Pain networks from the inside: Spatiotemporal analysis of brain responses leading from nociception to conscious perception

Conscious perception of painful stimuli needs the contribution of an extensive cortico‐subcortical network, and is completed in less than one second. While initial activities in operculo‐insular and mid‐cingulate cortices have been extensively assessed, the activation timing of most areas supporting conscious pain has barely been studied. Here we used intracranial EEG to investigate the dynamics of 16 brain regions (insular, parietal, prefrontal, cingulate, hippocampal and limbic) during the first second following nociceptive‐specific laser pulses. Three waves of activation could be defined according to their temporal relation with conscious perception, ascertained by voluntary motor responses. Pre‐conscious activities were recorded in the posterior insula, operculum, mid‐cingulate and amygdala. Antero‐insular, prefrontal and posterior parietal activities started later and developed during time‐frames consistent with conscious voluntary reactions. Responses from hippocampus, perigenual and perisplenial cingulate developed latest and persisted well after conscious perception occurred. Nociceptive inputs reach simultaneously sensory and limbic networks, probably through parallel spino‐thalamic and spino‐parabrachial pathways, and the initial limbic activation precedes conscious perception of pain. Access of sensory information to consciousness develops concomitant to fronto‐parietal activity, while late‐occurring responses in the hippocampal region, perigenual and posterior cingulate cortices likely underlie processes linked to memory encoding, self‐awareness and pain modulation. Hum Brain Mapp 37:4301–4315, 2016. © 2016 Wiley Periodicals, Inc.     

Cortical networks for working memory and executive functions sustain the conscious resting state in man

The cortical anatomy of the conscious resting state (REST) was investigated using a meta-analysis of nine positron emission tomography (PET) activation protocols that dealt with different cognitive tasks but shared REST as a common control state. During REST, subjects were in darkness and silence, and were instructed to relax, refrain from moving, and avoid systematic thoughts. Each protocol contrasted REST to a different cognitive task consisting either of language, mental imagery, mental calculation, reasoning, finger movement, or spatial working memory, using either auditory, visual or no stimulus delivery, and requiring either vocal, motor or no output. A total of 63 subjects and 370 spatially normalized PET scans were entered in the meta-analysis. Conjunction analysis revealed a network of brain areas jointly activated during conscious REST as compared to the nine cognitive tasks, including the bilateral angular gyrus, the left anterior precuneus and posterior cingulate cortex, the left medial frontal and anterior cingulate cortex, the left superior and medial frontal sulcus, and the left inferior frontal cortex. These results suggest that brain activity during conscious REST is sustained by a large scale network of heteromodal associative parietal and frontal cortical areas, that can be further hierarchically organized in an episodic working memory parieto-frontal network, driven in part by emotions, working under the supervision of an executive left prefrontal network.     

An fMRI Study of the Interactions Between the Attention and the Gustatory Networks

In a prior study, we showed that trying to detect a taste in a tasteless solution results in enhanced activity in the gustatory and attention networks. The aim of the current study was to use connectivity analyses to test if and how these networks interact during directed attention to taste. We predicted that the attention network modulates taste cortex, reflecting top-down enhancement of incoming sensory signals that are relevant to goal-directed behavior. fMRI was used to measure brain responses in 14 subjects as they performed two different tasks: (1) trying to detect a taste in a solution or (2) passively perceiving the same solution. We used psychophysiological interaction analysis to identify regions demonstrating increased connectivity during a taste attention task compared to passive tasting. We observed greater connectivity between the anterior cingulate cortex and the frontal eye fields, posterior parietal cortex, and parietal operculum and between the anterior cingulate cortex and the right anterior insula and frontal operculum. These results suggested that selective attention to taste is mediated by a hierarchical circuit in which signals are first sent from the frontal eye fields, posterior parietal cortex, and parietal operculum to the anterior cingulate cortex, which in turn modulates responses in the anterior insula and frontal operculum. We then tested this prediction using dynamic causal modeling. This analysis confirmed a model of indirect modulation of the gustatory cortex, with the strongest influence coming from the frontal eye fields via the anterior cingulate cortex. In summary, the results indicate that the attention network modulates the gustatory cortex during attention to taste and that the anterior cingulate cortex acts as an intermediary processing hub between the attention network and the gustatory cortex.     

