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W4238995000 abstract "Back to table of contents Previous article Next article SPECIALFull AccessA Psychological and Neuroanatomical Model of Obsessive-Compulsive DisorderEdward D. Huey M.D.Roland Zahn M.D., Ph.D.Frank Krueger Ph.D.Jorge Moll M.D., Ph.D.Dimitrios Kapogiannis M.D.Eric M. Wassermann M.D.Jordan Grafman Ph.D.Edward D. Huey M.D.Search for more papers by this authorRoland Zahn M.D., Ph.D.Search for more papers by this authorFrank Krueger Ph.D.Search for more papers by this authorJorge Moll M.D., Ph.D.Search for more papers by this authorDimitrios Kapogiannis M.D.Search for more papers by this authorEric M. Wassermann M.D.Search for more papers by this authorJordan Grafman Ph.D.Search for more papers by this authorPublished Online:1 Oct 2008AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail “…Continually tormented by an inner sense of imperfection, connected with the perception that actions or intentions have been incompletely achieved.” —Pierre Janet 1O bsessive-compulsive disorder (OCD) is a relatively common, and often disabling, psychiatric disorder. 2 , 3 It is characterized by obsessions (unwanted, recurrent intrusive thoughts that cause anxiety) and compulsions (repetitive behaviors that the patient feels driven to perform, often in response to an obsession) which generally coexist. 4 Imaging studies have consistently shown abnormalities in specific brain areas in patients with OCD. However, how the normal functioning of these brain areas is altered to produce the symptoms of OCD remains unknown. In this article, we assert that the completion of complex behaviors is normally accompanied by a reward signal, and that abnormalities in this process could account for some of the symptoms of OCD. We present evidence for this view and propose testable hypotheses. This article is separated into five parts. The first part reviews the literature on the brain areas associated with OCD. A review of imaging studies on OCD was conducted by performing a MEDLINE search through 2006 on the term “obsessive-compulsive disorder” and one of the following terms: “imaging,” “CT,” “computed tomography,” “MRI,” “magnetic resonance imaging,” “PET,” “positron emission tomography.” The resulting abstracts were screened by one of the authors (EDH), and relevant studies were reviewed. In addition, we evaluated selected reviews. 5 – 8 The second part of this article reviews recent findings from the field of cognitive neuroscience on the functions of these brain regions. We focus on the role of the orbitofrontal cortex (OFC) and reward structures in reinforcement, the basal ganglia in setting the threshold for activation of motor activity and complex behaviors, and the anterior cingulate cortex (ACC) for error detection (see Table 1 ). The third part discusses the role of the prefrontal cortex (PFC) in the execution and reinforcement of complex behaviors. The fourth part presents some previous models of OCD. Finally, the fifth part proposes a new model that integrates the findings presented in the first three parts of the paper. TABLE 1. Anatomic Areas of the BrainTABLE 1. Anatomic Areas of the BrainEnlarge tableThe Brain Areas Involved in OCD The majority of both structural and functional imaging studies have shown differences in the PFC, basal ganglia, ACC, and/or thalamus between patients with OCD and healthy comparison subjects (see Table 2 ). 5 A recent meta-analysis reviewed functional imaging studies in OCD and found that the OFC (orbital gyrus) and head of the caudate were the only brain areas that significantly and consistently demonstrated increased tracer uptake in OCD patients relative to comparison subjects. 8 We will discuss the OFC, basal ganglia, ACC, and thalamus in this review, but will focus on the OFC and basal ganglia because these brain areas are most consistently associated with OCD in imaging studies. 8TABLE 2. A Review of Imaging Studies of OCDTABLE 2. A Review of Imaging Studies of OCDEnlarge table The imaging findings reviewed in Table 2 are corroborated by the finding that disrupting connections between the OFC, ACC, thalamus, and basal ganglia by means of a cingulotomy, anterior capsulotomy, or subcaudate tractotomy results in a symptomatic improvement in most OCD patients. 6 , 9 – 14 Some studies have examined the development of symptoms of OCD after brain injury. 15 Damage to the basal ganglia (especially the caudate), the OFC, and the ACC 16 – 22 are associated with the acquisition of OCD symptoms following brain injury. 15 Dysfunction of the basal ganglia secondary to a streptococcal infection 23 or encephalitis lethargica 24 has also been associated with the development of OCD symptoms. One report showed an association between lesions in the mesial frontal region (including the ACC) and collecting behavior resembling OCD. 25 Another demonstrated that repetitive motor activity in patients with dementia is uniquely associated with right ACC hypometabolism. 