Functional Disturbances Within Frontostriatal Circuits Across Multiple Childhood Psychopathologies

doi:10.1176/appi.ajp.2009.08091354

Am J Psychiatry. Author manuscript; available in PMC 2009 August 28.

Published in final edited form as:

Am J Psychiatry. 2009 June; 166(6): 664–674.

Published online 2009 May 15. doi: 10.1176/appi.ajp.2009.08091354

PMCID: PMC2734479

NIHMSID: NIHMS121709

Functional Disturbances Within Frontostriatal Circuits Across Multiple Childhood Psychopathologies

Rachel Marsh, Ph.D., Tiago V. Maia, Ph.D., and Bradley S. Peterson, M.D.

From the Department of Psychiatry, Division of Child and Adolescent Psychiatry, Columbia College of Physicians and Surgeons, New York State Psychiatric Institute, New York.

Address correspondence and reprint requests to Dr. Marsh, Columbia University and the New York State Psychiatric Institute, 1051 Riverside Dr., Unit 74, New York, NY 10032; Email: MarshR/at/childpsych.columbia.edu (e-mail)

The publisher's final edited version of this article is available at Am J Psychiatry

See other articles in PMC that cite the published article.

Abstract

Objective

Neuroimaging studies of healthy individuals inform us about the normative maturation of the frontostriatal circuits that subserve self-regulatory control processes. Findings from these studies can be used as a reference frame against which to compare the aberrant development of these processes in individuals across a wide range of childhood psychopathologies.

Method

The authors reviewed extensive neuroimaging evidence for the presence of abnormalities in frontostriatal circuits in children and adults with Tourette’s syndrome and obsessive-compulsive disorder (OCD) as well as a more limited number of imaging studies of adolescents and adults with anorexia nervosa or bulimia nervosa that, together, implicate dysregulation of frontostriatal control systems in the pathogenesis of these eating disorders.

Results

The presence of an impaired capacity for self-regulatory control that derives from abnormal development of frontostriatal circuits likely interacts in similar ways with normally occurring somatic sensations and motor urges, intrusive thoughts, sensations of hunger, and preoccupation with body shape and weight to contribute, respectively, to the development of the tics of Tourette’s syndrome, the obsessions of OCD, the binge eating behaviors of bulimia, and the self-starvation of anorexia.

Conclusions

Analogous brain mechanisms in parallel frontostriatal circuits, or even in differing portions of the same frontostriatal circuit, may underlie the differing behavioral disturbances in these multiple disorders, although further research is needed to confirm this hypothesis.

Learning to control behaviors that conflict with societal norms is vital for the healthy psychological development of children, which is a component of their developing self-regulatory control and their progressive ability to organize their thoughts, emotions, and behaviors in order to attain their goals (1). Related constructs are cognitive control (2) and, more broadly, inhibitory control (3). In the present review, the term “self-regulatory control” is used to encompass these capacities as well as the ability to regulate emotional responses and to inhibit temptations or impulses for immediate gratification in the service of waiting for larger more delayed rewards (4). Disturbances in the maturation of these capacities likely contribute to the development of a variety of psychiatric disorders in which children have difficulty regulating their thoughts, emotions, and behaviors. These disturbances may release from regulatory control, for example, an underlying urge to move or to perform a compulsive behavior.

Substantial evidence suggests that frontostriatal circuits subserve the capacity for self-regulation in both health (5) and illness (6). These circuits comprise a portion of the broader cortico-striato-thalamo-cortical loops that direct information from the cerebral cortex to the subcortex and then back again to specific regions of the cortex (7, 8). At least five parallel loops have been identified within frontostriatal circuits, initiating from and projecting back to the 1) supplementary motor area, 2) frontal eye fields, 3) dorsolateral prefrontal cortex, 4) lateral orbitofrontal cortex, and 5) anterior cingulate cortex (7, 8). The first three of these loops pass through the dorsal striatum, and the last two pass through the ventromedial striatum, including the nucleus accumbens (8). Findings from both animal and human studies suggest that the dorsal striatum mediates habit-or stimulus-response learning (9), while the ventral striatum mediates reward, drive, and motivation (10). Although both the dorsal striatum and ventral striatum respond to rewards, the dorsal striatum appears to do so only when an action is required, consistent with its putative involvement in stimulus-response learning (11). The prefrontal components of these pathways have long been assigned a central role in controlling thought and behavior in accord with the pursuit of future goals (12).

Difficulty controlling ego-dystonic thoughts, urges, or behaviors is a common characteristic of several psychiatric disorders that arise in childhood or adolescence. Tourette’s syndrome and obsessive-compulsive disorder (OCD) are among the better studied of these disorders of self-regulation. The tics of Tourette’s syndrome are typically brief, nonpurposeful or semipurposeful behavioral fragments often enacted in response to internal or external sensory cues (13). Sensitivity to these cues is usually experienced as a compulsory urge that is only relieved by the performance of a tic (13). These urges and the preoccupation with them bear a phenomenological resemblance to the obsessional urges that typically precede compulsive behaviors. In fact, patients with Tourette’s syndrome are often affected with OCD (14). Extensive neuroimaging evidence suggests that the pathophysiology of both disorders involves disturbances in the frontostriatal circuits that subserve the capacity for self-regulation (15–19). Anorexia nervosa and bulimia nervosa seem to share with Tourette’s syndrome and OCD this phenomenological characteristic of disordered control over behaviors or the urges to perform them. Anorexia is defined by excessive food restriction, and bulimia is defined by frequent binge eating and a concomitant sense of loss of control. The recurrent binge eating episodes, the frequency of other accompanying impulsive behaviors (20), and the inability to inhibit the constant preoccupation with weight and body shape suggest the presence of an impaired capacity for self-regulation in bulimia. In contrast, the stringent control over food intake in anorexia suggests the presence of excessive self-regulatory control. However, anorexia shares with bulimia the inability to inhibit weight- and body shape-related thoughts, which may alternatively suggest that a reduced rather than enhanced capacity for self-regulation is present in anorexia. As with OCD, the repetitive, ritualistic, and highly controlled behaviors in persons with anorexia may represent attempts to compensate for their inability to control obsessive thoughts and anxiety (21). The high rates of diagnostic crossover from anorexia to bulimia further suggest that these disorders may share a common neural substrate (22). Consistent with the phenomenological similarities of these eating disorders with OCD, persons with anorexia and bulimia also have higher rates of OCD and obsessive-compulsive personality features than what is present in the general population (23). Thus, the dysregulation of frontostriatal circuits may also be a core characteristic of anorexia and bulimia.

All of these illnesses typically begin during childhood or adolescence (24, 25), periods during which the capacity for self-regulation develops rapidly (5, 26). The development of this capacity parallels and is thought to depend on the maturation of frontostriatal circuits (27–29). Thus, disturbances in the maturation of frontostriatal circuits may contribute to the shared difficulties controlling thoughts, urges, and behaviors across these seemingly disparate disorders.

Normative Development of the Capacity for Self-Regulation

Experimental paradigms that study self-regulatory processes typically require participants to inhibit a more automatic behavior in favor of a less automatic one. They are therefore regarded as experimental models for studying inhibitory control. Findings from developmental studies of self-regulatory processes show that performance on Stroop, flanker, go/no-go, and stop-signal reaction time tasks continues to improve over childhood, not reaching adult levels until at least 12 years of age (30, 31).

The Stroop task is one of the most commonly studied of these paradigms. Inhibiting the prepotent reading response during incongruent trials requires the mobilization of attentional resources and the resolution of cognitive conflict, with down-modulation of the more automatic reading response and up-modulation of the less automatic but more task-relevant color-naming response (32). Brain activity when naming the colors of incongruent stimuli is greater than when naming the colors of congruent stimuli, particularly in the anterior cingulate, prefrontal and parietal cortices, and striatum, in both adults (33) and children (34).

