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.

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.

The slowed brain: cortical oscillatory activity in hepatic encephalopathy.

Oscillatory activity of the human brain has received growing interest as a key mechanism of large-scale integration across different brain regions. Besides a crucial role of oscillatory activity in the emergence of other neurological and psychiatric diseases, recent evidence indicates a key role in the pathophysiology of hepatic encephalopathy (HE). This review summarizes the current knowledge on pathological alterations of oscillatory brain activity in association with liver dysfunction and HE in the context of spontaneous brain activity, motor symptoms, sensory processing, and attention. The existing literature demonstrates a prominent slowing of the frequency of oscillatory activity as shown for spontaneous brain activity at rest, with respect to deficits of motor behavior and motor symptoms, and in the context of visual attention processes. The observed slowing extends across different subsystems of the brain and has been confirmed across different frequency bands, providing evidence for ubiquitous changes of oscillatory activity in HE. For example, the frequency of cortico-muscular coherence in HE patients appears at the frequency of the mini-asterixis (⩽12Hz), while cirrhotics without overt signs of HE show coherence similar to healthy subjects, i.e. at 13-30Hz. Interestingly, the so-called critical flicker frequency (CFF) as a measure of the processing of an oscillating visual stimulus has emerged as a useful tool to quantify HE disease severity, correlating with behavioral and neurophysiological alterations. Moreover, the CFF reliably distinguishes patients with manifest HE from cirrhotics without any signs of HE and healthy controls using a cut-off frequency of 39Hz. In conclusion, oscillatory activity is globally slowed in HE in close association with HE symptoms and disease severity. Although the underlying causal mechanisms are not yet understood, these results indicate that pathological changes of oscillatory activity play an important role in the pathophysiology of HE.

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.

Sustained gamma band synchronization in early visual areas reflects the level of selective attention.

Cortical gamma band synchronization is associated with attention. Accordingly, directing attention to certain visual stimuli modulates gamma band activity in visual cortical areas. However, gradual effects of attention and behavior on gamma band activity in early visual areas have not yet been reported. In the present study, the degree of selective visual attention was gradually varied in a cued bimodal reaction time paradigm using audio-visual stimuli. Brain activity was recorded with magnetoencephalography (MEG) and analyzed with respect to time, frequency, and location of strongest response. Reaction times to visual and auditory stimuli reflected three presumed graded levels of visual attention (high, medium, and low). MEG data showed sustained gamma band synchronization in all three conditions in early visual areas (V1 and V2), while the intensity of gamma band synchronization increased with the level of visual attention (from low to high). Differences between conditions were seen for up to 1600 ms. The current results show that in early visual areas the level of gamma band synchronization is related to the level of attention directed to a visual stimulus. These gradual and long-lasting effects highlight the key role of gamma band synchronization in early visual areas for selective attention.

Lowered frequency and impaired modulation of gamma band oscillations in a bimodal attention task are associated with reduced critical flicker frequency.

Visual attention is associated with occipital gamma band activity. While gamma band power can be modulated by attention, the frequency of gamma band activity is known to decrease with age. The present study tested the hypothesis that reduced visual attention is associated with a change in induced gamma band activity. To this end, 26 patients with liver cirrhosis and 8 healthy controls were tested. A subset of patients showed symptoms of hepatic encephalopathy (HE), a frequent neuropsychiatric complication in liver disease, which comprises a gradual increase of cognitive dysfunction including attention deficits. All participants completed a behavioral task requiring shifts of attention between simultaneously presented visual and auditory stimuli. Brain activity was recorded using magnetoencephalography (MEG). The individual critical flicker frequency (CFF) was assessed as it is known to reliably reflect the severity of HE. Results showed correlations of behavioral data and HE severity, as indexed by CFF. Individual visual gamma band peak frequencies correlated positively with the CFF (r=0.41). Only participants with normal, but not with pathological CFF values showed a modulation of gamma band power with attention. The present results suggest that CFF and attentional performance are related. Moreover, a tight relation between the CFF and occipital gamma band activity both in frequency and power is shown. Thus, the present study provides evidence that a reduced CFF in HE, a disease associated with attention deficits, is closely linked to a slowing of gamma band activity and impaired modulation of gamma band power in a bimodal attention task.

