Operculo-insular Region Research Articles

Neurological morbidity of surgery for suprasylvian operculoinsular epilepsy.

The objective of this study was to identify risk factors associated with surgery-related neurological morbidity in patients with drug-resistant epilepsy undergoing suprasylvian operculoinsular resections. As secondary outcomes, we also analyzed the risk factors for ischemic lesion (IL) of corona radiata and seizure recurrence. A retrospective analysis was conducted on a cohort of patients who underwent suprasylvian operculoinsular resections for drug-resistant epilepsy. The association of several presurgical, surgical, and postsurgical factors with both primary (persistent neurological deficits) and secondary (structural abnormalities on postoperative magnetic resonance imaging [MRI] and seizure recurrence) postoperative outcomes was investigated with univariate and multivariate statistical analysis. The study included a total of 65 patients; 46.2% of patients exhibited postoperative neurological deficits, but only 12.3% experienced persistent deficits. On postoperative MRI, IL in the corona radiata and corticospinal tract Wallerian degeneration (CSTWd) were seen in 68% and 29% of cases, respectively. Only CSTWd was significantly associated with persistent neurological deficits (relative risk [RR] = 2.6). Combined operculoinsular resection (RR = 3.62) and surgery performed on the left hemisphere (RR = .37) were independently associated with IL in the corona radiata. Variables independently associated with CSTWd were the presence of malacic components in the IL (RR = 1.96), right central operculum resection (RR = 1.79), and increasing age at surgery (RR = 1.03). Sixty-two patients had a postoperative follow-up > 12 months (median = 56, interquartile range = 30.75-73.5), and 62.9% were in Engel class I at last outpatient control. The risk of seizure recurrence was reduced by selective opercular resection (RR = .25) and increased by the histological diagnosis of aspecific gliosis (RR = 1.39). This study provides insights into the risk factors associated with surgery-related neurological morbidity, as well as further evidence on the postoperative occurrence of subcortical injury and seizure recurrence in epileptic patients undergoing suprasylvian operculoinsular resections. The findings highlighted in this study may be useful to better understand the processes supporting the increased surgical risk in the operculoinsular region.

Cortical activity during the wind-up of flexion reflex and pain: a magnetoencephalographic study using time-frequency analysis.

Wind-up is a nociceptive-specific phenomenon in which pain sensations are facilitated, in a frequency-dependent manner, by the repeated application of noxious stimuli of constant intensity, with invariant tactile sensations. Thus, cortical activities during wind-up could be an alteration associated with pain potentiation. We aimed to investigate somatosensory-evoked cortical responses and induced brain oscillations during wind-up by recording magnetoencephalograms. Wind-up was produced by the application of 11 consecutive electrical stimuli to the sural nerve, repeated at a frequency of 1Hz without varying the intensity. The augmentation of flexion reflexes and pain rating scores were measured simultaneously as an index of wind-up. In the time-frequency analyses, the γ-band late event-related synchronization and the β-band event-related desynchronization were observed in the primary somatosensory region and the bilateral operculo-insular region, respectively. Repetitive exposure to the stimuli enhanced these activities, along with an increase in the flexion reflex magnitude. The evoked cortical activity reflected novelty, with no alteration to these repetitive stimuli. Observed oscillations enhanced by repetitive stimulation at a constant intensity could reflect a pain mechanism associated with wind-up.

Automated electrical source imaging with scalp EEG to define the insular irritative zone: Comparison with simultaneous intracranial EEG

