Representation of pain and somatic sensation in the human insula: a study of responses to direct electrical cortical stimulation

We studied painful and non-painful somaesthetic sensations elicited by direct electrical stimulations of the insular cortex performed in 43 patients with drug refractory temporal lobe epilepsy, using stereotactically implanted depth electrodes. Painful sensations were evoked in the upper posterior part of the insular cortex in 14 patients, mostly in the right hemisphere. Non-painful sensations were elicited in the posterior part of the insular cortex in 16 patients, in both hemispheres. Thus, painful and non-painful somaesthetic representations in the human insula overlap. Both types of responses showed a trend toward a somatotopic organization. These results agree with previous anatomical and unit recording studies in monkeys indicating a participation of the posterior part of the insular cortex in processing both noxious and innocuous somaesthetic stimuli. In humans, both a posterior and an anterior pain-related cortical area have been described within the insular cortex using functional imaging. Our results help to define the respective functional roles of these two insular areas. Finally, lateralization in the right hemisphere of sites where painful sensations were evoked is coherent with the hypothesis of a preponderant role of this hemisphere in species survival.     

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.     

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.     

Timing and spatial distribution of somatosensory responses recorded in the upper bank of the sylvian fissure (SII area) in humans

We studied responses of the parieto-frontal opercular cortex to electric stimuli, as recorded by intra-cortical electrodes during stereotactic EEG presurgical assessment of patients with drug-resistant temporal lobe epilepsy. After electrical stimulation of the median nerve at the wrist, we consistently recorded a negative-positive biphasic response peaking at 60 ms (N60) and 90 ms (P90) post-stimulus in the upper bank of the sylvian fissure contralateral to stimulation. Talairach stereotactic coordinates of the electrode contacts recording these responses covered the pre- and post-rolandic part of the upper bank of the sylvian fissure (25相似文献   

Somatotopic organization of human secondary somatosensory cortex

This fMRI study investigated the human somatosensory system, especially the secondary somatosensory cortex (SII), with respect to its potential somatotopic organization. Eight subjects received electrical stimulation on their right second finger, fifth finger and hallux. Within SII, the typical finding for both fingers was a representation site within the contralateral parietal operculum roughly halfway between the lip of the lateral sulcus and its fundus, whereas the representation site of the hallux was found more medially to this position at the fundus of the lateral sulcus, near the posterior pole of the insula. Somatotopy in SII seems to be less fine-grained than in primary somatosensory cortex (SI), as, in contrast to SI, no separate representations of the two fingers in SII were observed. A similar somatotopic representation pattern between fingers and the hallux was also observed within ipsilateral SII, indicating somatotopy of contra- as well as ipsilateral SII using unilateral stimulation. Further areas exhibiting activation were found in the superior and inferior parietal lobule, in the supplementary and cingulate motor area, and in the insula.     

Representations of pleasant and painful touch in the human orbitofrontal and cingulate cortices

The cortical areas that represent affectively positive and negative aspects of touch were investigated using functional magnetic resonance imaging (fMRI) by comparing activations produced by pleasant touch, painful touch produced by a stylus, and neutral touch, to the left hand. It was found that regions of the orbitofrontal cortex were activated more by pleasant touch and by painful stimuli than by neutral touch and that different areas of the orbitofrontal cortex were activated by the pleasant and painful touches. The orbitofrontal cortex activation was related to the affective aspects of the touch, in that the somatosensory cortex (SI) was less activated by the pleasant and painful stimuli than by the neutral stimuli. This dissociation was highly significant for both the pleasant touch (P < 0.006) and for the painful stimulus (P < 0.02). Further, it was found that a rostral part of the anterior cingulate cortex was activated by the pleasant stimulus and that a more posterior and dorsal part was activated by the painful stimulus. Regions of the somatosensory cortex, including SI and part of SII in the mid-insula, were activated more by the neutral touch than by the pleasant and painful stimuli. Part of the posterior insula was activated only in the pain condition and different parts of the brainstem, including the central grey, were activated in the pain, pleasant and neutral touch conditions. The results provide evidence that different areas of the human orbitofrontal cortex are involved in representing both pleasant touch and pain, and that dissociable parts of the cingulate cortex are involved in representing pleasant touch and pain.     