26 We have observed that repetitive motor activity is associated with right caudate and OFC atrophy in patients with frontotemporal dementia (Huey, presentation, UCSF 5th International Conference on Frontotemporal Dementia, 2006). The Functions of the Brain Areas Involved in OCDThe Orbitofrontal Cortex (OFC) In this section we discuss the role of the OFC in reward learning, emotion, and social behaviors ( Figure 1 ). In the final section of this article, we hypothesize how disruption of the normal functions of the OFC results in the symptoms of OCD. FIGURE 1. The Key Brain Structures Implicated in Reward and Emotion The position of the amygdala, orbitofrontal cortex and cingulate cortex are shown on a midsagittal view (top), and on a ventral view (bottom) of the human brain. Reproduced with permission from Luxenberg et al. 1988 ( 114 ) The OFC appears to be involved with reward learning and emotional processes, and with the integration of these processes in social tasks. 27 , 28 Rolls and colleagues 28 have demonstrated that neurons in the OFC of the macaque represent the reward value of tastes. Taste neurons in the OFC, in contrast to neurons in the primary taste cortex, 29 , 30 stop responding to the taste of a food if the monkey is fed to satiety with that food. 31 Also, monkeys will work to receive electrical stimulation of the OFC if they are hungry, but not if they are satiated. 32 , 33 A comparable role of the OFC in humans is supported by functional MRI (fMRI) studies that have demonstrated satiety-specific OFC activation to foods in humans. 34 , 35 The human OFC is activated by sensory stimuli such as taste and olfaction, 36 – 40 and by more abstract rewards such as money, 41 attractive faces, 42 cooperation, 43 and altruistic donation. 44 O’Doherty 45 and Knutson and Cooper 46 have reviewed imaging studies on reward in humans. Macaques with OFC lesions have difficulty learning which stimuli are rewarding and which are not, and they have particular difficulty modifying behavior when reward contingencies change. 47 For example, macaques with OFC damage continue to pick a response that was once rewarded, even if it is no longer rewarded. 47 – 49 Humans with ventromedial PFC damage typically demonstrate disruption of social and emotional behaviors with relative preservation of memory, language, and tests of executive function. 50 , 51The Basal Ganglia Imaging studies suggest that the basal ganglia can be involved in the pathogenesis of OCD. O’Reilly, Frank, and colleagues 52 – 54 have proposed a model for the interaction of the basal ganglia and OFC in reward learning. Their model is based on previous models that had been developed to explain the role of the basal ganglia in motor control, “[s]pecifically, in the motor domain, various authors suggest that the basal ganglia are specialized to selectively facilitate adaptive motor actions, while suppressing others. 55 This same functionality may hold for more advanced tasks, in which the “action” to facilitate is the updating of prefrontal working memory representations.” 52 – 54 In their model, the basal ganglia serve a gating function by biasing the activation of representations in the PFC (i.e., set the “gain” for activation of motor and action series in the frontal lobes). Graybiel and Rauch 56 have also stressed the role of the basal ganglia in influencing motor pattern generators in the brainstem and spinal cord, and influencing “cognitive pattern generators” in the cerebral cortex. The basal ganglia have two opposing pathways: the direct “Go” pathway and the indirect “NoGo” pathway (see Figure 2 ). Cells in the direct pathway primarily express excitatory D1, and cells in the indirect pathway express inhibitory D2, dopaminergic receptors. Thus reinforcement, coded by an increase in dopamine, can bias the gating of the basal ganglia toward future activation of the rewarded behavior (i.e., facilitate learning). O’Reilly, Frank, and colleagues 52 – 54 propose that the OFC exerts top-down control of the basal ganglia by representing reinforcement magnitudes to the basal ganglia. Thus, in their view, the basal ganglia and the OFC provide a dynamic system which both evaluates the reinforcement of current stimuli and reinforces rewarded behaviors. 54 In their model, the amygdala codes for stimulus intensity, but not valence. Their model is supported by findings that dopamine-dependent reward mechanisms are activated in motor and habit learning in rats and can be disrupted by striatal lesions, 57 findings with patients with Parkinson’s disease, 58 healthy control subjects given medications that affect the dopamine system, 59 and computational modeling. 52 , 54FIGURE 2. Model of Interaction of Basal Ganglia with Other Brain Structures GPi=internal segment of globus pallidus; GPe=external segment of globus pallidus; SNc=substantia nigra pars compacta; SNr=substantia nigra pars reticulata; VTA=ventral tegmental area; ABL=basolateral amygdala. Reproduced with permission from Frank et al. 2006 ( 54 ) Anterior Cingulate Cortex (ACC) The ACC also appears to be involved in OCD based on the imaging findings discussed above. The ACC plays a role in decision making. It responds to the occurrence of conflicts in information processing, 60 including errors 61 – 65 and increased likelihood of errors. 66 Errors appear to be detected as discrepancies between actual and intended events. 67 There is evidence that the ACC is associated with negative emotional states; activation of the ACC is observed with anxiety (including in disorders other than OCD) 68 and physical pain. 69Thalamus The thalamus shows more activation in patients with OCD compared to healthy comparison subjects. 