Marta Maia da Cunha Oliveira Safronova

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.

Gamma-band oscillations preferential for nociception can be recorded in the human insula

Abstract 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.

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- tumors. 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 T 1 ’ 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 T 1 ’) 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

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.