Simultaneous fMRI and EEG during the Multi-Source Interference Task

Background

fMRI and EEG are two non-invasive functional imaging techniques within cognitive neuroscience that have complementary advantages to obtain both temporal and spatial information. The multi-source interference task (MSIT) has been shown to generate robust activations of the dorsal anterior cingulate cortex (dACC) on both a single-subject level and in group averages, in fMRI studies. We have now simultaneously acquired fMRI and EEG during a cognitive interference task.

Materials and Methods

Healthy volunteers were tested in an MRI scanner with simultaneous EEG and fMRI recordings during the MSIT.

Results

The interference condition significantly increased the reaction time in the task. The fMRI analyses revealed activation of dACC as expected, in all subjects at the individual level and in group analyses. The posterior cingulate cortex was de-activated. Simultaneous EEG showed the expected anterior distribution of the interference effect, as it was restricted to frontal sites within a time frame of 80–120 ms post response.

Conclusion

The MSIT task is a reliable task for interference evaluation. fMRI shows robust activation of dACC and by adding EEG, an interference effect can be noticed within a temporal interval of 80–120 ms after the response, as a CRN (correct response negativity). This means that EEG could add a more detailed temporal aspect to the fMRI data from an interference task, and that despite the hostile environment within an MRI scanner, EEG data could be used.     

Decreased Chloride Channel Expression in the Dorsolateral Prefrontal Cortex in Schizophrenia

Alterations in GABAergic neurotransmission are implicated in several psychiatric illnesses, including schizophrenia. The Na-K-Cl and K-Cl cotransporters regulate intracellular chloride levels. Abnormalities in cotransporter expression levels could shift the chloride electrochemical gradient and impair GABAergic transmission. In this study, we performed Western blot analysis to investigate whether the Na-K-Cl and K-Cl cotransporter protein is abnormally expressed in the dorsal lateral prefrontal cortex and the anterior cingulate cortex in patients with schizophrenia versus a control group. We found decreased K-Cl cotransporter protein expression in the dorsal lateral prefrontal cortex, but not the anterior cingulate cortex, in subjects with schizophrenia, supporting the hypothesis of region level abnormal GABAergic function in the pathophysiology of schizophrenia. Subjects with schizophrenia off antipsychotic medication at the time of death had decreased K-Cl cotransporter protein expression compared to both normal controls and subjects with schizophrenia on antipsychotics. Our results provide evidence for KCC2 protein abnormalities in schizophrenia and suggest that antipsychotic medications might reverse deficits of this protein in the illness.     

Neural Correlates of Post-Conventional Moral Reasoning: A Voxel-Based Morphometry Study

Going back to Kohlberg, moral development research affirms that people progress through different stages of moral reasoning as cognitive abilities mature. Individuals at a lower level of moral reasoning judge moral issues mainly based on self-interest (personal interests schema) or based on adherence to laws and rules (maintaining norms schema), whereas individuals at the post-conventional level judge moral issues based on deeper principles and shared ideals. However, the extent to which moral development is reflected in structural brain architecture remains unknown. To investigate this question, we used voxel-based morphometry and examined the brain structure in a sample of 67 Master of Business Administration (MBA) students. Subjects completed the Defining Issues Test (DIT-2) which measures moral development in terms of cognitive schema preference. Results demonstrate that subjects at the post-conventional level of moral reasoning were characterized by increased gray matter volume in the ventromedial prefrontal cortex and subgenual anterior cingulate cortex, compared with subjects at a lower level of moral reasoning. Our findings support an important role for both cognitive and emotional processes in moral reasoning and provide first evidence for individual differences in brain structure according to the stages of moral reasoning first proposed by Kohlberg decades ago.     

