Pain-specific gamma-band oscillations recorded from the human insula

Introduction. Pain is a multi-dimensional experience, including sensory, affective, and cognitive components. How these different dimensions integrate into a unified and coherent percept remains an open question. Gamma-band oscillations (GBOs, 30-100 Hz) could represent a possible mechanism to integrate low-level cortical processing of basic stimulus features with high-level cognitive processes. In the present study, we used direct intracerebral recordings performed in humans to investigate whether nociceptive stimulation elicits nociceptive-specific GBOs in the insula, a region considered to play a major role in pain perception. Methods. Intracerebral activity was recorded from a total of 60 insular sites in 5 patients with deep multicontact electrodes, implanted for the presurgical evaluation of focal epilepsy. Patients received stimulation from four sensory modalities: thermonociceptive, tactile, auditory, and visual. Participants were instructed to rate the intensity of each stimulus on a numerical scale ranging from 0 to 10. Results. There was no significant difference in ratings of intensity across modalities. In 4/5 patients, nociceptive stimuli consistently elicited a clear enhancement of GBO power at insular contacts, peaking 245 ms ± 12 ms after stimulus onset (Fig. 1), but not at other intracerebral contacts. Vibrotactile, auditory, and visual stimuli did not elicit such high frequency responses at any of the recorded contacts. Conclusion. Nociceptive stimuli elicit consistent GBOs in the human insula. Because non-nociceptive stimuli do not elicit a similar response, these high frequency oscillations could reflect activity specific for nociception, possibly involved in the integration of stimulus-driven and top-down determinants of pain perception

Nociceptive local field potentials recorded from the human insula are not specific for nociception

Introduction. The insula, especially its posterior portion, is believed to play a specific role in nociception, as its injury can alter pain perception, and because electrical stimulation and epileptic seizures in this region may generate pain-related experiences. Depth recordings in humans have also shown that nociceptive stimuli elicit robust insular local field potentials (LFPs), often considered pain-specific. Taking advantage of the high spatial resolution of direct intracerebral recordings, we assessed whether the insula exhibits pain-specific responses. Methods. Five patients suffering from focal epilepsy were investigated using depth electrodes implanted in a total of 60 insular sites, in both the anterior and posterior insula. Patients received stimuli from four sensory modalities (thermonociceptive, vibrotactile, auditory, visual), and rated their intensity on a numerical scale ranging from 0 to 10. Results. All patients described nociceptive stimuli as painful and pricking. However, the average ratings for stimulus intensity did not differ significantly across modalities. Thermonociceptive stimulation elicited LFPs at the same electrode contacts as non-nociceptive vibrotactile, auditory, and visual stimulation, in the posterior and anterior insula (Fig. 1). A blind source separation procedure based on a probabilistic independent component analysis showed that the LFPs elicited by nociceptive stimulation could be entirely explained by multimodal neural activity also contributing to the LFPs elicited by non-nociceptive stimulation. Conclusion. Insular LFPs elicited by transient nociceptive stimuli reflect multimodal cortical activities unspecific for pain. These responses could reflect mechanisms of attentional re-orientation towards salient stimuli, including, but not limited to, painful stimuli

