***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: Functional magnetic resonance imaging was used to image pain-associated activity in three levels of the neuraxis : the medullary dorsal horn , thalamus , and primary somatosensory cortex . In nine subjects , noxious thermal stimuli ( 46 ° C ) were applied to the facial skin at sites within the three divisions of the trigeminal nerve ( V1 , V2 , and V3 ) and also to the ipsilateral thumb . Anatomical and functional data were acquired to capture activation across the spinothalamocortical pathway in each individual . Significant activation was observed in the ipsilateral spinal trigeminal nucleus within the medulla and lower pons in response to at least one of the three facial stimuli in all applicable data sets . Activation from the three facial stimulation sites exhibited a somatotopic organization along the longitudinal ( rostrocaudal ) axis of the brain stem that was consistent with the classically described “ onion skin ” pattern of sensory deficits observed in patients after trigeminal tractotomy . In the thalamus , activation was observed in the contralateral side involving the ventroposteromedial and dorsomedial nuclei after stimulation of the face and in the ventroposterolateral and dorsomedial nuclei after stimulation of the thumb . Activation in the primary somatosensory cortex displayed a laminar sequence that resembled the trigeminal nucleus , with V2 more rostral , V1 caudal , and V3 medial , abutting the region of cortical activation observed for the thumb . These results represent the first simultaneous imaging of pain-associated activation at three levels of the neuraxis in individual subjects . This approach will be useful for exploring central correlates of plasticity in models of experimental and clinical pain Pain perception is a multidimensional phenomenon , derived from sensory , affective , cognitive-evaluative and homeostatic information . Neuroimaging studies of pain perception have investigated the role of primary somatosensory cortex ( SI ) ; however , they have typically failed to demonstrate the expected somatotopy . An alternative network for the sensory component of pain has been proposed , involving a temperature and pain-specific nucleus of the thalamus ( VMpo ) and its projections to dorsal posterior insula ( dpIns ) . According to this hypothesis , projections to the insula should be arranged somatotopically . In order to test for the presence of somatotopy in the operculo-insular brain region , we delivered moderately painful thermal stimuli to the right face , h and and foot in 14 healthy subjects and recorded brain responses using high resolution functional magnetic resonance imaging at 3 T. For each subject , the thermode temperature was adjusted to produce pain ratings of 5 to 6 out of 10 , which corresponded to average temperatures for the face , h and and foot of 49.6 , 48.5 and 48.5 degrees C , respectively . Examination of mixed effects group activation maps suggested a pain-related somatotopy in the contralateral posterior insula and putamen . Construction of frequency maps revealed that face activation within the posterior insula was anterior to both h and and foot , whilst foot activation was located medially in the circular sulcus . Single subject analysis demonstrated that only coordinates for dpIns activation were significantly dependent on stimulus location ( Hotelling 's Trace , P = 0.012 ) . Coordinates for face ( paired t test , P = 0.004 ) and h and ( P < 0.001 ) activity were more lateral than those for foot , whilst face activation was anterior to the foot ( P = 0.037 ) . Based on single subject analyses , the average st and ard space ( MNI ) coordinates for face , h and and foot activity were ( -40,-16,11 ) , ( -40,-19,14 ) and ( -35,-21,11 ) respectively OBJECTIVE Current models propose that the experience of pain includes both sensory and affective components . Our purpose was to use functional MR imaging to determine areas of the brain engaged by the affective dimension of pain . SUBJECTS AND METHODS Twelve healthy adults underwent functional MR imaging  using a  gradient-echo echoplanar technique while a cold pressor test , consisting of cold and pain tasks , was applied first to one foot and then to the other . The cold task involved the application of cold water ( 14 - 20 degrees C ) that was not at a painful level . For the pain task , the water temperature was then lowered to a painful temperature ( 8 - 14 degrees C ) and subsequently to the pain threshold ( 3 - 8 degrees C ) . Images acquired at room temperature before the cold and pain tasks served as a baseline task . Composite maps of brain activation were generated by comparing the baseline task with the cold task and the cold task with the pain task . The significance of signal changes was estimated by r and omization of individual activation maps . RESULTS Cold-related activation ( p < 0.01 ) was found in the post