The role of the orbitofrontal cortex in normally developing compulsive-like behaviors and obsessive-compulsive disorder

Mounting evidence concerning obsessive-compulsive disorders points to abnormal functioning of the orbitofrontal cortices. First, patients with obsessive-compulsive disorder (OCD) perform poorly on tasks that rely on response suppression/motor inhibition functions mediated by the orbitofrontal cortex relative to both normal and clinical controls. Second, patients with OCD exhibit functional hyperactivity in lateral orbitofrontal and related structures corresponding with symptom severity. In this article, we compare these neurocognitive correlates of OCD with the executive and neural underpinnings of "compulsive-like" behaviors that are common in normal childhood. We discuss the phenomenology and natural history of normative compulsive-like behaviors as well as the behavioral, emotional, and cognitive continuities between typical and pathological obsessive-compulsive behaviors. We then examine associations between children's executive performance deficits and their observed compulsive-like characteristics. We relate these patterns to executive deficits shown by adults with OCD. Finally, we speculate on the developmental neurobiology of children's compulsive-like behaviors, with particular attention to orbitofrontal functions including behavioral and emotional regulation, and we suggest similarities and differences with the neurobiology of OCD. In making these comparisons, we hope to open a dialogue between researchers who study underlying brain pathologies associated with OCD and those who explore the neurocognitive bases of normal development.     

左侧眶额皮层在自动情绪调节下注意选择中的作用：来自经颅直流电刺激的证据

前人研究表明自动情绪调节能够自上而下地影响情绪及情绪性注意过程。近来有研究提示自动情绪调节与眶额皮层(orbitofrontal cortex, OFC)有关。也有研究表明左侧OFC的激活影响负性注意偏向。本研究采用经颅直流电刺激技术,考察阈下启动情绪控制目标条件下,抑制左侧眶额皮层兴奋性是否影响负性注意偏向。结果发现,使用阴极刺激抑制左侧OFC活动可以加快被试对与恐惧刺激位置一致的探测点的反应。该结果提示左侧眶额皮层是自动情绪调节下情绪性注意选择相关的重要脑区。     

The involvement of the orbitofrontal cortex in learning under changing task contingencies

Previous investigations examining the rat prefrontal cortex subregions in attentional-set shifting have commonly employed two-choice discriminations. To better understand how varying levels of difficulty influence the contribution of the prefrontal cortex to learning, the present studies examined the effects of orbitofrontal cortex inactivation in a two- or four-choice odor reversal learning test. Long-Evans rats were trained to dig in cups that contained distinct odors. In the two-choice odor discrimination, one odor cup was always associated with a cereal reinforcement in acquisition while the opposite odor cup was associated with a cereal reinforcement in reversal learning. In the four-choice odor discrimination, an additional two cups containing distinct odors were used that were never associated with reinforcement in acquisition or reversal learning. Bilateral infusions of the GABA-A agonist, muscimol (0.5 microg) into the orbitofrontal cortex did not impair acquisition of either the two- or four-choice discrimination task. However, muscimol infusions into the orbitofrontal cortex impaired two- and four-choice reversal learning. In the two-choice odor reversal, muscimol treatment selectively increased perseverative errors. In the four-choice odor reversal, muscimol treatment increased perseverative, regressive, as well as irrelevant errors. These findings suggest that the orbital prefrontal cortex not only enables task switching by supporting the initial inhibition of a previously relevant choice pattern, but under increasing task demands also enables the reliable execution of a new choice pattern and reduction of interference to irrelevant stimuli.     

Impairment in judgement of the moral emotion guilt following orbitofrontal cortex damage

Although neuroimaging studies have provided evidence for an association between moral emotions and the orbitofrontal cortex, studies on patients with focal lesions using experimental probes of moral emotions are scarce. Here, we addressed this topic by presenting a moral emotion judgement task to patients with focal brain damage. Four judgement tasks in a simple pairwise choice paradigm were given to 72 patients with cerebrovascular disease. These tasks consisted of a perceptual line judgement task as a control task; the objects’ preference task as a basic preference judgement task; and two types of moral emotion judgement task, an anger task and a guilt task. A multiple linear regression analysis was performed on each set of task performance scores to take into account potential confounders. Performance on the guilt emotion judgement task negatively correlated with the orbitofrontal cortex damage, but not with the other variables. Results for the other judgement tasks did not reach statistical significance. The close association between orbitofrontal cortex damage and a decrease in guilt emotion judgement consistency might suggest that the orbitofrontal cortex plays a key role in the sense of guilt, a hallmark of morality.     