Pain-specific gamma-band oscillations recorded from the human insula

Introduction: Pain is a multi­dimensional experience, including sensory­discriminative, affective­motivational, and cognitive­evaluative components. How these different dimensions integrate into a unified and coherent percept remains an open question (Moayedi 2014). Gamma­band oscillations (GBOs, 30­100 Hz) are considered to represent a possible mechanism to integrate low­level cortical processing of basic stimulus features with high­level cognitive processes. Zhang et al. (2012) reported that nociceptive stimuli elicit an enhancement of GBOs which can be measured using surface electroencephalograpy (EEG), and has been hypothesized to originate from the primary somatosensory cortex (SI). Because its magnitude appears to be specifically related to perceived pain intensity, this stimulus­evoked enhancement of GBOs in SI has been suggested to represent a specific biomarker for pain perception. The insula, especially its posterior portion, is considered to play a major role in pain perception, because insular lesions can alter pain perception, and because electrical stimulation and epileptic seizures in this region can generate pain­related experiences (Garcia­Larrea 2012). In the present study, we used direct intracerebral recordings performed in humans to investigate whether nociceptive stimulation elicits nociceptive­specific GBOs in the anterior and posterior insula. Methods: Insular activity was recorded from a total of 70 insular contacts in five patients with deep multicontact electrodes implanted for the presurgical evaluation of focal epilepsy (2 females, mean age: 29). The experiments comprised two sessions of four blocks each, one session per side of stimulation (right and left side of the body). The order of the blocks was randomized across participants. Each block consisted of 40 single­pulse stimuli, each lasting 40 ms, belonging to one of four sensory modalities: nociceptive, tactile, auditory and visual. Nociceptive stimuli consisted of CO2 laser pulses applied to the hand dorsum. Vibrotactile stimuli were delivered via a recoil­type vibrotactile transducer applied to the index fingertip. Visual stimuli were generated using a light­emitting diode placed on the hand dorsum. Auditory stimuli were lateralized 800­Hz sounds delivered through earphones. Participants were instructed to press a button as soon as they perceived each stimulus, and to rate its intensity on a numerical scale ranging from 0 to 10. Results: There was no significant difference in ratings of intensity across modalities (repeated­measures ANOVA, p=0.7). In four out of five patients, nociceptive stimuli consistently elicited a clear enhancement of GBO power at insular contacts, peaking 245 ms ± 12 ms after stimulus onset (Fig. 1), but not at other intracerebral contacts. Vibrotactile, auditory, and visual stimuli did not elicit such high frequency responses at any of the recorded contacts. Conclusions: Nociceptive stimuli elicit consistent GBOs in the human insula. Because non­nociceptive stimuli do not elicit a similar response, these high frequency oscillations could reflect activity specific for nociception, possibly involved in the integration of stimulus­driven and top­down determinants of pain perception

Nociceptive local field potentials recorded from the human insula are not specific for nociception

Introduction: The insula, and especially its posterior portion, is generally believed to play a specific role in nociception, as its injury can alter the perception of pain, and because electrical stimulation and epileptic seizures in this region may generate pain­related experiences (Garcia­Larrea 2012). Moreover, depth recordings in humans have shown that nociceptive stimuli elicit robust local field potentials (LFPs) in the insula, often regarded as pain­specific (Frot et al. 2014). Nevertheless, these observations are not sufficient to justify the conclusion that the posterior insula is specifically involved in the perception of pain, as this region is also involved in the processing of a wide range of non­nociceptive sensory inputs, and contributes to a large number of cognitive, affective and homeostatic functions (Cauda et al. 2012). Taking advantage of the high spatial resolution of direct intracerebral recordings performed in humans, we assessed whether the insula exhibits nociceptive­specific responses. Based on the results of previous EEG and functional magnetic resonance imaging (fMRI) experiments (Mouraux et al. 2009, 2011), and on findings showing multisensory responses in the insula (zu Eulenburg et al. 2013), we hypothesized that LFPs recorded in this region would not reflect nociceptive­specific activity, but instead, multimodal activity. Methods: Five patients (two females, mean age: 29) suffering from focal epilepsy were investigated using depth electrodes implanted at different locations, comprising the anterior and posterior insula, for a total of 70 insular sites. The experiment consisted of two sessions of four blocks, one session per side of stimulation (right and left side of the body). In each block, patients received stimuli belonging to one of four sensory modalities: thermonociceptive, vibrotactile, auditory, and visual. Each block comprised 40 stimuli, each lasting 40 ms. Nociceptive stimuli consisted of pulses of heat generated by a CO2 laser applied to the hand dorsum. Non­nociceptive somatosensory stimuli were delivered via a recoil­type vibrotactile transducer applied to the index fingertip. Visual stimuli were delivered by means of a light­emitting diode placed on the hand dorsum. Auditory stimuli consisted of loud, lateralized 800­ Hz sounds delivered through earphones. The order of the blocks was randomized across patients. Participants were asked to press a button as soon as they felt a stimulus, and to rate its intensity on a numerical scale ranging from 0 to 10. Results: All patients described the sensation elicited by the nociceptive stimuli as painful and pricking. However, the average ratings for stimulus intensity did not differ significantly across modalities (repeated­measures ANOVA, p=0.7). Nociceptive laser stimulation elicited LFPs at the same electrode contacts as non­nociceptive vibrotactile, auditory, and visual stimulation. All four types of stimuli elicited consistent LFPs in the posterior and anterior insula, appearing as large biphasic waves (Fig. 1). A blind source separation procedure based on a probabilistic independent component analysis (PICA) showed that the insular LFPs elicited by nociceptive stimulation can be entirely explained by multimodal neural activity also contributing to the LFPs elicited by non­nociceptive tactile, auditory and visual stimulation (Fig. 2). Conclusions: In contrast with current assumptions, our results indicate that insular LFPs elicited by transient nociceptive stimuli reflect multimodal cortical activities unspecific for pain. These responses could reflect mechanisms of attentional re­orientation towards salient stimuli, including, but not limited to, painful stimuli. This issue is particularly relevant, as these brain responses are commonly used to draw strong conclusions on how pain is represented in the brain (Bushnell et al. 2006; Tracey et al. 2007, 2008; Frot et al. 2013)

Mapping of global R1 and R2* values versus lipids R1 values as potential markers of hypoxia in human glial tumors: a feasibility study.

