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.

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.

EEG frequency tagging using ultra-slow periodic heat stimulation of the skin reveals cortical activity specifically related to C fiber thermonociceptors.

The recording of event-related brain potentials triggered by a transient heat stimulus is used extensively to study nociception and diagnose lesions or dysfunctions of the nociceptive system in humans. However, these responses are related exclusively to the activation of a specific subclass of nociceptive afferents: quickly-adapting thermonociceptors. In fact, except if the activation of Aδ fibers is avoided or if A fibers are blocked, these responses specifically reflect activity triggered by the activation of Type 2 quickly-adapting A fiber mechano-heat nociceptors (AMH-2). Here, we propose a novel method to isolate, in the human electroencephalogram (EEG), cortical activity related to the sustained periodic activation of heat-sensitive thermonociceptors, using very slow (0.2Hz) and long-lasting (75s) sinusoidal heat stimulation of the skin between baseline and 50°C. In a first experiment, we show that when such long-lasting thermal stimuli are applied to the hand dorsum of healthy volunteers, the slow rises and decreases of skin temperature elicit a consistent periodic EEG response at 0.2Hz and its harmonics, as well as a periodic modulation of the magnitude of theta, alpha and beta band EEG oscillations. In a second experiment, we demonstrate using an A fiber block that these EEG responses are predominantly conveyed by unmyelinated C fiber nociceptors. The proposed approach constitutes a novel mean to study C fiber function in humans, and to explore the cortical processing of tonic heat pain in physiological and pathological conditions.

Neonatal Alopecia Due to Birth Trauma: Case Report and Trichoscopic Findings.

A 4-day-old boy was referred for evaluation of an oval patch of occipital alopecia associated with caput succedaneum and ipsilateral eyelid ecchymoses. Based on the history of a prolonged, difficult labor with vacuum-assisted delivery, the diagnosis of neonatal alopecia associated with birth trauma was made. Trichoscopy showed purple dots corresponding to blood extravasation and follicular ostia. We also review the trichoscopic differential diagnosis of focal neonatal alopecia.

Assistive device with conventional, alternative, and brain-computer interface inputs to enhance interaction with the environment for people with amyotrophic lateral sclerosis: a feasibility and usability study.

OBJECTIVE: To evaluate the feasibility and usability of an assistive technology (AT) prototype designed to be operated with conventional/alternative input channels and a P300-based brain-computer interface (BCI) in order to provide users who have different degrees of muscular impairment resulting from amyotrophic lateral sclerosis (ALS) with communication and environmental control applications. DESIGN: Proof-of-principle study with a convenience sample. SETTING: An apartment-like space designed to be fully accessible by people with motor disabilities for occupational therapy, placed in a neurologic rehabilitation hospital. PARTICIPANTS: End-users with ALS (N=8; 5 men, 3 women; mean age ± SD, 60 ± 12 y) recruited by a clinical team from an ALS center. INTERVENTIONS: Three experimental conditions based on (1) a widely validated P300-based BCI alone; (2) the AT prototype operated by a conventional/alternative input device tailored to the specific end-user's residual motor abilities; and (3) the AT prototype accessed by a P300-based BCI. These 3 conditions were presented to all participants in 3 different sessions. MAIN OUTCOME MEASURES: System usability was evaluated in terms of effectiveness (accuracy), efficiency (written symbol rate, time for correct selection, workload), and end-user satisfaction (overall satisfaction) domains. A comparison of the data collected in the 3 conditions was performed. RESULTS: Effectiveness and end-user satisfaction did not significantly differ among the 3 experimental conditions. Condition III was less efficient than condition II as expressed by the longer time for correct selection. CONCLUSIONS: A BCI can be used as an input channel to access an AT by persons with ALS, with no significant reduction of usability.

Brain-machine interface in chronic stroke rehabilitation: a controlled study.

OBJECTIVE: Chronic stroke patients with severe hand weakness respond poorly to rehabilitation efforts. Here, we evaluated efficacy of daily brain-machine interface (BMI) training to increase the hypothesized beneficial effects of physiotherapy alone in patients with severe paresis in a double-blind sham-controlled design proof of concept study. METHODS: Thirty-two chronic stroke patients with severe hand weakness were randomly assigned to 2 matched groups and participated in 17.8 ± 1.4 days of training rewarding desynchronization of ipsilesional oscillatory sensorimotor rhythms with contingent online movements of hand and arm orthoses (experimental group, n = 16). In the control group (sham group, n = 16), movements of the orthoses occurred randomly. Both groups received identical behavioral physiotherapy immediately following BMI training or the control intervention. Upper limb motor function scores, electromyography from arm and hand muscles, placebo-expectancy effects, and functional magnetic resonance imaging (fMRI) blood oxygenation level-dependent activity were assessed before and after intervention. RESULTS: A significant group × time interaction in upper limb (combined hand and modified arm) Fugl-Meyer assessment (cFMA) motor scores was found. cFMA scores improved more in the experimental than in the control group, presenting a significant improvement of cFMA scores (3.41 ± 0.563-point difference, p = 0.018) reflecting a clinically meaningful change from no activity to some in paretic muscles. cFMA improvements in the experimental group correlated with changes in fMRI laterality index and with paretic hand electromyography activity. Placebo-expectancy scores were comparable for both groups. INTERPRETATION: The addition of BMI training to behaviorally oriented physiotherapy can be used to induce functional improvements in motor function in chronic stroke patients without residual finger movements and may open a new door in stroke neurorehabilitation.