The role of attentional strategies in moderating links between acute pain induction and subsequent psychological stress: evidence for symptom-specific reactivity among patients with chronic pain versus healthy nonpatients

Vulnerability to stressors after pain may depend on the degree to which the strategy used to process information about pain perpetuates thoughts of suffering and distress. Patients with chronic low back pain (CLBP) may show susceptibility to stress after pain through symptom-specific (lower paraspinal [LP]) muscle reactivity. Patients with CLBP (n = 100) and healthy nonpatients (n = 105) underwent a cold pressor, under sensory focus, distraction, suppression, or control conditions, and then performed mental arithmetic. Only patients under the suppression condition revealed increased LP tension during pain that was sustained during mental arithmetic and sustained systolic blood pressure after mental arithmetic. Patients with CLBP who suppress pain may detrimentally affect responses to the next noxious event, particularly through prolonged LP muscle tension, that may contribute to a cycle of pain-stress-pain.     

Novel visual stimuli activate a population of neurons in the primate orbitofrontal cortex

Neurons were found in the rhesus macaque anterior orbitofrontal cortex that respond to novel but not to familiar visual stimuli. Some of these neurons responded to all novel stimuli, and others to only a subset (e.g., to novel faces). The neurons have no responses to familiar reward- or punishment-associated visual stimuli, nor to taste, olfactory or somatosensory inputs. The responses of the neurons typically habituated with repeated presentations of a novel stimulus, and five presentations each 1s was the median number for the response to reach half-maximal. The neurons did not respond to stimuli which had been novel and shown a few times on the previous day, indicating that the neurons were involved in long-term memory. The median latency of the neuronal responses was 120 ms. The median spontaneous firing rate was 1.3 spikes/s, and the median response to novel visual stimuli was 6.0 spikes/s. These findings indicate that the long-term memory for visual stimuli is information that is represented in a region of the primate anterior orbitofrontal cortex.     

Role of the hippocampus and orbitofrontal cortex during the disambiguation of social cues in working memory

Human social interactions are complex behaviors requiring the concerted effort of multiple neural systems to track and monitor the individuals around us. Cognitively, adjusting our behavior on the basis of changing social cues such as facial expressions relies on working memory and the ability to disambiguate, or separate, the representations of overlapping stimuli resulting from viewing the same individual with different facial expressions. We conducted an fMRI experiment examining the brain regions contributing to the encoding, maintenance, and retrieval of overlapping identity information during working memory using a delayed match-to-sample task. In the overlapping condition, two faces from the same individual with different facial expressions were presented at sample. In the nonoverlapping condition, the two sample faces were from two different individuals with different expressions. fMRI activity was assessed by contrasting the overlapping and nonoverlapping conditions at sample, delay, and test. The lateral orbitofrontal cortex showed increased fMRI signal in the overlapping condition in all three phases of the delayed match-to-sample task and increased functional connectivity with the hippocampus when encoding overlapping stimuli. The hippocampus showed increased fMRI signal at test. These data suggest that lateral orbitofrontal cortex helps encode and maintain representations of overlapping stimuli in working memory, whereas the orbitofrontal cortex and hippocampus contribute to the successful retrieval of overlapping stimuli. We suggest that the lateral orbitofrontal cortex and hippocampus play a role in encoding, maintaining, and retrieving social cues, especially when multiple interactions with an individual need to be disambiguated in a rapidly changing social context in order to make appropriate social responses.     

