Functional connectivity between medial pulvinar and cortical networks as a predictor of arousal to noxious stimuli during sleep.

The interruption of sleep by a nociceptive stimulus is favoured by an increase in the pre-stimulus functional connectivity between sensory and higher level cortical areas. In addition, stimuli inducing arousal also trigger a widespread electroencephalographic (EEG) response reflecting the coordinated activation of a large cortical network. Because functional connectivity between distant cortical areas is thought to be underpinned by trans-thalamic connections involving associative thalamic nuclei, we investigated the possible involvement of one principal associative thalamic nucleus, the medial pulvinar (PuM), in the sleeper's responsiveness to nociceptive stimuli. Intra-cortical and intra-thalamic signals were analysed in 440 intracranial electroencephalographic (iEEG) segments during nocturnal sleep in eight epileptic patients receiving laser nociceptive stimuli. The spectral coherence between the PuM and 10 cortical regions grouped in networks was computed during 5 s before and 1 s after the nociceptive stimulus and contrasted according to the presence or absence of an arousal EEG response. Pre- and post-stimulus phase coherence between the PuM and all cortical networks was significantly increased in instances of arousal, both during N2 and paradoxical (rapid eye movement [REM]) sleep. Thalamo-cortical enhancement in coherence involved both sensory and higher level cortical networks and predominated in the pre-stimulus period. The association between pre-stimulus widespread increase in thalamo-cortical coherence and subsequent arousal suggests that the probability of sleep interruption by a noxious stimulus increases when it occurs during phases of enhanced trans-thalamic transfer of information between cortical areas.

Video versus ultrasound pupillometry for detecting increased pupillary diameters due to nociceptive stimuli: a prospective observational study.

PURPOSE: Ultrasound pupillometry (UP) is a potential alternative to video pupillometry (VP) for assessing changes in patients' pupillary diameter (ΔPD) due to surgical nociception, but the reproducibility of UP and VP has been unclear. We evaluated the reproducibility of nociceptive ΔPD measured with both methods. SUBJECTS AND METHODS: This prospective observational trial with 15 healthy volunteers aged ≥ 18 years was conducted at a Japanese teaching hospital. The ΔPD due to tetanic stimuli randomly applied at 10-60 mA was measured with VP and UP. The primary outcome was the correlation between the ΔPD measured with VP and that measured with UP. The secondary outcome was the agreement between the methods. We also evaluated ΔPD pattern changes due to the raised pain intensity in each method. RESULTS: The noxious ΔPD values of UP were weakly but significantly correlated with those of VP (Spearman's ρ = 0.38, p < 0.001). A significant constant error was identified between the two measurements (Bland-Altman: mean of the difference in ΔPD (VP - UP), - 0.4 [95% CI: - 0.52 to - 0.28, p < 0.001], generalized estimating equation: a beta estimator of ΔPD: 0.41, [95% CI: 0.26-0.56, p < 0.001]). The ΔPD pattern changes due to the raised tetanic stimuli were almost the same in the two methods. CONCLUSION: Due to the significant constant error, we consider the reproducibility of the measured ΔPD between UP and VP moderate. Trial registry number UMIN 000047145. Prior to the subjects' enrollment, the trial was registered with the University Hospital Medical Information Network (Principal investigator: Mao Konno, Date of registration: 3.11.2022). https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000053778 .

Intracortical Functional Connectivity Predicts Arousal to Noxious Stimuli during Sleep in Humans.

Nociceptive stimuli disrupt sleep, but may, or may not, entail an arousal. While arousal reactions go along with the activation of a widespread cortical network, the factors enabling such activation remain unknown. Here we used intracranial EEG in humans to test the relation between the cortical activity immediately preceding a noxious stimulus and the capacity of such a stimulus to trigger arousal. Intracranial EEG signals were analyzed during all-night sleep in 14 epileptic patients (4 women), who received laser stimuli slightly above their individual pain threshold. During 5 s preceding each stimulus, the functional correlation (spectral phase-coherence) between the main spinothalamic sensory area (posterior insula) and 12 other brain regions, grouped in four networks, as well as their spectral contents, were contrasted according to the presence of a stimulus-induced arousal, and then fed into a logistic regression model to assess their predictive value. Enhanced prestimulus phase-coherence between the sensory posterior insula and neocortical and limbic areas increased significantly the probability of arousal to nociceptive stimuli, in both slow-wave (N2) and rapid eye movements/paradoxical sleep. Furthermore, during N2 sleep, arousal was facilitated by stimulus delivery in periods of attenuated slow-wave activity. Together, these data indicate that sleep micro-states with enhanced interareal communication facilitate information transfer from sensory to higher-order cortical areas, and hence physiological arousal.SIGNIFICANCE STATEMENT Sleep is commonly subdivided into stages based on specific electrophysiological characteristics; however, within each single sleep stage, the functional state of the brain is continuously changing. Here we show that the probability for a phasic noxious stimulus to entail an arousal is modulated by the prestimulus interareal phase-coherence between sensory and higher-level cortical areas. Fluctuations in interareal communication immediately before the noxious stimulus may determine the responsiveness to incoming input by facilitating or preventing the transfer of noxious information from sensory to multiple higher-level cortical networks.

Thalamic Responses to Nociceptive-Specific Input in Humans: Functional Dichotomies and Thalamo-Cortical Connectivity.

