Temporal-spectral signaling of sensory information and expectations in the cerebral processing of pain.

The perception of pain is shaped by somatosensory information about threat. However, pain is also influenced by an individual's expectations. Such expectations can result in clinically relevant modulations and abnormalities of pain. In the brain, sensory information, expectations (predictions), and discrepancies thereof (prediction errors) are signaled by an extended network of brain areas which generate evoked potentials and oscillatory responses at different latencies and frequencies. However, a comprehensive picture of how evoked and oscillatory brain responses signal sensory information, predictions, and prediction errors in the processing of pain is lacking so far. Here, we therefore applied brief painful stimuli to 48 healthy human participants and independently modulated sensory information (stimulus intensity) and expectations of pain intensity while measuring brain activity using electroencephalography (EEG). Pain ratings confirmed that pain intensity was shaped by both sensory information and expectations. In contrast, Bayesian analyses revealed that stimulus-induced EEG responses at different latencies (the N1, N2, and P2 components) and frequencies (alpha, beta, and gamma oscillations) were shaped by sensory information but not by expectations. Expectations, however, shaped alpha and beta oscillations before the painful stimuli. These findings indicate that commonly analyzed EEG responses to painful stimuli are more involved in signaling sensory information than in signaling expectations or mismatches of sensory information and expectations. Moreover, they indicate that the effects of expectations on pain are served by brain mechanisms which differ from those conveying effects of sensory information on pain.

Neural oscillations and connectivity characterizing the state of tonic experimental pain in humans.

Pain is a complex phenomenon that is served by neural oscillations and connectivity involving different brain areas and frequencies. Here, we aimed to systematically and comprehensively assess the pattern of neural oscillations and connectivity characterizing the state of tonic experimental pain in humans. To this end, we applied 10-min heat pain stimuli consecutively to the right and left hand of 39 healthy participants and recorded electroencephalography. We systematically analyzed global and local measures of oscillatory brain activity, connectivity, and graph theory-based network measures during tonic pain and compared them to a nonpainful control condition. Local measures showed suppressions of oscillatory activity at alpha frequencies together with stronger connectivity at alpha and beta frequencies in sensorimotor areas during tonic pain. Furthermore, sensorimotor areas contralateral to stimulation showed significantly increased connectivity to a common area in the medial prefrontal cortex at alpha frequencies. Together, these observations indicate that the state of tonic experimental pain is associated with a sensorimotor-prefrontal network connected at alpha frequencies. These findings represent a step further toward understanding the brain mechanisms underlying long-lasting pain states in health and disease.

Prefrontal gamma oscillations reflect ongoing pain intensity in chronic back pain patients.

Chronic pain is a major health care issue characterized by ongoing pain and a variety of sensory, cognitive, and affective abnormalities. The neural basis of chronic pain is still not completely understood. Previous work has implicated prefrontal brain areas in chronic pain. Furthermore, prefrontal neuronal oscillations at gamma frequencies (60-90 Hz) have been shown to reflect the perceived intensity of longer lasting experimental pain in healthy human participants. In contrast, noxious stimulus intensity has been related to alpha (8-13 Hz) and beta (14-29 Hz) oscillations in sensorimotor areas. However, it is not fully understood how the intensity of ongoing pain as the key symptom of chronic pain is represented in the human brain. Here, we asked 31 chronic back pain patients to continuously rate their ongoing pain while simultaneously recording electroencephalography (EEG). Time-frequency analyses revealed a positive association between ongoing pain intensity and prefrontal beta and gamma oscillations. No association was found between pain and alpha or beta oscillations in sensorimotor areas. These findings indicate that ongoing pain as the key symptom of chronic pain is reflected by neuronal oscillations implicated in the subjective perception of longer lasting pain rather than by neuronal oscillations related to the processing of objective nociceptive input. The findings, thus, support a dissociation of pain intensity from nociceptive processing in chronic back pain patients. Furthermore, although possible confounds by muscle activity have to be taken into account, they might be useful for defining a neurophysiological marker of ongoing pain in the human brain.