Differential effects of inactivation of the orbitofrontal cortex on strategy set-shifting and reversal learning

Different subregions of the rodent prefrontal cortex (PFC) mediate dissociable types of behavioral flexibility. For example, lesions of the medial or orbitofrontal (OFC) regions of the PFC impair extradimensional shifts and reversal learning, respectively, when novel stimuli are used during different phases of the task. In the present study, we assessed the effects of inactivation of the OFC on strategy set-shifting and reversal learning, using a maze based set-shifting task mediated by the medial PFC. Long–Evans rats were trained initially on a visual-cue discrimination to obtain food. On the subsequent day, rats had to shift to using a response strategy (e.g., always turn left). On Day 3 (reversal), rats were required to reverse the direction of their turn (e.g., always turn right). Infusions of the local anesthetic bupivacaine into the OFC did not impair initial visual discrimination learning, nor did it impair performance on the set-shift. In contrast, inactivation of the OFC did impair reversal learning; yet, these rats ceased using the previously acquired response rule as readily as controls. Instead, rats receiving OFC inactivations made a disproportionate number of erroneous arm entries towards the visual-cue, suggested that these animals reverted back to using the original visual-cue based strategy. These findings, in addition to previous data, further support the notion that the OFC and medial PFC play dissociable roles in reversal learning and set-shifting. Furthermore, the lack of effect of OFC inactivations on the set-shift indicates that this type of behavioral flexibility does not require cognitive operations related to reversal learning.     

Hemispheric asymmetry in stress processing in rat prefrontal cortex and the role of mesocortical dopamine

The prefrontal cortex (PFC) is known to play an important role not only in the regulation of emotion, but in the integration of affective states with appropriate modulation of autonomic and neuroendocrine stress regulatory systems. The present review highlights findings in the rat which helps to elucidate the complex nature of prefrontal involvement in emotion and stress regulation. The medial PFC is particularly important in this regard and while dorsomedial regions appear to play a suppressive role in such regulation, the ventromedial (particularly infralimbic) region appears to activate behavioral, neuroendocrine and sympathetic autonomic systems in response to stressful situations. This may be especially true of spontaneous stress-related behavior or physiological responses to relatively acute stressors. The role of the medial PFC is somewhat more complex in conditions involving learned adjustments to stressful situations, such as the extinction of conditioned fear responses, but it is clear that the medial PFC is important in incorporating stressful experience for future adaptive behavior. It is also suggested that mesocortical dopamine plays an important adaptive role in this region by preventing excessive behavioral and physiological stress reactivity. The rat brain shows substantial hemispheric specialization in many respects, and while the right PFC is normally dominant in the activation of stress-related systems, the left may play a role in countering this activation through processes of interhemispheric inhibition. This proposed basic template for the lateralization of stress regulatory systems is suggested to be associated with efficient stress and emotional self-regulation, and also to be shaped by both early postnatal experience and gender differences.     

Delay-dependent involvement of the rat entorhinal cortex in habituation to a novel environment

Evidence has accumulated that the entorhinal cortex (EC) is involved in memory operations underlying formation of a long-term memory. Because entorhinal-lesioned rats are impaired for long delays in delayed matching and non-matching to sample tasks, it has been proposed that EC contributes to the maintenance of information in short-term memory. In the present study, we asked whether such a time-limited role applies also when learning complex spatial information in a novel environment. We therefore examined the effects of EC lesions on habituation in an object exploration task in which a delay of either 4 min or 10 min is imposed between successive sessions. EC-lesioned rats exhibited a deficit in habituation at 10 min but not 4 min delays. Following habituation, reactions to spatial change (object configuration) and non-spatial change (novel object) were also examined. EC-lesioned rats were impaired in detecting the spatial change but were able to detect a non-spatial change, irrespective of the delay. Overall, the results suggest that EC is involved in maintaining a large amount of novel, multidimensional information in short-term memory therefore enabling formation of long-term memory. Switching to a novelty detection mode would then allow the animal to rapidly adapt to environmental changes. In this mode, EC would preferentially process spatial information rather than non-spatial information.     

