The orbitofrontal cortex and reward

The primate orbitofrontal cortex contains the secondary taste cortex, in which the reward value of taste is represented. It also contains the secondary and tertiary olfactory cortical areas, in which information about the identity and also about the reward value of odors is represented. The orbitofrontal cortex also receives information about the sight of objects and faces from the temporal lobe cortical visual areas, and neurons in it learn and reverse the visual stimulus to which they respond when the association of the visual stimulus with a primary reinforcing stimulus (such as a taste reward) is reversed. However, the orbitofrontal cortex is involved in representing negative reinforcers (punishers) too, such as aversive taste, and in rapid stimulus-reinforcement association learning for both positive and negative primary reinforcers. In complementary neuroimaging studies in humans it is being found that areas of the orbitofrontal cortex (and connected subgenual cingulate cortex) are activated by pleasant touch, by painful touch, by rewarding and aversive taste, and by odor. Damage to the orbitofrontal cortex in humans can impair the learning and reversal of stimulus- reinforcement associations, and thus the correction of behavioral responses when these are no longer appropriate because previous reinforcement contingencies change. This evidence thus shows that the orbitofrontal cortex is involved in decoding and representing some primary reinforcers such as taste and touch; in learning and reversing associations of visual and other stimuli to these primary reinforcers; and in controlling and correcting reward-related and punishment-related behavior, and thus in emotion.     

Mechanical noxious stimuli cause bilateral activation of parietal operculum in callosotomized subjects

The patterns of cortical activation evoked by tactile and mechanical painful stimulation in six normal subjects and three patients with complete resection of the corpus callosum are described and compared, with emphasis on the parietal operculum. Stimulus-related cortical activation was investigated by functional magnetic resonance imaging. In both groups, painful stimulation activated the first somatosensory, insular and cingulate cortices in the contralateral hemisphere, and the parietal opercular cortex in both hemispheres. Comparison between the two patterns of cortical activation demonstrated that ipsilateral activation by unilateral painful stimulation is at least partially independent of the corpus callosum and suggests a different organization of the pain and touch systems.     

Somatosensory and pain responses to stimulation of the second somatosensory area (SII) in humans. A comparison with SI and insular responses

Somatosensory and pain responses to direct intracerebral stimulations of the SII area were obtained in 14 patients referred for epilepsy surgery. Stimulations were delivered using transopercular electrodes exploring the parietal opercular cortex (SII area), the suprasylvian parietal cortex (SI area) and the insular cortex. SII responses were compared to those from adjacent SI and insular cortex. In the three areas we elicited mostly somatosensory responses, including paresthesiae, temperature and pain sensations. The rate of painful sensations (10%) was similar in SII and in the insula, while no painful sensation was evoked in SI. A few non-somatosensory responses were evoked by SII stimulation. Conversely various types of non-somatosensory responses (auditory, vegetative, vestibular, olfacto-gustatory, etc.) were evoked only by insular stimulation, confirming that SII, like SI, are mostly devoted to the processing of somatosensory inputs whereas the insular cortex is a polymodal area. We also found differences in size and lateralization of skin projection fields of evoked sensations between the three studied areas, showing a spatial resolution of the somatotopic map in SII intermediate between those found in SI and insula. This study shows the existence of three distinct somatosensory maps in the suprasylvian, opercular and insular regions, and separate pain representations in SII and insular cortex.     

Somatotopy in Human Primary Somatosensory Cortex in Pain System

Background: Compared with somatotopical organization (somatotopy) in the postcentral gyrus in the tactile system, somatotopy in the pain system is not well understood. The aim of this study is to elucidate whether there is somatotopy in the human pain system.

Methods: To elucidate the somatotopy of nociceptive neurons in the postcentral gyrus, the authors recorded pain-evoked cortical responses to noxious intraepidermal electrical stimulation applied to the left hand and left foot in 11 male subjects, using magnetoencephalography.

Results: Brief painful stimuli evoked sustained cortical activity in the primary somatosensory cortex (SI) in the hemisphere contralateral to the stimulated side and in the secondary somatosensory cortex in both hemispheres. In SI, representations of the hand and foot were distinctly separated, with a more medial and posterior location for the foot, whereas no significant difference was found in the locations for the secondary somatosensory cortex dipole. The SI arrangement along the central sulcus was compatible with the homunculus revealed by Penfield using direct cortical stimulation during surgery.     