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.     

Somatosensory representation in patients who have undergone hemispherectomy: a functional magnetic resonance imaging study

OBJECT: Removal or disconnection of an entire cerebral hemisphere is occasionally used to treat refractory seizures. Patients who have undergone a hemispherectomy provide useful models to study the reorganization of cortical somatosensory representation. This plasticity may be a consequence of the pathological lesion, the hemispherectomy itself, or both. METHODS: Three patients who had undergone hemispherectomy were studied with functional magnetic resonance (fMR) imaging. Responses to sensory stimulation in normal hands and hands opposite the lesioned hemisphere were studied. Multislice T2*-weighted gradient-echo echoplanar images were obtained using a 1.5-tesla MR imager. The activation condition consisted of somatosensory stimulation of the index finger. A T1-weighted anatomical MR image was acquired. The fMR and anatomical MR images were coregistered, and statistically significant activation foci (p < 0.01) were identified. Stimulation of the normal hand produced activation in the primary somatosensory cortex (SI) in all patients. Stimulation of the impaired hand resulted in activation of the ipsilateral parietal operculum (second somatosensory area [SII]) and posterior parietal lobe (Brodmann's Area 7) in all cases, but no activation was elicited in the SI in any patient. In addition, other areas within the ipsilateral frontal and parietal lobes were activated in some individuals. CONCLUSIONS: Residual somatosensory function in the hand opposite the lesioned hemisphere is mediated by the SII and other cortical regions in the intact hemisphere, without involvement of the SI.     

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.     

Sensory inputs from whisking movements modify cortical whisker maps visualized with functional magnetic resonance imaging

Rodents vary the frequency of whisking movements during exploratory and discriminatory behaviors. The effect of whisking frequency on whisker cortical maps was investigated by simulating whisking at physiological frequencies and imaging the whisker representations with blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. Repetitive deflection of many right-sided whiskers at 10 Hz evoked a positive BOLD response that extended across contralateral primary somatosensory cortex (SI) and secondary somatosensory cortex (SII). In contrast, synchronous deflection of 2 adjacent whiskers (right C1 and C2) at 10 Hz evoked separate positive BOLD responses in contralateral SI and SII that were predominantly located in upper cortical layers. The positive BOLD responses were separated and partially surrounded by a negative BOLD response that was mainly in lower cortical layers. Two-whisker representations varied with the frequency of simulated whisking. Positive BOLD responses were largest with 7-Hz deflection. Negative BOLD responses were robust at 10 Hz but were weaker or absent with 7-Hz or 3-Hz deflection. Our findings suggest that sensory inputs attributable to the frequency of whisking movements modify whisker cortical representations.     

Auditory, somatosensory, and multisensory insular cortex in the rat

Compared with other areas of the forebrain, the function of insular cortex is poorly understood. This study examined the unisensory and multisensory function of the rat insula using high-resolution, whole-hemisphere, epipial evoked potential mapping. We found the posterior insula to contain distinct auditory and somatotopically organized somatosensory fields with an interposed and overlapping region capable of integrating these sensory modalities. Unisensory and multisensory responses were uninfluenced by complete lesioning of primary and secondary auditory and somatosensory cortices, suggesting a high degree of parallel afferent input from the thalamus. In light of the established connections of the posterior insula with the amygdala, we propose that integration of auditory and somatosensory modalities reported here may play a role in auditory fear conditioning.     

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.     

