Brain Rhythms of Pain
Authors: Markus Ploner, Christian Sorg, Joachim Gross
Journal: Trends in Cognitive Sciences (2016)

Pain is a vital phenomenon that depends on the dynamic integration of sensory and contextual processes. In chronic pain the adaptive integration of sensory and contextual processes is severely disturbed. Neuronal oscillations and synchrony at different frequencies provide evidence on information flow across brain areas. The flexible relationship between oscillations at different frequencies and pain indicates flexible routing of information flow in the cerebral processing of pain. The systematic assessment of oscillations and synchrony in the processing of pain provides insights into how sensory and contextual processes are flexibly integrated into a coherent percept and into abnormalities of these processes in chronic pain. Predictive coding frameworks might help us understand these integration processes. Pain is an integrative phenomenon that results from dynamic interactions between sensory and contextual (i.e., cognitive, emotional, and motivational) processes. In the brain the experience of pain is associated with neuronal oscillations and synchrony at different frequencies. However, an overarching framework for the significance of oscillations for pain remains lacking. Recent concepts relate oscillations at different frequencies to the routing of information flow in the brain and the signaling of predictions and prediction errors. The application of these concepts to pain promises insights into how flexible routing of information flow coordinates diverse processes that merge into the experience of pain. Such insights might have implications for the understanding and treatment of chronic pain. Pain is an integrative phenomenon that results from dynamic interactions between sensory and contextual (i.e., cognitive, emotional, and motivational) processes. In the brain the experience of pain is associated with neuronal oscillations and synchrony at different frequencies. However, an overarching framework for the significance of oscillations for pain remains lacking. Recent concepts relate oscillations at different frequencies to the routing of information flow in the brain and the signaling of predictions and prediction errors. The application of these concepts to pain promises insights into how flexible routing of information flow coordinates diverse processes that merge into the experience of pain. Such insights might have implications for the understanding and treatment of chronic pain. Pain results from dynamic interactions between sensory and contextual (i.e., cognitive, emotional, and motivational) processes [1Melzack R. Casey K.L. Sensory, motivational, and central control determinants of pain: a new conceptual model in pain.in: Kenshalo D.R.J. The Skin Senses. Charles C. Thomas, 1968: 423-439Google Scholar]. Pain is thus essentially an integrative phenomenon. In recent years it has been shown that oscillations and synchrony serve integrative functions by flexibly routing information flow in the brain [2Schnitzler A. Gross J. Normal and pathological oscillatory communication in the brain.Nat. Rev. Neurosci. 2005; 6: 285-296Crossref PubMed Scopus (618) Google Scholar, 3Akam T. Kullmann D.M. Oscillatory multiplexing of population codes for selective communication in the mammalian brain.Nat. Rev. Neurosci. 2014; 15: 111-122Crossref PubMed Scopus (75) Google Scholar, 4Fries P. Rhythms for cognition: communication through coherence.Neuron. 2015; 88: 220-235Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 5Saalmann Y.B. et al.The pulvinar regulates information transmission between cortical areas based on attention demands.Science. 