Pre- and post-stimulus alpha activity shows differential modulation with spatial attention during the processing of pain.

Extensive work using magneto- and electroencephalography (M/EEG) suggests that cortical alpha activity represents a top-down controlled gating mechanism employed by processes like attention across different modalities. However, it is not yet clear to what extent this presumed gating function of alpha activity also applies to the processing of pain. In the current study, a spatial attention paradigm was employed requiring subjects to attend to painful laser stimuli on one hand while ignoring stimuli on the other hand. Simultaneously, brain activity was recorded with MEG. In order to disentangle pre- and post-stimulus effects of attention, alpha activity was analyzed during time windows in anticipation of and in response to painful laser stimulation. Painful laser stimuli led to a suppression of alpha activity over both ipsi- and contralateral primary somatosensory areas irrespective if they were attended or ignored. Spatial attention was associated with a lateralization of anticipatory pre-stimulus alpha activity. Alpha activity was lower over primary somatosensory areas when the contralateral hand was attended compared to when the ipsilateral hand was attended, in line with the notion that oscillatory alpha activity regulates the flow of incoming information by engaging and/or disengaging early sensory areas. On the contrary, post-stimulus alpha activity, for stimuli on either hand, was consistently decreased with attention over contralateral areas. Most likely, this finding reflects an increased cortical activation and enhanced alerting if a painful stimulus is attended. The present results show that spatial attention results in a modulation of both pre- and post-stimulus alpha activity associated with pain. This flexible regulation of alpha activity matches findings from other modalities. We conclude that the assumed functional role of alpha activity as a top-down controlled gating mechanism includes pain processing and most likely represents a unified mechanism used throughout the brain.

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.

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.

From correlation towards causality: modulating brain rhythms of pain using transcranial alternating current stimulation.

INTRODUCTION: Accumulating evidence suggests that neural oscillations at different frequencies and their synchrony between brain regions play a crucial role in the processing of nociceptive input and the emergence of pain. Most findings are limited by their correlative nature, however, which impedes causal inferences. OBJECTIVE: To move from correlative towards causal evidence, methods that allow to experimentally manipulate oscillatory brain activity are needed. RESULTS: Transcranial alternating current stimulation (tACS) is a noninvasive brain stimulation technique designed to modulate neural oscillations in a frequency specific manner and as such a suitable method to investigate the contribution of oscillatory brain activity to pain. Despite its appeal, tACS has been barely applied in the field of pain research. In the present review, we address this issue and discuss how tACS can be used to gather mechanistic evidence for the relationship between pain and neural oscillations in humans. CONCLUSIONS: Transcranial alternating current stimulation holds great potential for the investigation of the neural mechanisms underlying pain and the development of new treatment approaches for chronic pain if necessary methodological precautions are taken.

Perceptual and motor responses directly and indirectly mediate the effects of noxious stimuli on autonomic responses.

Autonomic responses are an essential component of pain. They serve its adaptive function by regulating homeostasis and providing resources for protective and recuperative responses to noxious stimuli. To be adaptive and flexible, autonomic responses are not only determined by noxious stimulus characteristics, but likely also shaped by perceptual and motor responses to noxious stimuli. However, it is not fully known how noxious stimulus characteristics, perceptual responses, and motor responses interact in shaping autonomic responses. To address this question, we collected perceptual, motor, and autonomic responses to brief noxious laser stimuli of different intensities in 47 healthy human participants. Multilevel 2-path mediation analyses revealed that perceptual, but not motor responses mediated the translation of noxious stimuli into autonomic responses. Multilevel 3-path mediation analyses further specified that motor responses indirectly related to autonomic responses through their close association with perceptual responses. These findings confirm that autonomic responses are not only a reflexive reaction to noxious stimuli, but directly and indirectly shaped by perceptual and motor responses, respectively. These effects of motor and perceptual processes on autonomic responses likely allow for the integration of contextual processes into protective and regulatory autonomic responses, aiding adaptive and flexible coping with threat.