Functional magnetic resonance imaging of somatosensory cortex activity produced by electrical stimulation of the median nerve or tactile stimulation of the index finger

OBJECT: Functional magnetic resonance (fMR) imaging was used to determine patterns of cerebral blood flow changes in the somatosensory cortex that result from median nerve stimulation (MNS). METHODS: Ten healthy volunteers underwent stimulation of the right median nerve at frequencies of 5.1 Hz (five volunteers) and 50 Hz (five volunteers). The left median nerve was stimulated at frequencies of 5.1 Hz (two volunteers) and 50 Hz (five volunteers). Tactile stimulation (with a soft brush) of the right index finger was also applied (three volunteers). Functional MR imaging data were transformed into Talairach space coordinates and averaged by group. Results showed significant activation (p < 0.001) in the following regions: primary sensorimotor cortex (SMI), secondary somatosensory cortex (SII), parietal operculum, insula, frontal cortex, supplementary motor area, and posterior parietal cortices (Brodmann's Areas 7 and 40). Further analysis revealed no statistically significant difference (p > 0.05) between volumes of cortical activation in the SMI or SII resulting from electrical stimuli at 5.1 Hz and 50 Hz. There existed no significant differences (p > 0.05) in cortical activity in either the SMI or SII resulting from either left- or right-sided MNS. With the exception of the frontal cortex, areas of cortical activity in response to tactile stimulation were anatomically identical to those regions activated by electrical stimulation. In the SMI and SII, activation resulting from tactile stimulation was not significantly different (p > 0.05) from that resulting from electrical stimulation. CONCLUSIONS: Electrical stimulation of the median nerve is a reproducible and effective means of activating multiple somatosensory cortical areas, and fMR imaging can be used to investigate the complex network that exists between these areas.     

Top-down modulation of early sensory cortex

Data from nine previous studies of human visual information processing using positron emission tomography were reanalyzed to contrast blood flow responses during passive viewing and active discriminations of the same stimulus array. The analysis examined whether active visual processing (i) increases blood flow in medial visual regions early in the visual hierarchy and (ii) decreases blood flow in auditory and somatosensory cortex. Significant modulation of medial visual regions was observed in six of nine studies, indicating that top-down processes can affect early visual cortex. Modulations showed several task dependencies, suggesting that in some cases the underlying mechanism was selective (e.g. analysis-or feature-specific) rather than non- selective. Replicable decreases at or near auditory Brodmann area (BA) left 41/42 were observed in two of five studies, but in different locations. Analyses that combined data across studies yielded modest but significant decreases. Replicable decreases were not found in primary somatosensory cortex but were observed in an insular region that may be a somatosensory association area. Decreases were also noted in the parietal operculum (perhaps SII) and BA 40. These results are inconsistent with a model in which the precortical input to task- irrelevant sensory cortical areas is broadly suppressed.      

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.     

Thalamic stimulation and functional magnetic resonance imaging: localization of cortical and subcortical activation with implanted electrodes. Technical note

The utility of functional magnetic resonance (fMR) imaging in patients with implanted thalamic electrodes has not yet been determined. The aim of this study was to establish the safety of performing fMR imaging in patients with thalamic deep brain stimulators and to determine the value of fMR imaging in detecting cortical and subcortical activity during stimulation. Functional MR imaging was performed in three patients suffering from chronic pain and two patients with essential tremor. Two of the three patients with pain had undergone electrode implantation in the thalamic sensory ventralis caudalis (Vc) nucleus and the other had undergone electrode implantation in both the Vc and the periventricular gray (PVG) matter. Patients with tremor underwent electrode implantation in the ventralis intermedius (Vim) nucleus. Functional MR imaging was performed during stimulation by using a pulse generator connected to a transcutaneous extension lead. Clinically, Vc stimulation evoked paresthesias in the contralateral body, PVG stimulation evoked a sensation of diffuse internal body warmth, and Vim stimulation caused tremor arrest. Functional images were acquired using a 1.5-tesla MR imaging system. The Vc stimulation at intensities provoking paresthesias resulted in activation of the primary somatosensory cortex (SI). Stimulation at subthreshold intensities failed to activate the SI. Additional stimulation-coupled activation was observed in the thalamus, the secondary somatosensory cortex (SII), and the insula. In contrast, stimulation of the PVG electrode did not evoke paresthesias or activate the SI, but resulted in medial thalamic and cingulate cortex activation. Stimulation in the Vim resulted in thalamic, basal ganglia, and SI activation. An evaluation of the safety of the procedure indicated that significant current could be induced within the electrode if a faulty connecting cable (defective insulation) came in contact with the patient. Simple precautions, such as inspection of wires for fraying and prevention of their contact with the patient, enabled the procedure to be conducted safely. Clinical safety was further corroborated by performing 86 MR studies in patients in whom electrodes had been implanted with no adverse clinical effects. This is the first report of the use of fMR imaging during stimulation with implanted thalamic electrodes. The authors' findings demonstrate that fMR imaging can safely detect the activation of cortical and subcortical neuronal pathways during stimulation and that stimulation does not interfere with imaging. This approach offers great potential for understanding the mechanisms of action of deep brain stimulation and those underlying pain and tremor generation.     

