trials for each subject.

Within-group t tests were performed using random-effects analyses and a signifi cance threshold of p=0.01 height and p=0.01 extent, corrected for multiple comparisons. For all SPM5 analy-ses, the location of signifi cant clusters and the coordinates of peak voxels in Talairach space were determined using the mni2tal func-tion (http://imaging.mrc-cbu.cam.ac.uk/imaging/MniTalairach).

The three subject groups were compared using a two-step approach. First, a whole-brain analysis of variance (ANOVA) was performed in SPM5 in all three groups for the contrast of correct no-go versus go trials. Signifi cant clusters of activation associated with the main effect of group were identifi ed using a threshold of p=0.01 height and extent, equalling 80 voxels, uncorrected. Although this threshold is uncorrected, it is more stringent than that used in many fMRI studies and is appropriate for the initial step of this analysis identifying clusters of interest. In the second part of the analysis, the mean activation in each of the identifi ed clusters was extracted using the MarsBaR toolbox (http://mars-bar.sourceforge.net/) and transferred to SPSS (SPSS, Inc., Chi-cago) for follow-up t tests. The t tests, conducted in SPSS, included age as a covariate (because of group differences in age) and used a corrected signifi cance threshold of 0.0083. This threshold was determined as a p value of 0.05 divided by the number of clusters identifi ed in the SPM5 whole-brain analysis (see Results section). Limiting the follow-up t tests to regions of interest identifi ed by the three-group ANOVA reduced the probability of type I error. Extracting these regions of interest into SPSS allowed for correla-tion analyses with clinical and behavioral variables and examina-tion of distributions associated with each group. Behavioral and demographic data were also analyzed in SPSS using ANOVA and follow-up t tests when appropriate.

Whole brain correlations with task accuracy were conducted in SPM5 using multiple regression. A threshold of p=0.01 height and p=0.01 extent, corrected for multiple comparisons, was used to determine signifi cance.

Correlations between clinical and behavioral measures and brain activation in the extracted regions of interest were per-formed in SPSS using a Pearson’s correlation analysis. The most relevant clinical measures were chosen for analysis, including total scores on the Eating Disorder Examination, Beck Depres-sion Inventory (BDI), Behavioral Inhibition Scale, and Multidi-mensional Anxiety Scale for Children. A corrected alpha of 0.0125 (0.05/4 [four clinical measures]) was chosen as a signifi cance threshold.

Results

Two subjects with anorexia nervosa, restricting type, two with binge eating/purging behaviors, and three healthy comparison subjects were removed from the data analyses, either for excessive motion in the scan or for behavioral data with <50% correct responses, which suggested noncompliance with or misunderstanding of task instructions. The remaining subjects were 14 with anorexia nervosa, restricting type, 13 with binge eating/



dorsolateral prefrontal cortex: p=0.001 and p=0.001). When the analysis was repeated using age as a covari-ate, all of the group differences between patients with binge eating/purging behaviors and healthy comparison subjects remained. Greater activation in the binge eat-ing/purging group compared with the restricting type anorexia group remained only in the hypothalamus and the dorsolateral prefrontal cortex (Table 3). As mentioned previously, a corrected alpha of 0.0083 was used for signifi -cance (p=0.05/6 [six regions]).

Although the analyses were performed while covarying for the group difference in age, we further tested whether age had an effect on activation in any of the regions of interest. We conducted Pearson’s correlations between activation in each brain region and age, both within each group and across all groups. None of the correlations were signifi cant (at a threshold of 0.05), suggesting that age did not signifi cantly infl uence our results.