Risk-Taking Behavior in a Computerized Driving Task: Brain Activation Correlates of Decision-Making,Outcome, and Peer Influence in Male Adolescents

Increased propensity for risky behavior in adolescents, particularly in peer groups, is thought to reflect maturational imbalance between reward processing and cognitive control systems that affect decision-making. We used functional magnetic resonance imaging (fMRI) to investigate brain functional correlates of risk-taking behavior and effects of peer influence in 18–19-year-old male adolescents. The subjects were divided into low and high risk-taking groups using either personality tests or risk-taking rates in a simulated driving task. The fMRI data were analyzed for decision-making (whether to take a risk at intersections) and outcome (pass or crash) phases, and for the influence of peer competition. Personality test-based groups showed no difference in the amount of risk-taking (similarly increased during peer competition) and brain activation. When groups were defined by actual task performance, risk-taking activated two areas in the left medial prefrontal cortex (PFC) significantly more in low than in high risk-takers. In the entire sample, risky decision-specific activation was found in the anterior and dorsal cingulate, superior parietal cortex, basal ganglia (including the nucleus accumbens), midbrain, thalamus, and hypothalamus. Peer competition increased outcome-related activation in the right caudate head and cerebellar vermis in the entire sample. Our results suggest that the activation of the medial (rather than lateral) PFC and striatum is most specific to risk-taking behavior of male adolescents in a simulated driving situation, and reflect a stronger conflict and thus increased cognitive effort to take risks in low risk-takers, and reward anticipation for risky decisions, respectively. The activation of the caudate nucleus, particularly for the positive outcome (pass) during peer competition, further suggests enhanced reward processing of risk-taking under peer influence.     

The neural basis of metacognitive ability

Ability in various cognitive domains is often assessed by measuring task performance, such as the accuracy of a perceptual categorization. A similar analysis can be applied to metacognitive reports about a task to quantify the degree to which an individual is aware of his or her success or failure. Here, we review the psychological and neural underpinnings of metacognitive accuracy, drawing on research in memory and decision-making. These data show that metacognitive accuracy is dissociable from task performance and varies across individuals. Convergent evidence indicates that the function of the rostral and dorsal aspect of the lateral prefrontal cortex (PFC) is important for the accuracy of retrospective judgements of performance. In contrast, prospective judgements of performance may depend upon medial PFC. We close with a discussion of how metacognitive processes relate to concepts of cognitive control, and propose a neural synthesis in which dorsolateral and anterior prefrontal cortical subregions interact with interoceptive cortices (cingulate and insula) to promote accurate judgements of performance.     

Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action

Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the „dorsal nexus “(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression.     

Representation of Cognitive Reappraisal Goals in Frontal Gamma Oscillations

Recently, numerous efforts have been made to understand the neural mechanisms underlying cognitive regulation of emotion, such as cognitive reappraisal. Many studies have reported that cognitive control of emotion induces increases in neural activity of the control system, including the prefrontal cortex and the dorsal anterior cingulate cortex, and increases or decreases (depending upon the regulation goal) in neural activity of the appraisal system, including the amygdala and the insula. It has been hypothesized that information about regulation goals needs to be processed through interactions between the control and appraisal systems in order to support cognitive reappraisal. However, how this information is represented in the dynamics of cortical activity remains largely unknown. To address this, we investigated temporal changes in gamma band activity (35–55 Hz) in human electroencephalograms during a cognitive reappraisal task that was comprised of three reappraisal goals: to decease, maintain, or increase emotional responses modulated by affect-laden pictures. We examined how the characteristics of gamma oscillations, such as spectral power and large-scale phase synchronization, represented cognitive reappraisal goals. We found that left frontal gamma power decreased, was sustained, or increased when the participants suppressed, maintained, or amplified their emotions, respectively. This change in left frontal gamma power appeared during an interval of 1926 to 2453 ms after stimulus onset. We also found that the number of phase-synchronized pairs of gamma oscillations over the entire brain increased when participants regulated their emotions compared to when they maintained their emotions. These results suggest that left frontal gamma power may reflect cortical representation of emotional states modulated by cognitive reappraisal goals and gamma phase synchronization across whole brain regions may reflect emotional regulatory efforts to achieve these goals. Our study may provide the basis for an electroencephalogram-based neurofeedback system for the cognitive regulation of emotion.     