central gyrus bilaterally , laterally , and inferiorly to the primary motor-sensory area of the foot and at a site near the second somatosensory site . Activation also occurred in the frontal lobe ( the bilateral middle frontal gyri and the right inferior frontal gyrus ) , the left anterior insula , the left thalamus , and the superior aspect of the anterior cingulate gyrus ( seen at one slice location ) . Pain-related activation ( p < 0.01 ) included the anterior cingulate gyrus ( seen at four slice locations ) ; the superior frontal gyrus , especially on the right ; and the right cuneus . CONCLUSION Compared with the basic sensory processing of pain , the affective dimension of pain activates a cortical network that includes the right superior frontal gyrus , the right cuneus , and a large area of the anterior cingulate gyrus The experience of pain is subjectively different from the fear and anxiety caused by threats of pain . Functional magnetic resonance imaging in healthy humans was applied to dissociate neural activation patterns associated with acute pain and its anticipation . Expectation of pain activated sites within the medial frontal lobe , insular cortex , and cerebellum distinct from , but close to , locations mediating pain experience itself . Anticipation of pain can in its own right cause mood changes and behavioral adaptations that exacerbate the suffering experienced by chronic pain patients . Selective manipulations of activity at these sites may offer therapeutic possibilities for treating chronic pain Objective : To investigate pain perception and the potential analgesic effects of mindful states in experienced Zen meditators . Methods : Highly trained Zen meditators ( n = 13 ; > 1000 hours of practice ) and age/gender-matched control volunteers ( n = 13 ) received individually adjusted thermal stimuli to elicit moderate pain on the calf . Conditions included : a ) baseline-1 : no task ; b ) concentration : attend exclusively to the calf ; c ) mindfulness : attend to the calf and observe , moment to moment , in a nonjudgmental manner ; and d ) baseline-2 : no task . Results : Meditators required significantly higher temperatures to elicit moderate pain ( meditators : 49.9 ° C ; controls : 48.2 ° C ; p = .01 ) . While attending “ mindfully , ” meditators reported decreases in pain intensity whereas control subjects showed no change from baseline . The concentration condition result ed in increased pain intensity for controls but not for meditators . Changes in pain unpleasantness generally paralleled those found in pain intensity . In meditators , pain modulation correlated with slowing of the respiratory rate and with greater meditation experience . Covariance analyses indicated that mindfulness-related changes could be partially explained by changes in respiratory rates . Finally , the meditators reported higher tendencies to observe and be nonreactive of their own experience as measured on the Five Factor Mindfulness Question naire ; these factors correlated with individual differences in respiration . Conclusions : These results indicated that Zen meditators have lower pain sensitivity and experience analgesic effects during mindful states . Results may reflect cognitive/self-regulatory skills related to the concept of mindfulness and /or altered respiratory patterns . Prospect i ve studies investigating the effects of meditative training and respiration on pain regulation are warranted . ECG = electrocardiogram ; HF = high frequency ; HRV = heart rate variability ; LF = low frequency ; LF/HF = low/high frequency ratio ; FFMQ = Five Factor Mindfulness Question naire ; MBSR = Mindfulness Based Stress Reduction ; VAS = Visual Analogue Scale The ability to locate pain plays a pivotal role in immediate defence and withdrawal behaviour . However , it is unclear to what extent nociceptive information is relayed to and processed in subcortical structures relevant for motor preparation and possibly the generation of withdrawal behaviour . We used single-trial functional magnetic resonance imaging ( fMRI ) to assess whether nociceptive information is represented in the putamen in a somatotopic manner . We therefore applied thulium-YAG laser-evoked pain stimuli , which had no concomitant tactile component , to the dorsum of the left h and and foot to 15 healthy subjects in a r and omized order . In addition , 11 subjects were stimulated on the right body side . Differential representations of h and - and foot-related blood oxygen level dependent ( BOLD ) responses within the putamen were assessed using a single subject approach . Nociceptive stimuli significantly activated the putamen bilaterally . However , a somatotopic organization for h and - and foot-related responses was only present in the contralateral putamen . Here the foot was located anteriorly and medially to the h and , which parallels results from anatomical and microstimulation studies in monkeys and also human imaging