皮质下缺血性血管性认知损害扩散张量成像研究

目的通过扩散张量成像(DTI)探讨皮质下缺血性血管性认知损害患者白质微结构变化及其与认知功能之间的相关性。方法采集49例皮质下缺血性脑血管病患者[轻度血管性痴呆(VaD)10例、非痴呆型血管性认知损害(VCIND)20例、认知功能正常19例]DTI数据并观察皮质下白质微结构改变,分析VaD组患者DTI参数与认知功能间的相关性。结果与对照组相比,VaD组内侧前额叶、前扣带回、胼胝体干、双侧顶叶、右侧颞叶、双侧眶额叶,以及VCIND组右侧额下回、右侧海马、双侧楔前叶FA值减低(均P=0.000);与VCIND组比较,VaD组内侧前额叶、前扣带回、胼胝体、双侧顶叶、右侧颞叶FA值减低(P=0.000)。与对照组相比,VaD组内侧前额叶、胼胝体、双侧顶叶、双侧颞叶、前扣带回,以及VCIND组双侧楔前叶、右侧海马MD值升高(均P=0.000);与VCIND组相比,VaD组右侧内侧前额叶、前扣带回、胼胝体干、双侧顶叶、双侧颞叶MD值升高(均P=0.000)。VaD组内侧前额叶FA值与数字连线测验A时呈显著负相关(r=-0.782,P=0.007),双侧额下回MD值与数字连线试验A时程呈显著正相关(r=0.877,P=0.001)。结论 DTI对皮质下缺血性认知损害患者白质微结构改变更敏感,能够反映患者认知功能早期异常改变;内侧前额叶白质微结构的改变是影响患者执行能力的重要因素。     

Developmental changes in within- and between-network connectivity between late childhood and adulthood

A number of behavioral changes occur between late childhood and adulthood, including maturation of social cognition, reward receptivity, impulsiveness, risk-taking and cognitive control. Although some of these abilities show linear improvements with age, some abilities may temporarily worsen, reflecting both the restructuring and/or strengthening of connections within some brain systems. The current study uses resting state functional connectivity to examine developmental differences between late childhood and adulthood in task positive (TP) regions, which play a role in cognitive control functions, and task negative (TN) regions, which play a role in social cognition, self-referential, and internally-directed thought. Within the TP network, developmental differences in connectivity were found with the left dorsolateral prefrontal cortex. Within the TN network, developmental differences in connectivity were found with a broad area of the medial prefrontal cortex and the right parahippocampal gyrus. Connections between the two networks also showed significant developmental differences. Stronger anticorrelations were found in the TN maps of the adult group for the right anterior insula/inferior frontal gyrus, bilateral anterior inferior parietal lobule, bilateral superior parietal lobule and an anterior portion of the right posterior cingulate cortex. There was a significant brain–behavior relationship between the strength of anticorrelation in these regions and inhibitory control performance on two Go/No-go tasks suggesting that the development of anticorrelations between late childhood and adulthood supports mature inhibitory control. Overall, maturation of these networks occurred in specific regions which are associated with cognitive control of goal-directed behavior, including those involved in working memory, social cognition, and inhibitory control.     

Error-related brain activation during a Go/NoGo response inhibition task

Inhibitory control and performance monitoring are critical executive functions of the human brain. Lesion and imaging studies have shown that the inferior frontal cortex plays an important role in inhibition of inappropriate response. In contrast, specific brain areas involved in error processing and their relation to those implicated in inhibitory control processes are unknown. In this study, we used a random effects model to investigate error-related brain activity associated with failure to inhibit response during a Go/NoGo task. Error-related brain activation was observed in the rostral aspect of the right anterior cingulate (BA 24/32) and adjoining medial prefrontal cortex, the left and right insular cortex and adjoining frontal operculum (BA 47) and left precuneus/posterior cingulate (BA 7/31/29). Brain activation related to response inhibition and competition was observed bilaterally in the dorsolateral prefrontal cortex (BA 9/46), pars triangularis region of the inferior frontal cortex (BA 45/47), premotor cortex (BA 6), inferior parietal lobule (BA 39), lingual gyrus and the caudate, as well as in the right dorsal anterior cingulate cortex (BA 24). These findings provide evidence for a distributed error processing system in the human brain that overlaps partially, but not completely, with brain regions involved in response inhibition and competition. In particular, the rostal anterior cingulate and posterior cingulate/precuneus as well as the left and right anterior insular cortex were activated only during error processing, but not during response competition, inhibition, selection, or execution. Our results also suggest that the brain regions involved in the error processing system overlap with brain areas implicated in the formulation and execution of articulatory plans.     