5 This is likely related to the role of the thalamus as a relay and integrative site for other brain areas activated in OCD, such as the basal ganglia and the OFC. A large literature supports the existence of parallel circuits linking the basal ganglia, thalamus, and cortex with circuits communicating with separate areas of the frontal cortex. 70 , 71 These circuits have been the basis of several of the neuroanatomical models of OCD. The Prefrontal Cortex (PFC) in the Execution and Reinforcement of Complex BehaviorsInherent in our discussion so far is the assumption of a conservation of mechanisms of reward between nonhuman primates and humans and between events rewarding to nonhuman primates and humans (e.g., receiving food) and events that are specifically rewarding to humans (e.g., receiving money). However, comparing human and nonhuman reward raises the following question: what are the boundaries of the rewarding event for complex behaviors? Rewarding events for complex behaviors are often associated with several superordinate and subordinate rewarding events. For example, the rewarding experience of enjoying a dinner in a restaurant with a friend lasts a few hours, but it is a component of the larger rewarding friendship (which could last for a lifetime) and is composed of shorter rewarded events (e.g., enjoying a story your friend tells during the dinner). How are the boundaries set? Our laboratory has proposed that the PFC stores memories of behavioral sequences termed “structured event complexes” (SECs) that have beginnings and ends, but exist in nested hierarchies. For example, eating in a restaurant would be such an SEC, and it would exist as several different variants (e.g., eating at a fast-food restaurant, eating at a fancy French restaurant, etc.) which would come under the superordinate category of eating in a restaurant. We have proposed that these SECs are abstractly encoded in the PFC similar to the way in which memories of complex motor programs are encoded in more posterior cortexes. We hypothesize that the perceived boundaries of these SECs signal transitions for the purposes of reward, and that completing SECs can be inherently rewarding. In support of this hypothesis, prefrontal cortical neurons in macaques exhibit phasic peaks of spike activity at the beginning and endpoint of sequential tasks. 72 In this theory, representations in the PFC differ from other types of memories that people are more familiar with, for example, semantic memory processes ( Table 3 ). Semantic (knowing the capital of France) memory is usually explicit (associated with conscious awareness), but it can be implicitly primed. SECs, in contrast, are usually implicitly recalled and executed often over long periods of time in the absence of directly relevant stimuli. This mechanism is most similar to that of procedural memory in the premotor cortex and supplementary motor area; one is not consciously aware of the ability to swim or ride a bicycle, yet one can execute these motor memories with minimal conscious control. We hypothesize that behavioral programs in the human PFC evolved from simpler motor programs in more posterior cortex. 73TABLE 3. Some Types of MemoryTABLE 3. Some Types of MemoryEnlarge table The types of memory outlined in Table 3 work together in an integrated manner. For example, imagine you meet someone at a party and he or she gives you his or her telephone number. You will likely encode an episodic memory that this event occurred. You will keep the telephone number active in working memory until you can either write it down or encode the number in long-term memory through active rehearsal. If you dial the number enough, you may forget the actual digits and instead rely on the procedural memory of dialing the number on a touch-tone phone. Assuming that getting the other person’s number is a successful social outcome, you will encode a memory in the PFC of the behavioral sequence that led to this outcome, to be able to best repeat it in a similar situation. 73 – 75 This theory asserts that related SECs are neuroanatomically localized together in specific areas of the PFC, an assertion that has obtained empiric support. The frequency with which healthy subjects had experienced an event determined how anterior or posterior fMRI activation was observed when the subjects determined if the events were correctly ordered, 76 neurons in the lateral PFC of monkeys selectively exhibit activity for specific categories of behaviors 77 and when the monkeys remember and perform particular action sequences. 78 Patients with PFC lesions (and thus disruption of their SECs) should show deficits in ordering events into a coherent sequence. Patients with PFC damage have particular difficulty sequencing events, 79 can generate a normal number of actions, but have difficulty ordering those actions into a coherent script, 80 , 81 and appear to lose infrequently used SECs before frequently used (and thus overlearned) SECs. 80 , 82 Patients with dementias affecting the frontal lobes typically demonstrate deficits in social behaviors with relative preservation of episodic memory, while patients with dementia initially affecting the medial temporal lobes (e.g., Alzheimer’s disease) typically demonstrate initial deficits in episodic memory with relative preservation of social behavior. 