Brain oscillations differentially encode noxious stimulus intensity and pain intensity.

Noxious stimuli induce physiological processes which commonly translate into pain. However, under certain conditions, pain intensity can substantially dissociate from stimulus intensity, e.g. during longer-lasting pain in chronic pain syndromes. How stimulus intensity and pain intensity are differentially represented in the human brain is, however, not yet fully understood. We therefore used electroencephalography (EEG) to investigate the cerebral representation of noxious stimulus intensity and pain intensity during 10min of painful heat stimulation in 39 healthy human participants. Time courses of objective stimulus intensity and subjective pain ratings indicated a dissociation of both measures. EEG data showed that stimulus intensity was encoded by decreases of neuronal oscillations at alpha and beta frequencies in sensorimotor areas. In contrast, pain intensity was encoded by gamma oscillations in the medial prefrontal cortex. Contrasting right versus left hand stimulation revealed that the encoding of stimulus intensity in contralateral sensorimotor areas depended on the stimulation side. In contrast, a conjunction analysis of right and left hand stimulation revealed that the encoding of pain in the medial prefrontal cortex was independent of the side of stimulation. Thus, the translation of noxious stimulus intensity into pain is associated with a change from a spatially specific representation of stimulus intensity by alpha and beta oscillations in sensorimotor areas to a spatially independent representation of pain by gamma oscillations in brain areas related to cognitive and affective-motivational processes. These findings extend the understanding of the brain mechanisms of nociception and pain and their dissociations during longer-lasting pain as a key symptom of chronic pain syndromes.

Influence of pain on motor preparation in the human brain.

The protective function of pain depends on appropriate motor responses to avoid injury and promote recovery. The preparation and execution of motor responses is thus an essential part of pain. However, it is not yet fully understood how pain and motor processes interact in the brain. Here we used electroencephalography to investigate the effects of pain on motor preparation in the human brain. Twenty healthy human participants performed a motor task in which they performed button presses to stop increasingly painful thermal stimuli when they became intolerable. In another condition, participants performed button presses without concurrent stimulation. The results show that the amplitudes of preparatory event-related desynchronizations at alpha and beta frequencies did not differ between conditions. In contrast, the amplitude of the preparatory readiness potential was reduced when a button press was performed to stop a painful stimulus compared with a button press without concomitant pain. A control experiment with nonpainful thermal stimuli showed a similar reduction of the readiness potential when a button press was performed to stop a nonpainful thermal stimulus. Together, these findings indicate that painful and nonpainful thermal stimuli can similarly influence motor preparation in the human brain. Pain-specific effects on motor preparation in the human brain remain to be demonstrated.NEW & NOTEWORTHY Pain is inherently linked to motor processes, but the interactions between pain and motor processes in the human brain are not yet fully understood. Using electroencephalography, we show that pain reduces movement-preparatory brain activity. Further results indicate that this effect is not pain specific but independent of the modality of stimulation.

Prevalence of neuropathic pain in early multiple sclerosis.

BACKGROUND: Pain is considered a frequent symptom in multiple sclerosis. Neuropathic pain is the type of pain most closely related to the pathology of multiple sclerosis and its prevalence estimates vary largely. OBJECTIVE: We prospectively assessed the prevalence of neuropathic pain in patients with early multiple sclerosis and investigated the association of neuropathic pain with other clinical parameters. METHODS: A total of 377 outpatients with multiple sclerosis at an early disease stage were included in this prospective study. Mean disease duration was 4.2 years, mean Expanded Disability Status Scale (EDSS) score was 1.6, 96.8% of patients were classified as having relapsing-remitting multiple sclerosis. Neuropathic pain was assessed using the PainDETECT questionnaire (PDQ). Depression, fatigue and cognition were assessed using the Beck Depression Inventory (BDI), the Fatigue Scale for Motor and Cognitive Functions (FSMC) and the Paced Auditory Serial Addition Test. RESULTS: PDQ scores indicative of neuropathic pain were found in 4.2% of patients. Regression analysis revealed EDSS, BDI and FMSC scores as strongest predictors of PDQ scores. CONCLUSIONS: Neuropathic pain appears to be less frequent in early multiple sclerosis than expected and is significantly associated with disability, depression and fatigue. The assessment and therapy of pain in multiple sclerosis should thus take into account neuropsychiatric symptoms already at early disease stages.