2012; 337: 753-756Crossref PubMed Scopus (298) Google Scholar, 6Mejias J.F. et al.Feedforward and feedback frequency-dependent interactions in a large-scale laminar network of the primate cortex.Sci. Adv. 2016; 2: e1601335Crossref PubMed Google Scholar]. Thus, understanding the role of oscillations in the processing of pain promises insights into how functionally diverse processes dynamically merge into the experience of pain in health and disease. Here we review recent evidence on the role of neuronal oscillations and synchrony in the processing of pain. We begin with a brief discussion of the peculiarities of pain and its processing in the brain. We then summarize recent insights into the significance of neuronal oscillations and synchrony for the routing of information flow in the brain. On this basis we review evidence on the role of oscillations in the processing of pain. We specifically discuss how oscillations and synchrony serve the flexible routing of information flow in the integration of sensory and contextual factors into a coherent percept. Moreover, we review and discuss the role of these processes in pathological abnormalities of the pain experience in chronic pain. Finally, we consider perspectives and future directions for the study of the role of neuronal oscillations in the cerebral processing of pain. Pain is an unpleasant sensory and emotional experience that signals threat and promotes behavior to protect the individual. Commonly, the underlying process is that a noxious stimulus induces physiological processes, referred to as nociception (see Glossary), that translate into pain [1Melzack R. Casey K.L. Sensory, motivational, and central control determinants of pain: a new conceptual model in pain.in: Kenshalo D.R.J. The Skin Senses. Charles C. Thomas, 1968: 423-439Google Scholar]. This translation process is influenced by a broad variety of contextual factors. We routinely make use of this influence; for example, when comforting an injured child or when harnessing placebo effects for pain therapy. Pain thus results from the integration of nociceptive and contextual information mediated by feedforward and feedback processes in the human brain [7Wiech K. Deconstructing the sensation of pain: the influence of cognitive processes on pain perception.Science. 2016; 354: 584-587Crossref PubMed Scopus (0) Google Scholar]. This integration process is not static but has to be dynamically adjusted to the continuously changing demands of everyday life. For example, the same noxious input can yield no pain when a competing goal has to be achieved (e.g., during a long-distance run) but under other contextual conditions can result in strong pain (e.g., when a severe disease is feared). Thus, the dynamic integration of sensory and contextual processes plays a preeminent role in pain that probably exceeds its role in other modalities. In chronic pain states, pain often persists without objective threat to the body. Chronic pain is a disease in its own right that affects about a fifth of the adult population in the Western world [8Breivik H. et al.Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment.Eur. J. Pain. 2006; 10: 287-333Crossref PubMed Scopus (1993) Google Scholar, 9Kennedy J. et al.Prevalence of persistent pain in the U.S. adult population: new data from the 2010 national health interview survey.J. Pain. 2014; 15: 979-984Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar], imposes an enormous economic burden on society [10Breivik H. et al.The individual and societal burden of chronic pain in Europe: the case for strategic prioritisation and action to improve knowledge and availability of appropriate care.BMC Public Health. 2013; 13: 1229Crossref PubMed Scopus (93) Google Scholar, 11Gaskin D.J. Richard P. The economic costs of pain in the United States.J. Pain. 2012; 13: 715-724Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar], and causes severe suffering to individuals. In chronic pain the relationship between nociception and pain is often weak or lost [12Baliki M.N. Apkarian A.V. Nociception, pain, negative moods, and behavior selection.Neuron. 2015; 87: 474-491Abstract Full Text Full Text PDF PubMed Google Scholar] indicating abnormal integration of nociceptive and contextual information. In particular, there is a close and mutual relationship between contextual factors and chronic pain [13Flor H. Turk D.C. Chronic Pain. IASP Press, 2011Google Scholar]. For example, certain psychological factors such as passive coping strategies predispose to the development of chronic pain and, conversely, chronic pain yields severe cognitive, affective, and functional deficits [13Flor H. Turk D.C. Chronic Pain. IASP Press, 2011Google Scholar]. Thus, the adaptive integration of nociceptive and contextual processes is severely