Top-down control-signal dynamics in anterior cingulate and prefrontal cortex neurons following task switching

The prefrontal cortex (PFC) and anterior cingulate cortex (ACC) have both been implicated in cognitive control, but their relative roles remain unclear. Here we recorded the activity of single neurons in both areas while monkeys performed a task that required them to switch between trials in which they had to look toward a flashed stimulus (prosaccades) and trials in which they had to look away from the stimulus (antisaccades). We found that ACC neurons had a higher level of task selectivity than PFC neurons during the preparatory period on trials immediately following a task switch. In ACC neurons, task selectivity was strongest after the task switch and declined throughout the task block, whereas task selectivity remained constant in the PFC. These results demonstrate that the ACC is recruited when cognitive demands increase and suggest a role for both areas in task maintenance and the implementation of top-down control.     

Cognitive Control in Auditory Working Memory Is Enhanced in Musicians

Musical competence may confer cognitive advantages that extend beyond processing of familiar musical sounds. Behavioural evidence indicates a general enhancement of both working memory and attention in musicians. It is possible that musicians, due to their training, are better able to maintain focus on task-relevant stimuli, a skill which is crucial to working memory. We measured the blood oxygenation-level dependent (BOLD) activation signal in musicians and non-musicians during working memory of musical sounds to determine the relation among performance, musical competence and generally enhanced cognition. All participants easily distinguished the stimuli. We tested the hypothesis that musicians nonetheless would perform better, and that differential brain activity would mainly be present in cortical areas involved in cognitive control such as the lateral prefrontal cortex. The musicians performed better as reflected in reaction times and error rates. Musicians also had larger BOLD responses than non-musicians in neuronal networks that sustain attention and cognitive control, including regions of the lateral prefrontal cortex, lateral parietal cortex, insula, and putamen in the right hemisphere, and bilaterally in the posterior dorsal prefrontal cortex and anterior cingulate gyrus. The relationship between the task performance and the magnitude of the BOLD response was more positive in musicians than in non-musicians, particularly during the most difficult working memory task. The results confirm previous findings that neural activity increases during enhanced working memory performance. The results also suggest that superior working memory task performance in musicians rely on an enhanced ability to exert sustained cognitive control. This cognitive benefit in musicians may be a consequence of focused musical training.     

The integration of negative affect, pain and cognitive control in the cingulate cortex

It has been argued that emotion, pain and cognitive control are functionally segregated in distinct subdivisions of the cingulate cortex. However, recent observations encourage a fundamentally different view. Imaging studies demonstrate that negative affect, pain and cognitive control activate an overlapping region of the dorsal cingulate--the anterior midcingulate cortex (aMCC). Anatomical studies reveal that the aMCC constitutes a hub where information about reinforcers can be linked to motor centres responsible for expressing affect and executing goal-directed behaviour. Computational modelling and other kinds of evidence suggest that this intimacy reflects control processes that are common to all three domains. These observations compel a reconsideration of the dorsal cingulate's contribution to negative affect and pain.     

fMRI signal changes in response to forced expiratory loading in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) patients show impaired ventilatory responses to CO2 and hypoxia and reduced drive to breathe during sleep but retain appropriate breathing patterns in response to volition or increased exercise. Breath-by-breath influences on heart rate are also deficient. Using functional magnetic resonance imaging techniques, we examined responses over the brain to voluntary forced expiratory loading, a task that CCHS patients can perform but that results in impaired rapid heart rate variation patterns normally associated with the loading challenge. Increased signals emerged in control (n = 14) over CCHS (n = 13; ventilator dependent during sleep but not waking) subjects in the cingulate and right parietal cortex, cerebellar cortex and fastigial nucleus, and basal ganglia, whereas anterior cerebellar cortical sites and deep nuclei, dorsal midbrain, and dorsal pons showed increased signals in the patient group. The dorsal and ventral medulla showed delayed responses in CCHS patients. Primary motor and sensory areas bordering the central sulcus showed comparable responses in both groups. The delayed responses in medullary sensory and output regions and the aberrant reactions in cerebellar and pontine sensorimotor coordination areas suggest that rapid cardiorespiratory integration deficits in CCHS may stem from defects in these sites. Additional autonomic and perceptual motor deficits may derive from cingulate and parietal cortex aberrations.     