ObjectiveTo evaluate the accuracy of automatedinterictallow-density electrical source imaging (LD-ESI) to define the insular irritative zone (IZ) by comparing the simultaneous interictal ESI localization with the SEEG interictal activity. MethodsLong-term simultaneous scalp electroencephalography (EEG) and stereo-EEG (SEEG) with at least one depth electrode exploring the operculo-insular region(s) were analyzed. Automated interictal ESI was performed on the scalp EEG using standardized low-resolution brain electromagnetic tomography (sLORETA) and individual head models. A two-step analysis was performed: i) sublobar concordance betweencluster-based ESI localization and SEEG-based IZ; ii) time-locked ESI-/SEEG analysis. Diagnostic accuracy values were calculated using SEEG as reference standard. Subgroup analysis wascarried out, based onthe involvement of insular contacts in the seizure onset and patterns of insular interictal activity. ResultsThirty patients were included in the study. ESI showed an overall accuracy of 53% (C.I. 29–76%). Sensitivity and specificity were calculated as 53% (C.I. 29–76%), 55% (C.I. 23–83%) respectively. Higher accuracy was found in patients with frequent and dominant interictal insular spikes. ConclusionsLD-ESI defines with good accuracy the insular implication in the IZ, which is not possible with classical interictalscalpEEG interpretation. SignificanceAutomated LD-ESI may be a valuable additional tool to characterize the epileptogenic zone in epilepsies with suspected insular involvement.

The role of magnetoencephalography in the presurgical evaluation of patients with MRI-negative operculo-insular epilepsy

PurposeMagnetoencephalography (MEG) is considered to be a useful clinical tool to provide additional information for localising the epileptogenic zone or planning intracranial electrode implantation. This study aimed to evaluate the value of MEG in the presurgical localisation of the operculo-insular epileptogenic zone in patients with negative magnetic resonance imaging (MRI). MethodsThirteen patients with operculo-insular epilepsy and negative MRI who were identified by presurgical evaluation and underwent resective surgery from January 2011 to June 2015 were included and analysed in the study. ResultsIn presurgical evaluation, the ictal symptoms looked reliable enough to characterise operculo-insular seizures in four patients. MEG spike sources were shown in the operculo-insular region in 11 of 13 (84.6%) patients, including cluster spike sources in 7 patients and scatter spike sources in 4 patients. After MEG examination, the original plan of intracranial electrode implantation was changed in five patients. In these patients, electrodes exploring the operculo-insular cortex were not part of the original plan. The pathological examination showed focal cortical dysplasia (FCD) in 12 patients and FCD with heterotopia in 1 patient. Nine (69.2%)patients were seizure-free in 2–6 years’ follow-up. ConclusionsMEG played an additional and valuable role in the localisation of operculo-insular epilepsy for patients with a negative MRI finding.

Operculo-Insular Epilepsy: Scalp and Intracranial Electroencephalographic Findings.

Operculo-insular seizures are heterogeneous and may resemble seizures originating from the temporal, frontal, or parietal lobe. Although surface and invasive EEG recordings are often necessary to detect operculo-insular seizures, electrophysiological features of operculo-insular epilepsies remain poorly characterized. This study describes the EEG findings of patients with operculo-insular epilepsy. We reviewed electrophysiological data of all patients (n = 9) with operculo-insular seizures revealed by intracranial EEG and for whom operculo-insular epilepsy was confirmed by good seizure outcome after resective or radiosurgery at our center between 2005 and 2013. Patients were divided according to whether their seizure focus involved the anterior (group 1; n = 4) or posterior (group 2; n = 5) portion of the insula. Interictal scalp EEG was lateralizing and showed distinct topographical spike patterns between groups: frontal and temporal in group 1, temporal in group 2. Intracranial recordings showed abundant spikes limited to the operculo-insular region or involving distant areas in the frontal/temporal (group 1) and temporal/parietal lobes (group 2). Ictal intracranial EEG revealed discharges limited to the insula or simultaneously involving extrainsular contacts at onset, notably the orbitofrontal cortex (group 1) and the frontal and parietal opercula (group 2), and propagating to the frontal and temporal lobes in group 1 and to parietal and temporal lobes in group 2. Spike distribution and seizure propagation in operculo-insular epilepsy follows an anterior-to-posterior pattern mirroring an anterior or posterior insular focus localization. When presented with frontal and/or temporal epileptiform abnormalities, an operculo-insular focus should be considered.