Prefrontal Gamma Oscillations Encode Tonic Pain in Humans.

Under physiological conditions, momentary pain serves vital protective functions. Ongoing pain in chronic pain states, on the other hand, is a pathological condition that causes widespread suffering and whose treatment remains unsatisfactory. The brain mechanisms of ongoing pain are largely unknown. In this study, we applied tonic painful heat stimuli of varying degree to healthy human subjects, obtained continuous pain ratings, and recorded electroencephalograms to relate ongoing pain to brain activity. Our results reveal that the subjective perception of tonic pain is selectively encoded by gamma oscillations in the medial prefrontal cortex. We further observed that the encoding of subjective pain intensity experienced by the participants differs fundamentally from that of objective stimulus intensity and from that of brief pain stimuli. These observations point to a role for gamma oscillations in the medial prefrontal cortex in ongoing, tonic pain and thereby extend current concepts of the brain mechanisms of pain to the clinically relevant state of ongoing pain. Furthermore, our approach might help to identify a brain marker of ongoing pain, which may prove useful for the diagnosis and therapy of chronic pain.

Alpine salamanders at risk? The current status of an emerging fungal pathogen.

Amphibians globally suffer from emerging infectious diseases like chytridiomycosis caused by the continuously spreading chytrid fungi. One is Batrachochytrium salamandrivorans (Bsal) and its disease ‒ the 'salamander plague' ‒ which is lethal to several caudate taxa. Recently introduced into Western Europe, long distance dispersal of Bsal, likely through human mediation, has been reported. Herein we study if Alpine salamanders (Salamandra atra and S. lanzai) are yet affected by the salamander plague in the wild. Members of the genus Salamandra are highly susceptible to Bsal leading to the lethal disease. Moreover, ecological modelling has shown that the Alps and Dinarides, where Alpine salamanders occur, are generally suitable for Bsal. We analysed skin swabs of 818 individuals of Alpine salamanders and syntopic amphibians at 40 sites between 2017 to 2022. Further, we compiled those with published data from 319 individuals from 13 sites concluding that Bsal infections were not detected. Our results suggest that the salamander plague so far is absent from the geographic ranges of Alpine salamanders. That means that there is still a chance to timely implement surveillance strategies. Among others, we recommend prevention measures, citizen science approaches, and ex situ conservation breeding of endemic salamandrid lineages.

Decoding an individual's sensitivity to pain from the multivariate analysis of EEG data.

The perception of pain is characterized by its tremendous intra- and interindividual variability. Different individuals perceive the very same painful event largely differently. Here, we aimed to predict the individual pain sensitivity from brain activity. We repeatedly applied identical painful stimuli to healthy human subjects and recorded brain activity by using electroencephalography (EEG). We applied a multivariate pattern analysis to the time-frequency transformed single-trial EEG responses. Our results show that a classifier trained on a group of healthy individuals can predict another individual's pain sensitivity with an accuracy of 83%. Classification accuracy depended on pain-evoked responses at about 8 Hz and pain-induced gamma oscillations at about 80 Hz. These results reveal that the temporal-spectral pattern of pain-related neuronal responses provides valuable information about the perception of pain. Beyond, our approach may help to establish an objective neuronal marker of pain sensitivity which can potentially be recorded from a single EEG electrode.

DISCOVER-EEG: an open, fully automated EEG pipeline for biomarker discovery in clinical neuroscience.