disturbed in chronic pain. Pain is associated with the activation of an extended network of brain areas including the somatosensory, insular, cingulate, and prefrontal cortices, the thalamus, subcortical areas, and the brainstem [14Apkarian A.V. et al.Human brain mechanisms of pain perception and regulation in health and disease.Eur. J. Pain. 2005; 9: 463-484Crossref PubMed Scopus (1508) Google Scholar]. These areas do not constitute a dedicated pain system but belong to different functional systems of the brain that are transiently orchestrated in the processing of pain. None of these areas exclusively processes or singularly determines the experience of pain [15Legrain V. et al.The pain matrix reloaded: a salience detection system for the body.Prog. Neurobiol. 2011; 93: 111-124Crossref PubMed Scopus (317) Google Scholar] (see [16Segerdahl A.R. et al.The dorsal posterior insula subserves a fundamental role in human pain.Nat. Neurosci. 2015; 18: 499-500Crossref PubMed Google Scholar, 17Davis K.D. et al.Evidence against pain specificity in the dorsal posterior insula.F1000Res. 2015; 4: 362Crossref PubMed Scopus (0) Google Scholar, 18Lieberman M.D. Eisenberger N.I. The dorsal anterior cingulate cortex is selective for pain: results from large-scale reverse inference.Proc. Natl. Acad. Sci. U.S.A. 2015; 112: 15250-15255Crossref PubMed Scopus (11) Google Scholar, 19Wager T.D. et al.Pain in the ACC?.Proc. Natl. Acad. Sci. U.S.A. 2016; 113: E2474-E2475Crossref PubMed Scopus (0) Google Scholar] for an ongoing discussion of this topic). It is thus likely that the integration of neuronal activity across brain areas eventually determines pain. Structural connections represent the anatomical basis for this integration process. However, to continuously adjust pain to the momentary behavioral demands, the integration process has to be highly flexible. This flexibility requires dynamic changes of neuronal integration at timescales that can be provided not by changes of structural connections but rather by dynamic changes of functional connections. Such dynamic changes of functional connections in the processing of pain have recently been conceptualized as the dynamic pain connectome [20Kucyi A. Davis K.D. The dynamic pain connectome.Trends Neurosci. 2015; 38: 86-95Abstract Full Text Full Text PDF PubMed Google Scholar]. This concept does not conceive the cerebral processing of pain as a static phenomenon but emphasizes that the dynamics of functional connections flexibly determine the experience of pain. Pain is associated not only with a spatially extended network of dynamically recruited brain areas but also with complex temporal–spectral patterns of brain activity. In particular, pain-related neuronal oscillations at frequencies ranging from infraslow fluctuations below 0.1 Hz (Box 1) via theta (4–7 Hz), alpha (8–13 Hz), and beta (14–29 Hz) to gamma (30–100 Hz) oscillations [21Gross J. et al.Gamma oscillations in human primary somatosensory cortex reflect pain perception.PLoS Biol. 2007; 5: e133Crossref PubMed Scopus (53) Google Scholar, 22Hauck M. et al.Attention to painful stimulation enhances gamma-band activity and synchronization in human sensorimotor cortex.J. Neurosci. 2007; 27: 9270-9277Crossref PubMed Scopus (74) Google Scholar, 23Mouraux A. et al.Non-phase locked electroencephalogram (EEG) responses to CO2 laser skin stimulations may reflect central interactions between A∂- and C-fibre afferent volleys.Clin. Neurophysiol. 2003; 114: 710-722Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 24Ploner M. et al.Pain suppresses spontaneous brain rhythms.Cereb. Cortex. 2006; 16: 537-540Crossref PubMed Scopus (0) Google Scholar, 25Zhang Z.G. et al.Gamma-band oscillations in the primary somatosensory cortex – a direct and obligatory correlate of subjective pain intensity.J. Neurosci. 2012; 32: 7429-7438Crossref PubMed Scopus (0) Google Scholar, 26Baliki M.N. et al.The cortical rhythms of chronic back pain.J. Neurosci. 2011; 31: 13981-13990Crossref PubMed Scopus (104) Google Scholar, 27Malinen S. et al.Aberrant temporal and spatial brain activity during rest in patients with chronic pain.Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 6493-6497Crossref PubMed Scopus (0) Google Scholar, 28Napadow V. et al.Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia.Arthritis Rheum. 2012; 64: 2398-2403Crossref PubMed Scopus (101) Google Scholar, 29Alshelh Z. et al.Chronic neuropathic pain: it's about the rhythm.J. Neurosci. 2016; 36: 1008-1018Crossref PubMed Scopus (0) Google Scholar, 30Green A.L. et al.Neural signatures in patients with neuropathic pain.Neurology. 2009; 72: 569-571Crossref PubMed Scopus (0) Google Scholar, 31Huang Y. et al.Characteristics of local field potentials correlate with pain relief by deep brain stimulation.Clin. Neurophysiol. 2016; 127: 2573-2580Abstract Full Text Full Text PDF PubMed Google Scholar] have been observed. These oscillations have been recorded during different contextual conditions and at different timescales. However, an overarching framework for the significance of these oscillations for pain remains lacking.Box 1Infraslow Fluctuations and PainIn resting-state fMRI data, infraslow fluctuations of blood oxygenation level-dependent (BOLD) signals below 0.1 Hz have been observed [108Raichle M.E. The restless brain: how intrinsic activity organizes brain function.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2015; (Published online May 19, 2015)https://doi.org/10.1016/10.1098/rstb.2014.0172Crossref PubMed Google Scholar]. The synchronization of these infraslow fluctuations across brain areas defines intrinsic brain networks [108Raichle M.E. The restless brain: how intrinsic activity organizes brain function.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2015; (Published online May 19, 2015)https://doi.org/10.1016/10.1098/rstb.2014.0172Crossref PubMed Google Scholar]. Accumulating evidence indicates that particularly the activities of the default mode, salience, and sensorimotor networks are changed in chronic pain [26Baliki M.N. et al.The cortical rhythms of chronic back pain.J. Neurosci. 2011; 31: 13981-13990Crossref PubMed Scopus (104) Google Scholar, 27Malinen S. et al.Aberrant temporal and spatial brain activity during rest in patients with chronic pain.Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 6493-6497Crossref PubMed Scopus (0) Google Scholar, 28Napadow V. et al.Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia.Arthritis Rheum. 2012; 64: 2398-2403Crossref PubMed Scopus (101) Google Scholar, 29Alshelh Z. et al.Chronic neuropathic pain: it's about the rhythm.J. Neurosci. 2016; 36: 1008-1018Crossref PubMed Scopus (0) Google Scholar]. The findings show changes of connectivity not only within but also across [109Hemington K.S. et al.Abnormal cross-network functional connectivity in chronic pain and its association with clinical symptoms.Brain Struct. Funct. 2016; 221: 4203-4219Crossref PubMed Scopus (17) Google Scholar] these networks in chronic pain. Moreover, changes of the frequency pattern [26Baliki M.N. et al.The cortical rhythms of chronic back pain.J. Neurosci. 2011; 31: 13981-13990Crossref PubMed Scopus (104) Google Scholar, 27Malinen S. et al.Aberrant temporal and spatial brain activity during rest in patients with chronic pain.Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 6493-6497Crossref PubMed Scopus (0) Google Scholar] and the variability [110Rogachov A. et al.Regional brain signal variability: a novel indicator of pain sensitivity and coping.Pain. 2016; 157: 2483-2492Crossref PubMed Google Scholar] of infraslow fluctuations have been observed. Thus, the analysis of infraslow fluctuations is a promising approach to advance our understanding of the brain mechanisms of chronic pain. However, changes of infraslow fluctuations of BOLD signals are found not only in pain but in many neuropsychiatric disorders [111Greicius M. Resting-state functional connectivity in neuropsychiatric disorders.Curr. Opin. Neurol. 2008; 21: 424-430Crossref PubMed Google Scholar] so that the disease and symptom specificity of the observed changes remains an important question.Two physiological aspects of intrinsic brain networks might be of particular interest in the processing of pain. First, intrinsic brain networks relate to slowly propagating waves of neuronal activity at a timescale of about 1 s for the whole cortex [112Mitra A. et al.Lag threads organize the brain's intrinsic activity.Proc. Natl. Acad. Sci. U.S.A. 2015; 112: E2235-E2244Crossref PubMed Scopus (0) Google Scholar, 113Matsui T. et al.Transient neuronal coactivations embedded in globally propagating waves underlie resting-state functional connectivity.Proc. Natl. Acad. Sci. U.S.A. 2016; 113: 6556-6561Crossref PubMed Google Scholar]. These waves provide subthreshold depolarization to individual neurons indicating modulation of neuronal excitability [114Wu J.Y. et al.Propagating waves of activity in the neocortex: what they are, what they do.Neuroscientist. 