S44 Non-invasive presurgical evaluation of insular cortex epilepsy

Introduction Considering the variability in seizure semiology, recognition of operculo-insular epilepsy (OIE) may be challenging and confirmation by non-invasive tests is warranted although few studies have assessed their value. Methods Surface EEG (n = 9), MRI (n = 48), 1H-MRS (n = 12), ictal SPECT (n = 18), interictal PET (n = 17) and MEG (n = 14) findings of OIE cases proven by the presence of an insular epileptogenic lesion or good surgical outcome were reviewed. Results (1) Scalp EEG: spikes were found over fronto, temporal and central leads, generally allowing adequate lateralization; ictal discharges were also generally lateralizing but more extent in distribution; auras lacked EEG changes. (2) MRI identified a neoplastic lesion in 27%, a malformation of cortical development in 21%, a vascular malformation in 19% and atrophy/gliosis from an acquired insult in 17%. (3) No significant differences in insular [NAA] or NAA/Cr ratios were found between the OIE group, the non-OIE group and healthy controls. (4) Ictal SPECT showed maximum hyperperfusion in the operculo-insular region in 65%; PET findings were localizing in 29%, lateralizing in another 18%, falsely localizing in 24% and with no hypometabolism in 29%. (5) Tight anterior and posterior operculo-insular clusters of dipoles were observed in 50% and 14%, respectively, while 29% had diffuse perisylvian dipoles. Focal resection in 6/7 patients with anterior or posterior operculo-insular clusters of dipoles resulted in seizure freedom, whereas both surgically treated patients with scattered perisylvian spike sources had an Engel II seizure outcome. Discussion Detection of an insular lesion on MRI greatly facilitates the diagnosis. Scalp EEG findings in fronto-central and/or temporal derivations generally allow lateralization of the seizure focus. Ictal SPECT has moderate sensitivity while PET findings were less localizing. Among newer techniques, MEG was found to be highly beneficial while MRS currently has limited value. Conclusion When OIE is clinically suspected, non-invasive tests (MRI, SPECT and especially MEG) may provide additional supporting information.

Mapping altered brain connectivity and its clinical associations in adult moyamoya disease: A resting-state functional MRI study.

Detection of subtle ischemic injuries in moyamoya disease may enable optimization of timing of revascularization surgery, and could potentially improve functional outcomes. Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to study functional organization of the brain, but it remains unclear whether rs-fMRI could elucidate distinct characteristics in moyamoya disease. Here, we aimed to determine changes in a conventional rs-fMRI measure and analyze any associations with clinical symptoms and cerebral hemodynamics. Thirty-one adults with moyamoya disease and 25 adult controls underwent rs-fMRI, in which we measured brain connectivity via temporal correlations of low-frequency BOLD signals. We identified the extent of between-group differences with multivoxel pattern analysis. Seed-based analysis was performed to determine associations with vascular lesions, symptoms, and regional cerebral blood flow (rCBF). There was significantly altered connectivity in the precentral gyrus, operculo-insular region, precuneus, cingulate cortex, and middle frontal gyrus in moyamoya disease. There was reduced connectivity in the left insula, left precuneus, right precentral, and right middle frontal regions, which form part of the salience, default mode, motor, and central executive networks, respectively. Patients with ischemic motor-related symptoms showed significantly decreased connectivity in precentral homotopic regions compared with those without, while there were no differences in vascular lesions or rCBF. Connectivity between the right occipital and left hippocampus was significantly associated with cognitive performance and posterior cerebral artery involvement. Our results demonstrate distinct alterations in the temporal correlations of low-frequency BOLD signals, predominantly in resting-state networks in moyamoya disease. Additionally, rs-fMRI measures were associated with ischemic motor-related symptoms and cognitive performance in the patients. Thus, rs-fMRI may offer a useful non-invasive method of acquiring additional information beyond cerebral perfusion as part of clinical investigations in patients with moyamoya disease.

