Confidence of probabilistic predictions modulates the cortical response to pain.

Pain typically evolves over time, and the brain needs to learn this temporal evolution to predict how pain is likely to change in the future and orient behavior. This process is termed temporal statistical learning (TSL). Recently, it has been shown that TSL for pain sequences can be achieved using optimal Bayesian inference, which is encoded in somatosensory processing regions. Here, we investigate whether the confidence of these probabilistic predictions modulates the EEG response to noxious stimuli, using a TSL task. Confidence measures the uncertainty about the probabilistic prediction, irrespective of its actual outcome. Bayesian models dictate that the confidence about probabilistic predictions should be integrated with incoming inputs and weight learning, such that it modulates the early components of the EEG responses to noxious stimuli, and this should be captured by a negative correlation: when confidence is higher, the early neural responses are smaller as the brain relies more on expectations/predictions and less on sensory inputs (and vice versa). We show that participants were able to predict the sequence transition probabilities using Bayesian inference, with some forgetting. Then, we find that the confidence of these probabilistic predictions was negatively associated with the amplitude of the N2 and P2 components of the vertex potential: the more confident were participants about their predictions, the smaller the vertex potential. These results confirm key predictions of a Bayesian learning model and clarify the functional significance of the early EEG responses to nociceptive stimuli, as being implicated in confidence-weighted statistical learning.

Perceptual simultaneity between nociceptive and visual stimuli depends on their spatial congruence.

To protect our body against physical threats, it is important to integrate the somatic and extra-somatic inputs generated by these stimuli. Temporal synchrony is an important parameter determining multisensory interaction, and the time taken by a given sensory input to reach the brain depends on the length and conduction velocity of the specific pathways through which it is transmitted. Nociceptive inputs are transmitted through very slow conducting unmyelinated C and thinly myelinated Aδ nociceptive fibers. It was previously shown that to perceive a visual stimulus and a thermo-nociceptive stimulus applied on the hand as coinciding in time, the nociceptive stimulus must precede the visual one by 76 ms for nociceptive inputs conveyed by Aδ fibers and 577 ms for inputs conveyed by C fibers. Since spatial proximity is also hypothesized to contribute to multisensory interaction, the present study investigated the effect of spatial congruence between visual and nociceptive stimuli. Participants judged the temporal order of visual and nociceptive stimuli, with the visual stimuli flashed either next to the stimulated hand or next to the opposite unstimulated hand, and with nociceptive stimuli evoking responses mediated by either Aδ or C fibers. The amount of time by which the nociceptive stimulus had to precede the visual stimulus for them to be perceived as appearing concomitantly was smaller when the visual stimulus occurred near the hand receiving the nociceptive stimulus as compared to when it occurred near the contralateral hand. This illustrates the challenge for the brain to process the synchrony between nociceptive and non-nociceptive stimuli to enable their efficient interaction to optimize defensive reaction against physical dangers.

Poor preoperative performance at Clock Drawing Test is associated with postoperative decline in olfaction in older patients: an observational pilot study.

BACKGROUND: Decline in olfaction may occur after general anesthesia, but the exact incidence and underlying physiopathology remain scarcely investigated. Olfactory dysfunction arises with aging and is known to be linked to cognitive impairment. In this pilot study, we evaluated the incidence of immediate postoperative decline in olfaction and its association with a preoperative cognitive test, performance at Clock Drawing Test (CDT), in a group of older patients. METHODS: This pilot study is a sub-analysis of a prospective observational study. Patients ≥ 65 years old and scheduled for elective non-cardiac surgery under sevoflurane-based anesthesia were enrolled. CDT was part of the preoperative evaluation. We assessed olfaction on the day before and the day after surgery (between 16 and 26 h postoperatively) using the Sniffin' Sticks 12-item identification test, which consists of pen-like devices displaying 12 different odors. Postoperative decline in olfaction was defined as a decrease of at least 1 standard deviation in the olfactory score. RESULTS: We included a total of 93 patients, among whom 19 (20.4%) presented a postoperative decline in olfaction. The incidence of postoperative decline in olfaction was higher in the "CDT low-score" (score ≤ 5/8) group (11/34, 32.4%) than in the "CDT high-score" (score ≥ 6/8) group (8/58, 13.6%) (P = 0.030). Despite adjusting for confounding variables, CDT score remained independently associated with immediate postoperative decline in olfactory identification function (OR 0.67, 95% CI 0.48 to 0.94, P = 0.022). CONCLUSIONS: Postoperative decline in olfaction occurred in 20.4% of older patients and was associated with poor preoperative performance at CDT. TRIAL REGISTRATION: This study was retrospectively registered on https://clinicaltrials.gov/ under the NCT04700891 number (principal investigator: Victoria Van Regemorter), in December 2020.