83 The human brain can flexibly respond to events with an almost infinite variety of behaviors. How can such a large number of potential behaviors be encoded as memories? We hypothesize that humans (and other animals) can flexibly coactivate and combine SECs to form a large number of behaviors. This process could be analogous to language; a finite number of words and linguistic rules allow humans to form an almost infinite variety of expressions. In support of this, healthy adults are able to flexibly order the components of a plan while young children and patients with PFC damage tend to rigidly execute plans. 84 Also, rather than performing an infinite variety of behaviors, healthy comparison subjects generally perform a relatively small number of high frequency behaviors in their daily lives. 85So far, we have explained the reinforcing properties of performing SECs. However, the interaction between behavior and reward is bidirectional and dynamic. If performing a certain SEC is rewarding, being prevented from performing that sequence would be punishing. Completion of a punishing SEC would result in reinforcement when the punishment is removed after completion of the behavior. An example of this is doing one’s taxes. Few people enjoy doing their taxes, but they do enjoy the feeling of relief when they have completed this onerous, but necessary, task. Expectation of outcome can affect the reward value of an event. Schultz 86 has demonstrated the importance of “prediction error” in reward and learning. Prediction error refers to the difference (positive or negative) between the expected and received reward. Certain dopamine neurons in the pars compacta of the substantia nigra and the medially adjoining ventral tegmental area (groups A8, A9, and A10) and the OFC of macaques respond most to a stimulus that is paired with an unpredicted reward. 86 , 87 Thus, the same stimulus could be rewarding or punishing depending on expectation. For example, you could receive punishment by learning that one-half of your lottery winnings will go to taxes after learning that you have won the lottery, even though it is a large net financial gain. The dynamic nature of reward over time and the role of expectation make the concept of a “baseline” of reward state for an animal difficult to define. We believe that the reward state of an animal at any given time is, in part, a summation of the reward values associated with the many different SECs active and at different stages of completion at that moment (see Figure 3 ). FIGURE 3. Reward Values Associated with Active SECs at a Given TimeThis figure shows a hypothesized schematic representation of the changes in a few active motivational/reward states. The overall reward state at a given time of an animal will be the summation of the component reward states, and the emotional “flavor” of the reward state is provided through interactions with limbic structures.SECs=structured event complexesPrevious Models of OCD So far, we have presented research from Rolls 47 showing that the OFC is central for reward mechanisms. The ACC plays a central role in error detection for complex behaviors. Frank, O’Reilly, and colleagues 52 – 54 have proposed a model with the basal ganglia setting the “gain” for activation of representations in the PFC similar to the way in which the basal ganglia sets the “gain” for activation of motor programs in the supplemental motor area and premotor cortex. Our laboratory has asserted that SECs exist in the PFC similarly to motor programs contained in the supplementary motor area and premotor cortex, and that performance of those SECs is rewarded. Schultz and colleagues 86 , 87 have demonstrated that areas involved in reward, including the OFC, are activated by a difference between the expected and observed outcomes of events. In this part, we discuss some current models of OCD (see Table 4 for a comparison). In the next section we propose a new model that suggests that the symptoms of OCD arise from abnormalities in the reward mechanisms of complex behaviors. TABLE 4. A Comparison Between Some Models of OCDTABLE 4. A Comparison Between Some Models of OCDEnlarge tableThe Standard Model The most accepted neuroanatomic model of OCD is based on the finding that there are separate cortico-basal ganglia-thalamic-cortical loops, 70 , 71 (although recent evidence suggests that these loops are not as separate as previously thought). 