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Journal Article•DOI•

Central mechanisms of pain revealed through functional and structural MRI.

Karen D. Davis1, Karen D. Davis2, Massieh Moayedi1, Massieh Moayedi2•
University of Toronto1, University Health Network2
01 Jun 2013-Journal of Neuroimmune Pharmacology (Springer US)-Vol. 8, Iss: 3, pp 518-534
TL;DR: Functional and structural MRI findings point to brain and peripheral nerve abnormalities in patients with chronic pain, some of which are pre-existing and others that develop with prolonged pain (and related neuroinflammation) over time.
Abstract: MR-based brain imaging technologies provide a suite of functional and structural metrics that can be used to test hypotheses about the CNS mechanisms underlying pain perception and chronification, from a cellular level to a systems level. Two types of functional MRI discussed in this review provide insight into pain mechanisms: stimulus-evoked fMRI and task-free (“resting state”) fMRI. The former can assess how the brain responds to noxious or non-noxious stimuli normally or in a chronic pain state as a window into understanding pain, hyperalgesia and allodynia. The latter can assess functional connectivity reflecting synchronous ultra-slow frequency oscillation between brain areas. This provides insight into how brain areas work together as networks to produce pain and how these networks may be modified due to chronic pain. Perfusion MR (e.g., arterial spin labeling) can also provide task-free information pertaining to ongoing brain activity that may reflect spontaneous (ongoing) chronic pain. Structural MR techniques can be used to delineate gray and white matter abnormalities and markers of neuroinflammation associated with chronic pains. Functional and structural MRI findings point to brain and peripheral nerve abnormalities in patients with chronic pain, some of which are pre-existing and others that develop with prolonged pain (and related neuroinflammation) over time. Recent studies indicate that some structural brain abnormalities associated with chronic pain are reversible following effective pain treatment. These data together with findings from studies of individual differences suggest that some chronic pains arise from a combination of pre-existing vulnerabilities and sustained abnormal input.
Citations
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Journal Article•DOI•
Cognitive and emotional control of pain and its disruption in chronic pain

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M. Catherine Bushnell1, Marta Ceko1, Lucie A. Low1•
National Institutes of Health1
01 Jul 2013-Nature Reviews Neuroscience
TL;DR: The accumulating evidence that chronic pain itself alters brain circuitry, including that involved in endogenous pain control, is examined, suggesting that controlling pain becomes increasingly difficult as pain becomes chronic.
Abstract: Chronic pain is one of the most prevalent health problems in our modern world, with millions of people debilitated by conditions such as back pain, headache and arthritis. To address this growing problem, many people are turning to mind-body therapies, including meditation, yoga and cognitive behavioural therapy. This article will review the neural mechanisms underlying the modulation of pain by cognitive and emotional states - important components of mind-body therapies. It will also examine the accumulating evidence that chronic pain itself alters brain circuitry, including that involved in endogenous pain control, suggesting that controlling pain becomes increasingly difficult as pain becomes chronic.

1,359 citations

Journal Article•DOI•
Nociception, pain, negative moods and behavior selection

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Marwan N. Baliki1, A. Vania Apkarian1•
Northwestern University1
05 Aug 2015-Neuron
TL;DR: This work deconstructs chronic pain into four distinct phases, each with specific mechanisms, and outlines current state of knowledge regarding these mechanisms: the limbic brain imparting risk, and the mesolimbic learning processes reorganizing the neocortex into a chronic pain state.

451 citations

Cites background from "Central mechanisms of pain revealed..."

  • ...…with distinct chronic pain conditions, as well as the long-term and continued condition-specific reorganization of the brain across chronic pain diagnoses, justify the notion that chronic pain is a maladaptive neuropathological disease state (Davis and Moayedi, 2013; Tracey and Bushnell, 2009)....

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  • ...In early SBP (10–15 weeks after start of back pain), brain activity for back pain closely corresponds the activity for acute pain....