ID 226 – Inter-individual differences in laser-evoked potentials and operculo-insular morphology

Laser-evoked potentials are a useful tool to evaluate the functional state of the spino-thalamic system. While late vertex potentials N2 and P2 are commonly assessed, middle-latency components such as the N1–P1 are under-utilized, due to their smaller amplitude and high inter-individual variability. To optimize their use, we investigate the possible relationship between this variability and anatomo-morphological variations in the operculo-insular region. We recorded laser-evoked potentials using high-density EEG (128 electrodes) in 15 healthy participants. Over the 30 ms following the appearance of the first lateralized N1–P1 scalp topography, the electrodes recording a frontal maximum and a temporo-central minimum were selected. Their positions were put in relation with the orientation of several sulci in the posterior operculo-insular cortex, measured on individual T1-3D MRIs. In all but two participants, a clear lateralized dipolar structure appeared ∼154 ms (±18 ms) after stimulation. There was a significant correlation (r2 = 0.43, p = 0.02, n = 12) between the negative maximum (N1) electrode coordinate in a coronal plane and the orientation of the posterior superior operculo-insular fold (MRI coronal plane). N1–P1 topography is highly related to operculo-insular anatomo-morphology. It remains to be studied whether N1–P1 topography can predict operculo-insular anatomy at the individual level and be used in routine clinical settings.

Social information processing following resection of the insular cortex

The insula has been implicated in social cognition and empathy in several neuroimaging paradigms. Impairments in social information processing, including specific deficits in disgust recognition, have been described following isolated insular damage, although the evidence remains limited to a few case studies. The present study examines social cognition and empathy in a group of fifteen patients for whom the insula was removed as part of their epilepsy surgery. These patients were compared to a lesion-control group of 15 epileptic patients who had a surgery in the anterior temporal lobe that spared the insula, and to 20 healthy volunteers matched on age, sex, and education. Participants were assessed on an Emotion Recognition Task (ERT), the Reading the Mind in the Eyes test, and a self-administered empathy questionnaire. Patients who underwent insular resection showed poorer ability to recognize facial expressions of emotions and had lower scores of perspective taking on the empathy questionnaire than healthy controls. Using results from healthy controls as normative data, emotion recognition deficits were more frequent in insular patients than in both other groups. Specific emotion analyses revealed impairments in fear recognition in both groups of patients, whereas happiness and surprise recognition was only impaired in patients with insular resection. There was no evidence for a deficit in disgust recognition. The findings suggest that unilateral damage to the operculo-insular region may be associated with subtle impairments in emotion recognition, and provide further clinical evidence of a role of the insula in empathic processes. However, the description of 15 consecutive cases of insula-damaged patients with no specific deficit in disgust recognition seriously challenges the assumptions, based on previous case reports, that the insula is specifically involved in disgust processing.

35. Practical value of quantitative EEG in epilepsy surgery planning

Objective To assess whether available algorithms of quantitative EEG (qEEG) could practically help in localizing epileptogenic zone (EZ) and modify surgical planning in patients with focal intractable epilepsy. Methods We will present a case report of a 7-year-old boy with catastrophic epilepsy caused by focal cortical dysplasia located in the operculo-insular region of the right hemisphere. Due to the challenging localization of the presumed EZ, uncertain surgical borders and expected significant risks of the resection, the patient was stereotactically implanted with oblique depth electrodes. Intracranial EEG (iEEG) signal was analyzed using different qEEG methods. Our originally developed interictal epileptiform discharges (IED) detecting algorithm, which also extracts repetitive propagation patterns, was applied to localize sources of IED. We also used own network connectivity algorithm to analyze ictal (seizure) iEEG activity in detail. Employing results of qEEG analyses, 2D and 3D dynamic reconstructions of both interictal and ictal iEEG epileptiform changes were created and used to guide surgical approach. Results Both qEEG algorithms clearly proved the EZ localization in the dorso-caudal insular cortex of the right hemisphere and demonstrated sparing of initially suspected frontal opercular area. The dorso-caudal insular cortex generated 89% of IED; remaining 11% IED originated from the primary motor cortex. Surgical approach was adjusted to this qEEG-based hypothesis. Oblique depth electrodes were preserved intraoperatively to help precise targeting of the lesion. Continuous intraoperative motor-evoked potential monitoring was used to preserve motor functions. The boy has been followed for more than one year postoperatively. He is seizure-free with no motor deficit; with normal cognitive functions. Conclusions The case report demonstrates that currently available qEEG methods could help in guiding resective epilepsy surgery in complicated patients indicated for iEEG studies. We suggest our approach could increase patients’ chance to obtain seizure-free outcomes without new deficits and thus ultimately improve their quality of life. Supported by MH CZ–DRO, University Hospital Motol, Prague, Czech Republic 00064203 and IGA NT/11460-4.