Availability of an innocuous and repeatable technique for monitoring tumor oxygenation throughout therapeutic course should be a key-factor for adaptative therapeutic strategies. We previously qualified lipids R1 as a marker of oxygen level on experimental tumor models. The objectives of the present study were to assess the applicability of measuring lipids R1 in primary Central Nervous System malignancies in a clinical setting as well as to compare lipids R1 with global (water+lipids) R1 and R2* which are also sensitive to the oxygen environment. 25 patients with brain neuroepithelial tumors were examined on a clinical 3T MR system. Values obtained within regions of interest contouring contrast-enhanced tumor (C+), unenhanced tumor (C-), peritumoral edema, and normal appearing white matter (NAWM) were compared to those obtained for the normal brain parenchyma of 17 healthy volunteers. Global R1 and lipids R1 values were significantly lower in tumors than in NAWM of patients or healthy brain of normal volunteers. In contrast, R2* values were not significantly different in tumors compared to NAWM or healthy brains. None of them showed significant difference between C+ and C- tumor. Global R1 values within NAWM were significantly different from that of both tumor and peritumoral edema, but lacked sensitivity to differentiate between tumor and peritumoral edema. In turn, lipids R1 measurements enabled discrimination between tumor areas and peritumoral edema. In conclusion, global R1 and lipids R1 deserve further attention as potential markers of tumor hypoxia in primary brain tumors

Oxygen Mapping within Healthy and Acutely Infarcted Brain Tissue in Humans Using the NMR Relaxation of Lipids: A Proof-Of-Concept Translational Study.

The clinical applicability of brain oxygenation mapping using the MOBILE (Mapping of Oxygen By Imaging Lipids relaxation Enhancement) magnetic resonance (MR) technique was assessed in the clinical setting of normal brain and of acute cerebral ischemia as a founding proof-of-concept translational study. Changes in the oxygenation level within healthy brain tissue can be detected by analyzing the spin-lattice proton relaxation ('Global T1' combining water and lipid protons) because of the paramagnetic properties of molecular oxygen. It was hypothesized that selective measurement of the relaxation of the lipid protons ('Lipids T1') would result in enhanced sensitivity of pO2 mapping because of higher solubility of oxygen in lipids than in water, and this was demonstrated in pre-clinical models using the MOBILE technique. In the present study, 12 healthy volunteers and eight patients with acute (48-72 hours) brain infarction were examined with the same clinical 3T MR system. Both Lipids R1 (R1 = 1/T1) and Global R1 were significantly different in the infarcted area and the contralateral unaffected brain tissue, with a higher statistical significance for Lipids R1 (median difference: 0.408 s-1; p<0.0001) than for Global R1 (median difference: 0.154 s-1; p = 0.027). Both Lipids R1 and Global R1 values in the unaffected contralateral brain tissue of stroke patients were not significantly different from the R1 values calculated in the brain tissue of healthy volunteers. The main limitations of the present prototypic version of the MOBILE sequence are the long acquisition time (4 min), hampering robustness of data in uncooperative patients, and a 2 mm slice thickness precluding accurate measurements in small infarcts because of partial volume averaging effects

Nociceptive Local Field Potentials Recorded from the Human Insula Are Not Specific for Nociception

The insula, particularly its posterior portion, is often regarded as a primary cortex for pain. However, this interpretation is largely based on reverse inference, and a specific involvement of the insula in pain has never been demonstrated. Taking advantage of the high spatiotemporal resolution of direct intracerebral recordings, we investigated whether the human insula exhibits local field potentials (LFPs) specific for pain. Forty-seven insular sites were investigated. Participants received brief stimuli belonging to four different modalities (nociceptive, vibrotactile, auditory, and visual). Both nociceptive stimuli and non-nociceptive vibrotactile, auditory, and visual stimuli elicited consistent LFPs in the posterior and anterior insula, with matching spatial distributions. Furthermore, a blind source separation procedure showed that nociceptive LFPs are largely explained by multimodal neural activity also contributing to non-nociceptive LFPs. By revealing that LFPs elicited by nociceptive stimuli reflect activity unrelated to nociception and pain, our results confute the widespread assumption that these brain responses are a signature for pain perception and its modulation