Dissociable brain activation responses to 5-Hz electrical pain stimulation: a high-field functional magnetic resonance imaging study

BACKGROUND: To elucidate neural correlates associated with processing of tonic aching pain, the authors used high-field (3-T) functional magnetic resonance imaging with a blocked parametric study design and characterized regional brain responses to electrical stimulation according to stimulus intensity-response functions. METHODS: Pain was induced in six male volunteers using a 5-Hz electrical stimulus applied to the right index finger. Scanning sequences involved different levels of stimulation corresponding to tingling sensation (P1), mild pain (P2), or high pain (P3). Common effects across subjects were sought using a conjunction analyses approach, as implemented in statistical parametric mapping (SPM-99). RESULTS: The contralateral posterior/mid insula and contralateral primary somatosensory cortex were most associated with encoding stimulus intensity because they showed a positive linear relation between blood oxygenation level-dependent signal responses and increasing stimulation intensity (P1 < P2 < P3). The contralateral secondary somatosensory cortex demonstrated a response function most consistent with a role in pain intensity encoding because it had no significant response during the innocuous condition (P1) but proportionally increased activity with increasingly painful stimulus intensities (0 < P2 < P3). Finally, a portion of the anterior cingulate cortex (area 24) and supplementary motor area 6 demonstrated a high pain-specific response (P3). CONCLUSIONS: The use of response function modeling, conjunction analysis, and high-field imaging reveals dissociable regional responses to a tonic aching electrical pain. Most specifically, the primary somatosensory cortex and insula seem to encode stimulus intensity information, whereas the secondary somatosensory cortex encodes pain intensity information. The cingulate findings are consistent with its proposed role in processing affective-motivational aspects of pain.     

Functional magnetic resonance imaging studies of pain: an investigation of signal decay during and across sessions

BACKGROUND: Several investigations into brain activation caused by pain have suggested that the multiple painful stimulations used in typical block designs may cause attenuation over time of the signal within activated areas. The effect this may have on pain investigations using multiple tasks has not been investigated. The signal decay across a task of four repeating pain stimulations and between two serial pain tasks separated by a 4-min interval was examined to determine whether signal attenuation may significantly confound pain investigations. METHODS: The characteristics of the brain activation of six subjects were determined using whole brain blood oxygenation level-dependent functional magnetic resonance imaging on a 1.5-T scanner. Tasks included both tingling and pain induced by transcutaneous electrical stimulation of the median nerve. The average group maps were analyzed by general linear modeling with corrected cluster P values of less than 0.05. The time courses of individual voxels were further investigated by analysis of variance with P values of less than 0.05. RESULTS: Significant differences between pain and tingling were found in the ipsilateral cerebellum, contralateral thalamus, secondary somatosensory cortex, primary somatosensory cortex, and anterior cingulate cortex. Highly significant signal decay was found to exist across each single pain task, but the signal was found to be restored after a 4-min rest period. CONCLUSIONS: This work shows that serial pain tasks can be used for functional magnetic resonance imaging studies using electrical nerve stimulation as a stimulus, as long as sufficient time is allowed between the two tasks.     

Imaging pain modulation by subanesthetic S-(+)-ketamine

Little is known about the effects of low-dose S-(+)-ketamine on the cerebral processing of pain. We investigated the effects of subanesthetic IV S-(+)-ketamine doses on the perception of experimental painful heat stimuli. Healthy volunteers were evaluated with functional magnetic resonance imaging (fMRI) while receiving the painful stimuli in conjunction with placebo and increasing doses (0.05, 0.1, 0.15 mg x kg(-1) x h(-1)) of ketamine infusion. Vital variables were monitored and all subjects rated pain intensity and unpleasantness on a numerical rating scale. Alterations in consciousness were measured using a psycho-behavioral questionnaire. Pain unpleasantness declined as ketamine dosage was increased (55.1% decrease, placebo versus 0.15 mg x kg(-1) x h(-1) ketamine). Pain intensity ratings also decreased with increasing ketamine dosage but to a lesser extent (23.1% decrease). During placebo administration, a typical pain activation network (thalamus, insula, cingulate, and prefrontal cortex) was found, whereas decreased pain perception with ketamine was associated with a dose-dependent reduction of pain-induced cerebral activations. Analysis of the dose-dependent ketamine effects on pain processing showed a decreasing activation of the secondary somatosensory cortex (S2), insula and anterior cingulate cortex. This part of the anterior cingulate cortex (midcingulate cortex) has been linked with the affective pain component that underlines the potency of ketamine in modulating affective pain processing.     