Different localizations underlying cortical gelastic epilepsy: Case series and review of literature

BackgroundGelastic seizures (GS) are classically observed with hypothalamic hamartomas but they can also be associated with cortical epileptogenic foci. ObjectiveTo study the different cortical localizations associated with GS. MethodsWe reviewed the data from all patients with cortical GS investigated in our epilepsy unit from 1974 to 2012 and in the literature from 1956 to 2013. ResultsSixteen cases were identified in our database and 77 in the literature. Investigations provided confident focus localization in 9 and 18, respectively. In our series, the identified foci were located in the mesial temporal structures (2 left, 1 right), lateral temporal cortex (1 right), superior frontal gyrus (1 left), and operculoinsular region [3 right (orbitofrontal or frontal operculum extending into the anterior insula) and 1 left (frontal operculum extending into the anterior insula)]. In the literature, the identified foci (13 right/5 left) were located in the temporal lobe of 4 (1 right inferior, 1 right medial and inferior, 1 right posterior middle, inferior extending posteriorly to the lingual gyrus, and 1 left middle, inferior, and medial), in the frontal lobe of 12 [10 (6 right/4 left) medial (i.e., superior, medial frontal, and/or anterior cingulate gyri), 1 lateral (right anterior inferior frontal gyrus), and 1 right medioposterior orbitofrontal cortex] and in the parietal lobe of 2 (1 left superior parietal lobule and 1 right parietal operculum) patients. ConclusionIctal laughter is a poorly lateralizing and localizing feature as it may be encountered in patients with a focus in the left or right frontal, temporal, parietal, or insular lobe.

Imagerie cérébrale et douleur : perception unique, réseaux multiples

Here, the “pain matrix” is designed as a fluid system, made up of lots of networks interacting with each other. A nociceptive matrix receiving spinothalamic input (mainly the operculo-insular region) ensures the specific nature of somatic pain, and is the only thing that, if destroyed, results in selective impairment of heat and pain perception. The transition between a cortical nociception and conscious pain is dependent on a secondary network that includes at least the anterior, posterior parietal and prefrontal insular regions. These secondary regions are not specifically nociceptive: their stimulation does not lead to pain and when destroyed pain relief is not generated; their joint activation is necessary for the conscious perception of pain, its attentional modulation and the control of associated vegetative reactions. The immediate pain experience that ensues may even be transformed based on beliefs, emotions and expectations of the individual, through the activity of tertiary regions, including the perigeniculate cingulate, orbitofrontal and limbic networks. The pain that we remember is the result of continuous interactions between these sub-systems, and the substantial changes in the pain experience can be obtained by acting on each of them.

Spatial segregation of somato-sensory and pain activations in the human operculo-insular cortex

The role of operculo-insular region in the processing of somato-sensory inputs, painful or not, is now well established. However, available maps from previous literature show a substantial overlap of cortical areas activated by these stimuli, and the region referred to as the "secondary somatosensory area (SII)" is widely distributed in the parietal operculum. Differentiating SII from posterior insula cortex, which is anatomically contiguous, is not easy, explaining why the "operculo-insular" label has been introduced to describe activations by somatosensory stimuli in this cortical region. Based on the recent cyto-architectural parcellation of the human insular/SII cortices (Eickhoff et al., 2006, Kurth et al., 2010), the present study investigates with functional MRI (fMRI), whether these structural subdivisions could subserve distinct aspects of discriminative somato-sensory functions, including pain. Responses to five types of stimuli applied on the left hand of 25 healthy volunteers were considered: i) tactile stimuli; ii) passive movements; iii) innocuous cold stimuli; iv) non-noxious warm and v) heat pain. Our results show different patterns of activation depending on the type of somato-sensory stimulation. The posterior part of SII (OP1 area), contralateral to stimuli, was the only sub-region activated by all type of stimuli and might therefore be considered as a common cortical target for different types of somato-sensory inputs. Proprioceptive stimulation by passive finger movements activated the posterior part of SII (OP1 sub-region) bilaterally and the contralateral median part of insula (PreCG and MSG). Innocuous cooling activated the contralateral posterior part of SII (OP1) and the dorsal posterior and median part of insula (OP2, PostCG). Pain stimuli induced the most widespread and intense activation that was bilateral in SII (OP1, OP4) and distributed to all sub-regions of contralateral insula (except OP2) and to the anterior part of the ipsilateral insula (PreCG, MSG, ASG). However, the posterior granular part of insula contralateral to stimulus (Ig area) and the anterior part of SII bilaterally (OP4) were specifically activated during pain stimulation. This raises the question whether these latter areas could be the anatomical substrate of the sensory-discriminative processing of thermal pain.