Reward Sensitivity Modulates Brain Activity in the Prefrontal Cortex,ACC and Striatum during Task Switching

Current perspectives on cognitive control acknowledge that individual differences in motivational dispositions may modulate cognitive processes in the absence of reward contingencies. This work aimed to study the relationship between individual differences in Behavioral Activation System (BAS) sensitivity and the neural underpinnings involved in processing a switching cue in a task-switching paradigm. BAS sensitivity was hypothesized to modulate brain activity in frontal regions, ACC and the striatum. Twenty-eight healthy participants underwent fMRI while performing a switching task, which elicited activity in fronto-striatal regions during the processing of the switch cue. BAS sensitivity was negatively associated with activity in the lateral prefrontal cortex, anterior cingulate cortex and the ventral striatum. Combined with previous results, our data indicate that BAS sensitivity modulates the neurocognitive processes involved in task switching in a complex manner depending on task demands. Therefore, individual differences in motivational dispositions may influence cognitive processing in the absence of reward contingencies.     

Dynamic Changes in Brain Activations and Functional Connectivity during Affectively Different Tactile Stimuli

In the present study, we compared brain activations produced by pleasant, neutral and unpleasant touch, to the anterior lateral surface of lower leg of human subjects. It was found that several brain regions, including the contralateral primary somatosensory area (SI), bilateral secondary somatosensory area (SII), as well as contralateral middle and posterior insula cortex were commonly activated under the three touch conditions. In addition, pleasant and unpleasant touch conditions shared a few brain regions including the contralateral posterior parietal cortex (PPC) and bilateral premotor cortex (PMC). Unpleasant touch specifically activated a set of pain-related brain regions such as contralateral supplementary motor area (SMA) and dorsal parts of bilateral anterior cingulated cortex, etc. Brain regions specifically activated by pleasant touch comprised bilateral lateral orbitofrontal cortex (OFC), posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), intraparietal cortex and left dorsal lateral prefrontal cortex (DLPFC). Using a novel functional connectivity model based on graph theory, we showed that a series of brain regions related to affectively different touch had significant functional connectivity during the resting state. Furthermore, it was found that such a network can be modulated between affectively different touch conditions.     

Contributions of Subsurface Cortical Modulations to Discrimination of Executed and Imagined Grasp Forces through Stereoelectroencephalography

Stereoelectroencephalographic (SEEG) depth electrodes have the potential to record neural activity from deep brain structures not easily reached with other intracranial recording technologies. SEEG electrodes were placed through deep cortical structures including central sulcus and insular cortex. In order to observe changes in frequency band modulation, participants performed force matching trials at three distinct force levels using two different grasp configurations: a power grasp and a lateral pinch. Signals from these deeper structures were found to contain information useful for distinguishing force from rest trials as well as different force levels in some participants. High frequency components along with alpha and beta bands recorded from electrodes located near the primary motor cortex wall of central sulcus and electrodes passing through sensory cortex were found to be the most useful for classification of force versus rest although one participant did have significant modulation in the insular cortex. This study electrophysiologically corroborates with previous imaging studies that show force-related modulation occurs inside of central sulcus and insular cortex. The results of this work suggest that depth electrodes could be useful tools for investigating the functions of deeper brain structures as well as showing that central sulcus and insular cortex may contain neural signals that could be used for control of a grasp force BMI.     

Area-Specific Information Processing in Prefrontal Cortex during a Probabilistic Inference Task: A Multivariate fMRI BOLD Time Series Analysis

Introduction

Discriminating spatiotemporal stages of information processing involved in complex cognitive processes remains a challenge for neuroscience. This is especially so in prefrontal cortex whose subregions, such as the dorsolateral prefrontal (DLPFC), anterior cingulate (ACC) and orbitofrontal (OFC) cortices are known to have differentiable roles in cognition. Yet it is much less clear how these subregions contribute to different cognitive processes required by a given task. To investigate this, we use functional MRI data recorded from a group of healthy adults during a “Jumping to Conclusions” probabilistic reasoning task.