Common cortical and subcortical targets of the dorsolateral prefrontal and posterior parietal cortices in the rhesus monkey: evidence for a distributed neural network subserving spatially guided behavior

Common efferent projections of the dorsolateral prefrontal cortex and posterior parietal cortex were examined in 3 rhesus monkeys by placing injections of tritiated amino acids and HRP in frontal and parietal cortices, respectively, of the same hemisphere. Terminal labeling originating from both frontal and parietal injection sites was found to be in apposition in 15 ipsilateral cortical areas: the supplementary motor cortex, the dorsal premotor cortex, the ventral premotor cortex, the anterior arcuate cortex (including the frontal eye fields), the orbitofrontal cortex, the anterior and posterior cingulate cortices, the frontoparietal operculum, the insular cortex, the medial parietal cortex, the superior temporal cortex, the parahippocampal gyrus, the presubiculum, the caudomedial lobule, and the medial prestriate cortex. Convergent terminal labeling was observed in the contralateral hemisphere as well, most prominently in the principal sulcal cortex, the superior arcuate cortex, and the superior temporal cortex. In certain common target areas, as for example the cingulate cortices, frontal and parietal efferents terminate in an array of interdigitating columns, an arrangement much like that observed for callosal and associational projections to the principal sulcus (Goldman-Rakic and Schwartz, 1982). In other areas, frontal and parietal terminals exhibit a laminar complementarity: in the depths of the superior temporal sulcus, prefrontal terminals are densely distributed within laminae I, III, and V, whereas parietal terminals occupy mainly laminae IV and VI directly below the prefrontal bands. Subcortical structures also receive apposing or overlapping projections from both prefrontal and parietal cortices. The dorsolateral prefrontal and posterior parietal cortices project to adjacent, longitudinal domains of the neostriatum, as has been described previously (Selemon and Goldman-Rakic, 1985); these projections are also found in close apposition in the claustrum, the amygdala, the caudomedial lobule, and throughout the anterior medial, medial dorsal, lateral dorsal, and medial pulvinar nuclei of the thalamus. In the brain stem, both areas of association cortex project to the intermediate layers of the superior colliculus and to the midline reticular formation of the pons.(ABSTRACT TRUNCATED AT 400 WORDS)     

Neural correlates of memory for items and for associations: an event-related functional magnetic resonance imaging study

Although results from cognitive psychology, neuropsychology, and behavioral neuroscience clearly suggest that item and associative information in memory rely on partly different brain regions, little is known concerning the differences and similarities that exist between these two types of information as a function of memory stage (i.e., encoding and retrieval). We used event-related functional magnetic resonance imaging to assess neural correlates of item and associative encoding and retrieval of simple images in 18 healthy subjects. During encoding, subjects memorized items and pairs. During retrieval, subjects made item recognition judgments (old vs. new) and associative recognition judgments (intact vs. rearranged). Relative to baseline, item and associative trials activated bilateral medial temporal and prefrontal regions during both encoding and retrieval. Direct contrasts were then performed between item and associative trials for each memory stage. During en- coding, greater prefrontal, hippocampal, and parietal activation was observed for associations, but no significant activation was observed for items at the selected threshold. During recognition, greater activation was observed for associative trials in the left dorsolateral prefrontal cortex and superior parietal lobules bilaterally, whereas item recognition trials showed greater activation of bilateral frontal regions, bilateral anterior medial temporal areas, and the right temporo-parietal junction. Post hoc analyses suggested that the anterior medial temporal activation observed during item recognition was driven mainly by new items, confirming a role for this structure in novelty detection. These results suggest that although some structures such as the medial temporal and prefrontal cortex play a general role in memory, the pattern of activation in these regions can be modulated by the type of information (items or associations) interacting with memory stages.     

Common and distinct networks underlying reward valence and processing stages: a meta-analysis of functional neuroimaging studies

To better understand the reward circuitry in human brain, we conducted activation likelihood estimation (ALE) and parametric voxel-based meta-analyses (PVM) on 142 neuroimaging studies that examined brain activation in reward-related tasks in healthy adults. We observed several core brain areas that participated in reward-related decision making, including the nucleus accumbens (NAcc), caudate, putamen, thalamus, orbitofrontal cortex (OFC), bilateral anterior insula, anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC), as well as cognitive control regions in the inferior parietal lobule and prefrontal cortex (PFC). The NAcc was commonly activated by both positive and negative rewards across various stages of reward processing (e.g., anticipation, outcome, and evaluation). In addition, the medial OFC and PCC preferentially responded to positive rewards, whereas the ACC, bilateral anterior insula, and lateral PFC selectively responded to negative rewards. Reward anticipation activated the ACC, bilateral anterior insula, and brain stem, whereas reward outcome more significantly activated the NAcc, medial OFC, and amygdala. Neurobiological theories of reward-related decision making should therefore take distributed and interrelated representations of reward valuation and valence assessment into account.     

