Tonic thermonociceptive stimulation selectively modulates ongoing neural oscillations in the human posterior insula: Evidence from intracerebral EEG.

The human insula is an important target for spinothalamic input, but there is still no consensus on its role in pain perception and nociception. In this study, we show that the human insula exhibits activity preferential for sustained thermonociception. Using intracerebral EEG recorded from the insula of 8 patients (2 females) undergoing a presurgical evaluation of focal epilepsy (53 contacts: 27 anterior, 26 posterior), we "frequency-tagged" the insular activity elicited by sustained thermonociceptive and vibrotactile stimuli, by periodically modulating stimulation intensity at a fixed frequency of 0.2 Hz during 75 s. Both types of stimuli elicited an insular response at the frequency of stimulation (0.2 Hz) and its harmonics, whose magnitude was significantly greater in the posterior insula compared to the anterior insula. Compared to vibrotactile stimulation, thermonociceptive stimulation exerted a markedly greater 0.2 Hz modulation of ongoing theta-band (4-8 Hz) and alpha-band (8-12 Hz) oscillations. These modulations were also more prominent in the posterior insula compared to the anterior insula. The identification of oscillatory activities preferential for thermonociception could lead to new insights into the physiological mechanisms of nociception and pain perception in humans.

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.

Deep continuous theta burst stimulation of the operculo-insular cortex selectively affects Aδ-fibre heat pain.

KEY POINTS: Deep continuous theta burst stimulation (cTBS) of the right operculo-insular cortex delivered with a double cone coil selectively impairs the ability to perceive thermonociceptive input conveyed by Aδ-fibre thermonociceptors without concomitantly affecting the ability to perceive innocuous warm, cold or vibrotactile sensations. Unlike deep cTBS, superficial cTBS of the right operculum delivered with a figure-of-eight coil does not affect the ability to perceive thermonociceptive input conveyed by Aδ-fibre thermonociceptors. The effect of deep operculo-insular cTBS on the perception of Aδ-fibre input was present at both the contralateral and the ipsilateral hand. The magnitude of the increase in Aδ-heat detection threshold induced by the deep cTBS was significantly correlated with the intensity of the cTBS pulses. Deep cTBS delivered over the operculo-insular cortex is associated with a risk of transcranial magnetic stimulation-induced seizure. ABSTRACT: Previous studies have suggested a pivotal role of the insular cortex in nociception and pain perception. Using a double-cone coil designed for deep transcranial magnetic stimulation, our objective was to assess (1) whether continuous theta burst stimulation (cTBS) of the operculo-insular cortex affects differentially the perception of different types of thermal and mechanical somatosensory inputs, (2) whether the induced after-effects are lateralized relative to the stimulated hemisphere, and (3) whether the after-effects are due to neuromodulation of the insula or neuromodulation of the more superficial opercular cortex. Seventeen participants took part in two experiments. In Experiment 1, thresholds and perceived intensity of Aδ- and C-fibre heat pain elicited by laser stimulation, non-painful cool sensations elicited by contact cold stimulation and mechanical vibrotactile sensations were assessed at the left hand before, immediately after and 20 min after deep cTBS delivered over the right operculo-insular cortex. In Experiment 2, Aδ-fibre heat pain and vibrotactile sensations elicited by stimulating the contralateral and ipsilateral hands were evaluated before and after deep cTBS or superficial cTBS delivered using a flat figure-of-eight coil. Only the threshold to detect Aδ-fibre heat pain was significantly increased 20 min after deep cTBS. This effect was present at both hands. No effect was observed after superficial cTBS. Neuromodulation of the operculo-insular cortex using deep cTBS induces a bilateral reduction of the ability to perceive Aδ-fibre heat pain, without concomitantly affecting the ability to perceive innocuous warm, cold or vibrotactile sensations.

Insular responses to transient painful and non-painful thermal and mechanical spinothalamic stimuli recorded using intracerebral EEG.

