Left Medial Orbitofrontal Cortex Research Articles

Voxel-based morphometric gray matter correlates of daytime sleepiness

Sleep disorders such as narcolepsy, obstructive sleep apnea, and chronic insomnia have been associated with reduced gray matter volume of the ventromedial prefrontal cortex (VMPFC). Functional neuroimaging and behavioral data also implicate this region as important in sleep-related problems and the ability to resist the impairing effects of sleep loss on cognition. However, no study has linked gray matter volume within this region to normal self-reported levels of daytime sleepiness. We therefore hypothesized that reduced gray matter volume within the VMPFC would be related to greater self-reported levels of general daytime sleepiness, as assessed by the Epworth Sleepiness Scale (ESS) in a sample of 36 healthy non-clinical participants. Using voxel-based morphometry, scores of the ESS were correlated with gray matter volume, after controlling for age, gender, and whole brain volume. Daytime sleepiness correlated negatively with gray matter volume in a cluster of voxels within the left gyrus rectus and medial orbitofrontal cortex. Findings converge with prior evidence to suggest that the VMPFC and medial orbitofrontal cortex may play a particularly important role in sleep–wake related phenomena including sleep disorders and trait-like individual differences in vulnerability to the impairing effects of sleep deprivation on neurobehavioral performance, and also in normal variations in self-reported daytime sleepiness.

The influence of emotional priming on the neural substrates of memory: A prospective fMRI study using portrait art stimuli

Events coupled with an emotional context seem to be better retained than non-emotional events. The aim of our study was to investigate whether an emotional context could influence the neural substrates of memory associations with novel portrait art stimuli. In the current prospective fMRI study, we have investigated for one specific visual art form (modern artistic portraits with a high degree of abstraction) whether memory is influenced by priming with emotional facial pictures. In total forty healthy female volunteers in the same age range were recruited for the study. Twenty of these women participated in a prospective brain imaging memory paradigm and were asked to memorize a series of similar looking, but different portraits. After randomization, for twelve participants (Group 1), a third of the portraits was emotionally primed with approach-related pictures (smiling baby faces), a third with withdrawal-related pictures (baby faces with severe dermatological conditions), and another third with neutral images. Group 2 consisted of eight participants and they were not primed. Then, during an fMRI session 2h later, these portraits were viewed in random order intermixed with a set of new (previously unseen) ones, and the participants had to decide for each portrait whether or not they had already been seen. In a separate experiment, a different sample of twenty healthy females (Group 3) rated their mood after being exposed to the same art stimuli, without priming. The portraits did not evoke significant mood changes by themselves, supporting their initial neutral emotional character (Group 3). The correct decision on whether the portraits were Familiar of Unfamiliar led to similar neuronal activations in brain areas implicated in visual and attention processing for both groups (Groups 1 and 2). In contrast, whereas primed participants showed significant higher neuronal activities in the left midline superior frontal cortex (Brodmann area (BA) 6), unprimed volunteers displayed higher right medial frontal cortical (BA 10) activities. Furthermore, specifically in Group 1, correct retrieval of negatively primed portraits evoked increased neuronal activity in the left medial orbitofrontal cortex (BA 11) and in the right (posterior) insula, suggesting enhanced stress-related responses to the memory of withdrawal-related primed modern artistic portraits in this group. Our prospective memory data in healthy females indicate that, to reach a correct retrieval decision, different midline anterior neuronal networks are recruited for portraits that were emotionally primed than for the unprimed ones. Importantly, our results also suggest that the negative emotional context leads to the formation of associations that are reactivated during memory retrieval processes of the initially neutral art portraits. When correctly recognized, the portraits evoke neuronal activities consistent with the withdrawal-related character of the emotional visual stimuli with which they have been associated. Although our results show that abstract portrait art can be associated with emotional primes this doesn't mean that this effect is specific for art images.

