***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Neuroimaging studies have demonstrated activations in the anterior cingulate cortex ( ACC ) related to the affective component of pain , but not to stimulus intensity . However , it is possible that the low spatial resolution of positron emission tomography , as used in the majority of these studies , obscured areas coding stimulus intensity . We revisited this issue , using a parametric single-trial functional magnetic resonance imaging design , and investigated pain , stimulus intensity , and stimulus awareness ( i.e. , pain unrelated ) responses within the ACC in nine healthy volunteers .  Four different stimulus intensities ranging from warm to painful ( 300–600 mJ ) were applied with a thulium yttrium – aluminum granate infrared laser in a r and omized order and rated by the subjects on a five point scale ( P0–P4 ) . Pain-related regions in the ventral posterior ACC showed a response that did not distinguish between innocuous trials ( P0 and P1 ) but showed a positive linear relationship with the blood oxygenation level-dependent contrast signal for painful trials ( P2–P4 ) . Regions in the dorsal anterior ACC along the cingulate sulcus differentiated between P0 ( not perceived ) and P1 but exhibited no additional signal increase with P2 ; these regions are related to stimulus awareness and probably to cognitive processing . Most importantly , we identified a region in the dorsal posterior ACC showing a response that discriminated between nonpainful trials ( P0 and P1 ) ; therefor , this region was simply related to basic sensory processing and not to pain intensity . Stimulus-related activations were all located adjacent to the cingulate motor area , highlighting the strategic link of stimulus processing and response generation in the posterior ACC Although behavioral studies suggest that pain distress may alter the perception of somatic stimulation , neural correlates underlying such alteration remain to be clarified . The present study was aim ed to test the hypothesis that expectation of pain might amplify brain responses to somatosensory stimulation in the anterior cingulate cortex ( ACC ) and the region including parietal operculum and posterior insula ( PO/PI ) , both of which may play roles in regulating pain-dependent behavior . We compared brain responses with and subjective evaluation of physically identical nonpainful warm stimuli  between two psychologically different context s : one linked with pain expectation by presenting the nonpainful stimuli r and omly intermixed with painful stimuli and the other without . By applying the event-related functional magnetic resonance imaging technique , brain responses to the stimuli were assessed with respect to signal changes and activated volume , setting regions of interest on activated clusters in ACC and bilateral PO/PI defined by painful stimuli . As a result , the uncertain expectation of painful stimulus enhanced transient brain responses to nonpainful stimulus in ACC and PO/PI . The enhanced responses were revealed as a higher intensity of signal change in ACC and larger volume of activated voxels in PO/PI . Behavioral measurements demonstrated that expectation of painful stimulus amplified perceived unpleasantness of innocuous stimulus . From these findings , it is suggested that ACC and PO/PI are involved in modulation of affective aspect of sensory perception by the uncertain expectation of painful stimulus Abstract Although individual differences in fear and anxiety modulate the pain response and may even cause more suffering than the initiating physical stimulus , little is known about the neural systems mediating this relationship . The present study provided the first examination of the neural correlates of individual differences in the tendency to ( 1 ) feel anxious about the potentially negative implication s of physical sensations , as measured by the anxiety sensitivity index ( ASI ) , and ( 2 ) fear various types of physical pain , as indexed by the fear of pain question naire ( FPQ ) . In separate sessions , participants completed these question naires and experienced alternating blocks of noxious thermal stimulation ( 45–50 ° C ) and neutral thermal stimulation ( 38 ° C ) during the collection of whole‐brain fMRI data . Regression analyses demonstrated that during the experience of pain , ASI scores predicted activation of a medial prefrontal region associated with self‐focused attention , whereas FPQ scores predicted activation of a ventral lateral frontal region associated with response regulation and anterior and posterior cingulate regions associated with monitoring and evaluation of affective responses . These functional relationships can not be wholly explained by generalized anxiety ( indexed by STAI‐T scores ) , which did not significantly correlate with activation of any regions . The present findings may help clarify both the impact of individual differences in emotion on the neural correlates of pain , and the roles in anxiety , fear , and pain processing played by medial and orbitofrontal systems Cortical activity patterns to thermal painful stimuli of two different sizes were examined in normal volunteers using functional magnetic resonance imaging ( fMRI ) . Seven right-h and ed subjects were studied when the painful stimulus applied to the right h and fingers covered either 1,074-mm(2)-area large stimulator or 21-mm(2)-area small stimulator . Stimulus temperatures were adjusted to give rise to equivalent moderately painful ratings . fMRI signal increases and decreases were determined for the contralateral