Brief thermo-nociceptive stimuli elicit low-frequency phase-locked local field potentials (LFPs) and high-frequency gamma-band oscillations (GBOs) in the human insula. Although neither of these responses constitute a direct correlate of pain perception, previous findings suggest that insular GBOs may be strongly related to the activation of the spinothalamic system and/or to the processing of thermal information. To disentangle these different features of the stimulation, we compared the insular responses to brief painful thermonociceptive stimuli, non-painful cool stimuli, mechano-nociceptive stimuli, and innocuous vibrotactile stimuli, recorded using intracerebral electroencephalograpic activity in 7 epileptic patients (9 depth electrodes, 58 insular contacts). All four types of stimuli elicited consistent low-frequency phase-locked LFPs throughout the insula, possibly reflecting supramodal activity. The latencies of thermo-nociceptive and cool low-frequency phase-locked LFPs were shorter in the posterior insula compared to the anterior insula, suggesting a similar processing of thermal input initiating in the posterior insula, regardless of whether the input produces pain and regardless of thermal modality. In contrast, only thermo-nociceptive stimuli elicited an enhancement of insular GBOs, suggesting that these activities are not simply related to the activation of the spinothalamic system or to the conveyance of thermal information.

Habituation of phase-locked local field potentials and gamma-band oscillations recorded from the human insula.

Salient nociceptive and non-nociceptive stimuli elicit low-frequency local field potentials (LFPs) in the human insula. Nociceptive stimuli also elicit insular gamma-band oscillations (GBOs), possibly preferential for thermonociception, which have been suggested to reflect the intensity of perceived pain. To shed light on the functional significance of these two responses, we investigated whether they would be modulated by stimulation intensity and temporal expectation - two factors contributing to stimulus saliency. Insular activity was recorded from 8 depth electrodes (41 contacts) implanted in the left insula of 6 patients investigated for epilepsy. Thermonociceptive, vibrotactile, and auditory stimuli were delivered using two intensities. To investigate the effects of temporal expectation, the stimuli were delivered in trains of three identical stimuli (S1-S2-S3) separated by a constant 1-s interval. Stimulation intensity affected intensity of perception, the magnitude of low-frequency LFPs, and the magnitude of nociceptive GBOs. Stimulus repetition did not affect perception. In contrast, both low-frequency LFPs and nociceptive GBOs showed a marked habituation of the responses to S2 and S3 as compared to S1 and, hence, a dissociation with intensity of perception. Most importantly, although insular nociceptive GBOs appear to be preferential for thermonociception, they cannot be considered as a correlate of perceived pain.

Theta burst stimulation applied over primary motor and somatosensory cortices produces analgesia unrelated to the changes in nociceptive event-related potentials.

Continuous theta burst stimulation (cTBS) applied over the primary motor cortex (M1) can alleviate pain although the neural basis of this effect remains largely unknown. Besides, the primary somatosensory cortex (S1) is thought to play a pivotal role in the sensori-discriminative aspects of pain perception but the analgesic effect of cTBS applied over S1 remains controversial. To investigate cTBS-induced analgesia we characterized, in two separate experiments, the effect of cTBS applied either over M1 or S1 on the event-related brain potentials (ERPs) and perception elicited by nociceptive (CO2 laser stimulation) and non-nociceptive (transcutaneous electrical stimulation) somatosensory stimuli. All stimuli were delivered to the ipsilateral and contralateral hand. We found that both cTBS applied over M1 and cTBS applied over S1 significantly reduced the percept elicited by nociceptive stimuli delivered to the contralateral hand as compared to similar stimulation of the ipsilateral hand. In contrast, cTBS did not modulate the perception of non-nociceptive stimuli. Surprisingly, this side-dependent analgesic effect of cTBS was not reflected in the amplitude modulation of nociceptive ERPs. Indeed, both nociceptive (N160, N240 and P360 waves) and late-latency non-nociceptive (N140 and P200 waves) ERPs elicited by stimulation of the contralateral and ipsilateral hands were similarly reduced after cTBS, suggesting an unspecific effect, possibly due to habituation or reduced alertness. In conclusion, cTBS applied over M1 and S1 reduces similarly the perception of nociceptive inputs originating from the contralateral hand, but this analgesic effect is not reflected in the magnitude of nociceptive ERPs.