Intra-operative electroencephalogram frontal alpha-band spectral analysis and postoperative delirium in cardiac surgery: A prospective cohort study.

BACKGROUND: Postoperative delirium (POD) remains a frequent complication after cardiac surgery, with pre-operative cognitive status being one of the main predisposing factors. However, performing complete pre-operative neuropsychological testing is challenging. The magnitude of frontal electroencephalographic (EEG) α oscillations during general anaesthesia has been related to pre-operative cognition and could constitute a functional marker for brain vulnerability. OBJECTIVE: We hypothesised that features of intra-operative α-band activity could predict the occurrence of POD. DESIGN: Single-centre prospective observational study. SETTING: University hospital, from 15 May 2019 to 15 December 2021. PATIENTS: Adult patients undergoing elective cardiac surgery. MAIN OUTCOME MEASURES: Pre-operative cognitive status was assessed by neuropsychological tests and scored as a global z score. A 5-min EEG recording was obtained 30 min after induction of anaesthesia. Anaesthesia was maintained with sevoflurane. Power and peak frequency in the α-band were extracted from the frequency spectra. POD was assessed using the Confusion Assessment Method for Intensive Care Unit, the Confusion Assessment Method and a chart review. RESULTS: Sixty-five (29.5%) of 220 patients developed POD. Delirious patients were significantly older with median [IQR] ages of 74 [64 to 79] years vs. 67 [59 to 74] years; P  < 0.001) and had lower pre-operative cognitive z scores (-0.52 ±â€Š1.14 vs. 0.21 ±â€Š0.84; P  < 0.001). Mean α power (-14.03 ±â€Š4.61 dB vs. -11.59 ±â€Š3.37 dB; P  < 0.001) and maximum α power (-11.36 ±â€Š5.28 dB vs. -8.85 ±â€Š3.90 dB; P  < 0.001) were significantly lower in delirious patients. Intra-operative mean α power was significantly associated with the probability of developing POD (adjusted odds ratio, 0.88; 95% confidence interval (CI), 0.81 to 0.96; P  = 0.007), independently of age and only whenever cognitive status was not considered. CONCLUSION: A lower intra-operative frontal α-band power is associated with a higher incidence of POD after cardiac surgery. Intra-operative measures of α power could constitute a means of identifying patients at risk of this complication. TRIAL REGISTRATION: NCT03706989.

Investigating the Origin of TMS-evoked Brain Potentials Using Topographic Analysis.

The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) represents an increasingly popular tool to non-invasively probe cortical excitability in humans. TMS-evoked brain potentials (TEPs) are composed of successive components reflecting the propagation of activity from the site of stimulation, thereby providing information on the state of brain networks. However, TMS also generates peripherally evoked sensory activity which contributes to TEP waveforms and hinders their interpretation.In the present study, we examined whether topographic analysis of TEPs elicited by stimulation of two distinct cortical targets can disentangle confounding signals from the genuine TMS-evoked cortical response. In 20 healthy subjects, TEPs were evoked by stimulation of the left primary motor cortex (M1) and the left angular gyrus (AG). Topographic dissimilarity analysis and microstate analysis were used to identify target-specific TEP components. Furthermore, we explored the contribution of cortico-spinal activation by comparing TEPs elicited by stimulation below and above the threshold to evoke motor responses.We observed topographic dissimilarity between M1 and AG TEPs until approximately 80 ms post-stimulus and identified early TEP components that likely reflect specific TMS-evoked activity. Later components peaking at 100 and 180 ms were similar in both datasets and attributed to sensory-evoked activity. Analysis of sub- and supra-threshold M1 TEPs revealed a component at 17 ms that possibly reflects the cortico-spinal output of the stimulated area. Moreover, supra-threshold M1 activation influenced the topography of almost all later components. Together, our results demonstrate the utility of topographic analysis for the evaluation and interpretation of TMS-evoked EEG responses.