Cortical Activation Changes during Repeated Laser Stimulation: A Magnetoencephalographic Study

Repeated warm laser stimuli produce a progressive increase of the sensation of warmth and heat and eventually that of a burning pain. The pain resulting from repetitive warm stimuli is mediated by summated C fibre responses. To shed more light on the cortical changes associated with pain during repeated subnoxious warm stimution, we analysed magnetoencephalographic (MEG) evoked fields in eleven subjects during application of repetitive warm laser stimuli to the dorsum of the right hand. One set of stimuli encompassed 10 laser pulses occurring at 2.5 s intervals. Parameters of laser stimulation were optimised to elicit a pleasant warm sensation upon a single stimulus with a rise of skin temperature after repeated stimulation not exceeding the threshold of C mechano-heat fibres. Subjects reported a progressive increase of the intensity of heat and burning pain during repeated laser stimulation in spite of only mild (4.8°C) increase of skin temperature from the first stimulus to the tenth stimulus. The mean reaction time, evaluated in six subjects, was 1.33 s, confirming involvement of C fibres. The neuromagnetic fields were modelled by five equivalent source dipoles located in the occipital cortex, cerebellum, posterior cingulate cortex, and left and right operculo-insular cortex. The only component showing statistically significant changes during repetitive laser stimulation was the late component of the contralateral operculo-insular source peaking at 1.05 s after stimulus onset. The amplitude increases of the late component of the contralateral operculo-insular source dipole correlated with the subjects' numerical ratings of warmth and pain. Results point to a pivotal role of the contralateral operculo-insular region in processing of C-fibre mediated pain during repeated subnoxious laser stimulation.

Interoceptive cortex in the posterior insula: comment on Garcia-Larrea et al. 2010 Brain 133, 2528

ARTICLE Sir, In a recent publication in Brain , Garcia-Larrea et al . (2010) reported their identification of patients with post-stroke central pain and selective thermosensory dysfunction, but without other somatosensory abnormalities, and they suggested that the basis for such dissociated symptoms might be the presence of a ‘third somatosensory area’ specifically supporting temperature sensation in the operculo-insular region. In actuality, prior findings, which they did not cite, provide solid neurobiological evidence that the dorsal posterior insula contains the primary cortical sensory representation of temperature and pain in humans; indeed, these previous findings explain perfectly well these and other clinical observations by Garcia-Larrea and colleagues. In a carefully designed positron emission tomography study (Craig et al ., 2000), my colleagues and I examined cerebral activation associated with six different innocuous cool temperatures applied to the hand of awake human subjects, and by performing a regression analysis against stimulus temperature across scans, we obtained clear and unequivocal evidence that the only site in the contralateral cortex with activity directly (linearly) related to stimulus temperature was in the dorsal posterior insula (Fig. 1). We …

Multiple Somatotopic Representations of Heat and Mechanical Pain in the Operculo-Insular Cortex: A High-Resolution fMRI Study