Inner experience of pain: imagination of pain while viewing images showing painful events forms subjective pain representation in human brain

Pain is an unpleasant sensation, and at the same time, it is always subjective and affective. Ten healthy subjects viewed 3 counterbalanced blocks of images from the International Affective Picture System: images showing painful events and those evoking emotions of fear and rest. They were instructed to imagine pain in their own body while viewing each image showing a painful event (the imagination of pain). Using functional magnetic resonance imaging, we compared cerebral hemodynamic responses during the imagination of pain with those to emotions of fear and rest. The results show that the imagination of pain is associated with increased activity in several brain regions involved in the pain-related neural network, notably the anterior cingulate cortex (ACC), right anterior insula, cerebellum, posterior parietal cortex, and secondary somatosensory cortex region, whereas increased activity in the ACC and amygdala is associated with the viewing of images evoking fear. Our results indicate that the imagination of pain even without physical injury engages the cortical representations of the pain-related neural network more specifically than emotions of fear and rest; it also engages the common representation (i.e., in ACC) between the imagination of pain and the emotion of fear.     

The human parietal operculum. I. Cytoarchitectonic mapping of subdivisions

The human secondary somatosensory cortex (SII) is located on the parietal operculum, as shown by intraoperative stimulation and functional imaging studies. The position and extent of the anatomical correlates of this functionally defined region, however, are still unknown. We have therefore histologically mapped the putative anatomical correlates of the SII cortex in cell-body-stained histological sections of 10 human postmortem brains using quantitative cytoarchitectonic analysis. The gray level index (GLI), which is an indicator of the volume fraction of nerve cell bodies, was measured in the parietal operculum. GLI profiles as measures of the laminar pattern of the cortex were extracted perpendicular to cortical layers. Cytoarchitectonic borders were detected observer-independently by multivariate statistical analysis of the laminar profiles. Four cytoarchitectonic areas (termed OP 1-4) were identified. This cytoarchitectonic heterogeneity of the parietal operculum corresponds to results of functional imaging studies on the human SII cortex and data from non-human primates where multiple subregions within SII have been demonstrated by electrophysiological and connectivity studies.     

Corticocortical associative neurons expressing latexin: specific cortical connectivity formed in vivo and in vitro.

Latexin, a carboxypeptidase A inhibitor, is expressed in a subset of neurons in the infragranular layers of the lateral cortex in the rat. We here show that latexin-expressing neurons exhibit ultrastructural features common to cortical pyramidal neurons. We show in combined retrograde tracing and immunofluorescent experiments that latexin-expressing neurons contribute to specific corticocortical pathways. Thus, injections of the retrograde tracer fluorogold into either the primary somatosensory (SI) or the primary motor (MI) cortical area labeled many latexin-expressing neurons in the infragranular layers of the secondary somatosensory (SII) and visceral sensory (Vi) areas. In contrast, tracer injections involving the thalamus, striatum, or contralateral SII and Vi exclusively labeled latexin-nonexpressing neurons in both the SII and Vi. Finally, we show that the correct corticocortical projections can be formed in organotypic slice cultures in vitro from latexin-expressing neurons: when slices of developing SII were cocultured with those from the SI and the thalamus, latexin-immunoreactive neurons in the SII projected preferentially to their normal SI target. The specific connectivity formed in vivo and in vitro by this molecularly distinct neuronal population reveals its characteristic manner of cortical organization and provides a unique model system to analyze mechanisms underlying the formation of precise corticocortical pathways.     

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).