Cue-based modulation of pain stimulus expectation: do ongoing oscillations reflect changes in pain perception? A registered report.

A promising stream of investigations is targeting ongoing neural oscillations and whether their modulation could be related to the perception of pain. Using an electroencephalography (EEG) frequency-tagging approach, sustained periodic thermonociceptive stimuli perceived as painful have been shown to modulate ongoing oscillations in the theta, alpha and beta bands at the frequency of stimulation. Nonetheless, it remains uncertain whether these modulations are indeed linked to pain perception. To test this relationship, we modulated pain perception using a cue-based expectation modulation paradigm and investigated whether ongoing oscillations in different frequency bands mirror the changes in stimulus perception. Forty healthy participants were instructed that a visual cue can precede either a high- or low-intensity stimulation. These cues were paired with three different levels of sustained periodic thermonociceptive stimuli (low, medium and high). Despite a strong effect of expectation on perceived stimulus intensity, this effect was not reflected in the modulation of the ongoing oscillations, suggesting a potential dissociation of pain perception and these oscillatory activities. Rather, it seems that the intensity of stimulation is the primary generator of the frequency-tagged EEG responses. Importantly, these results need to be confirmed by further investigations that could allow the detection of smaller effects than originally estimated.

Electroencephalogram synchronization measure as a predictive biomarker of Vagus nerve stimulation response in refractory epilepsy: A retrospective study.

There are currently no established biomarkers for predicting the therapeutic effectiveness of Vagus Nerve Stimulation (VNS). Given that neural desynchronization is a pivotal mechanism underlying VNS action, EEG synchronization measures could potentially serve as predictive biomarkers of VNS response. Notably, an increased brain synchronization in delta band has been observed during sleep-potentially due to an activation of thalamocortical circuitry, and interictal epileptiform discharges are more frequently observed during sleep. Therefore, investigation of EEG synchronization metrics during sleep could provide a valuable insight into the excitatory-inhibitory balance in a pro-epileptogenic state, that could be pathological in patients exhibiting a poor response to VNS. A 19-channel-standard EEG system was used to collect data from 38 individuals with Drug-Resistant Epilepsy (DRE) who were candidates for VNS implantation. An EEG synchronization metric-the Weighted Phase Lag Index (wPLI)-was extracted before VNS implantation and compared between sleep and wakefulness, and between responders (R) and non-responders (NR). In the delta band, a higher wPLI was found during wakefulness compared to sleep in NR only. However, in this band, no synchronization difference in any state was found between R and NR. During sleep and within the alpha band, a negative correlation was found between wPLI and the percentage of seizure reduction after VNS implantation. Overall, our results suggest that patients exhibiting a poor VNS efficacy may present a more pathological thalamocortical circuitry before VNS implantation. EEG synchronization measures could provide interesting insights into the prerequisites for responding to VNS, in order to avoid unnecessary implantations in patients showing a poor therapeutic efficacy.

The role of ongoing oscillation in pain perception: Absence of modulation by a concomitant arithmetic task.

Sustained nociceptive stimuli have been shown to modulate the amplitude of ongoing neural oscillations in the theta, alpha and beta frequency bands at the frequency of stimulation, suggesting a relationship between these ongoing oscillations and pain perception. Yet, whether these ongoing oscillations are actually related to the pain experience remains unclear. If it were the case, then cognitive processes that are known to affect pain intensity should also affect these ongoing oscillations. To this end, we used electroencephalography (EEG) to investigate whether distraction - an attentional state known to affect pain perception - also modulates the amplitude of these neural oscillations. More specifically, we hypothesized that performing an unrelated arithmetic task during sustained nociceptive stimulation would lead to a decrease in the modulations of ongoing oscillations exerted by the stimulation. To assess the selectivity of this modulation for nociception, we compared the modulations of ongoing oscillations exerted by sustained periodic thermonociceptive and non-nociceptive vibrotactile stimulation (.2 Hz, 75 sec), while participants were either asked to solve an unrelated arithmetic task (distraction task) or received no specific instruction (baseline). The intensity of perception was significantly reduced by the arithmetic task in both the thermonociceptive and the vibrotactile modality, and the sustained periodic stimulation elicited a periodic response at the frequency of stimulation in both modalities. However, the distraction task did not show a differential effect for the two stimulation modalities in any of the frequency bands. The fact that, unlike pain perception, these oscillations did not appear to be affected by the task suggests that they are dissociable from pain perception. Whether a different task (leading to a stronger degree of distraction) could lead to different results is unclear.