The low rate of false alarms greatly reduced our ability to detect brain activation associated with false alarm tri-als. Typically, approximately 30 trials are needed to detect activation in an event-related study, corresponding to a false alarm rate of 40% (out of a possible 75 no-go trials). Only three comparison subjects and four restricting type anorexia patients made ≥40% false alarms, while no binge eating/purging patients made ≥40% false alarms. Instead,

Neuroimaging Findings

Functional MRI results showed that within each group, the right inferior and middle frontal gyri were activated during successful response inhibition trials (i.e., not pressing when observing the letter X) compared with successful response trials (no-go/go) (Figure 1, Table 2). Additionally, patients with binge eating/purging behav-iors showed right dorsal caudate and anterior cingulate cortex activation as well as widespread frontal activa-tion. Patients with restricting type anorexia also showed anterior cingulate cortex activation but not caudate activation. A three-group ANOVA showed a signifi cant main effect of group in the bilateral hypothalamus, right dorsolateral prefrontal cortex, right anterior cingulate cortex, right middle temporal gyrus, and bilateral pre-central gyri (Figure 2, Table 3). Follow-up between-group comparisons performed in SPSS (corrected p=0.0083) showed that all of the group differences were attributed to increased activation in the binge eating/purging group versus the healthy comparison group and versus the restricting type anorexia patients (left precentral gyrus: p=0.001 and p=0.011 [nearly signifi cant], respectively; right precentral gyrus: p=0.0001 and p=0.006; right ante-rior cingulate cortex: p=0.00001 and p=0.013 [nearly sig-nifi cant]; right middle/superior temporal gyrus: p=0.0001 and p=0.005; hypothalamus: p=0.001 and p=0.001; right

TABLE 2. Location of Signifi cantly Activated Regions Within Eating Disorder Patients and Healthy Comparison Subjectsa

Study Group and Region Brodmann’s Area Voxels T/Z at Peak Location of Peak

Healthy comparisonRight inferior frontal gyrus 45/47 967 7.36/4.45 42, 15, –6Right insula 13 6.53/4.19 42, 15, –2Right superior temporal gyrus 38 5.63/3.87 48, 13, –7Right middle temporal gyrus 22/21 1,639 6.44/4.16 67, –41, 4Right inferior temporal gyrus 37 6.41/4.15 66, –38, – 4Right superior frontal gyrus 9/8/10 3,053 7.21/4.4 24, 48, 36Right middle frontal gyrus 6/9/10/46 5.61/3.86 42, 49, 12

Binge eating/purging behaviorsRight middle frontal gyrus 9/46 10,820 11.01/5.29 46, 10, 36Right inferior frontal gyrus 45/47 4.75/3.5 34, 26, 2Right insula 13 4.5/3.39 24, 14, –8Right putamen 2.89/2.32 16, 12, 0Right anterior cingulate gyrus 32/24 4.85/3.54 4, 36, 26Right superior frontal gyrus 8 8.58/4.77 4, 24, 49Right inferior parietal lobe 40 7,754 8.83/4.83 46, –56, 45Right middle/inferior temporal gyrus 21/22/37 6.96/4.33 56, –34, –4Right precuneus 7 8.15/4.66 8, –71, 48Right superior parietal lobe 7 7.44/4.47 44, –58, 49

Anorexia nervosa, restricting typeRight supramarginal gyrus 40 3,515 8.3/4.81 61, –51, 34Right inferior parietal lobe 40 6.23/4.17 48, –60, 47Right superior parietal lobe 7 7.02/4.44 50, –64, 50Right middle frontal gyrus 10/46/6 4,936 6.04/4.1 44, 50, 20Right superior frontal gyrus 10 5.47/3.87 40, 51, 16Right inferior frontal gyrus 44 3.13/2.54 48, 10, 18Right anterior cingulate gyrus 32 3.75/5.05 0, 18, 42

a A signifi cance threshold was set for height and cluster extent (p=0.01, corrected).



superior temporal gyrus, but these were because of group differences in scores. Correlations between BDI scores and region of interest values were not signifi cant within each group separately. Scores on the Behavioral Inhibi-tion Scale were not correlated with activation in any of the regions of interest. The Multidimensional Anxiety Scale for Children was signifi cantly correlated with right supe-rior temporal gyrus activation across all groups (r=0.48, p=0.002). This was found to be attributable primarily to a signifi cant correlation between scores on this measure and right superior temporal gyrus activation within the binge eating/purging group (r=0.70, p=0.007) but was not signifi cant within the other groups.