Acetylcholine in the orbitofrontal cortex is necessary for the acquisition of a socially transmitted food preference

The social transmission of food preference task (STFP) has been used to examine the involvement of the hippocampus in learning and memory for a natural odor-odor association. However, cortical involvement in STFP has not been extensively studied. The orbitofrontal cortex (OFC) is important in odor-guided learning, and cholinergic depletion of the entire neocortex results in impairments in STFP. Here we examined the specific role of cholinergic modulation in the OFC by assessing the effect of 192 immunoglobulin G-saporin infusion directly into OFC prior to training on STFP. Cholinergic depletion in the OFC impaired expression of the socially transmitted odor association measured 2 d after training, indicating that cholinergic function in the OFC is essential for this form of associative learning.     

Dissociable contributions of the left and right posterior medial orbitofrontal cortex in motivational control of goal-directed behavior

Several findings from both human neuroimaging and nonhuman primate studies suggest that the posterior medial orbitofrontal cortex (OFC) may be critical for the motivational control of goal-directed behavior. The present study was conducted to clarify the role of the left and right posterior medial OFC in that function by examining the effects of focal unilateral lesions to this region on the performance on an incentive working memory task. The study covered patients who had undergone surgery for an ACoA aneurysm and normal control subjects (C). The patients were subdivided into three groups: those with resection of the left (LGR+) or right (RGR+) posterior part of the gyrus rectus, and without such a resection (GR−). Participants performed a 2-back working memory task under three motivational conditions (penalty, reward, and no-incentive). The C group performed worse in the penalty condition and better in the reward condition as compared to the no-incentive condition. Similar results were obtained for the GR− group. Performance of the LGR+ group did not depend on incentive manipulations, whereas the RGR+ group performed better in both the penalty and reward conditions than in the no-incentive condition. The results show that the posterior medial OFC is involved in the motivational modulation of working memory performance. Our findings also suggest that the left posterior medial OFC plays a crucial role in this function, whereas the right posterior medial OFC is particularly involved in the processing of the punishing aspect of salient events and it probably mediates in guiding behavior on the basis of negative outcomes of action.     

The role of emotion in decision-making: evidence from neurological patients with orbitofrontal damage

Most theories of choice assume that decisions derive from an assessment of the future outcomes of various options and alternatives through some type of cost-benefit analyses. The influence of emotions on decision-making is largely ignored. The studies of decision-making in neurological patients who can no longer process emotional information normally suggest that people make judgments not only by evaluating the consequences and their probability of occurring, but also and even sometimes primarily at a gut or emotional level. Lesions of the ventromedial (which includes the orbitofrontal) sector of the prefrontal cortex interfere with the normal processing of "somatic" or emotional signals, while sparing most basic cognitive functions. Such damage leads to impairments in the decision-making process, which seriously compromise the quality of decisions in daily life. The aim of this paper is to review evidence in support of "The Somatic Marker Hypothesis," which provides a systems-level neuroanatomical and cognitive framework for decision-making and suggests that the process of decision-making depends in many important ways on neural substrates that regulate homeostasis, emotion, and feeling. The implications of this theoretical framework for the normal and abnormal development of the orbitofrontal cortex are also discussed.     

Individual differences in the Behavioral Inhibition System are associated with orbitofrontal cortex and precuneus gray matter volume

The Behavioral Inhibition System (BIS) is described in Gray's Reinforcement Sensitivity Theory as a hypothetical construct that mediates anxiety in animals and humans. The neuroanatomical correlates of this system are not fully clear, although they are known to involve the amygdala, the septohippocampal system, and the prefrontal cortex. Previous neuroimaging research has related individual differences in BIS with regional volume and functional variations in the prefrontal cortex, amygdala, and hippocampal formation. The aim of the present work was to study BIS-related individual differences and their relationship with brain regional volume. BIS sensitivity was assessed through the BIS/BAS questionnaire in a sample of male participants (N = 114), and the scores were correlated with brain regional volume in a voxel-based morphometry analysis. The results show a negative correlation between the BIS and the volume of the right and medial orbitofrontal cortices and the precuneus. Our results and previous findings suggest that individual differences in anxiety-related personality traits and their related psychopathology may be associated with reduced brain volume in certain structures relating to emotional control (i.e., the orbitofrontal cortex) and self-consciousness (i.e., the precuneus), as shown by our results.     