Findings from a developmental functional magnetic resonance imaging (fMRI) study of the Stroop task among healthy participants (27) suggested that frontostriatal circuits mature as the capacity for self-regulation improves with advancing age. The study found that activation of the inferolateral prefrontal cortex and lenticular nucleus increased with age as well as response speed and accuracy, suggesting that increasing activity of frontostriatal circuits improves behavioral control as children mature. These interpretations are consistent with findings from previous developmental imaging studies of response inhibition using the go/no-go stop-signal reaction time or anti-Saccade tasks (26, 35, 36).

Increasing prefrontal activation during inhibitory tasks from childhood to adulthood (2, 27, 31) likely reflects synaptic pruning and increasing myelination in the frontal lobe (37). Anatomical magnetic resonance imaging (MRI) studies have tracked changes in brain volume, gray matter density, and cortical thickness longitudinally in healthy individuals (38–40). Findings suggest that the prefrontal cortices that mediate more advanced, higher-order control functions mature later than do areas that subserve more basic cognitive functions, such as sensation and movement (38–40). In addition, diffusion tensor imaging studies have shown changes in prefrontal white matter during development that presumably reflect the previously documented myelination of axons during childhood and adolescence. Ongoing myelination increases the speed of neuronal communication, thus enhancing cognitive processing with increasing age (41).

Normal maturational trajectories in frontostriatal systems provide a reference frame from which we can identify deviant patterns of development in individuals with Tourette’s syndrome, OCD, bulimia, and anorexia. To date, however, few studies have employed a developmental perspective to investigate the pathogenesis of these disorders, which would be best captured by longitudinal studies beginning at or before illness onset. A less definitive but also less costly way to investigate atypical neurodevelopment is to use trajectory-based analyses of cross-sectional data to compare anatomical and functional imaging findings across children and adults with and without illness. However, differences across diagnostic groups in the age trajectories of imaging measures in these studies could be confounded by systematic differences across age groups in the characteristics of the patients who are recruited into the study. For example, children and adults with a given disorder may differ in their durations of illness, rates of comorbidities, and disease subtypes (42). Thus, different imaging findings across children and adults with Tourette’s syndrome, for instance, may be produced by compensatory behavioral, cognitive, or emotional processes that may be more developed in adults who have had the illness longer (15). Finally, in the absence of imaging studies of children and adolescents who have eating disorders, we can only make crude inferences about pathogenesis based on findings from animal studies or from imaging studies of adult patients.

Self-Regulatory Disturbances in Tourette’s Syndrome

Tourette’s syndrome is a childhood-onset neuropsychiatric disorder defined by the presence of motor and vocal tics (43). It can be conceptualized as a disorder of impaired control of sensory urges and motor behaviors (44). Neuroimaging evidence from studies of children and adults with Tourette’s syndrome suggests the presence of both anatomical (15, 16) and functional (17, 45) abnormalities in the frontostriatal circuits that subserve self-regulatory capacities. Anatomical findings include decreased caudate volumes in children and adults (16) and larger dorsolateral prefrontal cortices in children but not in adults who have the disorder, relative to age-matched comparison subjects. The larger dorsolateral prefrontal volumes in children have accompanied less severe tic symptoms (15) and therefore may have represented a compensatory or adaptive process that attenuates tics, consistent with the role of the prefrontal cortex in inhibiting inappropriate impulses or behaviors.

Consistent with this interpretation of the anatomical hypertrophy of the frontal cortex, an fMRI study of tic suppression demonstrated that the suppression of tics in adults with Tourette’s syndrome produced changes in activity of frontostriatal systems. Findings from the study revealed that frontal cortices activated prominently, and the magnitude of frontal activation correlated significantly with increased activity in the caudate, which, in turn, was associated with greater decreases in activity of the putamen, globus pallidus, and thalamus. The magnitude of the activations (caudate) or deactivations (putamen, pallidum, and thalamus) during tic suppression correlated with tic severity in the month preceding the scan. Thus, a greater capacity of the cortex to modulate activity in the basal ganglia likely attenuates tic severity. Together, these anatomical and functional findings from individuals with Tourette’s syndrome suggest that when frontostriatal control systems fail, tics may be released from inhibitory control. Therefore, the nearly ubiquitous need to suppress tics in school and other social settings likely activates prefrontal cortices frequently and powerfully (45), possibly stimulating in them an activity-dependent neuroplastic hypertrophy.

In contrast, the smaller prefrontal volumes in adults who have Tourette’s syndrome may reflect an inability to produce this activity-dependent plastic response to repeated attempts to control tics (15). This inability could explain the failure of Tourette’s syndrome to remit during adolescence in the minority of patients who continue to experience tics in adulthood (46), which was true of the adults in these imaging studies. Consistent with this interpretation, fMRI studies have reported that adults, but not children, with Tourette’s syndrome rely on exaggerated activation of frontostriatal circuits in order to achieve normal performance on the Stroop task. Presumably, impaired frontally mediated inhibitory reserve confers a need for increased functional recruitment of these cortices in order to overcome enduring difficulties with self-regulation during performance of self-regulator tasks (17).

The prefrontal portions of cortico-striato-thalamo-cortical circuits project to specific regions of the striatum, which, in turn, project directly or indirectly to specific regions of the internal segment of the globus pallidus and the substantia nigra pars reticulata. These nuclei then project to the thalamus, which closes the loop by projecting back to the cortex (7). In each circuit, information flows predominantly through either a direct or an indirect pathway, both of which are modulated by dopamine (47). Positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies suggest that dopamine D₂ receptors are excessively sensitive in Tourette’s syndrome (48, 49). These findings, together with reports that the administration of dopamine antagonists reduces tic severity (50), suggest that hyperinnervation of the striatum by dopaminergic neurons may excessively stimulate the direct pathway while inhibiting the indirect pathway in individuals with Tourette’s syndrome, thereby contributing to their difficulty in regulating their tics (44).

Other anatomical imaging studies have identified abnormal thinning of the sensorimotor, primary motor, and premotor cortices in children with Tourette’s syndrome, with the degree of thinning proportional to the severity of their tics (51), as well as hypoplasia of the caudate nucleus in children and adults with the disorder (16). Together, these findings suggest that abnormal maturation of specific pathways in portions of cortico-striato-thalamo-cortical circuits, particularly those involving sensorimotor pathways looping between the cortex and basal ganglia, may contribute to the genesis of tic behaviors. These interpretations are consistent with a report (52) that activation of supplementary motor area, paralimbic regions (including the anterior cingulate and insular cortices), and parietal operculum accompanies the experience of the sensory cues that precede tics.

Children with Tourette’s syndrome are commonly affected with OCD (13). Family and twin studies indicate that these disorders are genetically related (53). Both tics and compulsions present as “habit-like” behaviors that have escaped regulatory control (13). These phenomenological similarities between tics and compulsions and their common genetic basis suggest that Tourette’s syndrome and pediatric OCD may be manifestations of the same underlying disease process, likely sharing a common neurobiological substrate.

Self-Regulatory Disturbances in OCD

OCD is characterized by recurrent intrusive thoughts, ideas, or images (obsessions) that are often accompanied by repetitive acts (compulsions) (43). Its age of onset is likely bimodal, with one mode at 10 to 12 years of age and the other occurring in early adulthood (54). The childhood-onset form most commonly occurs in the context of a personal or family history of tic disorder (tic-related OCD) (55).

Findings from neuropsychological studies suggest that individuals with OCD perform poorly on tasks requiring inhibitory control of behaviors and cognitions (56, 57). Furthermore, self-regulatory impairments on Stroop, go/no-go (56), and oculomotor suppression tasks (58) correlate with the severity of symptoms, suggesting that increasing degrees of functional disturbances in self-regulatory circuits may produce increasingly more severe symptoms. OCD symptoms may represent an individual’s incapacity to shift or self-regulate attentional resources away from his or her focus on obsessions (57), as well as a failure to regulate compulsory behaviors, similar to the failure to regulate tic behaviors in persons with Tourette’s syndrome.