Using brain-computer interfaces to overcome the extinction of goal-directed thinking in minimally conscious state patients.

Minimally conscious state (MCS) is a condition of severely altered consciousness, in which patients appear to be wakeful and exhibit fluctuating but reproducible signs of awareness. MCS patients do not respond and are therefore dependent on others. In agreement with the embodied cognition assumption that motor actions influence our cognition, the absence of movement and the decrease in consequences for any type of covert or overt response may cause an extinction of goal-directed thinking. Brain-computer interfaces, which allow a direct output without muscular involvement, may be used to promote goal-directed thinking by allowing the performance of spatial and motor imagery tasks and could facilitate the interaction of MCS patients with their environment, possibly regaining some degree of communication and autonomy.

Cognitive reserve and its implications for rehabilitation and Alzheimer's disease.

According to the Cognitive reserve hypothesis, several factors related to mental engagement, such as level of education, type of occupation, leisure activities and social network, appear to affect the risk of developing clinical dementia. The present article provides an overview of the studies that have investigated the effects of mental engagement and cognitive stimulation specifically on dementia of the Alzheimer's type (AD). Mental training and cognitive stimulation interventions in AD have been shown to be useful in increasing patients' ability in performing activities of daily living (ADL), allowing them to maintain relative independence. Since cognitive engagement and stimulation are known to modify the brain processes to perform tasks, by recruiting alternative and more efficient networks, this review is especially focused on cognitive rehabilitation in AD patients, which has been shown to improve their global functioning and cognition. This perspective stresses the idea that cognitive reserve is not a fixed factor, but can be continuously modified by life experiences, even when the brain is already affected by neuropathology.

Characterization of vagus nerve stimulation-induced pupillary responses in epileptic patients.

BACKGROUND: Modulation of the locus coeruleus (LC)-noradrenergic system is a key mechanism of vagus nerve stimulation (VNS). Activation of the LC produces pupil dilation, and the VNS-induced change in pupil diameter was demonstrated in animals as a possible dose-dependent biomarker for treatment titration. OBJECTIVE: This study aimed to characterize VNS-induced pupillary responses in epileptic patients. METHODS: Pupil diameter was recorded in ten epileptic patients upon four stimulation conditions: three graded levels of VNS intensity and a somatosensory control stimulation (cutaneous electrical stimulation over the left clavicle). For each block, the patients rated the intensity of stimulation on a numerical scale. We extracted the latency of the peak pupil dilation and the magnitude of the early (0-2.5 s) and late components (2.5-5 s) of the pupil dilation response (PDR). RESULTS: VNS elicited a peak dilation with longer latency compared to the control condition (p = 0.043). The magnitude of the early PDR was significantly correlated with the intensity of perception (p = 0.046), whereas the late PDR was not (p = 0.19). There was a significant main effect of the VNS level of intensity on the magnitude of the late PDR (p = 0.01) but not on the early PDR (p = 0.2). The relationship between late PDR magnitude and VNS intensity was best fit by a Gaussian model (inverted-U). CONCLUSIONS: The late component of the PDR might reflect specific dose-dependent effects of VNS, as compared to control somatosensory stimulation. The inverted-U relationship of late PDR with VNS intensity might indicate the engagement of antagonist central mechanisms at high stimulation intensities.

Transcutaneous auricular VNS applied to experimental pain: A paired behavioral and EEG study using thermonociceptive CO2 laser.

BACKGROUND: Transcutaneous auricular Vagal Nerve Stimulation (taVNS) is a non-invasive neurostimulation technique with potential analgesic effects. Several studies based on subjective behavioral responses suggest that taVNS modulates nociception differently with either pro-nociceptive or anti-nociceptive effects. OBJECTIVE: This study aimed to characterize how taVNS alters pain perception, by investigating its effects on event-related potentials (ERPs) elicited by different types of spinothalamic and lemniscal somatosensory stimuli, combined with quantitative sensory testing (detection threshold and intensity ratings). METHODS: We performed 3 experiments designed to study the time-dependent effects of taVNS and compare with standard cervical VNS (cVNS). In Experiment 1, we assessed the effects of taVNS after 3 hours of stimulation. In Experiment 2, we focused on the immediate effects of the duty cycle (OFF vs. ON phases). Experiments 1 and 2 included 22 and 15 healthy participants respectively. Both experiments consisted of a 2-day cross-over protocol, in which subjects received taVNS and sham stimulation sequentially. In addition, subjects received a set of nociceptive (thermonociceptive CO2 laser, mechanical pinprick) and non-nociceptive (vibrotactile, cool) stimuli, for which we recorded detection thresholds, intensity of perception and ERPs. Finally, in Experiment 3, we tested 13 epileptic patients with an implanted cVNS by comparing OFF vs. ON cycles, using a similar experimental procedure. RESULTS: Neither taVNS nor cVNS appeared to modulate the cerebral and behavioral aspects of somatosensory perception. CONCLUSION: The potential effect of taVNS on nociception requires a cautious interpretation, as we found no objective change in behavioral and cerebral responses to spinothalamic and lemniscal somatosensory stimulations.