Methods

We used a novel approach combining multivariate test statistics with bootstrap-based procedures to discriminate between different task stages reflected in the fMRI blood oxygenation level dependent signal pattern and to unravel differences in task-related information encoded by these regions. Furthermore, we implemented a new feature extraction algorithm that selects voxels from any set of brain regions that are jointly maximally predictive about specific task stages.

Results

Using both the multivariate statistics approach and the algorithm that searches for maximally informative voxels we show that during the Jumping to Conclusions task, the DLPFC and ACC contribute more to the decision making phase comprising the accumulation of evidence and probabilistic reasoning, while the OFC is more involved in choice evaluation and uncertainty feedback. Moreover, we show that in presumably non-task-related regions (temporal cortices) all information there was about task processing could be extracted from just one voxel (indicating the unspecific nature of that information), while for prefrontal areas a wider multivariate pattern of activity was maximally informative.

Conclusions/Significance

We present a new approach to reveal the different roles of brain regions during the processing of one task from multivariate activity patterns measured by fMRI. This method can be a valuable tool to assess how area-specific processing is altered in psychiatric disorders such as schizophrenia, and in healthy subjects carrying different genetic polymorphisms.     

Epileptic Discharges Affect the Default Mode Network – fMRI and Intracerebral EEG Evidence

Functional neuroimaging studies of epilepsy patients often show, at the time of epileptic activity, deactivation in default mode network (DMN) regions, which is hypothesized to reflect altered consciousness. We aimed to study the metabolic and electrophysiological correlates of these changes in the DMN regions. We studied six epilepsy patients that underwent scalp EEG-fMRI and later stereotaxic intracerebral EEG (SEEG) sampling regions of DMN (posterior cingulate cortex, Pre-cuneus, inferior parietal lobule, medial prefrontal cortex and dorsolateral frontal cortex) as well as non-DMN regions. SEEG recordings were subject to frequency analyses comparing sections with interictal epileptic discharges (IED) to IED-free baselines in the IED-generating region, DMN and non-DMN regions. EEG-fMRI and SEEG were obtained at rest. During IEDs, EEG-fMRI demonstrated deactivation in various DMN nodes in 5 of 6 patients, most frequently the pre-cuneus and inferior parietal lobule, and less frequently the other DMN nodes. SEEG analyses demonstrated decrease in gamma power (50–150 Hz), and increase in the power of lower frequencies (<30 Hz) at times of IEDs, in at least one DMN node in all patients. These changes were not apparent in the non-DMN regions. We demonstrate that, at the time of IEDs, DMN regions decrease their metabolic demand and undergo an EEG change consisting of decreased gamma and increased lower frequencies. These findings, specific to DMN regions, confirm in a pathological condition a direct relationship between DMN BOLD activity and EEG activity. They indicate that epileptic activity affects the DMN, and therefore may momentarily reduce the consciousness level and cognitive reserve.     

Reproducibility of human brain activity evoked by esophageal stimulation using functional magnetic resonance imaging

Functional MRI is a popular tool for investigating central processing of visceral pain in healthy and clinical populations. Despite this, the reproducibility of the neural correlates of visceral sensation by use of functional MRI remains unclear. The aim of the present study was to address this issue. Seven healthy right-handed volunteers participated in the study. Blood oxygen level-dependent contrast images were acquired at 1.5 T while subjects received nonpainful and painful phasic balloon distensions ("on-off" block design, 10 stimuli per "on" period, 0.3 Hz) to the distal esophagus. This procedure was repeated on two further occasions to investigate reproducibility. Painful stimulation resulted in highly reproducible activation over three scanning sessions in the anterior insula, primary somatosensory cortex, and anterior cingulate cortex. A significant decrease in strength of activation occurred from session 1 to session 3 in the anterior cingulate cortex, primary somatosensory cortex, and supplementary motor cortex, which may be explained by an analogous decrease in pain ratings. Nonpainful stimulation activated similar brain regions to painful stimulation, but with greater variability in signal strength and regions of activation between scans. Painful stimulation of the esophagus produces robust activation in many brain regions. A decrease in subjective perception of pain and brain activity from the first to the final scan suggests that serial brain imaging studies may be affected by habituation. These findings indicate that for brain imaging studies that require serial scanning, development of experimental paradigms that control for the effect of habituation is necessary.     