Anatomical findings suggest that abnormalities in frontostriatal circuits involving the orbitofrontal cortex, anterior cingulate cortex, and striatum may contribute to the development of OCD (18, 19, 59). However, the presence of undiagnosed comorbid tic disorders could also account for striatal abnormalities in children with OCD and in adults with childhood-onset OCD (18, 60). Findings of increased anterior cingulate volumes in children (18, 61) contrast with findings of normal volumes in adults with OCD (19, 59). Reports of increased gray matter in the orbitofrontal cortex of children with OCD (60) also contrast with findings of reduced volume of the orbitofrontal cortex in adults (19, 62). Longitudinal studies of child- and adult-onset OCD are needed to understand the developmental trajectories that produce these divergent morphological findings in frontostriatal pathways in studies of children and adults with OCD.

Increased activity within frontostriatal circuits during symptom provocation suggests that hyperactivity in frontostriatal circuits generates the symptoms of OCD (63). Alternatively, hyperactivation could represent attempts on the part of the person with OCD to inhibit the performance of compulsions or to suppress behavioral withdrawal when presented with the provoking stimulus during the scanning process (64). Greater activation of orbitofrontal cortices during symptom provocation in adults with OCD was in fact associated with a smaller increase in reported symptoms (65), suggesting that activation of orbitofrontal cortices may have inhibited rather than caused symptoms. Furthermore, inverse correlations of symptom severity with activity in the right orbitofrontal and dorsal anterior cingulate cortices during response inhibition on a go/no-go task suggested that the patients who activated these regions most were better at suppressing their unwanted thoughts and compulsions (66). Nevertheless, findings from a wide range of studies suggest that disturbances in orbitofrontal cortex may play a causal role in producing the symptoms of OCD (67). These findings include anatomical abnormalities in orbitofrontal cortices of adults with OCD, the development of OCD following various naturalistic lesions of the orbitofrontal cortex, and the improvement in symptoms following neurosurgical lesions of white matter tracts leading to and from the orbitofrontal cortex (68).

OCD may also involve abnormalities of the action monitoring or error detection system that is mediated by the anterior cingulate (69, 70). Event-related potential and fMRI studies have shown increased anterior cingulate activation in adults with OCD relative to healthy comparison subjects following errors or high-conflict trials on inhibitory control tasks (69–71). Furthermore, the degree of hyperactivation is proportional to symptom severity (69, 70). One event-related potential study reported increased error-related anterior cingulate activity in children with OCD relative to healthy children, although the degree of activation did not correlate with symptom severity (72). Children with OCD continued to show error-related hyperactivity of the anterior cingulate after successful treatment with cognitive behavior therapy, suggesting that higher activity in the anterior cingulate following errors may be a trait-like disturbance in OCD. In contrast, an fMRI study reported less error-related anterior cingulate activation in adolescents with partially remitted OCD relative to healthy comparison subjects (73). Most of the adolescents in this small sample were taking selective serotonin reuptake inhibitors (SSRIs), which may have blunted their error-related activity. Interpreting the relevance of error-related activity of the anterior cingulate cortex to the pathogenesis of OCD is difficult because this activity may simply reflect excessive worries about or exaggerated reactions to erring on the task. Conflict-related activation of the anterior cingulate cortex following correct responses (71) could similarly represent exaggerated arousal or even greater anxiety relative to comparison subjects while performing challenging tasks in an experimental setting.

Evidence suggests that the frontostriatal circuits that include the orbitofrontal and anterior cingulate cortices are functionally abnormal in adults with OCD and likely contribute to their symptoms of impaired regulation. The functioning of these circuits has not been investigated longitudinally in patients with OCD, however, and only two fMRI studies to date have assessed the functioning of these circuits in younger patients (73, 74), thereby precluding our understanding of the developmental origins of frontostriatal disturbances in OCD. Whereas the pathogenesis of Tourette’s syndrome involves frontostriatal circuits consisting of motor and premotor cortices and the dorsal striatum, OCD seems to involve disturbances in the orbitofrontal and anterior cingulate portions of frontostriatal circuits. These circuit-level distinctions of frontostriatal dysfunction may contribute to the phenotypic differences between these often co-occurring conditions. In other words, the differentially segregated cortical inputs and outputs of cortico-striato-thalamo-cortical circuits may provide a neuroanatomical basis for the differential release of either tics or compulsions from regulatory control in persons with Tourette’s syndrome or OCD, respectively (75).

Self-Regulatory Disturbances in Bulimia Nervosa

Bulimia nervosa is characterized by recurrent episodes of binge eating (the consumption of an excessive amount of food in a short period of time) that are followed by self-induced vomiting or other compensatory behaviors that avoid weight gain (43). Episodes of binge eating are associated with a severe sense of loss of control (76). Dysfunctional self-regulation may therefore contribute to binge eating by releasing feeding behaviors from regulatory control. Dysfunction in regulatory systems may also produce an inability of persons with bulimia to control their preoccupation with body shape and weight, thereby inducing purging behaviors. Mood instability and impulsive, aggressive, and compulsory behaviors are common in individuals with bulimia, perhaps indicating the presence of more pervasive difficulties in self-regulation (76).

Although fMRI studies of persons with bulimia are few, the available evidence suggests that dysfunctional frontal control systems may contribute to their binge eating and impulsivity (77). Binge eating behaviors in persons with bulimia, similar to the defining behaviors of Tourette’s syndrome and OCD, may arise from or may at least be facilitated by the presence of dysfunctional control systems that release from inhibitory control a preexisting vulnerability to developing this particular illness. In bulimia, this vulnerability may stem from altered functioning of serotonergic systems that can produce both impulsivity and decreased satiety (78). Feelings of hunger in turn produce urges to binge, which may be released inappropriately by dysfunctional control systems to produce binge eating episodes. Interactions with the aesthetic cultural ideals of thinness and physical fitness then likely produce purging behaviors to counteract the weight gain that binge eating would otherwise produce.

Disturbances of serotonin metabolism within frontal cortices (79, 80) may predispose to the development of bulimia by reducing feelings of satiety (79). Consistent with this possibility, treatment with SSRIs tends to decrease the frequency of binges (81). Moreover, serotonergic disturbances have been documented in both ill (82) and recovered (83) individuals with bulimia, suggesting that these may be trait-like disturbances in this population. Serotonergic abnormalities may contribute not only to feeding disturbances (84), but also to the high levels of impulsivity reported in persons with bulimia (85), consistent with a vast literature linking serotonin abnormalities with impulsivity in both humans and animals (86).

Our fMRI findings among women with bulimia suggest that their failure to engage frontostriatal circuits appropriately contributes to their impairments in behavioral self-regulation (87). Patients with bulimia responded impulsively and made more errors relative to comparison subjects on the Simon task, a nonverbal analogue of the Stroop task. Even when responding correctly on incongruent trials, patients failed to generate the same activity as comparison subjects in the frontostriatal pathways thought to subserve inhibitory control, including the in-ferolateral prefrontal and anterior cingulate cortices, inferior frontal gyrus, putamen, and caudate. In addition, those with the most severe bulimia symptoms engaged these regions the least and demonstrated the poorest performance on the task. Analyses of brain activity during the commission of errors indicated greater activation of the dorsal anterior cingulate cortex of patients during incorrect responses relative to correct responses on conflict trials, suggesting the presence of heightened error detection or performance monitoring activity. However, activation of this region did not modulate the impulsive performance of the patients on subsequent trials, since their reaction times did not slow following errors. These findings suggest that the inability of persons with bulimia to engage frontostriatal systems likely contributes to their binge eating and other impulsive behaviors.

Binge eating could also be caused by disturbances in the frontostriatal circuits that subserve motivation and reward, including the orbitofrontal cortex and ventral striatum that are involved in processing the hedonic value of food (88). The consumption of food is associated with increased dopamine release in these reward circuits (89), and increases in dopamine are associated with more motivated (food seeking) behavior in rats (90) and humans (91). Consistent with our model of self-regulatory disturbances in bulimia, binge eating may reflect an inability to control the temptation for immediate rewards (food consumption) in favor of a more delayed reward (a slimmer body) (92). Although fMRI studies have suggested that anorexia may involve dysfunction in reward circuits (93, 94), reward processing has not yet been assessed systematically in individuals with bulimia.