Vagus Nerve Stimulation Elicits Sleep EEG Desynchronization and Network Changes in Responder Patients in Epilepsy.

Neural desynchronization was shown as a key mechanism of vagus nerve stimulation (VNS) action in epilepsy, and EEG synchronization measures are explored as possible response biomarkers. Since brain functional organization in sleep shows different synchrony and network properties compared to wakefulness, we aimed to explore the effects of acute VNS on EEG-derived measures in the two different states of vigilance. EEG epochs were retrospectively analyzed from twenty-four VNS-treated epileptic patients (11 responders, 13 non-responders) in calm wakefulness and stage N2 sleep. Weighted Phase Lag Index (wPLI) was computed as connectivity measure of synchronization, for VNS OFF and VNS ON conditions. Global efficiency (GE) was computed as a network measure of integration. Ratios OFF/ON were obtained as desynchronization/de-integration index. Values were compared between responders and non-responders, and between EEG states. ROC curve and area-under-the-curve (AUC) analysis was performed for response classification. In responders, stronger VNS-induced theta desynchronization (p < 0.05) and decreased GE (p < 0.05) were found in sleep, but not in wakefulness. Theta sleep wPLI Ratio OFF/ON yielded an AUC of 0.825, and 79% accuracy as a response biomarker if a cut-off value is set at 1.05. Considering all patients, the VNS-induced GE decrease was significantly more important in sleep compared to awake EEG state (p < 0.01). In conclusion, stronger sleep EEG desynchronization in theta band distinguishes responders to VNS therapy from non-responders. VNS-induced reduction of network integration occurs significantly more in sleep than in wakefulness.

A patient with psoriasis and vitiligo treated with etanercept.

Psoriasis is a chronic, immune-mediated, inflammatory dermatosis whose aetiopathogenesis remains unclear, although tumour necrosis factor alpha (TNFalpha) appears to play a crucial role. The biological potential of TNFalpha inhibitors, such as etanercept, which reduce the inflammatory cascade, has radically changed the therapeutic management of patients with psoriasis and other immunomediated inflammatory diseases, associated with TNFalpha. The pathogenesis of the selective destruction of melanocytes in vitiligo is not fully understood, although there is growing evidence that several T helper type 1 cytokines, particularly TNFalpha, may be involved in the depigmentation process. A patient is described who presented with both psoriasis and vitiligo, and was treated with etanercept. After 24 weeks of therapy, the patient's psoriasis had improved markedly and the patient noted a mild improvement of vitiligo, with a reduction in macules and repigmentation in the scapular region.

Dynamics of the perception and EEG signals triggered by tonic warm and cool stimulation.

Thermosensation is crucial for humans to probe the environment and detect threats arising from noxious heat or cold. Over the last years, EEG frequency-tagging using long-lasting periodic radiant heat stimulation has been proposed as a means to study the cortical processes underlying tonic heat perception. This approach is based on the notion that periodic modulation of a sustained stimulus can elicit synchronized periodic activity in the neuronal populations responding to the stimulus, known as a steady-state response (SSR). In this paper, we extend this approach using a contact thermode to generate both heat- and cold-evoked SSRs. Furthermore, we characterize the temporal dynamics of the elicited responses, relate these dynamics to perception, and assess the effects of displacing the stimulated skin surface to gain insight on the heat- and cold-sensitive afferents conveying these responses. Two experiments were conducted in healthy volunteers. In both experiments, noxious heat and innocuous cool stimuli were applied during 75 seconds to the forearm using a Peltier-based contact thermode, with intensities varying sinusoidally at 0.2 Hz. Displacement of the thermal stimulation on the skin surface was achieved by independently controlling the Peltier elements of the thermal probe. Continuous intensity ratings to sustained heat and cold stimulation were obtained in the first experiment with 14 subjects, and the EEG was recorded in the second experiment on 15 subjects. Both contact heat and cool stimulation elicited periodic EEG responses and percepts. Compared to heat stimulation, the responses to cool stimulation had a lower magnitude and shorter latency. All responses tended to habituate along time, and this response attenuation was most pronounced for cool compared to warm stimulation, and for stimulation delivered using a fixed surface compared to a variable surface.

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.