data on the arrangement of movement related activity in the putamen . This result provides evidence for the hypothesis that behaviourally relevant nociceptive information without additional information from the tactile system is represented in the putamen and made available for pain related motor responses Glutamate , a major excitatory neurotransmitter , has been implicated as an important mediator in the neurotransmission , potentiation , and negative affect associated with pain . We present results showing that a painful stimulus elicits a dynamic increase in glutamate ( 9.3 % from baseline ) concentrations in the anterior cingulate cortex , detectable using proton Magnetic Resonance Spectroscopy ( (1)H-MRS ) . Increases in glutamine levels were also seen , which correlate strongly with the subjective level of pain experienced by participants ( r(2 ) = 0.58 , P < 0.01 ) . These novel findings are the first time a dynamic change in glutamate and glutamine levels from baseline in response to an external stimuli has been measured in a single proton MRS scanning session . As such , this report demonstrates the efficacy of (1)H-MRS as a non-invasive tool for the study of neural responses to pain in vivo . The paradigm used in this study demonstrates that dynamic glutamate/glutamine changes due to stimulation are measurable by proton MRS , and could provide a means of testing novel pharmaceutical agents and other treatments for chronic pain Regulation of stress response involves top-down mechanisms of the frontal-limbic glutamatergic system . As schizophrenia is associated with glutamatergic abnormalities , we hypothesized that schizophrenia patients may have abnormal glutamatergic reactivity within the dorsal anterior cingulate cortex ( dACC ) , a key region involved in perception of and reaction to stress . To test this , we developed a somatic stress paradigm involving pseudor and om application of safe but painfully hot stimuli to the forearm of participants while they were undergoing serial proton magnetic resonance spectroscopy to measure changes in glutamate and glutamine levels in the dACC . This paradigm was tested in a sample of 21 healthy controls and 23 patients with schizophrenia . Across groups , glutamate levels significantly decreased following exposure to thermal pain , while ratio of glutamine to glutamate significantly increased . However , schizophrenia patients exhibited an initial increase in glutamate levels during challenge that was significantly different from controls , after controlling for heat pain tolerance . Furthermore , in patients , the acute glutamate response was positively correlated with childhood trauma ( r = .41 , P = .050 ) and inversely correlated with working memory ( r = -.49 , P = .023 ) . These results provide preliminary evidence for abnormal glutamatergic response to stress in schizophrenia patients , which may point toward novel approaches to underst and ing how stress contributes to the illness Background Anatomic sites within the brain , which activate in response to noxious stimuli , can be identified with the use of functional magnetic resonance imaging . The aim of this study was to determine whether the analgesic effects of ketamine could be imaged . Methods Ketamine was administered to eight healthy volunteers with use of a target-controlled infusion to three predicted plasma concentrations : 0 ( saline ) , 50 ( subanalgesic ) , and 200 ng/ml ( analgesic , subanesthetic ) . Volunteers received noxious thermal stimuli and auditory stimuli and performed a motor task within a 3-T human brain imaging magnet . Activation of brain regions in response to noxious and auditory stimuli and during the motor task was compared with behavioral measures . Results The analgesic subanesthetic dose of ketamine significantly reduced the pain scores , and this matched a decrease in activity within brain regions that activate in response to noxious stimuli , in particular , the insular cortex and thalamus . A different pattern of activation was observed in response to an auditory task . In comparison , smaller behavioral and imaging changes were found for the motor paradigm . The lower dose of ketamine gave similar but smaller nonsignificant effects . Conclusion The analgesic effect can be measured within a more global effect of ketamine as shown by auditory and motor tasks , and the analgesia produced by ketamine occurs with a smaller degree of cortical processing in pain-related regions 
    Output:
    
To date , there is no evidence to suggest Glx , glutamate or glutamine levels decrease , suggesting an overall effect in favour of increased excitation to pain .
As for the studies we review ed , there was a limited number of brain areas were examined by studies included in our review .
MRS represents a promising tool to examine the brain in pain , functionally , and at rest with support for increased glutamate , glutamine and Glx levels in relation to pain .