While nociceptive cortical activation is now well characterized in humans, understanding of the nociceptive thalamus remains largely fragmentary. We used laser stimuli and intracerebral electrodes in 17 human subjects to record nociceptive-specific field responses in 4 human thalamic nuclei and a number of cortical areas. Three nuclei known to receive spinothalamic (STT) projections in primates (ventro-postero-lateral [VPL], anterior pulvinar [PuA], and central lateral [CL]) exhibited responses with similar latency, indicating their parallel activation by nociceptive afferents. Phase coherence analysis, however, revealed major differences in their functional connectivity: while VPL and PuA drove a limited set of cortical targets, CL activities were synchronized with a large network including temporal, parietal, and frontal areas. Our data suggest that STT afferents reach simultaneously a set of lateral and medial thalamic regions unconstrained by traditional nuclear borders. The broad pattern of associated cortical networks suggests that a single nociceptive volley is able to trigger the sensory, cognitive, and emotional activities that underlie the complex pain experience. The medial pulvinar, an associative nucleus devoid of STT input, exhibited delayed responses suggesting its dependence on descending cortico-thalamic projections. Its widespread cortical connectivity suggests a role in synchronizing parietal, temporal, and frontal activities, hence contributing to the access of noxious input to conscious awareness.

Pain networks from the inside: Spatiotemporal analysis of brain responses leading from nociception to conscious perception.

Conscious perception of painful stimuli needs the contribution of an extensive cortico-subcortical network, and is completed in less than one second. While initial activities in operculo-insular and mid-cingulate cortices have been extensively assessed, the activation timing of most areas supporting conscious pain has barely been studied. Here we used intracranial EEG to investigate the dynamics of 16 brain regions (insular, parietal, prefrontal, cingulate, hippocampal and limbic) during the first second following nociceptive-specific laser pulses. Three waves of activation could be defined according to their temporal relation with conscious perception, ascertained by voluntary motor responses. Pre-conscious activities were recorded in the posterior insula, operculum, mid-cingulate and amygdala. Antero-insular, prefrontal and posterior parietal activities started later and developed during time-frames consistent with conscious voluntary reactions. Responses from hippocampus, perigenual and perisplenial cingulate developed latest and persisted well after conscious perception occurred. Nociceptive inputs reach simultaneously sensory and limbic networks, probably through parallel spino-thalamic and spino-parabrachial pathways, and the initial limbic activation precedes conscious perception of pain. Access of sensory information to consciousness develops concomitant to fronto-parietal activity, while late-occurring responses in the hippocampal region, perigenual and posterior cingulate cortices likely underlie processes linked to memory encoding, self-awareness and pain modulation. Hum Brain Mapp 37:4301-4315, 2016. © 2016 Wiley Periodicals, Inc.

Stay or go? Neuronal activity in medial frontal cortex during a voluntary tactile preference task in head-fixed mice.

The decision to move is influenced by sensory, attentional, and motivational cues. One such cue is the quality of the tactile input, with noxious or unpleasant sensations causing an animal to move away from the cue. Processing of painful and unpleasant sensation in the cortex involves multiple brain regions, although the specific role of the brain areas involved in voluntary, rather than reflexive movement away from unpleasant stimuli is not well understood. Here, we focused on the medial subdivision of secondary motor cortex, which is proposed to link sensory and contextual cues to motor action, and tested its role in controlling voluntary movement in the context of an aversive tactile cue. We designed a novel, 3D-printed tactile platform consisting of innocuous (grid) and mildly noxious (spiked) surfaces (50:50 % of total area), which enabled monitoring neuronal activity in the medial frontal cortex by two-photon imaging during a sensory preference task in head-fixed mice. We found that freely moving mice spent significantly less time on a spiked-surface, and that this preference was eliminated by administration of a local anesthetic. At the neuronal level, individual neurons were differentially modulated specific to the tactile surface encountered. At the population level, the neuronal activity was analyzed in relation to the events where mice chose to "stop-on" or "go-from" a specific tactile surface and when they "switched" surfaces without stopping. Notably, each of these three scenarios showed population activity that differed significantly between the grid and spiked tactile surfaces. Collectively, these data provide evidence that tactile quality is encoded within medial frontal cortex. The task pioneered in this study provides a valuable tool to better evaluate mouse models of nociception and pain, using a voluntary task that allows simultaneous recording of preference and choice.

Evaluation of Autonomic Nervous System Function Using Heart Rate Variability Analysis During Transient Heart Rate Reduction Caused by Acupuncture.

Objective: Human studies have demonstrated that heart rate (HR) decreases during acupuncture stimulation, and pharmacologic studies have shown that this autonomic nervous system (ANS) response is parasympathetic-dominant. It has become clear that significant changes occur in the ANS after acupuncture, based on HR variability (HRV). However, it is inconclusive, according to HRV analysis, if acupuncture induces a significant change in autonomic function during stimulation. The aim of this study was to investigate ANS function using HRV analysis during HR reduction induced by manual acupuncture stimulation to the muscles. Materials and Methods: In this study, electrocardiograms of 25 adult men were analyzed. After resting for 20 minutes, participants underwent 15-20-mm deep acupuncture stimulation at the Shousanli (LI 10) point at 1 Hz for 2 minutes. Instantaneous HR was recorded. The index of parasympathetic nervous activity high-frequency (HF) normalized units (HFnu) and the ratio of sympathovagal balance (low frequency [LF]/HF) were calculated by HRV analysis. Results: HR during acupuncture was significantly lower, compared to HR both before and after acupuncture. HFnu during acupuncture were significantly higher, compared to HFnu both before and after acupuncture. The LF/HF ratio during acupuncture was significantly lower, compared to the ratio before acupuncture, and remained low after acupuncture, compared to before acupuncture. Conclusions: Acupuncture stimulation to the muscle can effectively reduce HR, increase HFnu, and decrease LF/HF that depends on autonomic regulation of both sympathovagal balances.