Management of attentional resources in within-modal and cross-modal divided attention tasks: an fMRI study

In the present study, we were interested in distinguishing the cortical representations of within-modal and cross-modal divided attention tasks by using functional magnetic resonance imaging. Sixteen healthy male subjects aged between 21 and 30 years underwent two within-modal (auditory/auditory, visual/visual) and one cross-modal (auditory/visual) divided attention task, as well as related selective attention control conditions. After subtraction of the corresponding control task the three divided attention tasks, irrespective of sensory modality, revealed significant activation in a predominantly right hemisphere network involving the prefrontal cortex, the inferior parietal cortex, and the claustrum. Under the cross-modal condition, however, the frontal and parietal activation was more extended and more bilateral and there also was stronger right hemisphere activation of the anterior cingulate cortex and the thalamus. In comparison to the within-modal conditions additional bilateral frontal and left inferior parietal activation was found for the cross-modal condition. The supplementary fronto-parietal, anterior cingulate cortex, and thalamus activation in the auditory/visual condition could be argued to reflect an additional demand for coordination of two ongoing cross-modal cognitive processes.     

Identification of human gustatory cortex by activation likelihood estimation

Over the last two decades, neuroimaging methods have identified a variety of taste-responsive brain regions. Their precise location, however, remains in dispute. For example, taste stimulation activates areas throughout the insula and overlying operculum, but identification of subregions has been inconsistent. Furthermore, literature reviews and summaries of gustatory brain activations tend to reiterate rather than resolve this ambiguity. Here, we used a new meta-analytic method [activation likelihood estimation (ALE)] to obtain a probability map of the location of gustatory brain activation across 15 studies. The map of activation likelihood values can also serve as a source of independent coordinates for future region-of-interest analyses. We observed significant cortical activation probabilities in: bilateral anterior insula and overlying frontal operculum, bilateral mid dorsal insula and overlying Rolandic operculum, and bilateral posterior insula/parietal operculum/postcentral gyrus, left lateral orbitofrontal cortex (OFC), right medial OFC, pregenual anterior cingulate cortex (prACC) and right mediodorsal thalamus. This analysis confirms the involvement of multiple cortical areas within insula and overlying operculum in gustatory processing and provides a functional "taste map" which can be used as an inclusive mask in the data analyses of future studies. In light of this new analysis, we discuss human central processing of gustatory stimuli and identify topics where increased research effort is warranted.     

At the heart of the ventral attention system: The right anterior insula

The anterior insula has been hypothesized to provide a link between attention‐related problem solving and salience systems during the coordination and evaluation of task performance. Here, we test the hypothesis that the anterior insula/medial frontal operculum (aI/fO) provides linkage across systems supporting task demands and attention systems by examining the patterns of functional connectivity during word recognition and spatial attention functional imaging tasks. A shared set of frontal regions (right aI/fO, right dorsolateral prefrontal cortex, bilateral anterior cingulate) were engaged, regardless of perceptual domain (auditory or visual) or mode of response (word production or button press). We present novel evidence that: (1) the right aI/fO is functionally connected with other frontal regions implicated in executive function and not just brain regions responsive to stimulus salience; and (2) that the aI/fO, but not the ACC, exhibits significantly correlated activity with other brain regions specifically engaged by tasks with varying perceptual and behavioral demands. These results support the hypothesis that the right aI/fO aids in the coordination and evaluation of task performance across behavioral tasks with varying perceptual and response demands. Hum Brain Mapp 2009. © 2008 Wiley‐Liss, Inc.     

A combined [11C]diprenorphine PET study and fMRI study of acupuncture analgesia

Functional neuroimaging studies suggest that a lateral network in the brain is associated with the sensory aspects of pain perception while a medial network is associated with affective aspects. The highest concentration of opioid receptors is in the medial network. There is significant evidence that endogenous opioids are central to the experience of pain and analgesia. We applied an integrative multimodal imaging approach during acupuncture. We found functional magnetic resonance imaging signal changes in the orbitofrontal cortex, insula, and pons and [11C]diprenorphine positron emission tomography signal changes in the orbitofrontal cortex, medial prefrontal cortex, insula, thalamus, and anterior cingulate cortex. These findings include brain regions within both the lateral and medial pain networks.     