Possible effects of weight restoration on outcome were examined. In the binge eating/purging group, only two subjects weighed <86% of their ideal body weight. How-ever, to determine whether this variable affected our results, we excluded the two low-weight subjects in this group and reran the comparisons with the healthy sub-jects. The results did not change for any of the six brain regions, even while covarying for age. Therefore, low weight did not appear to infl uence the comparisons between subjects in the binge eating/purging and healthy comparison groups. Comparisons with the restricting type anorexia group were not possible, since six of the 14 subjects were <86% of their ideal body weight, although none were extremely emaciated (e.g., <79% of the ideal body weight), as all were outpatients. Because hormonal function is related to nutritional status, we conducted an analysis excluding the single participant in the restricting type anorexia group who reported regular menstruation at the time of scanning and found no difference in activation patterns.

Because scores on the BDI were signifi cantly higher for the binge eating/purging group, we examined the possible infl uence of major depression on our fi ndings by remov-ing from the analysis the three subjects who had a diag-nosis of major depression. These were two subjects in the binge eating/purging group and one subject with anorexia nervosa, restricting type. None of the results changed. For

we performed a whole-brain correlation with the percent of correctly inhibited trials within each group, using a sig-nifi cance threshold of p=0.01 height and p=0.01 cluster extent, corrected for multiple comparisons. Therefore, this analysis suggests group-specifi c neural strategies that are successful (positive correlation) or unsuccess-ful (negative correlation). We found that only restricting type anorexia patients showed a signifi cant positive cor-relation with the percent of correctly inhibited trials in a single large cluster (cluster size=3,657 voxels; peak: Z=3.72; location: x=18, y=–80, z=28). The cluster included regions of the inferior parietal cortex (Brodmann’s area 7), precuneus (Brodmann’s area 19/31), and posterior cingu-late gyrus (Brodmann’s area 31). This suggests that within the restricting type anorexia group, successful inhibition is associated with greater recruitment of brain regions underlying visual attention (27) and visual working mem-ory (27) (e.g., the precuneus and inferior parietal cortex). Attention to detail is a cognitive feature associated with anorexia nervosa (17).

Association With Clinical Measures

Pearson’s correlation analysis was used to fi nd associa-tions between activation in the extracted regions of inter-est and relevant clinical measures, including scores on the Eating Disorder Examination, BDI, Behavioral Inhibition Scale, and Multidimensional Anxiety Scale for Children. A threshold of 0.0125 (0.05/4 [four clinical measures]) was required for signifi cance. Across all groups combined, the total Eating Disorder Examination score was signifi cantly correlated with activation in the bilateral precentral gyrus, right anterior cingulate cortex, right superior temporal gyrus, and hypothalamus. However, these correlations were attributable to group differences in the score. The correlations were repeated within each group separately and were not signifi cant. In addition, there were no signif-icant correlations with subscales on the Eating Disorder Examination or the number of bulimic episodes. Similarly, for BDI measures, signifi cant correlations across all groups were found with the bilateral precentral gyrus and right

TABLE 3. Signifi cant Clusters Determined by Analysis of Variance (Main Effect of Group) in 1) Patients With Anorexia Nervosa, Restricting Type, 2) Patients With Binge Eating/Purging Behaviors, and 3) Healthy Comparison Subjectsa

RegionBrodmann’s

Area Voxels F/Z at PeakLocation of Peak

(x, y, z)b

Between-Group Analyses

Comparison p

Left precentral gyrus 6/4 88 8.30/3.08 –10, –18, 64 2>3 0.001Right precentral gyrus 6 150 9.61/3.33 10, –18, 64 2>3 0.001Right anterior cingulate

gyrus24 132 9.24/3.26 8, 28, 15 2>3 0.001

Right middle/superior temporal gyrus

37 242 8.61/3.14 50, –55, –2 2>3 0.0001

Right/left hypothalamus N/A 222 11.22/3.61 4, 4, –7 2>3; 2>1 0.001; 0.003Right dorsolateral pre-

frontal cortex46 83 9.78/3.36 50, 30, 15 2>3; 2>1 0.003; 0.006

a A signifi cance threshold was set for analysis of variance main effect of group, p=0.01 height and extent 80. Analyses controlled for age.b Data indicate Talairach coordinates.



all of the regions of interest, activation in the binge eating/purging group remained signifi cantly greater than in the healthy comparison group (range for signifi cance: 0.002–0.0080, including covariance for age).