Improvement of Impulsivity and Decision Making by Transcranial Direct Current Stimulation of the Dorsolateral Prefrontal Cortex in a Patient with Gambling Disorder.

Gambling disorder (GD) is a form of behavioral addiction. In recent years, it has been suggested that the application of transcranial Direct Current Stimulation (tDCS) to the dorsolateral prefrontal cortex (DLPFC), which plays a key role in top-down inhibitory control and impulsivity, may represent a new therapeutic approach for treating addictions. Here we investigated the effectiveness of a novel low dose tDCS protocol (i.e. six sessions of right anodal/left cathodal tDCS for 20 min, with a current intensity of 1 mA) applied to DLPFC in a patient with GD. To evaluate the effect of the proposed intervention, cognitive, psychological and behavioural evaluations were performed at different time points, pre and post intervention. The results showed improvement of impulsivity, decision making, and cognitive functioning after tDCS intervention. Findings of the present study suggest that low doses of right anodal/left cathodal tDCS to DLPFC may effectively improve gambling behaviour. They also suggest to carefully evaluate the effects of this tDCS polarity on the patient's emotional state. The current protocol warrants further investigation in large groups of patients, as it may provide relevant insights into the design of effective, low dose treatments of gambling disorder.

Evidence for alterations to dynamic quantitative sensory tests in patients with chronic temporomandibular myalgia: A systematic review of observational studies with meta-analysis.

BACKGROUND: Conflicting results exist between somatosensory profiles of patients with temporomandibular myalgia (TMDm). The objective of this review was to examine whether adults with TMDm show altered responses to dynamic quantitative sensory tests compared with healthy controls. METHODS: We searched five electronic databases for studies, excluding those without suitable controls or where TMDm was associated with confounding non-musculoskeletal disorders. Risk of bias was assessed with the SIGN case-control study checklist. Findings were structured around dynamic quantitative sensory tests and their localization. Where possible, we performed meta-analysis with a random inverse variance model to compare patients with TMDm and healthy controls. Statistical heterogeneity was estimated with Chi² test and inconsistency index, I². RESULTS: We extracted data from 23 studies comprising 1284 adults with chronic TMDm and 2791 healthy controls. Risk of bias was assessed as high for 20 studies. Mechanical temporal summation, the most studied phenomenon (14 studies), is increased in the upper limb of patients with TMDm (SMD = 0.43; 95% CI: .11 to .75; p = .009) but not in the jaw area (p = .09) or in the cervical area (p = .29). Very little evidence for altered thermal temporal summation (five studies), conditioned pain modulation (seven studies), exercise-induced hypoalgesia (two studies), placebo analgesia (two studies), stress-induced hypoalgesia (one study) and offset analgesia (one study) was found. DISCUSSION: A major limitation of this review was the risk of bias of included studies. Future studies would benefit from following methodological guidelines and consideration of confounding factors.

Pharmacological Probes to Validate Biomarkers for Analgesic Drug Development.

There is an urgent need for analgesics with improved efficacy, especially in neuropathic and other chronic pain conditions. Unfortunately, in recent decades, many candidate analgesics have failed in clinical phase II or III trials despite promising preclinical results. Translational assessment tools to verify engagement of pharmacological targets and actions on compartments of the nociceptive system are missing in both rodents and humans. Through the Innovative Medicines Initiative of the European Union and EFPIA, a consortium of researchers from academia and the pharmaceutical industry was established to identify and validate a set of functional biomarkers to assess drug-induced effects on nociceptive processing at peripheral, spinal and supraspinal levels using electrophysiological and functional neuroimaging techniques. Here, we report the results of a systematic literature search for pharmacological probes that allow for validation of these biomarkers. Of 26 candidate substances, only 7 met the inclusion criteria: evidence for nociceptive system modulation, tolerability, availability in oral form for human use and absence of active metabolites. Based on pharmacokinetic characteristics, three were selected for a set of crossover studies in rodents and healthy humans. All currently available probes act on more than one compartment of the nociceptive system. Once validated, biomarkers of nociceptive signal processing, combined with a pharmacometric modelling, will enable a more rational approach to selecting dose ranges and verifying target engagement. Combined with advances in classification of chronic pain conditions, these biomarkers are expected to accelerate analgesic drug development.