Self-Regulatory Disturbances in Anorexia Nervosa

Anorexia nervosa and bulimia nervosa have similar phenotypes and clinical courses (25). Both primarily affect women, and both typically begin in adolescence. Anorexia includes a relentless preoccupation with body shape and weight and repetitive ritualized behaviors that maintain abnormally low body weight (43). Individuals with anorexia have perfectionist and obsessive temperaments that persist following recovery (95). Their rigid control over feeding behaviors seems to suggest the presence of pathological self-regulation.

Approximately one-third of adults with bulimia describe past histories of anorexia (96), and a significant proportion of patients with anorexia regularly binge eat or purge (25). The high rates of diagnostic crossover between these disorders (22) suggest that anorexia and bulimia, similar to Tourette’s syndrome and OCD, may be manifestations of the same or comparable underlying disease processes. In addition, their phenotypic similarities, such as an intense preoccupation with food and a high prevalence of OCD and obsessive-compulsive personality traits (97–99) that predict poor outcome (100), suggest that these disorders share neural substrates. Anorexia and bulimia therefore appear to lie on a spectrum of self-regulatory control over feeding behaviors, with excessive control present in anorexia restricting subtype, less control present in anorexia binge/purge subtype, and a paucity of control in bulimia (101). However, individuals with anorexia have difficulty controlling their obsessive preoccupation with thinness and their ritualistic behaviors that pertain to eating and exercising (102). Thus, similar to OCD, symptoms of anorexia may represent a failure to shift or to regulate attentional resources away from the intrusive thoughts that motivate calorie restriction and produce ritualistic behaviors. Alternatively, the ritualistic behaviors in anorexia and OCD may represent a failure to regulate the behaviors themselves.

Several lines of evidence point to abnormalities of the anterior cingulate cortex in both ill and recovered persons with anorexia. First, decreased volumes of the dorsal anterior cingulate cortex have been reported in ill (103) and recovered (104) adult patients relative to comparison subjects. Second, SPECT studies suggest that adults with anorexia have lower resting regional cerebral blood flow in the anterior cingulate cortex relative to comparison subjects, both before and after weight restoration (105). Third, PET studies report alterations in postsynaptic serotonin 5-HT_1A and 5-HT_2A receptors in the anterior cingulate cortex in both ill (106) and recovered (107) patients. These receptors mediate, respectively, the inhibitory and excitatory actions of 5-HT on cortical neurons (108); thus these alterations may produce further functional abnormalities in the anterior cingulate cortex. Given the central role of this region in self-regulatory control (27), these abnormalities seem likely to contribute to self-regulatory disturbances in patients with anorexia (78).

Although anorexia typically arises during adolescence (25), imaging data from adolescent patients are sparse, possibly because the confounding effects of malnutrition make findings from studies of patients in the underweight state difficult to interpret. Reduced volumes of total gray matter have been reported in both adolescents and adults with anorexia during acute illness (109, 110). One study (109) reported that these deficits persisted in the recovered state, but several additional studies (110–112) have reported that gray matter volumes normalize following recovery. Whether or not these anatomical abnormalities simply reflect the transitory effects of malnourishment is unknown.

Most fMRI studies of individuals with anorexia have used symptom provocation designs that expose participants to food-related stimuli (113, 114). In one study (114), for example, both ill and recovered women with anorexia activated the medial prefrontal and anterior cingulate cortices more than comparison subjects in response to food compared with nonfood stimuli, suggesting that activation of the frontal cortex to food stimuli represents trait rather than state markers in anorexia. Recovered patients engaged the lateral prefrontal cortex more than ill patients. Similar to findings from persons with OCD (65), activation of the lateral prefrontal cortex during symptom provocation may reflect the better ability of recovered patients to control their anxiety and preoccupation with food stimuli, consistent with the role that the lateral prefrontal cortex plays in cognitive control (12).

Findings from fMRI studies suggest that reward processing is dysfunctional in persons with anorexia. In one study that involved a guessing game (93), women with anorexia activated the ventral striatum similarly during their responses to both positive and negative feedback. Healthy participants, in contrast, activated the ventral striatum preferentially in response to positive feedback, consistent with prior findings of ventral striatal responses to reward but not punishment during this task in healthy participants (115). PET studies have also reported increased D₂/D₃ receptor binding in the ventral striatum both before and after recovery in patients with anorexia (94), possibly explaining their abnormal brain activity during reward processing. Dysfunction in the ventral striatum and related portions of frontostriatal circuits that subserve reward processing may contribute to a diminished motivation to eat in individuals with anorexia. Food may not be as rewarding to them as it is to others (116).

Dysfunction in this circuit, including abnormal activation of the ventral striatum during negative feedback (93), may also contribute to the diminished motivation of these individuals to avoid negative consequences, such as starvation and repeated hospitalization. Whereas decreases in the numbers of striatal D₂ receptors in obese individuals (117) may reduce self-regulatory control and promote overeating, increases in the numbers of D₂ receptors in persons with anorexia may enhance self-regulatory control and promote abstention from eating. Excessive control may thereby contribute to the remarkable capacity of individuals with anorexia to deny themselves the gratification of food ingestion in the service of attaining a thinner body.

Unrealistically high personal standards and excessive concerns with making mistakes are common in patients with either anorexia or OCD (118, 119). Consistent with these phenotypic traits, persons with OCD activated the anterior cingulate cortex more during the commission of errors than healthy comparison subjects on tasks that required inhibitory control, suggesting the presence of a hyperactive error monitoring system (69, 70, 120). However, acutely ill patients with anorexia activated the anterior cingulate cortex less than comparison subjects during the commission of errors on a flanker task (121). These differences in activity within error monitoring circuits across anorexia and OCD groups are surprising, given the perfectionism and excessive concern with making mistakes that are common in both disorders.

Conclusion

Substantial evidence suggests that the development of a capacity for self-regulation relies on the maturation of frontostriatal circuits. The clinical presentations of Tourette’s syndrome, OCD, bulimia, and anorexia suggest the presence of impaired control processes in each of these conditions, and converging lines of evidence suggest that the pathogenesis of each of these disorders involves anatomical and functional disturbances in frontostriatal circuits. Improving our knowledge of the maturation of self-regulatory processes and of the frontostriatal circuits that subserve them will allow us to determine how these systems can be derailed during development and how such disruptions may contribute to the development of these and other childhood disorders.

Sensory and motor urges, intrusive thoughts, hunger, and concern with body shape and weight are common in both healthy and ill individuals. Although a capacity for self-regulation keeps these urges, thoughts, and drives under control in healthy individuals, anatomical and functional disturbances of frontostriatal systems may release them from inhibitory control to allow expression of the tics in Tourette’s syndrome, the obsessions in OCD, the preoccupation with body shape and weight in anorexia, or the binge eating in bulimia (Figure 1). The obsessions in OCD, the obsessive preoccupation with body shape and weight in anorexia, and the fear of gaining weight from binge eating in bulimia are predominantly ego dystonic and therefore elicit compensatory behaviors that aim to alleviate the associated anxiety or discomfort, producing compulsions, starvation, or purging, respectively. Starvation in anorexia restricting subtype may alternatively arise directly from a heightened and excessive capacity for self-regulation (Figure 1).