Discussion

This preliminary study supports the hypothesis that differences in neural function can be identifi ed between anorexia nervosa, restricting type, and anorexia nervosa, binge eating/purging type, as well as between individuals

FIGURE 1. Signifi cant Activation During Correct No-Go Versus Go Trials in Patients With Eating Disorders and Healthy Com-parison Subjects

Healthy Comparison (N=13)

Anorexia Nervosa, Restricting Type (N=14)

Binge Eating/Purging Behaviors (N=13)

0

8642

10

0

8642

10

0

8642

10

+15+0 +12+9+6+3

+18 +30+27+24+21

+15+0 +12+9+6+3

+18 +30+27+24+21

+15+0 +12+9+6+3

+18 +30+27+24+21

with binge eating/purging behaviors and healthy compar-ison subjects during a task requiring inhibitory control. Patients with the binge-purge subtype showed increased activation in the right dorsolateral prefrontal cortex, an executive control region, suggesting ineffi cient or possibly compensatory activation (i.e., recruitment of additional brain regions and/or discrepant brain activation patterns leading to improved cognitive ability) (28). The fi nding of increased hypothalamic activation further suggests aberrant responses in a region associated with emotional function (29, 30). This fi nding might also indicate that the



control in patients with anorexia nervosa, restricting type. The neurofunctional correlates of these cognitive charac-teristics in binge eating/purging subjects are consistent with expected locations of activation related to executive function (18, 30, 33). However, there were no correlations between Eating Disorder Examination subscale scores or binge-purge episodes, but this may be a result of poor reli-ability of the subscales and low variability of the rates of binge eating and purging in this small sample. This could also imply that severity of behavioral symptoms (e.g., binge-purge rates) do not predict activation within this group.

Our preliminary fi ndings suggest that adolescent sub-jects with binge eating/purging behaviors and restricting type anorexia likely differ from each other on a neural level, and therefore risks and effective interventions may differ between these two groups. These fi ndings in an adolescent group not severely malnourished and with a relatively short duration of eating disorder symp-toms suggest that these neural processes occur prior to or early in the evolution of the disorder and may not be the result of chronic disease or state-dependent starva-tion. Longitudinal studies are needed to help distinguish primary and secondary neural processes. Other studies might also follow individuals with early symptoms of an eating disorder to track the development of behaviors and corresponding neural correlates. In addition, future studies might also examine the effects of cognitive thera-pies on these neural processes in subjects with restrict-ing type anorexia and those with binge eating/purging behavior (36).

There are a number of limitations to these fi ndings. The sample is small, and therefore other group differences may well have not been detected. The participants were female patients, and although most individuals with eating disor-ders are female patients, 10% are male patients, and these fi ndings may not generalize to a male population. The go/no-go task does not capture all aspects of inhibitory con-trol. Additional studies are needed to replicate and expand upon these preliminary fi ndings. It is also important to note that depression symptoms are associated with some of the regions of interest examined in this study (37, 38). Depression is a common comorbid condition in bulimia nervosa, and BDI scores were elevated in the binge eating/purging group. However, there was no correlation found between BDI scores and any of the regions of interest within this group in our study.