Somatotopy in human primary somatosensory cortex in pain system

BACKGROUND: Compared with somatotopical organization (somatotopy) in the postcentral gyrus in the tactile system, somatotopy in the pain system is not well understood. The aim of this study is to elucidate whether there is somatotopy in the human pain system. METHODS: To elucidate the somatotopy of nociceptive neurons in the postcentral gyrus, the authors recorded pain-evoked cortical responses to noxious intraepidermal electrical stimulation applied to the left hand and left foot in 11 male subjects, using magnetoencephalography. RESULTS: Brief painful stimuli evoked sustained cortical activity in the primary somatosensory cortex (SI) in the hemisphere contralateral to the stimulated side and in the secondary somatosensory cortex in both hemispheres. In SI, representations of the hand and foot were distinctly separated, with a more medial and posterior location for the foot, whereas no significant difference was found in the locations for the secondary somatosensory cortex dipole. The SI arrangement along the central sulcus was compatible with the homunculus revealed by Penfield using direct cortical stimulation during surgery. CONCLUSIONS: The human pain system contains a somatotopical representation in SI but with less somatotopical organization in the secondary somatosensory cortex. The current results provide supporting evidence of SI involvement in human pain perception and suggest that human SI subserves the localization of the stimulated site in nociceptive processing.     

Empathy for pain and touch in the human somatosensory cortex

Although feeling pain and touch has long been considered inherently private, recent neuroimaging and neurophysiological studies hint at the social implications of this experience. Here we used somatosensory-evoked potentials (SEPs) to investigate whether mere observation of painful and tactile stimuli delivered to a model would modulate neural activity in the somatic system of an onlooker. Viewing video clips showing pain and tactile stimuli delivered to others, respectively, increased and decreased the amplitude of the P45 SEP component that reflects the activity of the primary somatosensory cortex (S1). These modulations correlated with the intensity but not with the unpleasantness of the pain and touch ascribed to the model or the aversion induced in the onlooker by the video clips. Thus, modulation of S1 activity contingent upon observation of others' pain and touch may reflect the mapping of sensory qualities of observed painful and tactile stimuli. Results indicate that the S1 is not only involved in the actual perception of pain and touch but also plays an important role in extracting somatic features from social interactions.     

Dissociable Brain Activation Responses to 5-Hz Electrical Pain Stimulation: A High-field Functional Magnetic Resonance Imaging Study

Background: To elucidate neural correlates associated with processing of tonic aching pain, the authors used high-field (3-T) functional magnetic resonance imaging with a blocked parametric study design and characterized regional brain responses to electrical stimulation according to stimulus intensity-response functions.

Methods: Pain was induced in six male volunteers using a 5-Hz electrical stimulus applied to the right index finger. Scanning sequences involved different levels of stimulation corresponding to tingling sensation (P1), mild pain (P2), or high pain (P3). Common effects across subjects were sought using a conjunction analyses approach, as implemented in statistical parametric mapping (SPM-99).

Results: The contralateral posterior/mid insula and contralateral primary somatosensory cortex were most associated with encoding stimulus intensity because they showed a positive linear relation between blood oxygenation level-dependent signal responses and increasing stimulation intensity (P1 < P2 < P3). The contralateral secondary somatosensory cortex demonstrated a response function most consistent with a role in pain intensity encoding because it had no significant response during the innocuous condition (P1) but proportionally increased activity with increasingly painful stimulus intensities (0 < P2 < P3). Finally, a portion of the anterior cingulate cortex (area 24) and supplementary motor area 6 demonstrated a high pain-specific response (P3).     

Functional Magnetic Resonance Imaging Studies of Pain: An Investigation of Signal Decay during and across Sessions

Background: Several investigations into brain activation caused by pain have suggested that the multiple painful stimulations used in typical block designs may cause attenuation over time of the signal within activated areas. The effect this may have on pain investigations using multiple tasks has not been investigated. The signal decay across a task of four repeating pain stimulations and between two serial pain tasks separated by a 4-min interval was examined to determine whether signal attenuation may significantly confound pain investigations.