High-frequency electrical stimulation of cutaneous nociceptors differentially affects pain perception elicited by homotopic and heterotopic electrical stimuli.

Animal studies have shown that high-frequency electrical stimulation (HFS) of peripheral C-fiber nociceptors induces both homosynaptic and heterosynaptic long-term potentiation (LTP) within spinal nociceptive pathways. In humans, when HFS is applied onto the skin to activate nociceptors, single electrical stimuli are perceived more intense at the HFS site compared with a control site, a finding that was interpreted as a perceptual correlate of homosynaptic LTP. The present study aimed to investigate if after HFS the pain elicited by electrical stimuli delivered at the skin next to the HFS site is perceived as more intense compared with the pain at a control site (contralateral arm). To test this, HFS was applied to one of the two ventral forearms of 24 healthy participants. Before and after HFS, single electrical stimuli were delivered through the HFS electrode, through an identical electrode next to the HFS electrode and an identical electrode at the contralateral arm. After HFS, the pain elicited by the single electrical stimuli was reduced at all three sites, with the largest reduction at the HFS site. Nevertheless, electrical stimuli delivered to the skin next to the HFS site were perceived as more intense than control stimuli. This result indicates that higher pain ratings to electrical stimuli after HFS at the HFS site cannot solely be interpreted as a perceptual correlate of homosynaptic changes. Furthermore, we show for the first time, in humans, that HFS can reduce pain elicited by single electrical stimuli delivered through the same electrode.NEW & NOTEWORTHY High-frequency electrical stimulation (HFS) of cutaneous nociceptors can reduce pain perception to single electrical stimuli delivered through the same electrode. Moreover, single electrical stimuli delivered to the skin next to the site at which HFS was applied are perceived as more intense compared with that at the contralateral control site, indicating the presence of heterosynaptic effects for electrical stimuli.

Pupil-Linked Arousal Responds to Unconscious Surprisal.

Pupil size under constant illumination reflects brain arousal state, and dilates in response to novel information, or surprisal. Whether this response can be observed regardless of conscious perception is still unknown. In the present study, male and female adult humans performed an implicit learning task across a series of three experiments. We measured pupil and brain-evoked potentials to stimuli that violated transition statistics but were not relevant to the task. We found that pupil size dilated following these surprising events, in the absence of awareness of transition statistics, and only when attention was allocated to the stimulus. These pupil responses correlated with central potentials, evoking an anterior cingulate origin. Arousal response to surprisal outside the scope of conscious perception points to the fundamental relationship between arousal and information processing and indicates that pupil size can be used to track the progression of implicit learning.SIGNIFICANCE STATEMENT Pupil size dilates following increase in mental effort, surprise, or more generally global arousal. However, whether this response arises as a conscious response or reflects a more fundamental mechanism outside the scrutiny of awareness is still unknown. Here, we demonstrate that unexpected changes in the environment, even when processed unconsciously and without being relevant to the task, lead to an increase in arousal levels as reflected by the pupillary response. Further, we show that the concurrent electrophysiological response shares similarities with mismatch negativity, suggesting the involvement of anterior cingulate cortex. All in all, our results establish novel insights about the mechanisms driving global arousal levels, and it provides new possibilities for reliably measuring unconscious processes.

Processing of Laser-Evoked Potentials in Patients with Chronic Whiplash-Associated Disorders, Chronic Fatigue Syndrome, and Healthy Controls: A Case-Control Study.

OBJECTIVE: Laser-evoked potentials (LEPs) are among the reliable neurophysiological tools to investigate patients with neuropathic pain, as they can provide an objective account of the functional status of thermo-nociceptive pathways. The goal of this study was to explore the functioning of the nociceptive afferent pathways by examining LEPs in patients with chronic whiplash-associated disorders (cWAD), patients with chronic fatigue syndrome (CFS), and healthy controls (HCs). DESIGN: Case-control study. SETTING: A single medical center in Belgium. SUBJECTS: The LEPs of 21 patients with cWAD, 19 patients with CFS, and 18 HCs were analyzed in this study. METHODS: All participants received brief nociceptive CO2 laser stimuli applied to the dorsum of the left hand and left foot while brain activity was recorded with a 32-channel electroencephalogram (EEG). LEP signals and transient power modulations were compared between patient groups and HCs. RESULTS: No between-group differences were found for stimulus intensity, which was supraliminal for Aδ fibers. The amplitudes and latencies of LEP wave components N1, N2, and P2 in patients with cWAD and CFS were statistically similar to those of HCs. There were no significant differences between the time-frequency maps of EEG oscillation amplitude between HCs and both patient populations. CONCLUSIONS: EEG responses of heat-sensitive Aδ fibers in patients with cWAD and CFS revealed no significant differences from the responses of HCs. These findings thus do not support a state of generalized central nervous system hyperexcitability in those patients.