Nociceptive local field potentials recorded from the human insula are not specific for nociception

Introduction. Insular lesions can alter pain perception, and direct electrical stimulation of the insula can generate pain-related sensations. Furthermore, direct intracerebral recordings have shown that nociceptive stimulation can elicit robust local field potentials (LFPs) in the insula, interpreted as reflecting activity specifically involved in the encoding of pain and temperature sensations. Aims. Taking advantage of the high spatial resolution of direct intracerebral recordings performed in humans, our aim was to assess whether the insula exhibits responses that are specific to nociceptive stimulation. Methods. Six patients were investigated using depth electrodes implanted at different locations, comprising the anterior and posterior insula, for a total of 62 insular sites. Participants received brief stimuli belonging to each of the following four modalities: nociceptive laser stimuli, non-nociceptive tactile stimuli, auditory stimuli, and visual stimuli. The stimuli were delivered in blocks, both on the right and on the left side of the body. Results. All four types of stimuli elicited consistent LFPs in the posterior and anterior insula, appearing as large biphasic waves. The spatial distribution of the responses elicited by nociceptive stimulation at the different insular contacts was indistinguishable from the spatial distribution of the responses elicited by non-nociceptive tactile, auditory and visual stimulation. Conclusions Our results indicate that, in both the posterior and the anterior insula, LFPs elicited by transient nociceptive stimuli reflect cortical activities that are unspecific for pain. Importantly, this conclusion is not incompatible with the possible involvement of the insula in pain perception

Stimulus-evoked gamma-band oscillations recorded from the human insula may reflect early and nociceptive-specific stages of cortical processing

Introduction. Gamma-band oscillations (GBOs, 30-100 Hz) are considered to represent a mechanism for integrating low-level cortical processing of basic stimulus features with high-level cognitive processes. Several studies have shown that nociceptive stimuli elicit a transient enhancement of GBOs in the primary somatosensory (SI) and motor (MI) cortices whose magnitude relates to perceived pain intensity. GBOs may therefore constitute a specific and clinically relevant biomarker for the perception of pain. To this date, no study has ever investigated the presence of GBOs in the insula, a region considered to have a major role in pain representation. Aims. Using direct intracerebral recordings performed in humans, we investigate whether nociceptive stimulation elicits nociceptive-specific GBOs in the anterior and posterior insula. Methods. Six patients with deep multicontact electrodes implanted for the presurgical evaluation of focal epilepsy took part in the study. Insular activity was recorded from a total of 62 insular contacts. Patients received stimuli belonging to each of the following four sensory modalities: nociceptive somatosensory, non-nociceptive somatosensory, auditory, and visual. Results. In all patients, nociceptive stimuli consistently elicited GBOs at one or more insular electrodes, but not at other cortical and subcortical locations. In contrast, non-nociceptive somatosensory, auditory, and visual stimuli did not elicit such high frequency activities at any of the recorded contacts. Conclusions. Nociceptive stimuli elicit consistent GBOs in the insula. Because non-nociceptive stimuli do not elicit a similar response, these responses could reflect activity specific for nociception, possibly involved in the integration of stimulus-driven and top-down determinants of pain perception

Gamma-Band Oscillations Preferential for Nociception can be Recorded in the Human Insula

Transient nociceptive stimuli elicit robust phase-locked local field potentials (LFPs) in the human insula. However, these responses are not preferential for nociception, as they are also elicited by transient non-nociceptive vibrotactile, auditory, and visual stimuli. Here, we investigated whether another feature of insular activity, namely gamma-band oscillations (GBOs), is preferentially observed in response to nociceptive stimuli. Although nociception-evoked GBOs have never been explored in the insula, previous scalp electroencephalography and magnetoencephalography studies suggest that nociceptive stimuli elicit GBOs in other areas such as the primary somatosensory and prefrontal cortices, and that this activity could be closely related to pain perception. Furthermore, tracing studies showed that the insula is a primary target of spinothalamic input. Using depth electrodes implanted in 9 patients investigated for epilepsy, we acquired insular responses to brief thermonociceptive stimuli and similarly arousing non-nociceptive vibrotactile, auditory, and visual stimuli (59 insular sites). As compared with non-nociceptive stimuli, nociceptive stimuli elicited a markedly stronger enhancement of GBOs (150–300 ms poststimulus) at all insular sites, suggesting that this feature of insular activity is preferential for thermonociception. Although this activity was also present in temporal and frontal regions, its magnitude was significantly greater in the insula as compared with these other regions