FIGURE 1

The Role of Dysregulated Frontostriatal Systems in Tourette’s Syndrome, OCD, Anorexia, and Bulimiaa

A crucial question raised by this model is why individuals who have an impaired capacity for self-regulation do not typically develop the symptoms of all these disorders. Tourette’s syndrome and OCD likely arise from disturbances in differing portions of frontostriatal circuits. Whether anorexia and bulimia can be similarly distinguished by the involvement of different portions of frontostriatal circuits should be the focus of future research. However, anorexia and bulimia are also at least partly caused by cultural ideals of thinness (122), whereas the clinical presentations of Tourette’s syndrome and OCD are relatively uniform in prevalence and presentation across cultures (123), suggesting that they may have stronger biological determinants than anorexia and bulimia. Finally, differing predispositions to experience sensorimotor urges and preoccupation with food likely interact with differing capacities for self-regulation to determine who develops Tourette’s syndrome, OCD, anorexia, or bulimia and to what degree of clinical severity.

A current controversy in nosology is whether mental disorders, particularly developmental psychopathologies, are best characterized using a categorical or dimensional approach (124). The shared phenotypic characteristics that self-regulatory disturbances produce and the shared involvement of frontostriatal circuits across these varied disorders support, to some extent, a dimensional conceptualization of these predispositions, capacities, and manifest illnesses. However, if differing portions of frontostriatal circuits are indeed responsible for the development of one rather than another of these disorders, then categorical distinctions among them may still be most appropriate. Additional research on the neural bases of these disorders may help provide a biological resolution to this important nosological debate (125).

Acknowledgments

Supported in part by NIMH grants K02-74677, K01-MH077652, and MH068318; a grant from the National Alliance for Research on Schizophrenia and Depression (NARSAD); funding from the Sackler Institute for Developmental Psychobiology, Columbia University; and the Klingenstein Third Generation Foundation.

Clinical trial registry number: NCT00345943 (ClinicalTrials.gov).

Footnotes

The authors report no competing interests.

References

1. Posner MI, Rothbart MK. Developing mechanisms of self-regulation. Dev Psychopathol. 2000;12:427–441. [PubMed]

2. Casey BJ, Tottenham N, Fossella J. Clinical, imaging, lesion, and genetic approaches toward a model of cognitive control. Dev Psychobiol. 2002;40:237–254. [PubMed]

3. Konishi S, Nakajima K, Uchida I, Kikyo H, Kameyama M, Miyashita Y. Common inhibitory mechanism in human inferior prefrontal cortex revealed by event-related functional MRI. Brain. 1999;122(pt 5):981–991. [PubMed]

4. Mischel W, Shoda Y, Rodriguez MI. Delay of gratification in children. Science. 1989;244:933–938. [PubMed]

5. Diamond A. Abilities and neural mechanisms underlying AB performance. Child Dev. 1988;59:523–527. [PubMed]

6. Peterson BS. In: Neuroimaging studies of Tourette syndrome: a decade of progress, in Advances in Neurology, Tourette Syndrome and Associated Disorders. Cohen DJ, Goetz CG, Jankovic J, editors. Philadelphia: Lippincott Williams and Wilkins; 2000. pp. 179–196.

7. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357–381. [PubMed]

8. Alexander G, Crutcher M, DeLong M. Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “pre-frontal,” and “limbic” functions. Prog Brain Res. 1990;85:119–146. [PubMed]

9. Packard MG, Knowlton BJ. Learning and memory functions of the basal ganglia. Annu Rev Neurosci. 2002;25:563–593. [PubMed]

10. Wise RA. Dopamine, learning and motivation. Nat Rev Neurosci. 2004;5:483–494. [PubMed]

11. Tanaka SC, Balleine BW, O’Doherty JP. Calculating consequences: brain systems that encode the causal effects of actions. J Neurosci. 2008;28:6750–6755. [PMC free article] [PubMed]

12. Miller EK, Cohen JD. An integrative theory of prefrontal cortex function. Annu Rev Neurosci. 2001;24:167–202. [PubMed]

13. Leckman J, Riddle M. Tourette’s syndrome: when habit-forming systems form habits of their own? Neuron. 2000;28:349–354. [PubMed]

14. Peterson BS, Pine DS, Cohen P, Brook J. A prospective, longitudinal study of tic, obsessive-compulsive, and attention deficit-hyperactivity disorders in an epidemiological sample. J Am Acad Child Adolesc Psychiatry. 2001;40:685–695. [PubMed]

15. Peterson BS, Staib L, Scahill L, Zhang H, Anderson C, Leckman JF, Cohen DJ, Gore JC, Albert J, Webster R. Regional brain and ventricular volumes in Tourette syndrome. Arch Gen Psychiatry. 2001;58:427–440. [PubMed]

16. Peterson BS, Thomas P, Kane MJ, Scahill L, Zhang H, Bronen R, King RA, Leckman JF, Staib L. Basal ganglia volumes in patients with Gilles de la Tourette syndrome. Arch Gen Psychiatry. 2003;60:415–424. [PubMed]

17. Marsh R, Zhu H, Wang Z, Skudlarski P, Peterson BS. A developmental fMRI study of self-regulatory control in Tourette’s syndrome. Am J Psychiatry. 2007;164:955–966. [PMC free article] [PubMed]

18. Rosenberg DR, Keshavan MS. Toward a neurodevelopmental model of obsessive–compulsive disorder. Biol Psychiatry. 1998;43:623–640. [PubMed]

19. Pujol J, Soriano-Mas C, Alonso P, Cardoner N, Menchón JM, Deus J, Vallejo J. Mapping structural brain alterations in obsessive-compulsive disorder. Arch Gen Psychiatry. 2004;61:720–730. [PubMed]

20. Kaltiala-Heino R, Rissanen A, Rimpela M, Rantanen P. Bulimia and impulsive behaviour in middle adolescence. Psychother Psychosom. 2003;72:26–33. [PubMed]

21. Reuven-Magril O, Dar R, Liberman N. Illusion of control and behavioral control attempts in obsessive-compulsive disorder. J Abnorm Psychol. 2008;117:334–341. [PubMed]

22. Eddy KT, Dorer DJ, Franko DL, Tahilani K, Thompson-Brenner H, Herzog DB. Diagnostic crossover in anorexia nervosa and bulimia nervosa: implications for DSM-V. Am J Psychiatry. 2008;165:245–250. [PubMed]

23. Kaye WH, Bulik CM, Thornton L, Barbarich N, Masters K. Comorbidity of anxiety disorders with anorexia and bulimia nervosa. Am J Psychiatry. 2004;161:2215–2221. [PubMed]

24. Leckman JF, Zhang H, Vitale A, Lahnin F, Lynch K, Bondi C, Kim YS, Peterson BS. Course of tic severity in Tourette’s syndrome: the first two decades. Pediatrics. 1998;102:14–19. [PubMed]

25. Klein DA, Walsh BT. Eating disorders: clinical features and pathophysiology. Physiol Behav. 2004;81:359–374. [PubMed]

26. Luna B, Garver KE, Urban TA, Lazar NA, Sweeney JA. Maturation of cognitive processes from late childhood to adulthood. Child Dev. 2004;75:1357–1372. [PubMed]

27. Marsh R, Zhu H, Schultz RT, Quackenbush G, Royal J, Skudlarski P, Peterson BS. A developmental fMRI study of self-regulatory control. Hum Brain Mapp. 2006;27:848–863. [PMC free article] [PubMed]

28. Rubia K, Smith AB, Woolley J, Nosarti C, Heyman I, Taylor E, Brammer M. Progressive increase of frontostriatal brain activation from childhood to adulthood during event-related tasks of cognitive control. Hum Brain Mapp. 2006;27:973–993. [PubMed]

29. Casey BJ, Tottenham N, Liston C, Durston S. Imaging the developing brain: What have the authors learned about cognitive development? Trends Cogn Sci. 2005;9:104–110. [PubMed]

30. Durston S, Thomas KM, Yang Y, Ulug AM, Zimmerman RD, Casey BJ. A neural basis for the development of inhibitory control. Develop Sci. 2002;5:F9–F16.