Increased Medial Orbitofrontal and Amygdala Activation: Evidence for a Systems-Level Endophenotype of Bipolar I Disorder

Bipolar I disorder is highly heritable, but endophenotypes of the disorder mediating genetic risk are only beginning to be defined. The authors investigate state- and trait-related neural mechanisms related to motivation in euthymic bipolar patients and unaffected first-degree relatives of bipolar patients to define the status of motivational processing as a neural systems-level endophenotype. Our study comprised two samples; the first consisted of 19 euthymic bipolar patients and 19 matched comparison subjects, and the second included 22 relatives and 22 matched comparison subjects. Motivational processing was assessed with a probabilistic reversal learning task during event-related functional MRI. Data were analyzed using a region-of-interest approach restricting analysis to the medial and lateral orbitofrontal cortex, the amygdala, the anterior cingulate cortex, and the striatum. The authors observed increased activation in response to reward and reward reversal contingencies in the left medial orbitofrontal cortex in patients with bipolar disorder and in the right medial orbitofrontal cortex in their relatives. Activation of the amygdala in response to reward reversal was increased in patients and relatives. In response to reward, activation of the amygdala was greater only in relatives, but there was a significant negative correlation between medication and amygdala activation in patients. These results identify increased activity of the orbitofrontal cortex and the amygdala, related to heightened sensitivity to reward and deficient prediction error signal, as a candidate endophenotype of bipolar disorder. The results support a role of motivational processing in the risk architecture of bipolar disorder and identify a new systems-level therapeutic target for the illness.

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.

P.2.006 Lesions of the ventral medial prefrontal cortex enhance contextual fear generalisation in C57BL6/J mice

Sleep disorders such as narcolepsy, obstructive sleep apnea, and chronic insomnia have been associated with reduced gray matter volume of the ventromedial prefrontal cortex (VMPFC). Functional neuroimaging and behavioral data also implicate this region as important in sleep-related problems and the ability to resist the impairing effects of sleep loss on cognition. However, no study has linked gray matter volume within this region to normal self-reported levels of daytime sleepiness. We therefore hypothesized that reduced gray matter volume within the VMPFC would be related to greater self-reported levels of general daytime sleepiness, as assessed by the Epworth Sleepiness Scale (ESS) in a sample of 36 healthy non-clinical participants. Using voxel-based morphometry, scores of the ESS were correlated with gray matter volume, after controlling for age, gender, and whole brain volume. Daytime sleepiness correlated negatively with gray matter volume in a cluster of voxels within the left gyrus rectus and medial orbitofrontal cortex. Findings converge with prior evidence to suggest that the VMPFC and medial orbitofrontal cortex may play a particularly important role in sleep–wake related phenomena including sleep disorders and trait-like individual differences in vulnerability to the impairing effects of sleep deprivation on neurobehavioral performance, and also in normal variations in self-reported daytime sleepiness.

Gray matter alterations in parosmia

Parosmia is a common olfactory disorder. In this condition, odors are perceived in a different quality than usual. This distorted olfactory percept is typically reported to be unpleasant. Little is known about the pathophysiology of this phenomenon. Previous studies demonstrated smaller volumes of the olfactory bulbs in patients with parosmia compared to subjects without parosmia. In order to investigate structural brain alterations in areas beyond the olfactory bulb, in the current study voxel-based morphometry was applied. A group of 22 parosmic patients was compared with control subjects matched for age- and sex, who exhibited a similar performance in olfactory tests. Performing a whole brain analysis, we found profound gray matter volume loss in the left anterior insula in parosmic patients. In an additional volume of interest analysis including primary and secondary olfactory areas, we also found volume loss in the right anterior insula, the anterior cingulate cortex, the hippocampus bilaterally, and the left medial orbitofrontal cortex. Many of these areas are critically involved in olfactory quality discrimination and odor memory. The present results indicate that reduced gray matter volume in brain regions supporting odor discrimination and memory is related to disturbed olfactory sensation in parosmia.