Methods: The characteristics of the brain activation of six subjects were determined using whole brain blood oxygenation level-dependent functional magnetic resonance imaging on a 1.5-T scanner. Tasks included both tingling and pain induced by transcutaneous electrical stimulation of the median nerve. The average group maps were analyzed by general linear modeling with corrected cluster P values of less than 0.05. The time courses of individual voxels were further investigated by analysis of variance with P values of less than 0.05.

Results: Significant differences between pain and tingling were found in the ipsilateral cerebellum, contralateral thalamus, secondary somatosensory cortex, primary somatosensory cortex, and anterior cingulate cortex. Highly significant signal decay was found to exist across each single pain task, but the signal was found to be restored after a 4-min rest period.     

Neural mechanisms of antinociceptive effects of hypnosis

BACKGROUND: The neural mechanisms underlying the modulation of pain perception by hypnosis remain obscure. In this study, we used positron emission tomography in 11 healthy volunteers to identify the brain areas in which hypnosis modulates cerebral responses to a noxious stimulus. METHODS: The protocol used a factorial design with two factors: state (hypnotic state, resting state, mental imagery) and stimulation (warm non-noxious vs. hot noxious stimuli applied to right thenar eminence). Two cerebral blood flow scans were obtained with the 15O-water technique during each condition. After each scan, the subject was asked to rate pain sensation and unpleasantness. Statistical parametric mapping was used to determine the main effects of noxious stimulation and hypnotic state as well as state-by-stimulation interactions (i.e., brain areas that would be more or less activated in hypnosis than in control conditions, under noxious stimulation). RESULTS: Hypnosis decreased both pain sensation and the unpleasantness of noxious stimuli. Noxious stimulation caused an increase in regional cerebral blood flow in the thalamic nuclei and anterior cingulate and insular cortices. The hypnotic state induced a significant activation of a right-sided extrastriate area and the anterior cingulate cortex. The interaction analysis showed that the activity in the anterior (mid-)cingulate cortex was related to pain perception and unpleasantness differently in the hypnotic state than in control situations. CONCLUSIONS: Both intensity and unpleasantness of the noxious stimuli are reduced during the hypnotic state. In addition, hypnotic modulation of pain is mediated by the anterior cingulate cortex.     

Posterior cingulate cortex: sensory and oculomotor properties of single neurons in behaving cat.

The posterior cingulate cortex of the cat is strongly linked to cortical areas with sensory and oculomotor functions. We have now recorded from feline posterior cingulate neurons in order to determine whether they are active in conjunction with sensory events and eye movements. The results described here are based on monitoring the electrical activity of 195 single neurons in the posterior cingulate cortex of three cats equipped with surgically implanted scleral search coils and trained to fixate visual targets. Posterior cingulate neurons carry tonic orbital position signals and are phasically active in conjunction with saccadic eye movements. Activity related to eye movements and gaze is attenuated but not abolished by the elimination of visual feedback. Posterior cingulate neurons also are responsive to visual, auditory, and somatosensory stimulation. Systematic testing with visual stimuli revealed that responses are sharply reduced due to refractoriness at rates of stimulation greater than a few per second. These results conform to the theory that posterior cingulate cortex is involved in processes underlying visuospatial cognition.     

Human SII and posterior insula differently encode thermal laser stimuli

The SII area and the posterior insular region are both activated by thermal stimuli in functional imaging studies. However, controversy remains as to a possible differential encoding of thermal intensity by each of these 2 contiguous areas. Using CO(2) laser stimulations, we analyzed the modifications induced by increasing thermal energy on evoked potentials recorded with electrodes implanted within SII and posterior insula in patients referred for presurgical evaluation of epilepsy. Although increasing stimulus intensities enhanced both SII and insular responses, the "dynamics" of their respective amplitude changes were different. SII responses were able to encode gradually the intensity of stimuli from sensory threshold up to a level next to pain threshold but tended to show a ceiling effect for higher painful intensities. In contrast, the posterior insular cortex failed to detect nonnoxious laser pulses but reliably encoded stimulus intensity variations at painful levels, without showing saturation effects for intensities above pain threshold. According to these results, one can assume that insular cortex could be more involved in the triggering of affective recognition of, and motor reaction to, noxious stimuli, whereas SII would be more dedicated to finer-grain discrimination of stimulus intensity, from nonpainful to painful levels.     

