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Noninvasive brain imaging
Abstracts (663) Neck muscle length does not modulate glutamateevoked reflexes in rat neck and jaw muscles P. Shin, H. Vernon, B. Sessle, J. Hu; Faculty of Dentistry, University of Toronto, Toronto We have documented that the application of the inflammatory irritant mustard oil (MO) to the rat neck paraspinal muscles produces sustained but reversible increases in electromyographic (EMG) activity in neck and jaw muscles that is larger in stretched neck muscles than in nonstretched neck muscles. In this study we explored whether neck muscle length influences the effects of activating peripheral glutamate receptors, which have been previously shown to play a role in MO-evoked reflex activity. EMG activity from the deep neck, trapezius, and digastric muscles was recorded, rectified, and integrated (area under the curve, AUC) in male Sprague-Dawley rats under halothane anaesthesia. Three injections of 20L 0.5M glutamate (a non-inflammatory excitatory amino acid) or vehicle (isotonic saline) were administered in each of three different sequences of neck position: (1) non-stretched, nonstretched, non-stretched, (2) non-stretched, stretched, non-stretched and (3) stretched, non-stretched, stretched. In the non-stretched neck position, the rat was placed in a straight body position and glutamate injected into the left deep neck muscles. In the stretched neck position the rat was rotated 45° to the right at the neck and glutamate injected into the lengthened left deep neck muscles. Glutamate evoked repeatable and significant increases in neck and jaw EMG activity but there was no significant difference in activity (mean AUC) in the different muscle length conditions (One Way Repeated Measures ANOVA p⬎0.05). Vehicle did not produce significant neck or jaw EMG activity. Application of glutamate into deep neck muscles evokes EMG activity in neck and jaw muscles that are not modulated by muscle length. This suggests that the modulatory effect of muscle length on neck muscle nociceptive reflexes may depend on the presence of an inflammatory muscle condition and not on the activation of peripheral glutamate receptors. Supported by CIHR MOP-43905 and the CMCC.
B11 - Noninvasive Brain Imaging (664) Brain correlates of the voluntary mental evocation of pain P. Rainville, J. Chen, T. Grabowski, L. Bolinger, C. Smyser, A. Bechara, A. Damasio; Universite´ de Montre´ al, Montre´ al, QC Pain is consistently associated with the activation of a network of cerebral structures including S1, S2, insula (INS), and anterior cingulate cortex (ACC). This study examines the role of these structures in the mental representation of pain during voluntary mental imagery. BOLD signal acquired in 7 healthy volunteers was contrasted in four conditions: pain stimulation (contact heat at 46.5-49.0°C); warm stimulation (38.0°C); mental imagery of pain; and mental imagery of warmth. The contact probe was applied on the left leg for 9s, every 18s, in all conditions. In the imagery conditions, the temperature remained neutral (32.0°C) and subjects were instructed to imagine a WARM sensation or a highly unpleasant heat PAIN experience when the thermode touched the skin. Directed searches were conducted specifically on the four contralateral target areas using group analyses (t⬎2.55, p-corrected⬍.05). Contrasts between pain and warm stimulation conditions confirmed pain-related activation (t-value) in the posterior ACC (4.41), the anterior (3.93) and posterior (6.71) INS, the parietal operculum (2.64), and the leg area of S1 (2.59). Imagery of pain compared to warm significantly activated the ACC (3.28) and the parietal operculum (3.93) while INS activation was only marginally significant (peak-t⫽2.47) and no peak was found in S1 (t⬍2.00). A conjunction analysis of the pain vs. warm contrast in the stimulation and imagery conditions further confirmed the common activation of the posterior ACC (3.04), the parietal operculum (3.04), and a marginally significant effect in the posterior INS (2.54). Separate conjunction analyses revealed additional activations common to the stimulation and imagery conditions in the anterior INS in both the pain (3.20) and warm (2.65) conditions and in the anterior ACC in the warm condition (3.61). These results are consistent with the involvement of painrelated cortical areas in the mental evocation and imagery of pain experiences.