Using real-time fMRI to learn voluntary regulation of the anterior insula in the presence of threat-related stimuli

Previous studies have shown that healthy participants learn to control local brain activity with operant training by using real-time functional magnetic resonance imaging (rt-fMRI). Very little data exist, however, on the dynamics of interaction between critical brain regions during rt-fMRI-based training. Here, we examined self-regulation of stimulus-elicited insula activation and performed a psychophysiological interaction (PPI) analysis of real-time self-regulation data. During voluntary up-regulation of the left anterior insula in the presence of threat-related pictures, differential activations were observed in the ventrolateral prefrontal cortex, the frontal operculum, the middle cingulate cortex and the right insula. Down-regulation in comparison to no-regulation revealed additional activations in right superior temporal cortex, right inferior parietal cortex and right middle frontal cortex. There was a significant learning effect over sessions during up-regulation, documented by a significant improvement of anterior insula control over time. Connectivity analysis revealed that successful up-regulation of the activity in left anterior insula while viewing aversive pictures was directly modulated by dorsomedial and ventrolateral prefrontal cortex. Down-regulation of activity was more difficult to achieve and no learning effect was observed. More extensive training might be necessary for successful down-regulation. These findings illustrate the functional interactions between different brain areas during regulation of anterior insula activity in the presence of threat-related stimuli.     

The cerebellum plays a role in conscious episodic memory retrieval

The cerebellum has traditionally been considered to be primarily dedicated to motor functions. Its phylogenetic development and connectivity suggest, however, that it also may play a role in cognitive processes in the human brain. In order to examine a potential cognitive role for the cerebellum in human beings, a positron emission tomography (PET) study was conducted during a "pure thought experiment": subjects intentionally recalled a specific past personal experience (consciously retrieved episodic memory). Since there was no motor or sensory input or output, the design eliminated the possibility that cerebellar changes in blood flow were due to motor activity. During silent recall of a consciously retrieved episodic memory, activations were observed in the right lateral cerebellum, left medial dorsal thalamus, medial and left orbital frontal cortex, anterior cingulate, and a left parietal region. These activations confirm a cognitive role for the cerebellum, which may participate in an interactive cortical-cerebellar network that initiates and monitors the conscious retrieval of episodic memory.     

Default mode network activity in schizophrenia studied at resting state using probabilistic ICA

Alterations in brain function in schizophrenia and other neuropsychiatric disorders are evident not only during specific cognitive challenges, but also from functional MRI data obtained during a resting state. Here we apply probabilistic independent component analysis (pICA) to resting state fMRI series in 25 schizophrenia patients and 25 matched healthy controls. We use an automated algorithm to extract the ICA component representing the default mode network (DMN) as defined by a DMN-specific set of 14 brain regions, resulting in z-scores for each voxel of the (whole-brain) statistical map. While goodness of fit was found to be similar between the groups, the region of interest (ROI) as well as voxel-wise analysis of the DMN showed significant differences between groups. Healthy controls revealed stronger effects of pICA-derived connectivity measures in right and left dorsolateral prefrontal cortices, bilateral medial frontal cortex, left precuneus and left posterior lateral parietal cortex, while stronger effects in schizophrenia patients were found in the right amygdala, left orbitofrontal cortex, right anterior cingulate and bilateral inferior temporal cortices. In patients, we also found an inverse correlation of negative symptoms with right anterior prefrontal cortex activity at rest and negative symptoms. These findings suggest that aberrant default mode network connectivity contributes to regional functional pathology in schizophrenia and bears significance for core symptoms.     

Tactile discrimination of grating orientation: fMRI activation patterns

Grating orientation discrimination is employed widely to test tactile spatial acuity. We used functional magnetic resonance imaging (fMRI) to investigate the neural circuitry underlying performance of this task. Two studies were carried out. In the first study, an extensive set of parietal and frontal cortical areas was activated during covert task performance, relative to a rest baseline. The active regions included the postcentral sulcus bilaterally and foci in the left parietal operculum, left anterior intraparietal sulcus, and bilateral premotor and prefrontal cortex. The second study examined selective recruitment of cortical areas during discrimination of grating orientation (a task with a macrospatial component) compared to discrimination of grating spacing (a purely microspatial task). The foci activated on this contrast were in the left anterior intraparietal sulcus, right postcentral sulcus and gyrus, left parieto-occipital cortex, bilateral frontal eye fields, and bilateral ventral premotor cortex. These findings not only confirm and extend previous studies of the neural processing underlying grating orientation discrimination, but also demonstrate that a distributed network of putatively multisensory areas is involved.     