Motor cortex stimulation in patients with deafferentation pain: activation of the posterior insula and thalamus

OBJECT: The mechanisms underlying deafferentation pain are not well understood. Motor cortex stimulation (MCS) is useful in the treatment of this kind of chronic pain, but the detailed mechanisms underlying its effects are unknown. METHODS: Six patients with intractable deafferentation pain in the left hand were included in this study. All were righthanded and had a subdural electrode placed over the right precentral gyrus. The pain was associated with brainstem injury in one patient, cervical spine injury in one patient, thalamic hemorrhage in one patient, and brachial plexus avulsion in three patients. Treatment with MCS reduced pain; visual analog scale (VAS) values for pain were 82 +/- 20 before MCS and 39 +/- 20 after MCS (mean +/- standard error). Regional cerebral blood flow (rCBF) was measured by positron emission tomography with H2(15)O before and after MCS. The obtained images were analyzed with statistical parametric mapping software (SPM99). RESULTS: Significant rCBF increases were identified after MCS in the left posterior thalamus and left insula. In the early post-MCS phase, the left posterior insula and right orbitofrontal cortex showed significant rCBF increases, and the right precentral gyrus showed an rCBF decrease. In the late post-MCS phase, a significant rCBF increase was detected in the left caudal part of the anterior cingulate cortex (ACC). CONCLUSIONS: These results suggest that MCS modulates the pathways from the posterior insula and orbitofrontal cortex to the posterior thalamus to upregulate the pain threshold and pathways from the posterior insula to the caudal ACC to control emotional perception. This modulation results in decreased VAS scores for deafferentation pain.     

Neural Mechanisms of Antinociceptive Effects of Hypnosis

Background: The neural mechanisms underlying the modulation of pain perception by hypnosis remain obscure. In this study, we used positron emission tomography in 11 healthy volunteers to identify the brain areas in which hypnosis modulates cerebral responses to a noxious stimulus.

Methods: The protocol used a factorial design with two factors: state (hypnotic state, resting state, mental imagery) and stimulation (warm non-noxious vs. hot noxious stimuli applied to right thenar eminence). Two cerebral blood flow scans were obtained with the 15O-water technique during each condition. After each scan, the subject was asked to rate pain sensation and unpleasantness. Statistical parametric mapping was used to determine the main effects of noxious stimulation and hypnotic state as well as state-by-stimulation interactions (i.e., brain areas that would be more or less activated in hypnosis than in control conditions, under noxious stimulation).

Results: Hypnosis decreased both pain sensation and the unpleasantness of noxious stimuli. Noxious stimulation caused an increase in regional cerebral blood flow in the thalamic nuclei and anterior cingulate and insular cortices. The hypnotic state induced a significant activation of a right-sided extrastriate area and the anterior cingulate cortex. The interaction analysis showed that the activity in the anterior (mid-)cingulate cortex was related to pain perception and unpleasantness differently in the hypnotic state than in control situations.     

Discrete changes in cortical activation during experimentally induced referred muscle pain: a single-trial fMRI study

Noxious stimulation of skeletal muscle evokes pain that is often referred into distal areas. Despite referred pain being of significant clinical importance, the brain regions responsible for the perception of referred pain remain unexplored. The aim of this investigation is to define these regions using functional magnetic resonance imaging. We induced muscle pain by hypertonic saline injections (0.5 ml) into the tibialis anterior (TA) or flexor carpi radialis (FCR) muscle. TA injections evoked pain that was referred to the ankle/foot in 10/17 subjects, whereas FCR injections evoked pain that was projected into the wrist/hand in 6/12 subjects. Regional brain responses were statistically tested by convolving the temporal profile of the subjective pain intensity rating with the hemodynamic response function. For all subjects, signal increased in the region of primary somatosensory cortex (SI), which represents the leg or arm, that is, the area corresponding to the injection site. However, for those subjects who reported referred pain, signal intensity increases also occurred in the SI region representing the foot or hand. Interestingly, differential signal changes also occurred in anterior cingulate, cerebellar, and insular cortices. This is the first study to provide evidence of cortical differentiation in the processing of primary and referred pain.     

