Noninvasive vagus nerve stimulation alters neural response and physiological autonomic tone to noxious thermal challenge.

The mechanisms by which noninvasive vagal nerve stimulation (nVNS) affect central and peripheral neural circuits that subserve pain and autonomic physiology are not clear, and thus remain an area of intense investigation. Effects of nVNS vs sham stimulation on subject responses to five noxious thermal stimuli (applied to left lower extremity), were measured in 30 healthy subjects (n = 15 sham and n = 15 nVNS), with fMRI and physiological galvanic skin response (GSR). With repeated noxious thermal stimuli a group × time analysis showed a significantly (p < .001) decreased response with nVNS in bilateral primary and secondary somatosensory cortices (SI and SII), left dorsoposterior insular cortex, bilateral paracentral lobule, bilateral medial dorsal thalamus, right anterior cingulate cortex, and right orbitofrontal cortex. A group × time × GSR analysis showed a significantly decreased response in the nVNS group (p < .0005) bilaterally in SI, lower and mid medullary brainstem, and inferior occipital cortex. Finally, nVNS treatment showed decreased activity in pronociceptive brainstem nuclei (e.g. the reticular nucleus and rostral ventromedial medulla) and key autonomic integration nuclei (e.g. the rostroventrolateral medulla, nucleus ambiguous, and dorsal motor nucleus of the vagus nerve). In aggregate, noninvasive vagal nerve stimulation reduced the physiological response to noxious thermal stimuli and impacted neural circuits important for pain processing and autonomic output

Mapping cortical responses to somatosensory stimuli in human infants with simultaneous near-infrared spectroscopy and event-related potential recording

Near-infrared spectroscopy (NIRS) and electroencephalography (EEG) have recently provided fundamental new information about how the newborn brain processes innocuous and noxious somatosensory information. However, results derived independently from these two techniques are not entirely consistent, raising questions about the relationship between hemodynamic and electrophysiological responses in the study of touch and pain processing in the newborn. To address this, we have recorded NIRS and EEG responses simultaneously for the first time in the human infant following noxious (time-locked clinically required heel lances) and innocuous tactile cutaneous stimulation in 30 newborn infants. The results show that both techniques can be used to record quantifiable and distinct innocuous and noxious evoked activity at a group level in the newborn cortex. Noxious stimulation elicits a peak hemodynamic response that is 10-fold larger than that elicited by an innocuous stimulus (HbO2: 2.0 vs 0.3 µm) and a distinct nociceptive-specific N3P3 waveform in electrophysiological recordings. However, a novel single-trial analysis revealed that hemodynamic and electrophysiological responses do not always co-occur at an individual level, although when they do (64% of noxious test occasions), they are significantly correlated in magnitude. These data show that, while hemodynamic and electrophysiological touch and pain brain activity in newborn infants are comparable in group analyses, important individual differences remain. These data indicate that integrated and multimodal brain monitoring is required to understand central touch and pain processing in the newborn

Doing it … wild? On the role of the cerebral cortex in human sexual activity

BACKGROUND: We like to think about sexual activity as something fixed, basic and primal. However, this does not seem to fully capture reality. Even when we relish sex, we may be capable of mentalizing, talking, voluntarily postponing orgasm, and much more. This might indicate that the central control mechanisms of sexual activity are quite flexible and susceptible to learning mechanisms, and that cortical brain areas play a critical part. OBJECTIVE: This study aimed to identify those cortical areas and mechanisms most consistently implicated in sexual activity. DESIGN: A comprehensive review of the human functional neuroimaging literature on sexual activity, i.e. genital stimulation and orgasm, is made. RESULTS: Genital stimulation recruits the classical somatosensory matrix, but also areas far beyond that. The posterior insula may be particularly important for processing input from the engorged penis and coordinating penile responses. Extrastriate visual cortex tracks sexual arousal and responds to genital stimulation even when subjects have their eyes closed. The ventromedial prefrontal cortex is also tightly coupled to sexual arousal, but low activity in this area predicts high sexual arousal. CONCLUSION: This review has indicated cortical sites where activity is moderated by tactile genital inflow and high sexual arousal. Behavioral implications are discussed and where possible the relevance for learning mechanisms is indicated. Overall, it is clear that the cerebral cortex has something to say about sexual activity