Reduced Thickness of Medial Orbitofrontal Cortex in Smokers

Structural deficiencies within the prefrontal cortex might be related to drug-taking behavior that prevails in smokers. Cortical thickness has been found to be a structural modulator of cerebral function and cognition and a subtle correlate of mental disorders. However, to date an analysis of cortical thickness in smokers compared with never-smokers has not been undertaken. We acquired high-resolution magnetic resonance imaging scans from 22 smokers and 21 never-smokers and used FreeSurfer to model the gray-white and pial surfaces for each individual cortex to compute the distance between these surfaces to obtain a measure of cortical thickness. The main cortical folds were aligned across individuals with FreeSurfer's surface-based averaging technique to compare whole brain differences in cortical thickness between smokers and never-smokers. Relative to never-smokers, smokers showed greater cortical thinning in the left medial orbitofrontal cortex (mOFC). Cortical thickness measures extracted from mOFC correlated negatively with the amount of cigarettes consumed/day and the magnitude of lifetime exposure to tobacco smoke. The brains of smokers are structurally different from those of never-smokers in a dose-dependent manner. The cortical thinning in mOFC in smokers relative to never-smokers might imply dysfunctions of the brain's reward, impulse control, and decision-making circuits. Related behavioral correlates are suggested to be relevant for smoking initiation and maintenance.

Phospholipase A2 activity is associated with structural brain changes in schizophrenia

Regional structural brain changes are among the most robust biological findings in schizophrenia, yet the underlying pathophysiological changes remain poorly understood. Recent evidence suggests that abnormal neuronal/dendritic plasticity is related to alterations in membrane lipids. We examined whether serum activity of membrane lipid remodelling/repairing cytosolic phospholipase A2 (PLA2) were related to regional brain structure in magnetic resonance images (MRI). The study involved 24 schizophrenia patients, who were either drug-naïve or off antipsychotic medication, and 25 healthy controls. Using voxel-based morphometry (VBM) analysis of T1-high-resolution MRI-images, we correlated both gray matter and white matter changes with serum PLA2-activity. PLA2 activity was increased in patients, consistent with previous findings. VBM group comparison of patients vs. controls showed abnormalities of frontal and medial temporal cortices/hippocampus, and left middle/superior temporal gyrus in first-episode patients. Group comparison of VBM/PLA2-correlations revealed a distinct pattern of disease-related interactions between gray/white matter changes in patients and PLA2-activity: in first-episode patients (n=13), PLA2-activity was associated with structural alterations in the left prefrontal cortex and the bilateral thalamus. Recurrent-episode patients (n=11) showed a wide-spread pattern of associations between PLA2-activity and structural changes in the left (less right) prefrontal and inferior parietal cortex, the left (less right) thalamus and caudate nucleus, the left medial temporal and orbitofrontal cortex and anterior cingulum, and the cerebellum. Our findings demonstrate a potential association between membrane lipid biochemistry and focal brain structural abnormalities in schizophrenia. Differential patterns in first-episode vs. chronic patients might be related to PLA2-increase at disease-onset reflecting localized regenerative activity, whereas correlations in recurrent-episode patients might point to less specific neurodegenerative aspects of disease progression.

I know the pain you feel—how the human brain's default mode predicts our resonance to another's suffering

Introspective and self-referential in nature, the human brain's default mode network (DMN) is presumed to influence our behavior in response to the environment in predictive manner [Raichle ME, Gusnard DA (2005) J Comp Neurol 493:167–176; Bar M (2009) Philos Trans R Soc Lond B Biol Sci 364:1235–1243]. In the current study, we hypothesize that the strength of DMN-connectivity contributes to distinct introspective psychological processes in every-day social life such as the intuitive understanding of other people through inner representation of their affective states −e. g. his or her pain. 19 healthy individuals underwent functional MRI scanning, which consisted of a resting-state-scan followed by the presentation of visual stimuli depicting human limbs in painful and non-painful situations. After scanning, participants were asked to evaluate the stimuli in terms of pain intensity perceived from the first person perspective. Independent component analysis (ICA) demonstrated that higher integration of the left medial orbitofrontal cortex (BA 32) into the anterior default mode network (aDMN) was associated with higher post-scan pain ratings. Furthermore, the exposition to the “Pain”-pictures led to relative increases of aDMN-activity compared to “No Pain”-stimuli which were also correlated with the subjective pain intensity. The behaviorally predictive functional architecture during a task-free period supports the notion that the DMN serves as a “memory of the future” [Ingvar DH (1985) Hum Neurobiol 4:127–136] in terms of a neuronal cache, storing “a priori scripts,” which are recalled to deal efficiently with upcoming environmental events. In addition, our results suggest that an individual predisposition to identify oneself with another's pain influences the automatic response of the DMN during the observation of painful situations.