31. Rubia K, Overmeyer S, Taylor E, Brammer M, Williams SC, Simmons A, Andrew C, Bullmore ET. Functional frontalisation with age: mapping neurodevelopmental trajectories with fMRI. Neurosci Biobehav Rev. 2000;24:13–19. [PubMed]

32. Cohen JD, Aston-Jones G. In: A systems-level perspective on attention and cognitive control: guided activation, adaptive gating, conflict monitoring, and exploitation versus exploration, in Cognitive Neuroscience of Attention. Posner M, editor. New York: Guilford Press; 2004. pp. 71–90.

33. Peterson BS, Skudlarski P, Gatenby JC, Zhang H, Anderson AW, Gore JC. An fMRI study of Stroop word-color interference: evidence for cingulate subregions subserving multiple distributed attentional systems. Biol Psychiatry. 1999;45:1237–1258. [PubMed]

34. Adleman NE, Menon V, Blasey CM, White CD, Warsofsky IS, Glover GH, Reiss AL. A developmental fMRI study of the Stroop color-word task. Neuroimage. 2002;16:61–75. [PubMed]

35. Bunge SA, Dudukovic NM, Thomason ME, Vaidya CJ, Gabrieli JD. Immature frontal lobe contributions to cognitive control in children: evidence from fMRI. Neuron. 2002;33:301–311. [PubMed]

36. Casey BJ, Trainor R, Giedd J, Vauss Y, Vaituzis CK, Hamburger S, Kozuch P, Rapoport JL. The role of the anterior cingulate in automatic and controlled processes: a developmental neuroanatomical study. Dev Psychobiol. 1997;30:61–69. [PubMed]

37. Huttenlocher PR. Synaptic density in human frontal cortex: developmental changes and effects of aging. Brain Res. 1979;163:195–205. [PubMed]

38. Giedd JN, Blumenthal J, Jeffries NO, Castellanos FX, Liu H, Zijdenbos A, Paus T, Evans AC, Rapoport JL. Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci. 1999;2:861–863. [PubMed]

39. Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, Nugent TF, 3rd, Herman DH, Clasen LS, Toga AW, Rapoport JL, Thompson PM. Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci U S A. 2004;101:8174–8179. [PubMed]

40. Sowell ER, Thompson PM, Leonard CM, Welcome SE, Kan E, Toga AW. Longitudinal mapping of cortical thickness and brain growth in normal children. J Neurosci. 2004;24:8223–8231. [PubMed]

41. Cascio CJ, Gerig G, Piven J. Diffusion tensor imaging: application to the study of the developing brain. J Am Acad Child Adolesc Psychiatry. 2007;46:213–223. [PubMed]

42. Kraemer HC, Yesavage JA, Taylor JL, Kupfer D. How can the authors learn about developmental processes from cross-sectional studies, or can the authors? Am J Psychiatry. 2000;157:163–171. [PubMed]

43. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Publishing; 1994.

44. Marsh R, Leckman JF, Bloch MH, Yazgan Y, Peterson BS. In: Tics and compulsions: disturbances of self-regulatory control in the development of habitual behaviors, in Handbook of Developmental Cognitive Neuroscience. 2nd ed. Nelson CA, Luciana M, editors. Cambridge, Mass: Massachusetts Institute of Technology; 2008. pp. 717–737.

45. Peterson BS, Skudlarski P, Anderson AW, Zhang H, Gatenby JC, Lacadie CM, Leckman JF, Gore JC. A functional magnetic resonance imaging study of tic suppression in Tourette syndrome. Arch Gen Psychiatry. 1998;55:326–333. [PubMed]

46. Bloch MH, Leckman JF, Zhu H, Peterson BS. Caudate volumes in childhood predict symptom severity in adults with Tourette syndrome. Neurology. 2005;65:1253–1258. [PMC free article] [PubMed]

47. Graybiel AM. Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci. 1990;13:244–254. [PubMed]

48. Wolf SS, Jones DW, Knable MB, Gorey JG, Lee KS, Hyde TM, Coppola R, Weinberger DR. Tourette syndrome: prediction of phenotypic variation in monozygotic twins by caudate nucleus D₂ receptor binding. Science. 1996;273:1225–1227. [PubMed]

49. Wong DF, Singer HS, Brandt J, Shaya E, Chen C, Brown J, Kimball AW, Gjedde A, Dannals RF, Ravert HT, Wilson PD, Wagner HN., Jr D₂-like dopamine receptor density in Tourette syndrome measured by PET. J Nucl Med. 1997;38:1243–1247. [PubMed]

50. Scahill L, Leckman JF, Schultz RT, Katsovich L, Peterson BS. A placebo-controlled trial of risperidone in Tourette syndrome. Neurology. 2003;60:1130–1135. [PubMed]

51. Sowell ER, Kan E, Yoshii J, Thompson PM, Bansal R, Xu D, Toga AW, Peterson BS. Thinning of sensorimotor cortices in children with Tourette syndrome. Nat Neurosci. 2008;11:637–639. [PMC free article] [PubMed]

52. Bohlhalter S, Goldfine A, Matteson S, Garraux G, Hanakawa T, Kansaku K, Wurzman R, Hallett M. Neural correlates of tic generation in Tourette syndrome: an event-related functional MRI study. Brain. 2006;129(pt 8):2029–2037. [PubMed]

53. Khalifa N, von Knorring AL. Tourette syndrome and other tic disorders in a total population of children: clinical assessment and background. Acta Paediatr. 2005;94:1608–1614. [PubMed]

54. Valleni-Basile LA, Garrison CZ, Waller JL, Addy CL, McKeown RE, Jackson KL, Cuffe SP. Incidence of obsessive-compulsive disorder in a community sample of young adolescents. J Am Acad Child Adolesc Psychiatry. 1996;35:898–906. [PubMed]

55. Eichstedt JA, Arnold SL. Childhood-onset obsessive-compulsive disorder: a tic-related subtype of OCD? Clin Psychol Rev. 2001;21:137–157. [PubMed]

56. Bannon S, Gonsalvez CJ, Croft RJ, Boyce PM. Response inhibition deficits in obsessive-compulsive disorder. Psychiatry Res. 2002;110:165–174. [PubMed]

57. Chamberlain SR, Blackwell AD, Fineberg NA, Robbins TW, Sahakian BJ. The neuropsychology of obsessive compulsive disorder: the importance of failures in cognitive and behavioural inhibition as candidate endophenotypic markers. Neurosci Biobehav Rev. 2005;29:399–419. [PubMed]

58. Rosenberg DR, Averbach DH, O’Hearn KM, Seymour AB, Birmaher B, Sweeney JA. Oculomotor response inhibition abnormalities in pediatric obsessive-compulsive disorder. Arch Gen Psychiatry. 1997;54:831–838. [PubMed]

59. Atmaca M, Yildirim H, Ozdemir H, Tezcan E, Poyraz AK. Volumetric MRI study of key brain regions implicated in obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:46–52. [PubMed]

60. Szeszko PR, Christian C, Macmaster F, Lencz T, Mirza Y, Taormina SP, Easter P, Rose M, Michalopoulou GA, Rosenberg DR. Gray matter structural alterations in psychotropic drug-naive pediatric obsessive-compulsive disorder: an optimized voxel-based morphometry study. Am J Psychiatry. 2008;165:1299–1307. [PubMed]

61. Szeszko PR, MacMillan S, McMeniman M, Chen S, Baribault K, Lim KO, Ivey J, Rose M, Banerjee SP, Bhandari R, Moore GJ, Rosenberg DR. Brain structural abnormalities in psychotropic drug-naive pediatric patients with obsessive-compulsive disorder. Am J Psychiatry. 2004;161:1049–1056. [PubMed]

62. Szeszko PR, Robinson D, Alvir JM, Bilder RM, Lencz T, Ashtari M, Wu H, Bogerts B. Orbital frontal and amygdala volume reductions in obsessive-compulsive disorder. Arch Gen Psychiatry. 1999;56:913–919. [PubMed]

63. Evans DW, Lewis MD, Iobst E. The role of the orbitofrontal cortex in normally developing compulsive-like behaviors and obsessive-compulsive disorder. Brain Cogn. 2004;55:220–234. [PubMed]