Brain dysfunction in chronic pain patients assessed by resting-state electroencephalography.

Chronic pain is a common and severely disabling disease whose treatment is often unsatisfactory. Insights into the brain mechanisms of chronic pain promise to advance the understanding of the underlying pathophysiology and might help to develop disease markers and novel treatments. Here, we systematically exploited the potential of electroencephalography to determine abnormalities of brain function during the resting state in chronic pain. To this end, we performed state-of-the-art analyses of oscillatory brain activity, brain connectivity, and brain networks in 101 patients of either sex suffering from chronic pain. The results show that global and local measures of brain activity did not differ between chronic pain patients and a healthy control group. However, we observed significantly increased connectivity at theta (4-8 Hz) and gamma (>60 Hz) frequencies in frontal brain areas as well as global network reorganization at gamma frequencies in chronic pain patients. Furthermore, a machine learning algorithm could differentiate between patients and healthy controls with an above-chance accuracy of 57%, mostly based on frontal connectivity. These results suggest that increased theta and gamma synchrony in frontal brain areas are involved in the pathophysiology of chronic pain. Although substantial challenges concerning the reproducibility of the findings and the accuracy, specificity, and validity of potential electroencephalography-based disease markers remain to be overcome, our study indicates that abnormal frontal synchrony at theta and gamma frequencies might be promising targets for noninvasive brain stimulation and/or neurofeedback approaches.

Distinct patterns of brain activity mediate perceptual and motor and autonomic responses to noxious stimuli.

Pain is a complex phenomenon involving perceptual, motor, and autonomic responses, but how the brain translates noxious stimuli into these different dimensions of pain is unclear. Here, we assessed perceptual, motor, and autonomic responses to brief noxious heat stimuli and recorded brain activity using electroencephalography (EEG) in humans. Multilevel mediation analysis reveals that each pain dimension is subserved by a distinct pattern of EEG responses and, conversely, that each EEG response differentially contributes to the different dimensions of pain. In particular, the translation of noxious stimuli into autonomic and motor responses involved the earliest N1 wave, whereas pain perception was mediated by later N2 and P2 waves. Gamma oscillations mediated motor responses rather than pain perception. These findings represent progress towards a mechanistic understanding of the brain processes translating noxious stimuli into pain and suggest that perceptual, motor, and autonomic dimensions of pain are partially independent rather than serial processes.

Motor Responses to Noxious Stimuli Shape Pain Perception in Chronic Pain Patients.

Pain serves vital protective functions, which crucially depend on appropriate motor responses to noxious stimuli. Such responses not only depend on but can themselves shape the perception of pain. In chronic pain, perception is often decoupled from noxious stimuli and motor responses are no longer protective, which suggests that the relationships between noxious stimuli, pain perception, and behavior might be changed. We here performed a simple experiment to quantitatively assess the relationships between noxious stimuli, perception and behavior in 22 chronic pain patients and 22 age-matched healthy human participants. Brief noxious and tactile stimuli were applied to the participants' hands and participants performed speeded motor responses and provided perceptual ratings of the stimuli. Multi-level moderated mediation analyses assessed the relationships between stimulus intensity, perceptual ratings and reaction times for both stimulus types. The results revealed a significantly stronger involvement of motor responses in the translation of noxious stimuli into perception than in the translation of tactile stimuli into perception. This significant influence of motor responses on pain perception was found for both chronic pain patients and healthy participants. Thus, stimulus-perception-behavior relationships appear to be at least partially preserved in chronic pain patients and motor-related as well as behavioral interventions might harness these functional relationships to modulate pain perception.