Effective connectivity between amygdala and orbitofrontal cortex differentiates the perception of facial expressions

Emotion research is guided both by the view that emotions are points in a dimensional space, such as valence or approach–withdrawal, and by the view that emotions are discrete categories. We determined whether effective connectivity of amygdala with medial orbitofrontal cortex (MOFC) and lateral orbitofrontal cortex (LOFC) differentiates the perception of emotion faces in a manner consistent with the dimensional and/or categorical view. Greater effective connectivity from left MOFC to amygdala differentiated positive and neutral expressions from negatively valenced angry, disgust, and fear expressions. Greater effective connectivity from right LOFC to amygdala differentiated emotion expressions conducive to perceiver approach (happy, neutral, and fear) from angry expressions that elicit perceiver withdrawal. Finally, consistent with the categorical view, there were unique patterns of connectivity in response to fear, anger, and disgust, although not in response to happy expressions, which did not differ from neutral ones.

Automated MRI parcellation study of regional volume and thickness of prefrontal cortex (PFC) in antipsychotic‐naïve schizophrenia

Prefrontal cortical dysfunction is considered to be critical in the pathogenesis of schizophrenia. However, structural magnetic resonance imaging (MRI) studies on the PFC have yielded inconsistent results because of various confounding factors. In this study we examined the volume and thickness abnormalities of the PFC in antipsychotic-naïve schizophrenia patients (n = 51) in comparison with age-, sex-, and handedness-matched (as a group) healthy comparison subjects (n = 47) using a newly described automated MRI parcellation analysis. Schizophrenia patients showed i) significant volume deficits in bilateral lateral orbitofrontal and left medial orbitofrontal cortices as well as bilateral pars triangularis; and ii) significant thickness deficit in bilateral medial orbitofrontal cortices. Negative syndrome score had a significant negative correlation with the thickness of the left medial orbitofrontal cortex. The study findings emphasize that prefrontal deficit in schizophrenia is differential and involves primarily the regions essential for 'social cognition'.

Cross-modal integration of intranasal stimuli: A functional magnetic resonance imaging study

Most odorants, in addition to the olfactory system, also activate the intranasal trigeminal system. Recent studies have shown that pure trigeminal stimulation activates somatosensory regions as well as regions traditionally thought of as primary olfactory areas. As a main aim of this study we wished to a) ascertain which brain regions are responsive to an “artificially” bimodal odor composed of a trigeminal (CO 2) and an olfactory stimulant (phenyl ethyl alcohol, PEA) and b) determine if presenting CO 2 and PEA simultaneously activates different brain regions than when presenting them individually. Fifteen men were scanned using functional magnetic resonance imaging while smelling PEA, CO 2, and a mixture of both stimuli (CO 2PEA) presented simultaneously. Odors were presented monorhinally to the right nostril in a block design. The contrast between CO 2PEA and baseline revealed areas implicated in the processing of both olfactory and trigeminal stimuli. When the mixture was contrasted with the sum of its single components (CO 2PEA−{CO 2+PEA}), activations in integration centers (left superior temporal and right intraparietal sulcus) and in orbitofrontal areas (left medial and lateral orbitofrontal cortex) were detected. The opposite contrast ({CO 2+PEA}−CO 2PEA) did not reveal any significant activation. In contrast to studies which have used natural mixed olfactory/trigeminal stimuli, we have shown that the perception of an artificial mixed olfactory/trigeminal stimulus activates, as opposed to inhibiting the olfactory cortex. Further, we also conclude that a mixed olfactory/trigeminal stimulus appears to lead to higher cortical activations than the sum of its parts.