Whereas studies of somatotopic representation of touch have been useful to distinguish multiple somatosensory areas within primary (SI) and secondary (SII) somatosensory cortex regions, no such analysis exists for the representation of pain across nociceptive modalities. Here we investigated somatotopy in the operculo-insular cortex with noxious heat and pinprick stimuli in 11 healthy subjects using high-resolution (2 × 2 × 4 mm) 3T functional magnetic resonance imaging (fMRI). Heat stimuli (delivered using a laser) and pinprick stimuli (delivered using a punctate probe) were directed to the dorsum of the right hand and foot in a balanced design. Locations of the peak fMRI responses were compared between stimulation sites (hand vs. foot) and modalities (heat vs. pinprick) within four bilateral regions of interest: anterior and posterior insula and frontal and parietal operculum. Importantly, all analyses were performed on individual, non-normalized fMRI images. For heat stimuli, we found hand-foot somatotopy in the contralateral anterior and posterior insula [hand, 9 ± 10 (SD) mm anterior to foot, P < 0.05] and in the contralateral parietal operculum (SII; hand, 7 ± 10 mm lateral to foot, P < 0.05). For pinprick stimuli, we also found somatotopy in the contralateral posterior insula (hand, 9 ± 10 mm anterior to foot, P < 0.05). Furthermore, the response to heat stimulation of the hand was 11 ± 12 mm anterior to the response to pinprick stimulation of the hand in the contralateral (left) anterior insula (P < 0.05). These results indicate the existence of multiple somatotopic representations for pain within the operculo-insular region in humans, possibly reflecting its importance as a sensory-integration site that directs emotional responses and behavior appropriately depending on the body site being injured.

Laser-Evoked Potentials Are Graded and Somatotopically Organized Anteroposteriorly in the Operculoinsular Cortex of Anesthetized Monkeys

The operculoinsular cortical region has a major role in the representation of noxious stimuli, based on functional imaging observations, clinical lesion studies, and EEG recordings of specifically pain-related laser-evoked potentials (LEPs) in humans. The source of LEPs has not been identified, and several somatic representations and cytoarchitectonic areas may be present in this complex region. To overcome the limitations of human studies, a primate model is needed in which the main LEP generator in this region can be localized and characterized using invasive methods. We obtained EEG recordings of evoked responses to noxious laser stimulation at different intensities and performed dipole source analyses in three anesthetized macaque monkeys. We show that LEPs can be recorded that 1) grade with stimulus intensity, 2) display two distinct responses corresponding to the "late" (Adelta-fiber) and the "ultralate" (C-fiber) LEPs recorded in humans, and 3) originate deep within the operculoinsular region, thus establishing a valid primate model for experimental analysis of LEPs. Further, we found that LEPs elicited from the leg, arm, and ear display a global somatotopy organized in the posteroanterior direction (leg posterior and arm and ear anterior), which contrasts starkly with the mediolateral (leg to face) gradient of the somatotopic representations in primary and secondary somatosensory cortices. These results provide evidence that the main generator of pain-related activity in operculoinsular cortex may participate in both the somatic localization and the intensity discrimination of pain sensations, and they indicate that it may be distinct from the traditional somatosensory cortices.

High opiate receptor binding potential in the human lateral pain system

To determine how opiate receptor distribution is co-localized with the distribution of nociceptive areas in the human brain, eleven male healthy volunteers underwent one PET scan with the subtype-nonselective opioidergic radioligand [ 18F]fluoroethyl-diprenorphine under resting conditions. The binding potential (BP), a parameter for the regional cerebral opioid receptor availability, was computed using the occipital cortex as reference region. The following regions of interest (ROIs) were defined on individual MR images: thalamus, sensory motor strip (SI/MI area), frontal operculum, parietal operculum, anterior insular cortex, posterior insular cortex, anterior cingulate cortex (ACC; peri- and subgenual part of “classical ACC” only), midcingulate cortex (MCC, posterior part of “classical ACC”), putamen, caudate nucleus and the amygdala. BP for [ 18F]fluoroethyl-diprenorphine was lowest in the sensory motor strip (0.30). Highest BP was found in thalamus (1.36), basal ganglia (putamen 1.22, caudate 1.16) and amygdala (1.21). In the cingulate cortex, ACC (1.11) had higher BP than MCC (0.86). In the operculo-insular region, we found high BPs in all ROIs: anterior insula (1.16), posterior insula (1.05), frontal operculum (0.99) and parietal operculum (0.77). Factor analysis of interindividual variability of opiate receptor BP revealed four factors (95% explained variance): (1) operculo-insular areas, ACC, MCC and putamen, (2) amygdala and thalamus, (3) caudate and thalamus, (4) SI/MI and MCC. Nociceptive areas of the lateral pain system (frontoparietal operculum and insula) have opiate receptor BPs significantly higher than SI/MI, comparable to anterior and midcingulate areas of the medial pain system. These findings suggest that the cortical anti-nociceptive effects of opiates are not only mediated by ACC and MCC, but also by the operculo-insular cortex, if it can be assumed that opioid binding mediates anti-nociception in those structures.