CEREBRAL ACTIVATION DURING THERMAL STIMULATION OF BURNING MOUTH DISORDER PATIENTS: AN fMRI STUDY

Functional magnetic resonance imaging (fMRI) has been widely used to study cortical and subcortical mechanisms related to pain. The pathophysiology of burning mouth disorder (BMD) is not clearly understood. Central neuropathic mechanisms are thought to be main players in BMD. This study aimed to compare the location and extension of brain activation following thermal stimulation of the trigeminal nerve with fMRI blood oxygenation level dependent (BOLD) signal. This study included 8 female patients with BMD and 8 matched pain-free volunteers. Qualitative and quantitative differences in brain activation patterns between the two study groups were demonstrated. There were differences in the activation maps regarding the location of activation, with patients displaying greater BOLD signal changes in the right anterior cingulate cortex (ACC BA 32/24) and bilateral precuneus (pandlt;0.005). The control group showed larger BOLD signal changes in the bilateral thalamus, right middle frontal gyrus, right pre-central gyrus, left lingual gyrus and cerebellum (pandlt;0.005). It was also demonstrated that patients had far less volumetric activation throughout the entire brain compared to the control group. These data are discussed in light of recent findings suggesting brain hypofunction as a key player in chronic neuropathic pain conditions

Neurophysiological mechanisms of longer-lasting experimental pain in humans

Pain serves the protection of the body. Consequently, noxious stimuli or, more precisely, the thereby induced neurophysiological processes commonly lead to pain perception. Identical noxious stimuli, however, do not always translate into the same pain experience depending on multiple factors. To acknowledge this variability, the distinction between nociception as the neural process elicited by noxious stimuli and pain as subjective multifactorial experience is essential. During longer-lasting experimental pain and chronic pain, nociception and pain can substantially dissociate. Moreover, longer-lasting experimental pain resembles chronic pain regarding certain perceptual features such as prolonged pain duration and intensity fluctuations. Thus, longer-lasting experimental pain offers the opportunity to gain new insights into both the differential neural representation of noxious stimuli and pain and the neuronal mechanisms associated with the state of longer- lasting pain. We applied 10 minutes of painful heat stimulation to the left and right hand of 39 healthy participants while we recorded continuous pain ratings, electroencephalography (EEG), and autonomic responses. Data were analyzed in three distinct projects aiming at different aspects of neuronal mechanisms underlying longer-lasting pain. Project 1 assessed whether stimulus intensity as proxy of nociception and pain intensity relate to distinct patterns of oscillatory brain activity. EEG recordings revealed that increases in stimulus intensity were reflected by suppressions of alpha and beta oscillations in sensorimotor areas contralateral to the stimulated hand. In contrast, increases in pain intensity were associated with enhanced gamma oscillations in the medial prefrontal cortex. More importantly, the encoding of stimulus intensity by alpha and beta oscillations in the sensorimotor areas was spatially specific, i.e. depended on the stimulus location, whereas the encoding of pain intensity by gamma oscillations in the medial prefrontal cortex was independent of stimulus location. Thus, prefrontal gamma oscillations might reflect higher- order aspects of noxious stimuli, such as salience, valence, and motivational aspects rather than precise sensory features. Project 2 investigated the relationship between stimulus intensity, pain intensity, autonomic responses, and brain activity. Skin conductance measures, as markers of sympathetic activity, co-varied more closely with stimulus intensity than with pain intensity. Correspondingly, skin conductance measures were related to suppressions of alpha and beta oscillations in the sensorimotor area contralateral to the stimulated hand. These finding suggest that skin conductance measures are in part directly elicited by nociceptive processes and, thus, at least partially independent of perceptual processes during longer-lasting pain. Hence, these observations corroborate concepts of pain in which sensory, motivational, and autonomic processes partially independently contribute to the experience of pain. Finally, project 3 incorporated the systematic and comprehensive assessment of oscillatory brain activity, functional connectivity, and graph- theory based network measures during the state of longer-lasting pain. Longer-lasting pain was associated with suppressions of oscillatory brain activity at alpha frequencies in addition to stronger connectivity at alpha and beta frequencies in sensorimotor areas. Furthermore, sensorimotor areas contralateral to stimulation showed increased connectivity to a common area in the medial prefrontal cortex at alpha frequencies and built a sensorimotor-prefrontal network during longer-lasting pain. This network might be involved in the integration of sensory, cognitive, and motivational-affective information and, consequently, in the translation of a noxious stimulus into a subjective pain experience. All three projects contribute to a better understanding of neuronal mechanisms underlying longer-lasting experimental pain, which serves as an experimental model for chronic pain. Since the treatment of chronic pain has remained insufficient and unsatisfactory, the current results might provide EEG-based targets for urgently needed new treatment approaches, such as non-invasive brain stimulation and neurofeedback