Visuomotor Correlates of Conflict Expectation in the Context of Motor Decisions.

Many behaviors require choosing between conflicting options competing against each other in visuomotor areas. Such choices can benefit from top-down control processes engaging frontal areas in advance of conflict when it is anticipated. Yet, very little is known about how this proactive control system shapes the visuomotor competition. Here, we used electroencephalography in human subjects (male and female) to identify the visual and motor correlates of conflict expectation in a version of the Eriksen Flanker task that required left or right responses according to the direction of a central target arrow surrounded by congruent or incongruent (conflicting) flankers. Visual conflict was either highly expected (it occurred in 80% of trials; mostly incongruent blocks) or very unlikely (20% of trials; mostly congruent blocks). We evaluated selective attention in the visual cortex by recording target- and flanker-related steady-state visual-evoked potentials (SSVEPs) and probed action selection by measuring response-locked potentials (RLPs) in the motor cortex. Conflict expectation enhanced accuracy in incongruent trials, but this improvement occurred at the cost of speed in congruent trials. Intriguingly, this behavioral adjustment occurred while visuomotor activity was less finely tuned: target-related SSVEPs were smaller while flanker-related SSVEPs were higher in mostly incongruent blocks than in mostly congruent blocks, and incongruent trials were associated with larger RLPs in the ipsilateral (nonselected) motor cortex. Hence, our data suggest that conflict expectation recruits control processes that augment the tolerance for inappropriate visuomotor activations (rather than processes that downregulate their amplitude), allowing for overflow activity to occur without having it turn into the selection of an incorrect response.SIGNIFICANCE STATEMENT Motor choices made in front of discordant visual information are more accurate when conflict can be anticipated, probably due to the engagement of top-down control from frontal areas. How this control system modulates activity within visual and motor areas is unknown. Here, we show that, when control processes are recruited in anticipation of conflict, as evidenced by higher midfrontal theta activity, visuomotor activity is less finely tuned: visual processing of the goal-relevant location was reduced and the motor cortex displayed more inappropriate activations, compared with when conflict was unlikely. We argue that conflict expectation is associated with an expansion of the distance-to-selection threshold, improving accuracy while the need for online control of visuomotor activity is reduced.

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.

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.

The search for pain biomarkers in the human brain.

Non-invasive functional brain imaging is used more than ever to investigate pain in health and disease, with the prospect of finding new means to alleviate pain and improve patient wellbeing. The observation that several brain areas are activated by transient painful stimuli, and that the magnitude of this activity is often graded with pain intensity, has prompted researchers to extract features of brain activity that could serve as biomarkers to measure pain objectively. However, most of the brain responses observed when pain is present can also be observed when pain is absent. For example, similar brain responses can be elicited by salient but non-painful auditory, tactile and visual stimuli, and such responses can even be recorded in patients with congenital analgesia. Thus, as argued in this review, there is still disagreement on the degree to which current measures of brain activity exactly relate to pain. Furthermore, whether more recent analysis techniques can be used to identify distributed patterns of brain activity specific for pain can be only warranted using carefully designed control conditions. On a more general level, the clinical utility of current pain biomarkers derived from human functional neuroimaging appears to be overstated, and evidence for their efficacy in real-life clinical conditions is scarce. Rather than searching for biomarkers of pain perception, several researchers are developing biomarkers to achieve mechanism-based stratification of pain conditions, predict response to medication and offer personalized treatments. Initial results with promising clinical perspectives need to be further tested for replicability and generalizability.

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.

Quickly responding C-fibre nociceptors contribute to heat hypersensitivity in the area of secondary hyperalgesia.