parietal and motor areas . When the overall activity in these regions was compared across subjects , increased fMRI activity was observed over more brain volume with the larger stimulator , whereas decreased fMRI activity was seen in more brain volume for the smaller stimulator . The individual subject and group-averaged activity patterns indicated regional specific differences in increased and decreased fMRI activity . The small stimulator result ed in decreased fMRI responses throughout the upper body representation in both primary somatosensory and motor cortices . In contrast , no decreased fMRI signals were seen in the secondary somatosensory cortex and in the insula . In another seven volunteers , the effects of the size of the thermal painful stimulus on vibrotactile thresholds were examined psychophysically . Painful stimuli were delivered to the fingers and vibrotactile thresholds were measured on the arm just distal to the elbow . Consistent with the fMRI results in the primary somatosensory cortex , painful thermal stimuli using the small stimulator increased vibrotactile thresholds on the forearm , whereas similarly painful stimuli using the large stimulator had no effect on forearm vibrotactile thresholds . These results are discussed in relation to the cortical dynamics for pain perception and in relation to the center-surround organization of cortical neurons Activation studies have shown that in response to evocative visual stimuli , brain activity increases in the visual cortex and limbic areas . However , non-affective characteristics of these images , such as color composition and visual complexity , confound the interpretation of these results . To address this issue , we had subjects rate over 100 images on aversive intensity ( facial mutilation , dead bodies ) and semantic complexity ( number of objects subjects could name ) . From these images , we assembled digitized image sets of non-aversive , mild and strong intensity , balanced on semantic complexity and content ( human faces and figures ) , and adjusted for color composition . A fourth condition consisted of a fixation cross on a blank screen .  Thirteen subjects underwent eight positron emission tomography scans using the [ (15)O ] water methodology . Measurement of skin conductance was recorded simultaneously . All picture conditions , relative to the blank screen , activated the amygdalae and bilateral orbitofrontal cortex , while we found activation trends associated with increasing aversive content in the sub-lenticular region . Skin conductance increased during all picture conditions . Relative to the non-aversive pictures , aversive image content caused modulation of occipital and occipital-temporal cortex . These results demonstrated activation of the amygdala to salient , arousing stimuli , and not just aversive stimuli . In addition , they suggest that pictorial complexity , as indexed by our semantic measure , does not account for the modulation of visual cortex by aversive , emotional stimuli Previous functional neuroimaging studies have characterized brain systems mediating associative learning using classical delay conditioning paradigms . In the present study , we used event-related functional magnetic resonance imaging to characterize neuronal responses mediating aversive trace conditioning . During conditioning , neutral auditory tones were paired with an aversive sound [ unconditioned stimulus ( US ) ] . We compared neuronal responses evoked by conditioned ( CS+ ) and nonconditioned ( CS− ) stimuli in which a 50 % pairing of CS+ and the US enabled us to limit our analysis to responses evoked by the CS+ alone . Differential responses  ( CS+ vs CS− ) , related to conditioning , were observed in anterior cingulate and anterior insula , regions previously implicated in delay fear conditioning . Differential responses were also observed in the amygdala and hippocampus that were best characterized with a time × stimulus interaction , indicating rapid adaptation of CS+-specific responses in medial temporal lobe . These results are strikingly similar to those obtained with a previous delay conditioning experiment and are in accord with a preferential role for medial temporal lobe structures during the early phase of conditioning . However , an additional activation of anterior hippocampus in the present experiment supports a view that its role in trace conditioning is to maintain a memory trace between the offset of the CS+ and the delayed onset of the US to enable associative learning in trace conditioning Functional neuroimaging studies in humans have shown that nociceptive stimuli elicit activity in a wide network of cortical areas commonly labeled as the " pain matrix " and thought to be preferentially involved in the perception of pain . Despite the fact that this " pain matrix " has been used extensively to build models of where and how nociception is processed in the human brain , convincing experimental evidence demonstrating that this network is specifically related to nociception is lacking . The aim of the present study was to determine whether there is at least a subset of the " pain matrix " that responds uniquely to nociceptive somatosensory stimulation . In a first experiment , we compared the fMRI brain responses elicited by a  r and om sequence of brief nociceptive somatosensory , non-nociceptive somatosensory , auditory and visual stimuli  , all presented within a similar attentional context . We found that the fMRI responses triggered by nociceptive stimuli can be largely explained by a combination of ( 1 ) multimodal neural activities ( i.e. , activities elicited by all stimuli regardless of sensory modality ) and ( 2 ) somatosensory-specific but not nociceptive-specific neural activities ( i.e. , activities elicited by both nociceptive and non-nociceptive somatosensory stimuli ) . The magnitude of multimodal activities correlated significantly with the perceived saliency of the stimulus . In a second experiment , we compared these multimodal activities to the fMRI responses elicited by auditory stimuli presented using an oddball paradigm . We found that the spatial distribution of the responses elicited by novel non-target and novel target auditory stimuli resembled closely that of the multimodal responses identified in the first experiment . Taken together , these findings suggest that the largest part of the fMRI responses elicited by phasic nociceptive stimuli reflects non nociceptive-specific cognitive processes The amygdala has been implicated in fundamental functions for the survival of the organism , such as fear and pain . In accord with this , several studies have shown increased amygdala activity during fear conditioning and the processing of fear-relevant material in human subjects . In contrast , functional neuroimaging studies of pain have shown a decreased amygdala activity . It has previously been proposed that the observed deactivations of the amygdala in these studies indicate a cognitive strategy to adapt to a distressful but in the experimental setting unavoidable painful event . In this positron emission tomography study , we show that a simple context ual manipulation , immediately preceding a painful stimulation , that increases the anticipated duration of the painful event leads to a decrease in amygdala activity and modulates the autonomic response during the noxious stimulation . On a behavioral level , 7 of the 10 subjects reported that they used coping strategies more intensely in this context . We suggest that the altered activity in the amygdala may be part of a mechanism to attenuate pain-related stress responses in a context that is perceived as being more aversive . The study also showed an increased activity in the rostral part of anterior cingulate cortex in the same context in which the amygdala activity decreased , further supporting the idea that this part of the cingulate cortex is involved in the modulation of emotional and pain networks The allocation of attention modulates negative emotional processing in the amygdala . However , the role of passive exposure time to emotional signals in the modulation of amygdala activity during active task performance has not been examined . In two functional Magnetic Resonance Imaging ( fMRI ) experiments conducted in two different groups of healthy human subjects , we examined activation in the amygdala due to cued anticipation of painful stimuli while subjects performed a simple continuous performance task ( CPT ) with either a fixed or a parametrically varied trial duration . In the first experiment ( N = 16 ) , engagement in the CPT during a task with fixed trial duration produced the expected attenuation of amygdala activation , but close analysis suggested that the attenuation occurred during the period of active engagement in CPT , and that amygdala activity increased proportionately during the remainder of each trial , when subjects were passively exposed to the pain cue . In the second experiment ( N = 12 ) , the duration of each trial was parametrically varied , and we found that amygdala activation was linearly related to the time of passive exposure to the anticipatory cue . We suggest that amygdala activation during negative anticipatory processing depends directly on the passive exposure time to the negative cue Although pathological muscle pain involves a significantly larger population than any other pain condition , the central mechanisms are less explored than those of cutaneous pain . The aims of the study were to establish the pain matrix for muscle pain in the full head volume and , further , to explore the possibility of a functional segregation to nonpainful and painful stimuli within the area of the parasylvian cortex corresponding to the secondary somatosensory area . Additionally , we speculate that a r and omization of nonpainful and painful stimuli may target specific structures related to stimulus salience . We used event-related functional magnetic resonance imaging ( MRI ) and the high sensitivity of the 3-T MRI scanner to study the central processing of acute muscle pain induced by intramuscular electrostimulation . Brief nonpainful and painful stimuli ( 1-ms duration , interst 
    Output:
    
Results Animal and human data combined to show a core aversion-related network , consisting of similar cortical ( i.e. MCC , PCC , AI , DMPFC , RTG , SMA , VLOFC ; see results section or abbreviation section for full names ) and subcortical ( i.e. Amyg , BNST , DS , Hab , Hipp/Parahipp , Hyp , NAc , NTS , PAG , PBN , raphe , septal nuclei , Thal , LC , midbrain ) regions .
In addition , a number of regions appeared to be more involved in pain-related ( e.g. sensory cortex ) or non-pain-related ( e.g. amygdala ) aversive processing .
Conclusions This investigation suggests that aversive processing , at the most basic level , relies on similar neural substrates , and that differential responses may be due , in part , to the recruitment of additional structures as well as the spatio-temporal dynamic activity of the network .
This network perspective may provide a clearer underst and ing of why components of this circuit appear dysfunctional in some psychiatric and pain-related disorders