25 (665) Quantifying the time dependence of Remifentanil analgesia in the human brain using functional magnetic resonance imaging R. Wise, P. Williams, I. Tracey; Oxford University, Oxford, UK To understand and exploit centrally acting analgesic drugs requires reliable measures of their time-course of action in the human brain. Functional magnetic resonance imaging (FMRI) can measure non-invasively, drug-induced changes in pain-related human brain activity. Here, we have characterized the time of onset of action and the effective half-life of action of a clinically relevant dose of the opioid analgesic agent, remifentanil. Nine male volunteers underwent FMRI (BOLD contrast EPI) at 3T for 30mins (TR⫽3s, TE⫽30ms, resolution 4mm, 21x6mm slices). Consistent painful hot stimuli (duration 3s) were applied to the dorsum of the left hand (mean interval⫽65s). Subjects rated stimuli for pain intensity (5-point scale). Remifentanil was intravenously infused to an estimated plasma concentration of 1.0ng/ml and then cleared as imaging continued. The temporal variation of the amplitude of the BOLD FMRI response to pain, in the insular region contralateral to the stimulus (known to respond to painful stimuli), and the perceived pain intensity were modelled using simple exponential functions. From these we estimated the half-lives of drug onset (equilibration time t ⁄ ke0) and offset (context sensitive half-life t ⁄ ) of action. Onset time (t ⁄ ke0) measured from FMRI was 1.83 (-2.17,5.83) min and offset half-life (t ⁄ ) was 3.07 (1.09,5.05) min. Onset time measured from pain intensity scores was 2.80 (-0.12,5.73) min and offset half-life was 2.80 (1.12,4.48) min. 95% confidence intervals are given in parentheses. Onset and offset times of drug action from the insular cortical FMRI signal agreed with the reported analgesia and with previously reported EEG measurements (Minto,C.F. et al. 1997). We demonstrate for the first time, the use of FMRI to measure pharmacokinetic parameters for an analgesic drug from its effect on pain-related activity in a specific brain region, the insular cortex. Acknowledgements: RGW: The Dr Hadwen Trust and The Wellcome Trust. PW: GlaxoSmithKline. 12
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(666) Common patterns of cerebral activation exist during matched unpleasant visceral and somatic stimulation in humans P. Dunckley, R. Wise, D. Painter, J. Brooks, I. Tracey, Q. Aziz, L. Chang Department of Clinical Neurology and Human Anatomy and Genetics, University of Oxford, Oxford, UK The pathways for processing visceral and somatic noxious events differ in several well-known aspects: poor localisation of visceral pain and its ability to be referred to somatic structures. The perception, however, of pain intensity and affect in visceral and somatic pain syndromes are often different, with visceral noxious events reported as more unpleasant. To determine whether the underlying anatomical differences in the visceral and somatic pain processing pathways account for these observed behavioural differences we need non-invasive imaging tools to examine the neural correlates of visceral and somatic events when the behaviour has been isolated and matched for either unpleasantness or pain intensity. In this study we matched the unpleasantness of both somatic and visceral sensations and imaged the neural representation of this perception using FMRI in 8 healthy right-handed subjects (4 female). Each subject received noxious thermal stimuli to the left foot and midline lower back and balloon distension of the rectum whilst being scanned at 3 Tesla. Stimuli were matched to the same unpleasantness rating, producing a mild-moderate pain intensity for somatic stimuli but an intensity below the pain threshold for the visceral stimuli. We found a similar bilateral network of cortical activation during somatic and visceral stimulation, with no significant differences in mean parameter estimate for brain regions known to be involved in processing noxious events: thalamus, mid-cingulate, insular, and secondary somatosensory cortices. These findings confirm that despite significant differences in the reported pain intensity of visceral and somatic stimulation, brain regions encompassing affective and sensory/discriminatory areas are found similarly active, when the unpleasantness is matched. This suggests that processing of visceral and somatic events within the brain is similar but the ratio of magnitude of activation to the reported pain intensity diverges between visceral and somatic stimuli.
B11 - Noninvasive Brain Imaging (664) Brain correlates of the voluntary mental evocation of pain P. Rainville, J. Chen, T. Grabowski, L. Bolinger, C. Smyser, A. Bechara, A. Damasio; Universite´ de Montre´ al, Montre´ al, QC Pain is consistently associated with the activation of a network of cerebral structures including S1, S2, insula (INS), and anterior cingulate cortex (ACC). This study examines the role of these structures in the mental representation of pain during voluntary mental imagery. BOLD signal acquired in 7 healthy volunteers was contrasted in four conditions: pain stimulation (contact heat at 46.5-49.0°C); warm stimulation (38.0°C); mental imagery of pain; and mental imagery of warmth. The contact probe was applied on the left leg for 9s, every 18s, in all conditions. In the imagery conditions, the temperature remained neutral (32.0°C) and subjects were instructed to imagine a WARM sensation or a highly unpleasant heat PAIN experience when the thermode touched the skin. Directed searches were conducted specifically on the four contralateral target areas using group analyses (t⬎2.55, p-corrected⬍.05). Contrasts between pain and warm stimulation conditions confirmed pain-related activation (t-value) in the posterior ACC (4.41), the anterior (3.93) and posterior (6.71) INS, the parietal operculum (2.64), and the leg area of S1 (2.59). Imagery of pain compared to warm significantly activated the ACC (3.28) and the parietal operculum (3.93) while INS activation was only marginally significant (peak-t⫽2.47) and no peak was found in S1 (t⬍2.00). A conjunction analysis of the pain vs. warm contrast in the stimulation and imagery conditions further confirmed the common activation of the posterior ACC (3.04), the parietal operculum (3.04), and a marginally significant effect in the posterior INS (2.54). Separate conjunction analyses revealed additional activations common to the stimulation and imagery conditions in the anterior INS in both the pain (3.20) and warm (2.65) conditions and in the anterior ACC in the warm condition (3.61). These results are consistent with the involvement of painrelated cortical areas in the mental evocation and imagery of pain experiences.