Imaging human cerebral pain modulation by dose-dependent opioid analgesia: a positron emission tomography activation study using remifentanil

BACKGROUND: Previous imaging studies have demonstrated a number of cortical and subcortical brain structures to be activated during noxious stimulation and infusion of narcotic analgesics. This study used O-water and positron emission tomography to investigate dose-dependent effects of the short-acting mu-selective opioid agonist remifentanil on regional cerebral blood flow during experimentally induced painful heat stimulation in healthy male volunteers. METHODS: Positron emission tomography measurements were performed with injection of 7 mCi O-water during nonpainful heat and painful heat stimulation of the volar forearm. Three experimental conditions were used during both sensory stimuli: saline, 0.05 microg x kg x min remifentanil, and 0.15 microg x kg x min remifentanil. Cardiovascular and respiratory parameters were monitored noninvasively. Across the three conditions, dose-dependent effects of remifentanil on regional cerebral blood flow were analyzed on a pixel-wise basis using a statistical parametric mapping approach. RESULTS: During saline infusion, regional cerebral blood flow increased in response to noxious thermal stimulation in a number of brain regions as previously reported. There was a reduction in pain-related activations with increasing doses of remifentanil in the thalamus, insula, and anterior and posterior cingulate cortex. Increasing activation occurred in the cingulofrontal cortex (including the perigenual anterior cingulate cortex) and the periaqueductal gray. CONCLUSIONS: Remifentanil induced regional cerebral blood flow increases in the cingulofrontal cortex and periaqueductal gray during pain stimulation, indicating that mu-opioidergic activation modulates activity in pain inhibitory circuitries. This provides direct evidence that opioidergic analgesia is mediated by activation of established descending antinociceptive pathways.     

The contribution of neuroimaging techniques to the understanding of supraspinal pain circuits: implications for orofacial pain.

The aim of this article was to give an overview of the current knowledge of supraspinal pain mechanisms derived from neuroimaging studies, and to present data related to chronic orofacial pain disorders. The available studies implied that the anterior cingulate cortex plays a role in the emotional-affective component of pain, as well as in pain-related attention and anxiety. The somatosensory cortices may be involved in encoding spatial, temporal, and intensity aspects of noxious input. The insula may mediate both affective and sensory-discriminative aspects of the pain experience. The thalamus appears to be a multifunctional relay system. The prefrontal cortex has been implied in the pain-related attention processing; it does not have intensity encoding properties. Chronic pain conditions were associated with increased activity in the somatosensory cortices, anterior cingulate cortex, and the prefrontal cortex, and with decreased activity in the thalamus. Few neuroimaging studies used experimental stimuli to the trigeminal system or included orofacial pain patients. However, the available studies appeared to be in agreement with those using stimuli to other body parts and those concerning other chronic pain conditions. Overall, the available data suggest that chronic (orofacial) pain states may be related to a dysfunctional brain network and may involve a compromised descending inhibitory control system. The somatosensory cortices, anterior cingulate cortex, thalamus, and prefrontal cortex may play a vital role in the pathophysiology of chronic pain and should be the main focus of future neuroimaging studies in chronic pain patients.     

Visualisierung von Phantom- und Rückenschmerzen durch bildgebende Verfahren

If patients with chronic low back pain are stimulated in the painful region, an expanded representation of the back in the primary somatosensory cortex becomes visible that increases with chronicity. This "pain memory" might play an important role in the chronicity process. In patients with phantom limb pain, e.g. subsequent to the amputation of an arm or leg, a shift in the representation of neighboring areas into the deafferented area in primary somatosensory cortex has been observed. This reorganization of functional brain maps is not present in congenital amputees or amputees without phantom limb pain. The magnitude of such pain is positively correlated with this reorganization. We present a model of phantom limb pain that assigns an important role to pre-existing chronic pain. The modulation of plasticity and phantom limb pain by anesthesiological manipulation, the use of NMDA receptor antagonists and opioids is presented. Behaviorally relevant stimulation, e.g. by the use of a myoelectric prosthesis or sensory discrimination training can also influence the cortical somatosensory pain memory. More recent studies focus also on brain areas such as the cingulate gyrus believed to be involved in the affective processing of pain.