Anatomical measurements of the orbitofrontal cortex in child and adolescent patients with bipolar disorder

Imaging studies indicate smaller orbitofrontal cortex (OFC) volume in mood disorder patients compared with healthy subjects. We sought to determine whether child and adolescent patients with bipolar disorder have smaller OFC volumes than healthy controls. Fourteen children and adolescents meeting DSM-IV criteria for bipolar disorder (six males and eight females with a mean age ± S.D. = 15.5 ± 3.2 years) and 20 healthy controls (11 males and nine females with mean age ± S.D. = 16.9 ± 3.8 years) were studied. Orbitofrontal cortex volume was measured using magnetic resonance imaging. Male bipolar patients had smaller gray matter volumes in medial ( p = 0.044), right medial (0.037) and right ( p = 0.032) lateral OFC subdivisions compared to male controls. In contrast, female patients had larger gray matter volumes in left ( p = 0.03), lateral ( p = 0.012), left lateral ( p = 0.007), and trends for larger volumes in right lateral and left medial OFC subdivisions compared with female controls. Male patients exhibit smaller gray matter volumes, while female patients exhibit larger volumes in some OFC sub-regions. Gender differences in OFC abnormalities may be involved in illness pathophysiology among young bipolar patients.

Neural substrates of faulty decision-making in abstinent marijuana users

Persistent dose-related cognitive decrements have been reported in 28-day abstinent heavy marijuana (MJ) users. However, the neural substrates of these decrements in cognitive performance are not known. This study aimed to determine if 25-day abstinent MJ users show persistent dose-related alterations in performance and brain activity using PET H 2 15O during the Iowa Gambling Task-IGT (a decision-making task). Eleven heavy MJ users and 11 non-drug users participated. The MJ group resided in an inpatient research unit at the NIH/NIDA-IRP for 25 days prior to testing to ensure abstinence. A dose-related association was found between increased MJ use and lower IGT performance and alterations in brain activity. The MJ group showed greater activation in the left cerebellum and less activation in the right lateral orbitofrontal cortex (OFC) and the right dorsolateral prefrontal cortex (DLPFC) than the Control group. When the MJ group was divided into Moderate (8–35 joints/week) and Heavy users (53–84 joints/week), the Heavy MJ group showed less activation in the left medial OFC and greater activation in the left cerebellum than the Moderate group. However, brain activity and task performance were similar between the Moderate MJ users and the Control group, suggesting a “threshold effect”. These preliminary findings indicate that very heavy users of MJ have persistent decision-making deficits and alterations in brain activity. Specifically, the Heavy MJ users may focus on only the immediate reinforcing aspects of a situation (i.e., getting high) while ignoring the negative consequences. Thus, faulty decision-making could make an individual more prone to addictive behavior and more resistant to treatment. Finally, it is unclear if these neurologic findings will become progressively worse with continued heavy MJ use or if they will resolve with abstinence from MJ use.

Risky decision making and the anterior cingulate cortex in abstinent drug abusers and nonusers

Risky decision making is a hallmark behavioral phenotype of drug abuse; thus, an understanding of its biological bases may inform efforts to develop therapies for addictive disorders. A neurocognitive task that measures this function (Rogers Decision-Making Task; RDMT) was paired with measures of regional cerebral perfusion to identify brain regions that may underlie deficits in risky decision making in drug abusers. Subjects were abstinent drug abusers (≥3 months) and healthy controls who underwent positron emission tomography scans with H 2 15O. Drug abusers showed greater risk taking and heightened sensitivity to rewards than control subjects. Both drug abusers and controls exhibited significant activations in a widespread network of brain regions, primarily in the frontal cortex, previously implicated in decision-making tasks. The only significant group difference in brain activation, however, was found in the left pregenual anterior cingulate cortex, with drug abusers exhibiting less task-related activation than control subjects. There were no significant correlations between neural activity and task performance within the control group. In the drug abuse group, on the other hand, increased risky choices on the RDMT negatively correlated with activation in the right hippocampus, left anterior cingulate gyrus, left medial orbitofrontal cortex, and left parietal lobule, and positively correlated with activation in the right insula. Drug abuse severity was related positively to right medial orbitofrontal activity. Attenuated activation of the pregenual ACC in the drug abusers relative to the controls during performance on the RDMT may underlie the abusers' tendency to choose risky outcomes.

The neural bases of cooperation and competition: an fMRI investigation

Cooperation and competition are two basic modes of social cognition that necessitate monitoring of both one's own and others' actions, as well as adopting a specific mental set. In this fMRI, study individuals played a specially designed computer game, according to a set of predefined rules, either in cooperation with or in competition against another person. The hemodynamic response during these conditions was contrasted to that of the same subjects playing the game independently. Both cooperation and competition stances resulted in activation of a common frontoparietal network subserving executive functions, as well as the anterior insula, involved in autonomic arousal. Moreover, distinct regions were found to be selectively associated with cooperation and competition, notably the orbitofrontal cortex in the former and the inferior parietal and medial prefrontal cortices in the latter. This pattern reflects the different mental frameworks implicated in being cooperative versus competitive with another person. In accordance with evidence from evolutionary psychology as well as from developmental psychology, we argue that cooperation is a socially rewarding process and is associated with specific left medial orbitofrontal cortex involvement.