25 (665) Quantifying the time dependence of Remifentanil analgesia in the human brain using functional magnetic resonance imaging R. Wise, P. Williams, I. Tracey; Oxford University, Oxford, UK To understand and exploit centrally acting analgesic drugs requires reliable measures of their time-course of action in the human brain. Functional magnetic resonance imaging (FMRI) can measure non-invasively, drug-induced changes in pain-related human brain activity. Here, we have characterized the time of onset of action and the effective half-life of action of a clinically relevant dose of the opioid analgesic agent, remifentanil. Nine male volunteers underwent FMRI (BOLD contrast EPI) at 3T for 30mins (TR⫽3s, TE⫽30ms, resolution 4mm, 21x6mm slices). Consistent painful hot stimuli (duration 3s) were applied to the dorsum of the left hand (mean interval⫽65s). Subjects rated stimuli for pain intensity (5-point scale). Remifentanil was intravenously infused to an estimated plasma concentration of 1.0ng/ml and then cleared as imaging continued. The temporal variation of the amplitude of the BOLD FMRI response to pain, in the insular region contralateral to the stimulus (known to respond to painful stimuli), and the perceived pain intensity were modelled using simple exponential functions. From these we estimated the half-lives of drug onset (equilibration time t ⁄ ke0) and offset (context sensitive half-life t ⁄ ) of action. Onset time (t ⁄ ke0) measured from FMRI was 1.83 (-2.17,5.83) min and offset half-life (t ⁄ ) was 3.07 (1.09,5.05) min. Onset time measured from pain intensity scores was 2.80 (-0.12,5.73) min and offset half-life was 2.80 (1.12,4.48) min. 95% confidence intervals are given in parentheses. Onset and offset times of drug action from the insular cortical FMRI signal agreed with the reported analgesia and with previously reported EEG measurements (Minto,C.F. et al. 1997). We demonstrate for the first time, the use of FMRI to measure pharmacokinetic parameters for an analgesic drug from its effect on pain-related activity in a specific brain region, the insular cortex. Acknowledgements: RGW: The Dr Hadwen Trust and The Wellcome Trust. PW: GlaxoSmithKline. 12
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(666) Common patterns of cerebral activation exist during matched unpleasant visceral and somatic stimulation in humans P. Dunckley, R. Wise, D. Painter, J. Brooks, I. Tracey, Q. Aziz, L. Chang Department of Clinical Neurology and Human Anatomy and Genetics, University of Oxford, Oxford, UK The pathways for processing visceral and somatic noxious events differ in several well-known aspects: poor localisation of visceral pain and its ability to be referred to somatic structures. The perception, however, of pain intensity and affect in visceral and somatic pain syndromes are often different, with visceral noxious events reported as more unpleasant. To determine whether the underlying anatomical differences in the visceral and somatic pain processing pathways account for these observed behavioural differences we need non-invasive imaging tools to examine the neural correlates of visceral and somatic events when the behaviour has been isolated and matched for either unpleasantness or pain intensity. In this study we matched the unpleasantness of both somatic and visceral sensations and imaged the neural representation of this perception using FMRI in 8 healthy right-handed subjects (4 female). Each subject received noxious thermal stimuli to the left foot and midline lower back and balloon distension of the rectum whilst being scanned at 3 Tesla. Stimuli were matched to the same unpleasantness rating, producing a mild-moderate pain intensity for somatic stimuli but an intensity below the pain threshold for the visceral stimuli. We found a similar bilateral network of cortical activation during somatic and visceral stimulation, with no significant differences in mean parameter estimate for brain regions known to be involved in processing noxious events: thalamus, mid-cingulate, insular, and secondary somatosensory cortices. These findings confirm that despite significant differences in the reported pain intensity of visceral and somatic stimulation, brain regions encompassing affective and sensory/discriminatory areas are found similarly active, when the unpleasantness is matched. This suggests that processing of visceral and somatic events within the brain is similar but the ratio of magnitude of activation to the reported pain intensity diverges between visceral and somatic stimuli.