64. Peterson BS. Conceptual, methodological, and statistical challenges in brain imaging studies of developmentally based psychopathologies. Develop Psychopath. 2003;15:811–832. [PubMed]

65. Adler CM, McDonough-Ryan P, Sax KW, Holland SK, Arndt S, Strakowski SM. fMRI of neuronal activation with symptom provocation in unmedicated patients with obsessive compulsive disorder. J Psychiatr Res. 2000;34:317–324. [PubMed]

66. Roth RM, Saykin AJ, Flashman LA, Pixley HS, West JD, Mamourian AC. Event-related functional magnetic resonance imaging of response inhibition in obsessive-compulsive disorder. Biol Psychiatry. 2007;62:901–909. [PubMed]

67. Maia TV, Cooney RE, Peterson BS. The neural bases of obsessive-compulsive disorder in children and adults. Develop Psychopathol. 2008;20:1251–1283. [PMC free article] [PubMed]

68. Greenberg BD, Price LH, Rauch SL, Friehs G, Noren G, Malone D, Carpenter LL, Rezai AR, Rasmussen SA. Neurosurgery for intractable obsessive-compulsive disorder and depression: critical issues. Neurosurg Clin N Am. 2003;14:199–212. [PubMed]

69. Gehring WJ, Himle J, Nisenson LG. Action-monitoring dysfunction in obsessive-compulsive disorder. Psychol Sci. 2000;11:1–6. [PubMed]

70. Ursu S, Stenger VA, Shear MK, Jones MR, Carter CS. Overactive action monitoring in obsessive-compulsive disorder: evidence from functional magnetic resonance imaging. Psychol Sci. 2003;14:347–353. [PubMed]

71. Maltby N, Tolin DF, Worhunsky P, O’Keefe TM, Kiehl KA. Dysfunctional action monitoring hyperactivates frontal-striatal circuits in obsessive-compulsive disorder: an event-related fMRI study. Neuroimage. 2005;24:495–503. [PubMed]

72. Hajcak G, Franklin ME, Foa EB, Simons RF. Increased error-related brain activity in pediatric obsessive-compulsive disorder before and after treatment. Am J Psychiatry. 2008;165:116–123. [PubMed]

73. Woolley J, Heyman I, Brammer M, Frampton I, McGuire PK, Rubia K. Brain activation in paediatric obsessive compulsive disorder during tasks of inhibitory control. Br J Psychiatry. 2008;192:25–31. [PubMed]

74. Lazaro L, Caldu X, Junque C, Bargalló N, Andrés S, Morer A, Castro-Fornieles J. Cerebral activation in children and adolescents with obsessive-compulsive disorder before and after treatment: a functional MRI study. J Psychiatr Res. 2008;42:1051–1059. [PubMed]

75. Mink JW. Basal ganglia dysfunction in Tourette’s syndrome: a new hypothesis. Pediatr Neurol. 2001;25:190–198. [PubMed]

76. Kaye W, Strober M, Jimerson DC. In: The neurobiology of eating disorders, in The Neurobiology of Mental Illness. Charney D, Nestler EJ, editors. New York: Oxford University Press; 2004. pp. 1112–1128.

77. Frank GK, Bailer UF, Henry S, Wagner A, Kaye WH. Neuroimaging studies in eating disorders. CNS Spectr. 2004;9:539–548. [PubMed]

78. Kaye W. Neurobiology of anorexia and bulimia nervosa. Physiol Behav. 2008;94:121–135. [PMC free article] [PubMed]

79. Wolfe BE, Metzger E, Jimerson DC. Research update on serotonin function in bulimia nervosa and anorexia nervosa. Psychopharmacol Bull. 1997;33:345–354. [PubMed]

80. Kaye WH, Frank GK, Bailer UF, Henry SE, Meltzer CC, Price JC, Mathis CA, Wagner A. Serotonin alterations in anorexia and bulimia nervosa: new insights from imaging studies. Physiol Behav. 2005;85:73–81. [PubMed]

81. Mayer LE, Walsh BT. The use of selective serotonin reuptake inhibitors in eating disorders. J Clin Psychiatry. 1998;59 suppl 15:28–34. [PubMed]

82. Steiger H, Israel M, Gauvin L, Ng Ying Kin NM, Young SN. Implications of compulsive and impulsive traits for serotonin status in women with bulimia nervosa. Psychiatry Res. 2003;120:219–229. [PubMed]

83. Kaye WH, Frank GK, Meltzer CC, Price JC, McConaha CW, Crossan PJ, Klump KL, Rhodes L. Altered serotonin 2A receptor activity in women who have recovered from bulimia nervosa. Am J Psychiatry. 2001;158:1152–1155. [PubMed]

84. Brewerton TD. Toward a unified theory of serotonin dysregulation in eating and related disorders. Psychoneuroendocrinology. 1995;20:561–590. [PubMed]

85. Steiger H, Young SN, Kin NM, Koerner N, Israel M, Lageix P, Paris J. Implications of impulsive and affective symptoms for serotonin function in bulimia nervosa. Psychol Med. 2001;31:85–95. [PubMed]

86. Winstanley CA, Dalley JW, Theobald DE, Robbins TW. Fractionating impulsivity: contrasting effects of central 5-HT depletion on different measures of impulsive behavior. Neuropsychopharmacology. 2004;29:1331–1343. [PubMed]

87. Marsh R, Steinglass JE, Gerber AJ, Graziano O'Leary K, Wang Z, Murphy D, Walsh BT, Peterson BS. Deficient activity in the neural systems that mediate self-regulatory control in bulimia nervosa. Arch Gen Psychiatry. 2009;66:51–63. [PMC free article] [PubMed]

88. Berridge KC, Kringelbach ML. Affective neuroscience of pleasure: reward in humans and animals. Psychopharmacology (Berl) 2008;199:457–480. [PMC free article] [PubMed]

89. Hauber W, Fuchs H. Dopamine release in the rat globus pallidus characterised by in vivo microdialysis. Behav Brain Res. 2000;111:39–44. [PubMed]

90. Roitman MF, Stuber GD, Phillips PE, Wightman RM, Carelli RM. Dopamine operates as a subsecond modulator of food seeking. J Neurosci. 2004;24:1265–1271. [PubMed]

91. Wang GJ, Volkow ND, Fowler JS. The role of dopamine in motivation for food in humans: implications for obesity. Expert Opin Ther Targets. 2002;6:601–609. [PubMed]

92. van den Bos R, de Ridder D. Evolved to satisfy our immediate needs: self-control and the rewarding properties of food. Appetite. 2006;47:24–29. [PubMed]

93. Wagner A, Aizenstein H, Venkatraman VK, Fudge J, May JC, Mazurkewicz L, Frank GK, Bailer UF, Fischer L, Nguyen V, Carter C, Putnam K, Kaye WH. Altered reward processing in women recovered from anorexia nervosa. Am J Psychiatry. 2007;164:1842–1849. [PubMed]

94. Frank GK, Bailer UF, Henry SE, Drevets W, Meltzer CC, Price JC, Mathis CA, Wagner A, Hoge J, Ziolko S, Barbarich-Marsteller N, Weissfeld L, Kaye WH. Increased dopamine D₂/D₃ receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [¹¹C]raclopride. Biol Psychiatry. 2005;58:908–912. [PubMed]

95. Halmi KA, Tozzi F, Thornton LM, Crow S, Fichter MM, Kaplan AS, Keel P, Klump KL, Lilenfeld LR, Mitchell JE, Plotnicov KH, Pollice C, Rotondo A, Strober M, Woodside DB, Berrettini WH, Kaye WH, Bulik CM. The relation among perfectionism, obsessive-compulsive personality disorder and obsessive-compulsive disorder in individuals with eating disorders. Int J Eat Disord. 2005;38:371–374. [PubMed]

96. Sullivan PF, Bulik CM, Carter FA, Gendall KA, Joyce PR. The significance of a prior history of anorexia in bulimia nervosa. Int J Eat Disord. 1996;20:253–261. [PubMed]