Right and Left Medial Orbitofrontal Volumes Show an Opposite Relationship to Agreeableness in FTD

Recent investigations of the neuroanatomy of complex social behaviors suggest that the underlying brain circuits involve multiple cortical and subcortical structures. The neuroanatomic origins of agreeableness have not yet been clearly elucidated. However, frontotemporal dementia (FTD) patients can evidence dramatic alterations in agreeableness arising from frontal and temporal lobe damage. Based on previous research, we hypothesized that agreeableness would be negatively correlated with left medial orbitofrontal cortex size and positively correlated with right amygdala volume. First-degree relatives of 27 FTD patients (diagnosed according to the Lund-Manchester criteria) were asked to fill out the NEO-Five Factor Inventory to assess the patients’ current level of agreeableness, a construct comprised of the facets trust, straightforwardness, altruism, compliance, modesty, and tender-mindedness. These patients underwent T₁-weighted MRI imaging, and gray matter volumes for right and left orbitofrontal lobes and amygdalas were derived via segmentation and region of interest tracing, normalizing for total intracranial volume. Regression analysis revealed that 38% of the variance in the NEO agreeableness score was predicted by a model in which right orbitofrontal volume (β = 0.731) was positively correlated with agreeableness, and left orbitofrontal lobe volume (β = –0.638) was negatively correlated with agreeableness (p < 0.01). Contrary to our hypothesis, amygdala volume did not significantly predict agreeableness. This finding partly replicates a previous study that used a different measure of social functioning, the Interpersonal Adjective Scale, to delineate a left frontal-right amygdala circuit for agreeableness. These data support the hypothesis that regulation of agreeableness arises from a balanced, mutually inhibitory circuit involving both hemispheres.

Sex-related Differences in a Gambling Task and Its Neurological Correlates

We investigated sex-related differences in task performance and brain activity in the orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) during performance of a decision-making task (the Iowa Gambling Task). When men and women were examined separately, men activated extensive regions of the right lateral OFC and right DLPFC, as well as the left lateral OFC. In contrast, women activated the left medial OFC. Examining sex differences directly, men showed better task performance and greater lateralized brain activity to the right hemisphere than women. This was exemplified by greater activation in a large area of the right lateral OFC of men during their performance of the Iowa Gambling Task. In contrast, women had greater activation in the left DLPFC, left medial frontal gyrus and temporal lobe during this task. Thus, brain mechanisms engaged by men and women when solving the same decision-making task are different. These observations indicate that sex-related differences contribute to the heterogeneity observed in both normal and abnormal brain functioning. These results also provide further evidence of sexual dimorphism in neurocognitive performance and brain function.

Ventromedial prefrontal cortex mediates guessing

Guessing is an important component of everyday cognition. The present study examined the neural substrates of guessing using a simple card-playing task in conjunction with functional magnetic resonance imaging (fMRI). Subjects were scanned under four conditions. In two, they were shown images of the back of a playing card and had to guess either the colour or the suit of the card. In the other two they were shown the face of a card and had to report either the colour or the suit. Guessing compared to reporting was associated with significant activations in lateral prefrontal cortex (right more than left), right orbitofrontal cortex, anterior cingulate, bilateral inferior parietal cortex and right thalamus. Increasing the guessing demands by manipulating the number of alternative outcomes was associated with activation of the left lateral and medial orbitofrontal cortex. These data suggest that while simple two choice guessing depends on an extensive neural system including regions of the right lateral prefrontal cortex, activation of orbitofrontal cortex increases as the probabilistic contingencies become more complex. Guessing thus involves not only systems implicated in working memory processes but also depends upon orbitofrontal cortex. This region is not typically activated in working memory tasks and its activation may reflect additional requirements of dealing with uncertainty.