Lipid reactivity to stress: I. Comparison of chronic and acute stress responses in middle-aged airline pilots.

Lipids increase during psychological stress, but no studies have compared the effects of acute and chronic stressors on lipid responsivity in the same individuals. One hundred middle-aged men (n = 92) and women (n = 8) were examined during high chronic occupational stress, low chronic stress, and acute laboratory stressors. In addition to measures of perceived stress and affect, an extensive battery of lipid and lipoprotein measures was undertaken at each time point. Most lipid parameters were significantly increased during the chronic and acute stressors, although the responses to the different stressors were not consistently associated. For example, significant correlations among the chronic and acute stress responses were apparent for the apoproteins, but not for total, low density lipoprotein, or high density lipoprotein cholesterol. The factors and processes regulating these variables during stress may be different during acute and chronic stressors.     

Behavioural arousal and its habituation in the squirrel fish, Holocentrus rufus: the role of the telecephalon

Squirrel fish were captured, maintained for 2 days and then tested for their responses to stimuli in laboratory aquaria. A tap on the side of the aquarium or a shadow moving overhead elicited an arousal response involving a reduction in opercular movements, movement of the pectoral fins, and erection of the spiny dorsal fin. This latter response, when regularly provoked by a moving shadow at 15-s intervals, decreased in duration and habituated. When fish were restricted in a wire mesh trough and the stimulus was the onset of illumination to one eye at 15-s intervals, responses were quantitatively similar although shorter in duration. A series of stimuli delivered to one eye until habituation followed by a series to the other eye reduced the duration of initial responses and the number of trials for habituation of responses to stimuli delivered to the second eye. Responses were equivalent regardless of which eye (left or right) was first presented with stimuli. Section of the telencephalic anterior commissure considerably restricted the transfer of information about experience of stimuli presented to the first eye. Commissural section, combined with unilateral lesions in the posterior-medial telencephalon, severely impaired habituation of responses to the contralateral eye. Lateral lesions had no effect. The results are discussed in relation to the visual projection in Holocentrus and telecephalic involvement in arousal and its habituation in teleosts as a whole.     

Contextual factors in neophobia and its habituation: The role of absolute and relative novelty

In four experiments we investigated the role of contextual cues in the habituation of neophobia in rats. Experiment 1 showed that the consumption of a novel flavour increased across a series of presentations in one context (A) but fell when the flavour was subsequently presented in a second, novel, context (B). In Experiments 2 and 3, subjects again received exposure to a flavour in context A, but also were familiarized with the test context, B. These subjects consumed the flavour with equal readiness, whether it was presented in Context A or in Context B at test. Experiment 4 replicated the results of Experiment 1 and also showed that the consumption of a novel flavour was not influenced by whether it was presented in a novel or a familiar context. Several mechanisms by which the novelty or familiarity of the context might interact with the novelty or familiarity of the flavour were discussed.     

Neural coding of reward magnitude in the orbitofrontal cortex of the rat during a five-odor olfactory discrimination task

The orbitofrontal cortex (OBFc) has been suggested to code the motivational value of environmental stimuli and to use this information for the flexible guidance of goal-directed behavior. To examine whether information regarding reward prediction is quantitatively represented in the rat OBFc, neural activity was recorded during an olfactory discrimination “go”/“no-go” task in which five different odor stimuli were predictive for various amounts of reward or an aversive reinforcer. Neural correlates related to both actual and expected reward magnitude were observed. Responses related to reward expectation occurred during the execution of the behavioral response toward the reward site and within a waiting period prior to reinforcement delivery. About one-half of these neurons demonstrated differential firing toward the different reward sizes. These data provide new and strong evidence that reward expectancy, regardless of reward magnitude, is coded by neurons of the rat OBFc, and are indicative for representation of quantitative information concerning expected reward. Moreover, neural correlates of reward expectancy appear to be distributed across both motor and nonmotor phases of the task.