Biomarker discovery in neurological and psychiatric disorders critically depends on reproducible and transparent methods applied to large-scale datasets. Electroencephalography (EEG) is a promising tool for identifying biomarkers. However, recording, preprocessing, and analysis of EEG data is time-consuming and researcher-dependent. Therefore, we developed DISCOVER-EEG, an open and fully automated pipeline that enables easy and fast preprocessing, analysis, and visualization of resting state EEG data. Data in the Brain Imaging Data Structure (BIDS) standard are automatically preprocessed, and physiologically meaningful features of brain function (including oscillatory power, connectivity, and network characteristics) are extracted and visualized using two open-source and widely used Matlab toolboxes (EEGLAB and FieldTrip). We tested the pipeline in two large, openly available datasets containing EEG recordings of healthy participants and patients with a psychiatric condition. Additionally, we performed an exploratory analysis that could inspire the development of biomarkers for healthy aging. Thus, the DISCOVER-EEG pipeline facilitates the aggregation, reuse, and analysis of large EEG datasets, promoting open and reproducible research on brain function.

Local brain oscillations and interregional connectivity differentially serve sensory and expectation effects on pain.

Pain emerges from the integration of sensory information about threats and contextual information such as an individual's expectations. However, how sensory and contextual effects on pain are served by the brain is not fully understood so far. To address this question, we applied brief painful stimuli to 40 healthy human participants and independently varied stimulus intensity and expectations. Concurrently, we recorded electroencephalography. We assessed local oscillatory brain activity and interregional functional connectivity in a network of six brain regions playing key roles in the processing of pain. We found that sensory information predominantly influenced local brain oscillations. In contrast, expectations exclusively influenced interregional connectivity. Specifically, expectations altered connectivity at alpha (8 to 12 hertz) frequencies from prefrontal to somatosensory cortex. Moreover, discrepancies between sensory information and expectations, i.e., prediction errors, influenced connectivity at gamma (60 to 100 hertz) frequencies. These findings reveal how fundamentally different brain mechanisms serve sensory and contextual effects on pain.

γ Oscillations are involved in the sensorimotor transformation of pain.

Pain signals threat and initiates motor responses to avoid harm. The transformation of pain into a motor response is thus an essential part of pain. Here, we investigated the neural mechanisms subserving the sensorimotor transformation of pain at the cortical level by using electroencephalography. In a simple reaction time experiment, brief painful stimuli were delivered to the left hand of healthy human subjects who responded with button presses of the right hand. The results show that the simple reaction time task was associated with neuronal responses at delta/theta, alpha/beta, and gamma frequencies. The analysis of the relationship between neuronal activity and response speed revealed that gamma oscillations, which were temporally coupled to the painful stimuli, but not temporally coupled to the motor response, predicted reaction times. Lateralization of gamma oscillations indicates that they originate from motor areas rather than from sensory areas. We conclude that gamma oscillations are involved in the sensorimotor transformation of pain whose efficiency they reflect. We hypothesize that the relationship between stimulus-locked gamma oscillations and reaction times reflects a direct thalamo-motor route of nociceptive information that is central to the biological function of pain.

Neurophysiological coding of traits and states in the perception of pain.

Perception is not a simple reflection of sensory information but varies within and between individuals. This applies particularly to the perception of pain, which, in the brain, is associated with neuronal responses at different frequencies. Here, we show how these different neuronal responses subserve interindividual and intraindividual variations in the perception of identical painful stimuli. A time-frequency analysis of single trial electroencephalographic data indicates that pain-related responses in the theta frequency range but not at higher gamma frequencies code for interindividual variations in the perception of pain. In contrast, both pain-related theta and gamma responses provide different and complementary information on intraindividual variations in the pain experience. We conclude that theta responses reflect rather constant physiological and psychological traits of the individual, whereas gamma responses relate to short-term modulations of the individual's state. These findings reveal how neuronal responses at different frequencies differentially contribute to the translation of sensory information into a subjective percept.

Longitudinal resting-state electroencephalography in patients with chronic pain undergoing interdisciplinary multimodal pain therapy.