KEY POINTS: A recent animal study showed that high frequency electrical stimulation (HFS) of C-fibres induces a gliogenic heterosynaptic long-term potentiation at the spinal cord that is hypothesized to mediate secondary hyperalgesia in humans. Here this hypothesis was tested by predominantly activating C-fibre nociceptors in the area of secondary mechanical hyperalgesia induced by HFS in humans. It is shown that heat perception elicited by stimuli predominantly activating C-fibre nociceptors is greater, as compared to the control site, after HFS in the area of secondary mechanical hyperalgesia. This is the first study that confirms in humans the involvement of C-fibre nociceptors in the changes in heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS. ABSTRACT: It has recently been shown that high frequency electrical stimulation (HFS) of C-fibres induces a gliogenic heterosynaptic long-term potentiation (LTP) at the spinal cord in animals, which has been hypothesized to be the underlying mechanism of secondary hyperalgesia in humans. Here we tested this hypothesis using a method to predominantly activate quickly responding C-fibre nociceptors in the area of secondary hyperalgesia induced by HFS in humans. HFS was delivered to one of the two volar forearms in 18 healthy volunteers. Before, 20 min and 45 min after HFS, short-lasting (10 ms) high-intensity CO2 laser heat stimuli delivered to a very small area of the skin (0.15 mm2 ) were applied to the area of increased mechanical pinprick sensitivity at the HFS-treated arm and the homologous area of the contralateral control arm. During heat stimulation the electroencephalogram, reaction times and intensity of perception (numerical rating scale 0-100) were measured. After HFS, we observed a greater heat sensitivity, an enhancement in the number of detected trials, faster reaction times and an enhancement of the N2 wave of C-fibre laser-evoked potentials at the HFS-treated arm compared to the control arm. This is the first study that confirms in humans the involvement of C-fibre nociceptors in enhanced heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS.

Fast periodic visual stimulation to study tool-selective processing in the human brain.

Because tools are manipulated for the purpose of action, they are often considered to be a specific object category that associates perceptual and motor properties. Their neural processing has been studied extensively by comparing the cortical activity elicited by the separate presentation of tool and non-tool objects, assuming that observed differences are solely due to activity selective for processing tools. Here, using a fast periodic visual stimulation (FPVS) paradigm, we isolated EEG activity selectively related to the processing of tool objects embedded in a stream of non-tool objects. Participants saw a continuous sequence of tool and non-tool images at a 3.7 Hz presentation rate, arranged as a repeating pattern of four non-tool images followed by one tool image. We expected the stimulation to generate an EEG response at the frequency of image presentation (3.7 Hz) and its harmonics, reflecting activity common to the processing of tool and non-tool images. Most importantly, if tool and non-tool images evoked different neural responses, we expected this differential activity to generate an additional response at the frequency of tool images (3.7 Hz/5 = 0.74 Hz). To ensure that this response was not due to unaccounted for systematic differences in low-level visual features, we also tested a phase-scrambled version of the sequence. The periodic insertion of tool stimuli within a stream of non-tool stimuli elicited a significant EEG response at the tool-selective frequency and its harmonics. This response was reduced when the images were phase-scrambled. We conclude that FPVS is a promising technique to selectively measure tool-related activity.

EEG Frequency-Tagging and Input-Output Comparison in Rhythm Perception.

The combination of frequency-tagging with electroencephalography (EEG) has recently proved fruitful for understanding the perception of beat and meter in musical rhythm, a common behavior shared by humans of all cultures. EEG frequency-tagging allows the objective measurement of input-output transforms to investigate beat perception, its modulation by exogenous and endogenous factors, development, and neural basis. Recent doubt has been raised about the validity of comparing frequency-domain representations of auditory rhythmic stimuli and corresponding EEG responses, assuming that it implies a one-to-one mapping between the envelope of the rhythmic input and the neural output, and that it neglects the sensitivity of frequency-domain representations to acoustic features making up the rhythms. Here we argue that these elements actually reinforce the strengths of the approach. The obvious fact that acoustic features influence the frequency spectrum of the sound envelope precisely justifies taking into consideration the sounds used to generate a beat percept for interpreting neural responses to auditory rhythms. Most importantly, the many-to-one relationship between rhythmic input and perceived beat actually validates an approach that objectively measures the input-output transforms underlying the perceptual categorization of rhythmic inputs. Hence, provided that a number of potential pitfalls and fallacies are avoided, EEG frequency-tagging to study input-output relationships appears valuable for understanding rhythm perception.