88 The standard anatomic model of OCD proposes that the symptoms of OCD are caused by dysfunction of elements of a PFC-basal ganglia-thalamic-PFC loop 89 – 93 ( Figure 4 ). The imaging findings presented above support that these structures are involved in OCD. In addition, surgical interruption 6 , 9 – 14 or deep brain stimulation 94 of the anterior internal capsule can reduce the symptoms of OCD. Overactivation of this loop is suggested by the hypermetabolism of these structures observed in the imaging studies presented in the first part of this article. FIGURE 4. The Standard Model of OCDOCD=obsessive-compulsive disorder. Excitatory connections are labeled +; inhibitory connections are labeled −. Reproduced with Permission from Rauch et al. 2006 ( 94 ) The advantage of this model is that it is consistent with the evidence collected to date on OCD. This model forms the neuroanatomic basis of most subsequent models. The limitation of the standard model is that while it specifies the brain structures involved, it does not provide a psychological explanation for the specific symptoms of OCD.Direct/Indirect Striatal Pathways The standard anatomic model has been refined by specifying that overactivation of the direct pathway in the basal ganglia relative to the indirect pathway results in an orbitofrontal-subcortical hyperactivity ( Figure 5 ). According to this model, “[p]atients with OCD, however, may have a low threshold for system ‘capture’ by socioterritorial stimuli, possibly caused by excess ‘tone’ in the direct relative to the indirect orbitofrontal-subcortical pathway, allowing for concerns about danger, violence, hygiene, order, and sex to rivet attention to themselves.” 95FIGURE 5. A Neuroanatomical Model That Incorporates Direct and Indirect Striatal PathwaysGPi=globus pallidus interna; SNr=substantia nigra pars reticulata In OCD, the direct pathway is strongly activated in relation to the indirect pathway resulting in OFC-subcortical hyperactivity. Large arrows represent inputs that are strengthened in patients with OCD. Reproduced with permission from Stein 2006 ( 96 ) This model adds explanatory power to the standard model by proposing a specific mechanism within the striatum that results in overactivation of the neuroanatomical loop of the standard model. In support of this model, patients with excessive nigrostriatal dopaminergic input (such as patients with Huntington’s disease) have excessive motor output. 95 This model is supported by the imaging findings presented in the first part of this article and because damage to specific basal ganglia structures (e.g., caudate) is associated with the development of symptoms of OCD. The limitation of this model, similar to the standard neuroanatomical model, is that it does not specify or explain the psychological mechanisms of OCD. For example, how do concerns “rivet attention to themselves?” It also focuses on dysfunction in the basal ganglia, but does not specify the role of the OFC or explain how patients with OFC lesions can develop aspects of the OCD syndrome. Models Based on Other Brain Areas Other theorists have focused more on the orbitofrontal cortex (OFC) in modeling OCD. Chamberlain et al. 7 discuss the failure of inhibition in patients with OFC lesions and propose that a similar failure to inhibit contributes to symptoms of OCD. Some have implicated the anterior cingulate cortex (ACC) by proposing that faulty error detection may be central to the pathogenesis of OCD. 91 , 96 Others have suggested that dysfunction of reward mechanisms may contribute to the symptoms of OCD. 6“Release” Models Baxter 92 demonstrated the role of the basal ganglia in “releasing” territorial display programs in lizards and proposed that the basal ganglia in patients with OCD may inappropriately “release” territorial behaviors. Stein and Lochner 97 have conceptualized OCD as a “dysfunction in the control of procedural strategies with inappropriate release of symptoms ranging from simple motoric stereotypies to more complex behavioral programs.” In the same paper, they note that many of the structures involved in OCD are also involved in learning and reward. They also observe that dopaminergic agonists can increase the symptoms of OCD and putative OCD spectrum disorders, including Tourette’s syndrome. Where in the brain and how these “behavioral programs” are represented, or why they are inappropriately released in OCD, is not specified. Graybeil and Rauch 56 hypothesized that anxiety suffered by OCD patients may indicate a “lack of loop closure between expected outcomes and the chunks of behavior that should generate them.” “Feeling of Knowing” Models Szechtman and Woody 98 have proposed a model of OCD based on the hypothesis that the symptoms of OCD arise from an inability to generate a normal “feeling of knowing” that would otherwise signal task completion. This deficit results in an overactivation of neural systems designed to respond to danger in the environment (which they term the “security motivation system”). They base their work on earlier cognitive theories of OCD including those of Janet, 1 Pitman, 99 and Reed. 100 Their theory is supported by interviews that revealed that the majority of OCD patients describe their symptoms as being “unable to stop” the behavior rather than being forced to continue. 100 , 101 Also, patients with OCD often engage in few but extended episodes of compulsive behavior during the day rather than excessively frequent episodes but normal duration, which is consistent with an inability to stop the compulsive behavior. 102The “Structured Event Complex” Model of OCD The Structured Event Complex (SEC)/OCD model builds upon those proposed by Stein and Lochner 97 and Szechtman and Woody. 98 However, in the SEC/OCD model we specify how abnormal interactions of representations of complex behaviors in the PFC, reward information in the OFC, error detection in the ACC, and reward and limbic structures can result in the symptoms of OCD. To our knowledge, this is the first model of OCD to full" @default.
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