Ultralow-frequency neural entrainment to pain

Nervous systems exploit regularities in the sensory environment to predict sensory input, adjust behavior, and thereby maximize fitness. Entrainment of neural oscillations allows retaining temporal regularities of sensory information, a prerequisite for prediction. Entrainment has been extensively described at the frequencies of periodic inputs most commonly present in visual and auditory landscapes (e.g., >0.5 Hz). An open question is whether neural entrainment also occurs for regularities at much longer timescales. Here, we exploited the fact that the temporal dynamics of thermal stimuli in natural environment can unfold very slowly. We show that ultralow-frequency neural oscillations preserved a long-lasting trace of sensory information through neural entrainment to periodic thermo-nociceptive input as low as 0.1 Hz. Importantly, revealing the functional significance of this phenomenon, both power and phase of the entrainment predicted individual pain sensitivity. In contrast, periodic auditory input at the same ultralow frequency did not entrain ultralow-frequency oscillations. These results demonstrate that a functionally significant neural entrainment can occur at temporal scales far longer than those commonly explored. The non-supramodal nature of our results suggests that ultralow-frequency entrainment might be tuned to the temporal scale of the statistical regularities characteristic of different sensory modalities

Ultralow-frequency neural entrainment to pain

Nervous systems exploit regularities in the sensory environment to predict sensory input, adjust behavior, and thereby maximize fitness. Entrainment of neural oscillations allows retaining temporal regularities of sensory information, a prerequisite for prediction. Entrainment has been extensively described at the frequencies of periodic inputs most commonly present in visual and auditory landscapes (e.g., >0.5 Hz). An open question is whether neural entrainment also occurs for regularities at much longer timescales. Here, we exploited the fact that the temporal dynamics of thermal stimuli in natural environment can unfold very slowly. We show that ultralow-frequency neural oscillations preserved a long-lasting trace of sensory information through neural entrainment to periodic thermo-nociceptive input as low as 0.1 Hz. Importantly, revealing the functional significance of this phenomenon, both power and phase of the entrainment predicted individual pain sensitivity. In contrast, periodic auditory input at the same ultralow frequency did not entrain ultralow-frequency oscillations. These results demonstrate that a functionally significant neural entrainment can occur at temporal scales far longer than those commonly explored. The non-supramodal nature of our results suggests that ultralow-frequency entrainment might be tuned to the temporal scale of the statistical regularities characteristic of different sensory modalities

Dynamic modulation of beta band cortico-muscular coupling induced by audio-visual rhythms

Human movements often spontaneously fall into synchrony with auditory and visual environmental rhythms. Related behavioral studies have shown that motor responses are automatically and unintentionally coupled with external rhythmic stimuli. However, the neurophysiological processes underlying such motor entrainment remain largely unknown. Here we investigated with electroencephalography (EEG) and electromyography (EMG) the modulation of neural and muscular activity induced by periodic audio and/or visual sequences. The sequences were presented at either 1 Hz or 2 Hz while participants maintained constant finger pressure on a force sensor. The results revealed that although there was no change of amplitude in participants’ EMG in response to the sequences, the synchronization between EMG and EEG recorded over motor areas in the beta (12–40 Hz) frequency band was dynamically modulated, with maximal coherence occurring about 100 ms before each stimulus. These modulations in beta EEG–EMG motor coherence were found for the 2 Hz audio-visual sequences, confirming at a neurophysiological level the enhancement of motor entrainment with multimodal rhythms that fall within preferred perceptual and movement frequency ranges. Our findings identify beta band cortico-muscular coupling as a potential underlying mechanism of motor entrainment, further elucidating the nature of the link between sensory and motor systems in humans

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

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

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

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