2008; 14: 487-502Crossref PubMed Scopus (0) Google Scholar]. Changes of infraslow BOLD fluctuations in chronic pain might therefore indicate impairment of slowly propagating waves. As slowly propagating waves are intimately linked to slow waves during sleep and memory consolidation [115Mitra A. et al.Propagated infra-slow intrinsic brain activity reorganizes across wake and slow wave sleep.Elife. 2015; 4: 10781Crossref Google Scholar], changes of infraslow BOLD fluctuations might relate to abnormal learning and memory consolidation processes in chronic pain [13Flor H. Turk D.C. Chronic Pain. IASP Press, 2011Google Scholar]. Second, infraslow fluctuations are linked to fluctuations of faster oscillations at alpha and gamma frequencies [116Mantini D. et al.Electrophysiological signatures of resting state networks in the human brain.Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 13170-13175Crossref PubMed Scopus (923) Google Scholar, 117Brookes M.J. et al.Investigating the electrophysiological basis of resting state networks using magnetoencephalography.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 16783-16788Crossref PubMed Scopus (310) Google Scholar] indicating cross-frequency coupling with infraslow fluctuations shaping faster oscillations. In chronic pain, abnormal infraslow fluctuations, particularly in the salience and default mode networks [26Baliki M.N. et al.The cortical rhythms of chronic back pain.J. Neurosci. 2011; 31: 13981-13990Crossref PubMed Scopus (104) Google Scholar, 27Malinen S. et al.Aberrant temporal and spatial brain activity during rest in patients with chronic pain.Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 6493-6497Crossref PubMed Scopus (0) Google Scholar, 28Napadow V. et al.Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia.Arthritis Rheum. 2012; 64: 2398-2403Crossref PubMed Scopus (101) Google Scholar, 29Alshelh Z. et al.Chronic neuropathic pain: it's about the rhythm.J. Neurosci. 2016; 36: 1008-1018Crossref PubMed Scopus (0) Google Scholar], might interfere with faster oscillations and the flexible routing of information flow in the brain.In summary, infraslow fluctuations provide a mechanistic framework that connects slow wave propagation and learning processes to oscillations at higher frequencies and flexible cerebral information flow. Abnormalities of infraslow fluctuations and their synchronization might signal abnormal slow wave propagation and related learning processes and contribute to abnormal routing of information flow in chronic pain. In resting-state fMRI data, infraslow fluctuations of blood oxygenation level-dependent (BOLD) signals below 0.1 Hz have been observed [108Raichle M.E. The restless brain: how intrinsic activity organizes brain function.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2015; (Published online May 19, 2015)https://doi.org/10.1016/10.1098/rstb.2014.0172Crossref PubMed Google Scholar]. The synchronization of these infraslow fluctuations across brain areas defines intrinsic brain networks [108Raichle M.E. The restless brain: how intrinsic activity organizes brain function.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2015; (Published online May 19, 2015)https://doi.org/10.1016/10.1098/rstb.2014.0172Crossref PubMed Google Scholar]. Accumulating evidence indicates that particularly the activities of the default mode, salience, and sensorimotor networks are changed in chronic pain [26Baliki M.N. et al.The cortical rhythms of chronic back pain.J. Neurosci. 2011; 31: 13981-13990Crossref PubMed Scopus (104) Google Scholar, 27Malinen S. et al.Aberrant temporal and spatial brain activity during rest in patients with chronic pain.Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 6493-6497Crossref PubMed Scopus (0) Google Scholar, 28Napadow V. et al.Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia.Arthritis Rheum. 2012; 64: 2398-2403Crossref PubMed Scopus (101) Google Scholar, 29Alshelh Z. et al.Chronic neuropathic pain: it's about the rhythm.J. Neurosci. 2016; 36: 1008-1018Crossref PubMed Scopus (0) Google Scholar]. The findings show changes of connectivity not only within but also across [109Hemington K.S. et al.Abnormal cross-network functional connectivity in chronic pain and its association with clinical symptoms.Brain Struct. Funct. 2016; 221: 4203-4219Crossref PubMed Scopus (17) Google Scholar] these networks in chronic pain. Moreover, changes of the frequency pattern [26Baliki M.N. et al.The cortical rhythms of chronic back pain.J. Neurosci. 2011; 31: 13981-13990Crossref PubMed Scopus (104) Google Scholar, 27Malinen S. et al.Aberrant temporal and spatial brain activity during rest in patients with chronic pain.Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 6493-6497Crossref PubMed Scopus (0) Google Scholar] and the variability [110Rogachov A. et al.Regional brain signal variability: a novel indicator of pain sensitivity and coping.Pain. 2016; 157: 2483-2492Crossref PubMed Google Scholar] of infraslow fluctuations have been observed. Thus, the analysis of infraslow fluctuations is a promising approach to advance our understanding of the brain mechanisms of chronic pain. However, changes of infraslow fluctuations of BOLD signals are found not only in pain but in many neuropsychiatric disorders [111Greicius M. Resting-state functional connectivity in neuropsychiatric disorders.Curr. Opin. Neurol. 2008; 21: 424-430Crossref PubMed Google Scholar] so that the disease and symptom specificity of the observed changes remains an important question. Two physiological aspects of intrinsic brain networks might be of particular interest in the processing of pain. First, intrinsic brain networks relate to slowly propagating waves of neuronal activity at a timescale of about 1 s for the whole cortex [112Mitra A. et al.Lag threads organize the brain's intrinsic activity.Proc. Natl. Acad. Sci. U.S.A. 2015; 112: E2235-E2244Crossref PubMed Scopus (0) Google Scholar, 113Matsui T. et al.Transient neuronal coactivations embedded in globally propagating waves underlie resting-state functional connectivity.Proc. Natl. Acad. Sci. U.S.A. 2016; 113: 6556-6561Crossref PubMed Google Scholar]. These waves provide subthreshold depolarization to individual neurons indicating modulation of neuronal excitability [114Wu J.Y. et al.Propagating waves of activity in the neocortex: what they are, what they do.Neuroscientist. 2008; 14: 487-502Crossref PubMed Scopus (0) Google Scholar]. Changes of infraslow BOLD fluctuations in chronic pain might therefore indicate impairment of slowly propagating waves. As slowly propagating waves are intimately linked to slow waves during sleep and memory consolidation [115Mitra A. et al.Propagated infra-slow intrinsic brain activity reorganizes across wake and slow wave sleep.Elife. 2015; 4: 10781Crossref Google Scholar], changes of infraslow BOLD fluctuations might relate to abnormal learning and memory consolidation processes in chronic pain [13Flor H. Turk D.C. Chronic Pain. IASP Press, 2011Google Scholar]. Second, infraslow fluctuations are linked to fluctuations of faster oscillations at alpha and gamma frequencies [116Mantini D. et al.Electrophysiological signatures of resting state networks in the human brain.Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 13170-13175Crossref PubMed Scopus (923) Google Scholar, 117Brookes M.J. et al.Investigating the electrophysiological basis of resting state networks using magnetoencephalography.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 16783-16788Crossref PubMed Scopus (310) Google Scholar] indicating cross-frequency coupling with infraslow fluctuations shaping faster oscillations. In chronic pain, abnormal infraslow fluctuations, particularly in the salience and default mode networks [26Baliki M.N. et al.The cortical rhythms of chronic back pain.J. Neurosci. 2011; 31: 13981-13990Crossref PubMed Scopus (104) Google Scholar, 27Malinen S. et al.Aberrant temporal and spatial brain activity during rest in patients with chronic pain.Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 6493-6497Crossref PubMed Scopus (0) Google Scholar, 28Napadow V. et al.Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia.Arthritis Rheum. 2012; 64: 2398-2403Crossref PubMed Scopus (101) Google Scholar, 29Alshelh Z. et al.Chronic neuropathic pain: it's about the rhythm.J. Neurosci. 2016; 36: 1008-1018Crossref PubMed Scopus (0) Google Scholar], might interfere with faster oscillations and the flexible routing of information flow in the brain. In summary, infraslow fluctuations provide a mechanistic framework that connects slow wave propagation and learning processes to oscillations at higher frequencies and flexible cerebral information flow. Abnormalities of infraslow fluctuations and their synchronization might signal abnormal slow wave propagation and related learning processes and contribute to abnormal routing of information flow in chronic pain. The close relationship between chronic pain and psychological factors [13Flor H. Turk D.C. Chronic Pain. IASP Press, 2011Google Scholar] and the substantial comorbidity of chronic pain and mental disorders [32Fishbain D.A. Psychiatric pain-associated co-morbidities.in: McMahon S.B. Wall and Melzack's Textbook of Pain. Elsevier, 2013: 273-282Google Scholar] indicates that brain dysfunction plays a central role in the development and maintenance of chronic pain. Recent neurobiological investigations corroborate the crucial role of the brain in chronic pain by showing substantial structural and metabolic changes of the brain in chronic pain [12Baliki M.N. Apkarian A.V. Nociception, pain, negative moods, and behavior selection.Neuron. 2015; 87: 474-491Abstract Full Text Full Text PDF PubMed Google Scholar, 33Rauschecker J.P. et al.Frontostriatal gating of tinnitus and chronic pain.Trends Cogn. Sci. 2015; 19: 567-578Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar]. Moreover, neurophysiological and functional imaging studies found abnormalities of the frequency spectrum of brain activity ranging from infraslow fluctuations (Box 1) to gamma oscillations in patients with chronic pain [26Baliki M.N. et al.The cortical rhythms of chronic back pain.J. Neurosci. 2011; 31: 13981-13990Crossref PubMed Scopus (104) Google Scholar, 27Malinen S. et al.Aberrant temporal and spatial brain activity during rest in patients with chronic pain.Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 6493-6497Crossref PubMed Scopus (0) Google Scholar, 34Sarnthein J. et al.Increased EEG power and slowed dominant frequency in patients with neurogenic pain.Brain. 2006; 129: 55-64Crossref PubMed Scopus (154) Google Scholar, 35Stern J. et al.Persistent EEG overactivation in the cortical pain matrix of neurogenic pain patients.Neuroimage. 2006; 31: 721-731Crossref PubMed Scopus (103) Google Scholar]. Most recent evidence indicates that some of these changes are causally involved in the development and maintenance of chronic pain [36Baliki M.N. et al.Corticostriatal functional connectivity predicts transition to chronic back pain.Nat. Neurosci. 2012; 15: 1117-1119Crossref PubMed Scopus (293) Google Scholar, 37Vachon-Presseau E. et al.Corticolimbic anatomical characteristics predetermine risk for chronic pain.Brain. 2016; 139: 1958-1970Crossref PubMed Scopus (0) Google Scholar]. Brain rhythms or brain oscillations refer to rhythmic fluctuations of neural mass signals recorded by local field potentials (LFPs), electroencephalography (EEG), or magnetoencephalography (MEG) [38Panzeri S. et al.Neural population coding: combining insights from microscopic and mass signals.Trends Cogn. Sci. 2015; 19: 162-172Abstract Full Text Full Text PDF PubMed Google Scholar]. Brain oscillations are most prominent at frequencies between 1 and 100 Hz [39Buzsaki G. Draguhn A. Neuronal oscillations in cortical networks.Science. 2004; 304: 1926-1929Crossref PubMed Scopus (2405) Google Scholar]. They originate from the dynamic interplay of excitation and inhibition of neuronal populations leading to periodic synchronization of action potentials. In addition, infraslow fluctuations of brain activity are observed at frequencies below 0.1 Hz by functional magnetic resonance imaging (fMRI) (Box 1). At any frequency the synchronization of brain activity can occur bo