ABSTRACT: Chronic pain is a major healthcare issue posing a large burden on individuals and society. Converging lines of evidence indicate that chronic pain is associated with substantial changes of brain structure and function. However, it remains unclear which neuronal measures relate to changes of clinical parameters over time and could thus monitor chronic pain and treatment responses. We therefore performed a longitudinal study in which we assessed clinical characteristics and resting-state electroencephalography data of 41 patients with chronic pain before and 6 months after interdisciplinary multimodal pain therapy. We specifically assessed electroencephalography measures that have previously been shown to differ between patients with chronic pain and healthy people. These included the dominant peak frequency; the amplitudes of neuronal oscillations at theta, alpha, beta, and gamma frequencies; as well as graph theory-based measures of brain network organization. The results show that pain intensity, pain-related disability, and depression were significantly improved after interdisciplinary multimodal pain therapy. Bayesian hypothesis testing indicated that these clinical changes were not related to changes of the dominant peak frequency or amplitudes of oscillations at any frequency band. Clinical changes were, however, associated with an increase in global network efficiency at theta frequencies. Thus, changes in chronic pain might be reflected by global network changes in the theta band. These longitudinal insights further the understanding of the brain mechanisms of chronic pain. Beyond, they might help to identify biomarkers for the monitoring of chronic pain.

Exploring Dynamic Connectivity Biomarkers of Neuropsychiatric Disorders.

A recent study by Lee et al. showed that a dynamic functional connectivity pattern induced by tonic experimental pain might serve as a biomarker of chronic pain. The study illustrates key topics in translational neuroscience: the differentiation of biomarker functions, the multimodal integration of biomarkers, and the functional relevance of dynamic connectivity.

Modulating Brain Rhythms of Pain Using Transcranial Alternating Current Stimulation (tACS) - A Sham-Controlled Study in Healthy Human Participants.

Chronic pain is a major health care problem. A better mechanistic understanding and new treatment approaches are urgently needed. In the brain, pain has been associated with neural oscillations at alpha and gamma frequencies, which can be targeted using transcranial alternating current stimulation (tACS). Thus, we investigated the potential of tACS to modulate pain and pain-related autonomic activity in an experimental model of chronic pain in 29 healthy participants. In 6 recording sessions, participants completed a tonic heat pain paradigm and simultaneously received tACS over prefrontal or somatosensory cortices at alpha or gamma frequencies or sham tACS. Concurrently, pain ratings and autonomic responses were collected. Using the present setup, tACS did not modulate pain or autonomic responses. Bayesian statistics confirmed a lack of tACS effects in most conditions. The only exception was alpha tACS over somatosensory cortex where evidence was inconclusive. Taken together, we did not find significant tACS effects on tonic experimental pain in healthy humans. Based on our present and previous findings, further studies might apply refined stimulation protocols targeting somatosensory alpha oscillations. TRIAL REGISTRATION: The study protocol was pre-registered at ClinicalTrials.gov (NCT03805854). PERSPECTIVE: Modulating brain oscillations is a promising approach for the treatment of pain. We therefore applied transcranial alternating current stimulation (tACS) to modulate experimental pain in healthy participants. However, tACS did not modulate pain, autonomic responses, or EEG oscillations. These findings help to shape future tACS studies for the treatment of pain.

Dynamics of brain function in patients with chronic pain assessed by microstate analysis of resting-state electroencephalography.

ABSTRACT: Chronic pain is a highly prevalent and severely disabling disease that is associated with substantial changes of brain function. Such changes have mostly been observed when analyzing static measures of resting-state brain activity. However, brain activity varies over time, and it is increasingly recognized that the temporal dynamics of brain activity provide behaviorally relevant information in different neuropsychiatric disorders. Here, we therefore investigated whether the temporal dynamics of brain function are altered in chronic pain. To this end, we applied microstate analysis to eyes-open and eyes-closed resting-state electroencephalography data of 101 patients suffering from chronic pain and 88 age- and sex-matched healthy controls. Microstate analysis describes electroencephalography activity as a sequence of a limited number of topographies termed microstates that remain stable for tens of milliseconds. Our results revealed that sequences of 5 microstates, labelled with the letters A to E, consistently described resting-state brain activity in both groups in the eyes-closed condition. Bayesian analysis of the temporal characteristics of microstates revealed that microstate D has a less predominant role in patients than in controls. As microstate D has previously been related to attentional networks and functions, these abnormalities might relate to dysfunctional attentional processes in chronic pain. Subgroup analyses replicated microstate D changes in patients with chronic back pain, while patients with chronic widespread pain did not show microstates alterations. Together, these findings add to the understanding of the pathophysiology of chronic pain and point to changes of brain dynamics specific to certain types of chronic pain.