Regional brain activation changes and abnormal functional connectivity of the ventrolateral prefrontal cortex during working memory processing in adults with attention‐deficit/hyperactivity disorder

Previous studies on working memory (WM) function in adults with attention‐deficit/hyperactivity disorder (ADHD) suggested aberrant activation of the prefrontal cortex and the cerebellum. Although it has been hypothesized that activation differences in these regions most likely reflect aberrant frontocerebellar circuits, the functional coupling of these brain networks during cognitive performance has not been investigated so far. In this study, functional magnetic resonance imaging (fMRI) and both univariate and multivariate analytic techniques were used to investigate regional activation changes and functional connectivity differences during cognitive processing in healthy controls (n = 12) and ADHD adults (n = 12). Behavioral performance during a parametric verbal WM paradigm did not significantly differ between adults with ADHD and healthy controls. During the delay period of the activation task, however, ADHD patients showed significantly less activation in the left ventrolateral prefrontal cortex (VLPFC), as well as in cerebellar and occipital regions compared with healthy control subjects. In both groups, independent component analyses revealed a functional network comprising bilateral lateral prefrontal, striatal, and cingulate regions. ADHD adults had significantly lower connectivity in the bilateral VLPFC, the anterior cingulate cortex, the superior parietal lobule, and the cerebellum compared with healthy controls. Increased connectivity in ADHD adults was found in right prefrontal regions, the left dorsal cingulate cortex and the left cuneus. These findings suggest both regional brain activation deficits and functional connectivity changes of the VLPFC and the cerebellum as well as functional connectivity abnormalities of the anterior cingulate and the parietal cortex in ADHD adults during WM processing. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.     

Insula of the old world monkey. II: Afferent cortical input and comments on the claustrum

The afferent connections of the insula in the rhesus monkey were studied with axonal transport methods. Injections of horseradish peroxidase (HRP) in the insula revealed labeled neurons in the prefrontal cortex, the lateral orbital region, the frontopariefal operculum, the cingulate gyrus and adjacent medial cortex, the prepiriforrn olfactory cortex, the temporal pole, the cortex of the superior temporal sulcus, the rhinal cortex, the supratem-poral plane, and the posterior parietal lobe. Tritiated amino acid (TAA) injections in some of the cortical regions which contained retrogradely labeled neurons confirmed projections to the insula from prefrontal granular cortex, orbital frontal cortex, prepiriform cortex, temporal pole, rhinal cortex, cingulate gyrus, frontal operculum, and parietal cortex. In these studies, cortical areas that projected to the insula also projected to the claustrum. However, the topographic and quantitative relationships between the projections into the insula and those into the claustrum were inconsistent. Moreover, the claustrum has additional connections which it does not share with the insula. A selected review of the literature suggests that the claustrum and insula differ widely also with respect to ontogenesis and functional specialization.     

Neocortical modulation of the amygdala response to fearful stimuli.

BACKGROUND: The cortical circuitry involved in conscious cognitive processes and the subcortical circuitry involved in fear responses have been extensively studied with neuroimaging, but their interactions remain largely unexplored. A recent functional magnetic resonance imaging (fMRI) study demonstrated that the engagement of the right prefrontal cortex during the cognitive evaluation of angry and fearful facial expressions is associated with an attenuation of the response of the amygdala to these same stimuli, providing evidence for a functional neural network for emotional regulation. METHODS: In the current study, we have explored the generalizability of this functional network by using threatening and fearful non-face stimuli derived from the International Affective Picture System (IAPS), as well as the influence of this network on peripheral autonomic responses. RESULTS: Similar to the earlier findings with facial expressions, blood oxygen level dependent fMRI revealed that whereas perceptual processing of IAPS stimuli was associated with a bilateral amygdala response, cognitive evaluation of these same stimuli was associated with attenuation of this amygdala response and a correlated increase in response of the right prefrontal cortex and the anterior cingulate cortex. Moreover, this pattern was reflected in changes in skin conductance. CONCLUSIONS: The current results further implicate the importance of neocortical regions, including the prefrontal and anterior cingulate cortices, in regulating emotional responses mediated by the amygdala through conscious evaluation and appraisal.