Neurophysiological mechanisms of longer-lasting experimental pain in humans

Pain serves the protection of the body. Consequently, noxious stimuli or, more precisely, the thereby induced neurophysiological processes commonly lead to pain perception. Identical noxious stimuli, however, do not always translate into the same pain experience depending on multiple factors. To acknowledge this variability, the distinction between nociception as the neural process elicited by noxious stimuli and pain as subjective multifactorial experience is essential. During longer-lasting experimental pain and chronic pain, nociception and pain can substantially dissociate. Moreover, longer-lasting experimental pain resembles chronic pain regarding certain perceptual features such as prolonged pain duration and intensity fluctuations. Thus, longer-lasting experimental pain offers the opportunity to gain new insights into both the differential neural representation of noxious stimuli and pain and the neuronal mechanisms associated with the state of longer- lasting pain. We applied 10 minutes of painful heat stimulation to the left and right hand of 39 healthy participants while we recorded continuous pain ratings, electroencephalography (EEG), and autonomic responses. Data were analyzed in three distinct projects aiming at different aspects of neuronal mechanisms underlying longer-lasting pain. Project 1 assessed whether stimulus intensity as proxy of nociception and pain intensity relate to distinct patterns of oscillatory brain activity. EEG recordings revealed that increases in stimulus intensity were reflected by suppressions of alpha and beta oscillations in sensorimotor areas contralateral to the stimulated hand. In contrast, increases in pain intensity were associated with enhanced gamma oscillations in the medial prefrontal cortex. More importantly, the encoding of stimulus intensity by alpha and beta oscillations in the sensorimotor areas was spatially specific, i.e. depended on the stimulus location, whereas the encoding of pain intensity by gamma oscillations in the medial prefrontal cortex was independent of stimulus location. Thus, prefrontal gamma oscillations might reflect higher- order aspects of noxious stimuli, such as salience, valence, and motivational aspects rather than precise sensory features. Project 2 investigated the relationship between stimulus intensity, pain intensity, autonomic responses, and brain activity. Skin conductance measures, as markers of sympathetic activity, co-varied more closely with stimulus intensity than with pain intensity. Correspondingly, skin conductance measures were related to suppressions of alpha and beta oscillations in the sensorimotor area contralateral to the stimulated hand. These finding suggest that skin conductance measures are in part directly elicited by nociceptive processes and, thus, at least partially independent of perceptual processes during longer-lasting pain. Hence, these observations corroborate concepts of pain in which sensory, motivational, and autonomic processes partially independently contribute to the experience of pain. Finally, project 3 incorporated the systematic and comprehensive assessment of oscillatory brain activity, functional connectivity, and graph- theory based network measures during the state of longer-lasting pain. Longer-lasting pain was associated with suppressions of oscillatory brain activity at alpha frequencies in addition to stronger connectivity at alpha and beta frequencies in sensorimotor areas. Furthermore, sensorimotor areas contralateral to stimulation showed increased connectivity to a common area in the medial prefrontal cortex at alpha frequencies and built a sensorimotor-prefrontal network during longer-lasting pain. This network might be involved in the integration of sensory, cognitive, and motivational-affective information and, consequently, in the translation of a noxious stimulus into a subjective pain experience. All three projects contribute to a better understanding of neuronal mechanisms underlying longer-lasting experimental pain, which serves as an experimental model for chronic pain. Since the treatment of chronic pain has remained insufficient and unsatisfactory, the current results might provide EEG-based targets for urgently needed new treatment approaches, such as non-invasive brain stimulation and neurofeedback

Measures, Mechanisms and Effects of Spinal and Cerebral Nociceptive Processing during General Anaesthesia