Operculoinsular cortex encodes pain intensity at the earliest stages of cortical processing as indicated by amplitude of laser-evoked potentials in humans

Converging evidence from different functional imaging studies indicates that the intensity of activation of different nociceptive areas (including the operculoinsular cortex, the primary somatosensory cortex, and the anterior cingulate gyrus) correlates with perceived pain intensity in the human brain. Brief radiant laser pulses excite selectively Aδ and C nociceptors in the superficial skin layers, provide a purely nociceptive input, and evoke brain potentials (laser-evoked potentials, LEPs) that are commonly used to assess nociceptive pathways in physiological and clinical studies. Aδ-related LEPs are constituted of different components. The earliest is a lateralised, small negative component (N1) which could be generated by the operculoinsular cortex. The major negative component (N2) seems to be mainly the result of activation in the bilateral operculoinsular cortices and contralateral primary somatosensory cortex, and it is followed by a positive component (P2) probably generated by the cingulate gyrus. Currently, early and late LEP components are considered to be differentially sensitive to the subjective variability of pain perception: the late N2-P2 complex strongly correlates with perceived pain, whereas the early N1 component is thought to be a pre-perceptual sensory response. To obtain physiological information on the roles of the pain-related brain areas in healthy humans, we examined the relationship between perceived pain intensity and latency and amplitude of the early (N1) and late (N2, P2) LEP components. We found that the amplitude of the N1 component correlated significantly with the subjective pain ratings, both within and between subjects. Furthermore, we showed that the N2 and P2 late LEP components are differentially sensitive to the perceived sensation, and demonstrated that the N2 component mainly explains the previously described correlation between perceived pain and the amplitude of the N2-P2 vertex complex of LEPs. Our findings confirm the notion that pain intensity processing is distributed over several brain areas, and suggest that the intensity coding of a noxious stimulus occurs already at the earliest stage of perception processing, in the operculoinsular region and, possibly, the primary somatosensory area.

Role of Operculoinsular Cortices in Human Pain Processing: Converging Evidence from PET, fMRI, Dipole Modeling, and Intracerebral Recordings of Evoked Potentials

Insular and SII cortices have been consistently shown by PET, fMRI, EPs, and MEG techniques to be activated bilaterally by a nociceptive stimulation. The aim of the present study was to refer to, and to compare within a common stereotactic space, the nociceptive responses obtained in humans by (i) PET, (ii) fMRI, (iii) dipole modeling of scalp LEPs, and (iv) intracerebral recordings of LEPs. PET, fMRI, and scalp LEPs were obtained from normal subjects during thermal pain. Operculoinsular LEPs were obtained from 13 patients using deep brain electrodes implanted for presurgical evaluation of drug-resistant epilepsy. Whatever the technique, we obtained responses which were located bilaterally in the insular and SII cortices. In electrophysiological responses (LEPs) the SII insular contribution peaked between 150 and 250 ms poststimulus and corresponded to the earliest portions of the whole cerebral response. Group analysis of PET and fMRI data showed highly consistent responses contralateral to stimulation. On single-subject analysis, LEPs and fMRI activations were concentrated in relatively restricted volumes even though spatial sampling was quite different for both techniques. Despite our multimodal approach, however, it was not possible to separate insular from SII activities. Individual variations in the anatomy and function of SII and insular cortices may explain this limitation. This multimodal study provides, however, cross-validated spatial and temporal information on the pain-related processes occurring in the operculoinsular region, which thus appears as a major site for the early cortical pain encoding in the human brain.