Infantile Hemangioma: A Review of Current Pharmacotherapy Treatment and Practice Pearls.

Infantile hemangioma (IH) is the most common vascular tumor of infancy, affecting as many as 5% to 10% of all infants. The exact cause is unclear, but specific risk factors, such as low birth weight, prematurity, female sex, white race, and family history are associated with IH development. Most IHs are benign and self-resolving, but a small subset of patients with IHs are at risk of severe or life-threatening outcomes. Systemic and topical ß-blockers are effective and safe for use in pediatric patients and considered first-line treatment for both complicated and uncomplicated IHs. Recently published guidelines provide a thorough review of IH and management. This article focuses on IH pharmacotherapy and provides practice pearls to support health care providers in IH medication management.

Cognitive impairment in early MS: contribution of white matter lesions, deep grey matter atrophy, and cortical atrophy.

BACKGROUND: Cognitive impairment (CI) is a frequent and debilitating symptom in MS. To better understand the neural bases of CI in MS, this magnetic resonance imaging (MRI) study aimed to identify and quantify related structural brain changes and to investigate their relation to each other. METHODS: We studied 51 patients with CI and 391 patients with cognitive preservation (CP). We analyzed three-dimensional T1-weighted and FLAIR scans at 3 Tesla. We determined mean cortical thickness as well as volumes of cortical grey matter (GM), deep GM including thalamus, cerebellar cortex, white matter, corpus callosum, and white matter lesions (WML). We also analyzed GM across the whole brain by voxel-wise and surface-based techniques. RESULTS: Mean disease duration was 5 years. Comparing MS patients with CI and CP, we found higher volumes of WML, lower volumes of deep and cortical GM structures, and lower volumes of the corpus callosum (all corrected p values < 0.05). Effect sizes were largest for WML and thalamic volume (standardized ß values 0.25 and - 0.25). By logistic regression analysis including both WML and thalamic volume, we found a significant effect only for WML volume. Inclusion of the interaction term of WML and thalamic volume increased the model fit and revealed a highly significant interaction of WML and thalamic volume. Moreover, voxel-wise and surface-based comparisons of MS patients with CI and CP showed regional atrophy of both deep and cortical GM independent of WML volume and overall disability, but effect sizes were lower. CONCLUSION: Although several mechanisms contribute to CI already in the early stage of MS, WML seem to be the main driver with thalamic atrophy primarily intensifying this effect.

Longitudinal prevalence and determinants of pain in multiple sclerosis: results from the German National Multiple Sclerosis Cohort study.

Pain is frequent in multiple sclerosis (MS) and includes different types, with neuropathic pain (NP) being most closely related to MS pathology. However, prevalence estimates vary largely, and causal relationships between pain and biopsychosocial factors in MS are largely unknown. Longitudinal studies might help to clarify the prevalence and determinants of pain in MS. To this end, we analyzed data from 410 patients with newly diagnosed clinically isolated syndrome or relapsing-remitting MS participating in the prospective multicenter German National MS Cohort Study (NationMS) at baseline and after 4 years. Pain was assessed by self-report using the PainDETECT Questionnaire. Neuropsychiatric assessment included tests for fatigue, depression, and cognition. In addition, sociodemographic and clinical data were obtained. Prevalence of pain of any type was 40% and 36% at baseline and after 4 years, respectively, whereas prevalence of NP was 2% and 5%. Pain of any type and NP were both strongly linked to fatigue, depression, and disability. This link was even stronger after 4 years than at baseline. Moreover, changes in pain, depression, and fatigue were highly correlated without any of these symptoms preceding the others. Taken together, pain of any type seems to be much more frequent than NP in early nonprogressive MS. Moreover, the close relationship between pain, fatigue, and depression in MS should be considered for treatment decisions and future research on a possible common pathophysiology.