Intact cannabinoid CB1 receptors in the Alzheimer's disease cortex

The cannabinoid CB1 receptor has gained much attention as a potential pharmacotherapeutic target in various neurodegenerative diseases including Alzheimer's disease (AD). However, the relation of CB1 receptors to cognitive function in AD is at present unclear. In this study, postmortem brain tissues from a cohort of prospectively assessed, neuropathologically confirmed AD patients and aged controls were used to measure CB1 receptors by immunoblotting, and a subset of subjects also had [(3)H]SR141716A binding. Correlational analyses were then performed for the neurochemical and cognitive data. We found that CB1 receptor levels in were unchanged AD in the brain regions assessed (frontal cortex, anterior cingulate gyrus, hippocampus, caudate nucleus). Within the AD group, frontal cortical CB1 immunoreactivity correlated with cognitive scores assessed within a year of death. Our study suggests that CB1 receptors are intact in AD and may play a role in preserving cognitive function. Therefore, CB1 receptors should be further assessed as a potential therapeutic target in AD.     

Letter to the Editor: Seasonal Pattern of Births in Patients with Optic Neuritis

Attentional processes are fundamental to good cognitive functioning of human operators. The purpose of this study was to analyze the activity of neuronal networks involved in the orienting attention and executive control processes from the perspective of diurnal variability. Twenty-three healthy male volunteers meeting magnetic resonance (MR) inclusion criteria performed the Stroop Color-Word task (block design) in the MR scanner five times/day (06:00, 10:00, 14:00, 18:00, 22:00 h). The first scanning session was scheduled 1–1.5 h after waking. Between MR sessions, subjects performed simulated driving tasks in stable environmental conditions, with controlled physical activity and diet. Significant activation was found in brain regions related to the orienting attentional system: the parietal lobe (BA40) and frontal eye-fields (FEFs). There were also activations in areas of the executive control system: the fronto-insular cortex (FIC), dorsal anterior cingulate cortex (dACC), presupplementary motor area (preSMA), supplementary motor area (SMA), basal ganglia, middle temporal (MT; BA21), and dorsolateral prefrontal cortex (DLPFC), as a part of the central executive network. Significant deactivations were observed in the rostral anterior cingulate cortex (rACC), posterior cingulate cortex (PCC), superior frontal gyrus (SF), parietal lobe (BA39), and parahippocampal that are thought to comprise the default mode network (DMN). Additionally, the activated regions included bilaterally lingual gyrus and fusiform gyrus. The insula was bilaterally deactivated. Visual attention controlled by the goal-oriented attention system and comprising top-down and bottom-up mechanisms, activated by Stroop-like task, turned out to be prone to diurnal changes. The study results show the occurrence of time-of-day–related variations in neural activity of brain regions linked to the orienting attentional system (left parietal lobe—BA40, left and right FEFs), simultaneously providing arguments for temporal stability of the executive system and default mode network. These results also seem to suggest that the involuntary, exogenous (bottom-up) mechanism of attention is more vulnerable to circadian and fatigue factors than the voluntary (top-down) mechanism, which appear to be maintained at the same functional level during the day. The above phenomena were observed at the neural level. (Author correspondence: marek@uj.edu.pl)     

Neural activity in the human brain relating to uncertainty and arousal during anticipation

We used functional magnetic resonance neuroimaging to measure brain activity during delay between reward-related decisions and their outcomes, and the modulation of this delay activity by uncertainty and arousal. Feedback, indicating financial gain or loss, was given following a fixed delay. Anticipatory arousal was indexed by galvanic skin conductance. Delay-period activity was associated with bilateral activation in orbital and medial prefrontal, temporal, and right parietal cortices. During delay, activity in anterior cingulate and orbitofrontal cortices was modulated by outcome uncertainty, whereas anterior cingulate, dorsolateral prefrontal, and parietal cortices activity was modulated by degree of anticipatory arousal. A distinct region of anterior cingulate was commonly activated by both uncertainty and arousal. Our findings highlight distinct contributions of cognitive uncertainty and autonomic arousal to anticipatory neural activity in prefrontal cortex.