An ongoing debate in the diagnostic literature is the potential crossover between anorexia nervosa, restricting type; anorexia nervosa, binge eating/purging type; and bulimia nervosa, particularly whether eating disorders are best considered a single transdiagnostic disorder or sepa-rate clinical entities (39). The present study provides pre-liminary evidence that at least during adolescence, eating disorder subtypes may be distinguishable in terms of neu-ral correlates of inhibitory control. This distinction is also

binge eating/purging behaviors group experienced greater stress during response inhibition (31), possibly related to the additional effort needed to successfully complete the task. Binge eating/purging subjects use greater anterior cingulate cortex resources as well, suggesting increased activity related to monitoring response confl ict (32). This fi nding differs from that identifi ed by Marsh et al. (11) and Uher et al. (33), who reported decreased activation in the frontostriatal region in adults with bulimia nervosa. Addi-tionally, Marsh et al. found that adult patients with bulimia nervosa had impaired task performance, while our study did not. These differences could result from task differ-ences (Simon task [13])—a response inhibition task with incongruent spatial stimuli that may be more challenging than the go/no-go task [34, 35])—developmental differ-ences (age, cognitive maturity), clinical severity or chro-nicity (duration of illness, binge eating/purging behavior frequency), diagnosis (binge eating/purging behavior versus bulimia nervosa), or comorbidity. The fact that our younger age group activated several additional brain regions not observed in the Marsh et al. study (e.g., hypo-thalamus, dorsolateral prefrontal cortex) might also refl ect the infl uence of brain maturation on cognitive processing.

In a whole-brain correlation with the percent correct on no-go trials within each group, only patients with restrict-ing type anorexia showed a signifi cant positive correlation with activation in a cluster that included the inferior pari-etal cortex, precuneus, and posterior cingulate gyrus. The other groups showed no signifi cant correlations with the percent correct on no-go trials.

Clinically, adolescents with restricting type anorexia display characteristics of greater inhibitory control than healthy comparison subjects and those with bulimia nervosa or anorexia nervosa, binge eating/purging type, while subjects with bulimia nervosa or binge eating/purg-ing type anorexia display decreased inhibitory control relative to healthy comparison subjects and those with restricting type anorexia. Our fi ndings show putative neu-ral correlates of decreased inhibitory control in female adolescents who binge eat and purge, but we did not fi nd evidence of comparable correlates of increased inhibitory

FIGURE 2. Clusters of Signifi cant Activation During Cor-rect No-Go Versus Go Trials From a Three-Group Analysis of Variance in Patients With Eating Disorders and Healthy Comparison Subjectsa

0

8642

10DLPFCRight

RightACC

HypothalBilateral

a The images depict the main effect of group. Talairach coordinates: y=27 (left) and 0 (right). The color bar indicates F values. Abbrevia-tions: DLPFC=dorsolateral prefrontal cortex; ACC=anterior cingu-late cortex; Hypothal=hypothalamus.



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consistent with clinical reports of the later onset of binge eating and purging in general and in anorexia nervosa, binge eating/purging type, in particular (26). At the same time, the fronto-striatal circuit is known to be involved in a variety of psychiatric disorders (e.g., Tourette’s syn-drome, bipolar disorder, OCD, attention defi cit hyper-activity disorder, depression). Thus, these fi ndings should be considered in this larger context (18). Addressing inhibitory control as an aspect of treatment in adolescents with eating disorders is another important consideration. Strategies to address response inhibition, as well as cog-nitive fl exibility and perseverative thinking, using cogni-tive remediation therapy have been preliminarily studied in adults with chronic anorexia nervosa and may be a promising adjunctive treatment to standard interventions aimed at weight restoration and eating disorder-related cognitions (36).

Previously presented in part as a poster at the 56th Annual Meet-ing of the American Academy of Child and Adolescent Psychiatry, Honolulu, October 27–November 1, 2009. Received Jan. 13, 2010; revisions received April 30 and June 29, 2010; accepted July 15, 2010 (doi: 10.1176/appi.ajp.2010.10010056). From the Department of Psy-chiatry and Behavioral Sciences, Stanford University School of Medi-cine. Address correspondence and reprint requests to Dr. Lock, De-partment of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Rd., Stanford, CA 94305; [email protected] (e-mail).

The authors report no fi nancial relationships with commercial in-terests.

Supported by an unrestricted fund for pediatric research from Lu-cile Packard Children’s Hospital, Stanford University.

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Aberrant Brain Activation During a Response Inhibition Task in Adolescent Eating Disorder Subtypes

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