97. Anderluh MB, Tchanturia K, Rabe-Hesketh S, Treasure J. Childhood obsessive-compulsive personality traits in adult women with eating disorders: defining a broader eating disorder phenotype. Am J Psychiatry. 2003;160:242–247. [PubMed]

98. Wonderlich SA, Lilenfeld LR, Riso LP, Engel S, Mitchell JE. Personality and anorexia nervosa. Int J Eat Disord. 2005;37 suppl:S68–S71. discussion S87–S89. [PubMed]

99. Strober M, Freeman R, Lampert C, Diamond J. The association of anxiety disorders and obsessive compulsive personality disorder with anorexia nervosa: evidence from a family study with discussion of nosological and neurodevelopmental implications. Int J Eat Disord. 2007;40 suppl:S46–S51. [PubMed]

100. Crane AM, Roberts ME, Treasure J. Are obsessive-compulsive personality traits associated with a poor outcome in anorexia nervosa? a systematic review of randomized controlled trials and naturalistic outcome studies. Int J Eat Disord. 2007;40:581–588. [PubMed]

101. Marsh R, Steinglass JE, Graziano K, Peterson BS, Walsh BT. Self-regulatory control and habit learning in the development of eating disorders. Curr Psychiatr Rev. 2007;3:73–83.

102. Halmi KA, Sunday SR, Klump KL, Strober M, Leckman JF, Fichter M, Kaplan A, Woodside B, Treasure J, Berrettini WH, Al Shabboat M, Bulik CM, Kaye WH. Obsessions and compulsions in anorexia nervosa subtypes. Int J Eat Disord. 2003;33:308–319. [PubMed]

103. McCormick LM, Keel PK, Brumm MC, Bowers W, Swayze V, Andersen A, Andreasen N. Implications of starvation-induced change in right dorsal anterior cingulate volume in anorexia nervosa. Int J Eat Disord. 2008;41:602–610. [PubMed]

104. Muhlau M, Gaser C, Ilg R, Conrad B, Leibl C, Cebulla MH, Backmund H, Gerlinghoff M, Lommer P, Schnebel A, Wohlschläger AM, Zimmer C, Nunnemann S. Gray matter decrease of the anterior cingulate cortex in anorexia nervosa. Am J Psychiatry. 2007;164:1850–1857. [PubMed]

105. Kojima S, Nagai N, Nakabeppu Y, Muranaga T, Deguchi D, Nakajo M, Masuda A, Nozoe S, Naruo T. Comparison of regional cerebral blood flow in patients with anorexia nervosa before and after weight gain. Psychiatry Res. 2005;140:251–258. [PubMed]

106. Bailer UF, Frank GK, Henry SE, Price JC, Meltzer CC, Mathis CA, Wagner A, Thornton L, Hoge J, Ziolko SK, Becker CR, McConaha CW, Kaye WH. Exaggerated 5-HT_1A but normal 5-HT_2A receptor activity in individuals ill with anorexia nervosa. Biol Psychiatry. 2007;61:1090–1099. [PubMed]

107. Bailer UF, Frank GK, Henry SE, Price JC, Meltzer CC, Weissfeld L, Mathis CA, Drevets WC, Wagner A, Hoge J, Ziolko SK, McConaha CW, Kaye WH. Altered brain serotonin 5-HT_1A receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [carbonyl ¹¹C]WAY-100635. Arch Gen Psychiatry. 2005;62:1032–1041. [PubMed]

108. Santana N, Bortolozzi A, Serrats J, Mengod G, Artigas F. Expression of serotonin_1A and serotonin_2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb Cortex. 2004;14:1100–1109. [PubMed]

109. Katzman DK, Zipursky RB, Lambe EK, Mikulis DJ. A longitudinal magnetic resonance imaging study of brain changes in adolescents with anorexia nervosa. Arch Pediatr Adolesc Med. 1997;151:793–797. [PubMed]

110. Castro-Fornieles J, Bargalló N, Lázaro L, Andrés S, Falcon C, Plana MT, Junqué C. A cross-sectional and follow-up voxel-based morphometric MRI study in adolescent anorexia nervosa. J Psychiatr Res. 2009;43:331–340. [PubMed]

111. Swayze VW, 2nd, Andersen AE, Andreasen NC, Arndt S, Sato Y, Ziebell S. Brain tissue volume segmentation in patients with anorexia nervosa before and after weight normalization. Int J Eat Disord. 2003;33:33–44. [PubMed]

112. Wagner A, Greer P, Bailer UF, Frank GK, Henry SE, Putnam K, Meltzer CC, Ziolko SK, Hoge J, McConaha C, Kaye WH. Normal brain tissue volumes after long-term recovery in anorexia and bulimia nervosa. Biol Psychiatry. 2006;59:291–293. [PubMed]

113. Santel S, Baving L, Krauel K, Munte TF, Rotte M. Hunger and satiety in anorexia nervosa: fMRI during cognitive processing of food pictures. Brain Res. 2006;1114:138–148. [PubMed]

114. Uher R, Brammer MJ, Murphy T, Campbell IC, Ng VW, Williams SC, Treasure J. Recovery and chronicity in anorexia nervosa: brain activity associated with differential outcomes. Biol Psychiatry. 2003;54:934–942. [PubMed]

115. Delgado MR, Nystrom LE, Fissell C, Noll DC, Fiez JA. Tracking the hemodynamic responses to reward and punishment in the striatum. J Neurophysiol. 2000;84:3072–3077. [PubMed]

116. Davis C, Woodside DB. Sensitivity to the rewarding effects of food and exercise in the eating disorders. Compr Psychiatry. 2002;43:189–194. [PubMed]

117. Volkow ND, Wang GJ, Telang F, Fowler JS, Thanos PK, Logan J, Alexoff D, Ding YS, Wong C, Ma Y, Pradhan K. Low dopamine striatal D₂ receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors. Neuroimage. 2008;42:1537–1543. [PMC free article] [PubMed]

118. Bulik CM, Tozzi F, Anderson C, Mazzeo SE, Aggen S, Sullivan PF. The relation between eating disorders and components of perfectionism. Am J Psychiatry. 2003;160:366–368. [PubMed]

119. Ye HJ, Rice KG, Storch EA. Perfectionism and peer relations among children with obsessive-compulsive disorder. Child Psychiatry Hum Dev. 2008;39:414–426. [PubMed]

120. Fitzgerald KD, Welsh RC, Gehring WJ, Abelson JL, Himle JA, Liberzon I, Taylor SF. Error-related hyperactivity of the anterior cingulate cortex in obsessive-compulsive disorder. Biol Psychiatry. 2005;57:287–294. [PubMed]

121. Pieters GL, de Bruijn ER, Maas Y, Hulstijn W, Vandereycken W, Peuskens J, Sabbe BG. Action monitoring and perfectionism in anorexia nervosa. Brain Cogn. 2007;63:42–50. [PubMed]

122. Becker AE. Television, disordered eating, and young women in Fiji: negotiating body image and identity during rapid social change. Cult Med Psychiatry. 2004;28:533–559. [PubMed]

123. Sasson Y, Zohar J, Chopra M, Lustig M, Iancu I, Hendler T. Epidemiology of obsessive-compulsive disorder: a world view. J Clin Psychiatry. 1997;58 (suppl) 12:7–10. [PubMed]

124. Hudziak JJ, Achenbach TM, Althoff RR, Pine DS. A dimensional approach to developmental psychopathology. Int J Methods Psychiatr Res. 2007;16 suppl:S16–S23. [PubMed]

125. Casey BJ. In: Disruption of inhibitory control in developmental disorders: a mechanistic model of implicated frontostriatal circuitry, in Mechanisms of Cognitive Development: The Carnegie Mellon Symposia on Cognition. McClelland JL, Siegler RS, editors. vol 29. Hillsdale, NJ: Lawrence Erlbaum; 2001. pp. 327–352.