Next to unconsciousness, the suppression of nociception – i. e. the neuronal processing of noxious stimuli – is a central component of general anaesthesia. While unconsciousness can be monitored fairly accurately using electroencephalography (EEG)-derived measures, there is no reliable measure that allows quantifying the level of nociception in unconscious humans available to this day. Therefore, this dissertation aimed at developing a multimodal measure of nociceptive processing in humans and applying this measure to investigate the spinal and cerebral processing of innocuous and noxious somatosensory stimuli during general anaesthesia. Using a setup that combined functional magnetic resonance imaging (fMRI) with simultaneous EEG and spinal nociceptive reflex monitoring, we were able for the first time to (i) concurrently investigate spinal and cerebral effects of general anaesthetics on the processing of somatosensory stimuli and to (ii) investigate intense noxious stimuli at intensities comparable to surgical stimuli. During unconsciousness, we found an anaesthetic dose-dependent change of nociceptive processing in a variety of brain regions including higher-order association cortices. The changes in processing were accompanied by changes in functional connectivity between nociceptive brain regions, in accordance with the notion that general anaesthetics induce unconsciousness by altering the information transfer patterns in the brain. We found that profound spinal and cerebral nociceptive-evoked activation persisted even at levels of general anaesthesia that are deeper than applied in clinical practice. Currently used clinical indicators of analgesic efficacy (e. g. haemodynamic responses to noxious stimuli) were absent at far lower levels of general anaesthesia, demonstrating that the absence of these clinical responses is not indicative of absent nociceptive processing. Due to the unavailability of reliable measures of intraoperative nociception, it is not known whether persisting nociception during general anaesthesia contributes to adverse effects on patient outcomes such as pain chronification. We therefore supplemented the primary experimental research of this dissertation by a clinical study, in which we showed that the level of intraoperative analgesia was related to persistent postoperative pain. As the analgesic dosings were in the range in which we found profound persistent nociceptive processing in our experimental studies, these results suggest that persistent nociception during currently used levels of intraoperative analgesia indeed contributes to long-term harm on patient outcomes.Neben der Bewusstlosigkeit ist die Unterdrückung von Nozizeption – also der neuronalen Verarbeitung von potenziell gewebeschädigenden Reizen – eine zentrale Komponente der Allgemeinanästhesie. Während Bewusstlosigkeit relativ genau mittels Elektroenzephalographie (EEG) überwacht werden kann, existiert bis heute kein zuverlässiges Verfahren, um das Nozizeptionsniveau in bewusstlosen Menschen zu quantifizieren. Ziel dieser Dissertation war es daher ein multimodales Maß der nozizeptiven Verarbeitung im Menschen zu entwickeln und dieses Maß zu verwenden, um die spinale und zerebrale Verarbeitung von nozizeptiven Reizen unter Allgemeinanästhesie zu untersuchen. Durch Kombination von funktioneller Magnetresonanztomographie (fMRT) mit simultaner EEG und spinalen nozizeptiven Reflexen waren wir erstmalig in der Lage (i) gleichzeitig spinale und zerebrale Effekte von Allgemeinanästhetika auf die Verarbeitung somatosensorischer Reize zu untersuchen und (ii) sehr starke nozizeptive Reize, deren Intensität vergleichbar mit der von chirurgischen Reizen ist, zu verwenden. Unter Bewusstlosigkeit konnten wir eine dosisabhängige Veränderung der nozizeptiven Verarbeitung in einer Reihe von Hirnarealen, darunter Assoziationsareale, mit einhergehender Modulation der funktionellen Konnektivität zwischen nozizeptions-assoziierten Hirnarealen finden. Dies bestärkt die Vermutung, dass Allgemeinanästhetika Bewusstlosigkeit durch Veränderung der Informationsverbeitungspfade des Gehirns erzeugen. Unter allen untersuchten Narkosetiefen bis hin zu tieferer Narkose als in der derzeitigen klinischen Praxis verwendet konnten wir umfassende spinale und zerebrale nozizeptive Aktivierungen nachweisen. Klinisch verwendete Indikatoren überschießender Nozizeption (bspw. hämodynamische Reaktionen auf nozizeptive Reize) waren bereits bei wesentlich geringeren Narkosetiefen nicht mehr nachweisbar. Das Ausbleiben dieser klinischen Reaktionen bedeutet daher nicht ein Ausbleiben von nozizeptiver Verarbeitung. Aufgrund des Fehlens von zuverlässigen Maßen intraoperativer Nozizeption ist bisher nicht bekannt, ob bestehende Nozizeption unter Allgemeinanästhesie zu klinisch relevanten Auswirkungen wie bspw. Schmerzchronifizierung beiträgt. In einer klinischen Patientenstudie konnten wir zeigen, dass das Niveau der intraoperativen Analgesie mit dem Auftreten von chronischen postoperativen Schmerzen assoziiert ist. Da die intraoperative Analgesie der Patienten in dem Bereich war, in dem wir noch umfassende nozizeptive Verarbeitung in den experimentellen Studien fanden, deuten diese Resultate darauf hin, dass persistierende Nozizeption bei heute gebräuchlicher intraoperativer Analgesie tatsächlich zu langfristigen Schäden von Patienten beitragen kann