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Journal Article•DOI•
The dynamic pain connectome

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Aaron Kucyi1, Aaron Kucyi2, Karen D. Davis•
University Health Network1, University of Toronto2
01 Feb 2015-Trends in Neurosciences
TL;DR: How recent progress in understanding of individual differences in intrinsic attention to pain and neural network dynamics in chronic pain can facilitate development of personalized pain therapies is described and the concept of a dynamic 'pain connectome' in the brain is introduced.

403 citations

Journal Article•DOI•
Theories of pain: from specificity to gate control

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Massieh Moayedi1, Karen D. Davis2, Karen D. Davis1•
University of Toronto1, University Health Network2
01 Jan 2013-Journal of Neurophysiology
TL;DR: A historical overview of the major contributions, ideas, and competing theories of pain from ancient civilizations to Melzack and Wall's Gate Control Theory of Pain is provided.
Abstract: Several theoretical frameworks have been proposed to explain the physiological basis of pain, although none yet completely accounts for all aspects of pain perception. Here, we provide a historical overview of the major contributions, ideas, and competing theories of pain from ancient civilizations to Melzack and Wall's Gate Control Theory of Pain.

362 citations

Cites background from "Central mechanisms of pain revealed..."

  • ...…of persistent and chronic pain are still not fully understood, it is now clear that peripheral and central plasticity can arise following repeated nociceptive stimulation in healthy subjects (Bingel et al. 2008; Teutsch et al. 2008) and in chronic pain [for a review, see Davis and Moayedi (2012)]....

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Journal Article•DOI•
Central sensitization in fibromyalgia? A systematic review on structural and functional brain MRI.

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Barbara Cagnie1, Iris Coppieters1, Sien Denecker1, Jasmien Six1, Lieven Danneels1, Mira Meeus2 •
Ghent University1, University of Antwerp2
01 Aug 2014-Seminars in Arthritis and Rheumatism
TL;DR: There is moderate evidence for a significant imbalance of the connectivity within the pain network during rest in patients with fibromyalgia and an increased activity in the pain matrix related to central sensitization.

267 citations

Cites background from "Central mechanisms of pain revealed..."

  • ...An increasing number of studies have reported macroscopic changes in gray matter volume in pain-processing brain regions [10]....

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  • ...This approach can be used to determine how healthy individuals respond to painful stimuli and how individuals with chronic pain respond to either noxious or innocuous stimuli [10]....

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References
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Journal Article•DOI•
A default mode of brain function.

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Marcus E. Raichle1, Ann Mary MacLeod1, Abraham Z. Snyder1, William J. Powers, Debra A. Gusnard1, Gordon L. Shulman1 •
Washington University in St. Louis1
16 Jan 2001-Proceedings of the National Academy of Sciences of the United States of America
TL;DR: A baseline state of the normal adult human brain in terms of the brain oxygen extraction fraction or OEF is identified, suggesting the existence of an organized, baseline default mode of brain function that is suspended during specific goal-directed behaviors.
Abstract: A baseline or control state is fundamental to the understanding of most complex systems. Defining a baseline state in the human brain, arguably our most complex system, poses a particular challenge. Many suspect that left unconstrained, its activity will vary unpredictably. Despite this prediction we identify a baseline state of the normal adult human brain in terms of the brain oxygen extraction fraction or OEF. The OEF is defined as the ratio of oxygen used by the brain to oxygen delivered by flowing blood and is remarkably uniform in the awake but resting state (e.g., lying quietly with eyes closed). Local deviations in the OEF represent the physiological basis of signals of changes in neuronal activity obtained with functional MRI during a wide variety of human behaviors. We used quantitative metabolic and circulatory measurements from positron-emission tomography to obtain the OEF regionally throughout the brain. Areas of activation were conspicuous by their absence. All significant deviations from the mean hemisphere OEF were increases, signifying deactivations, and resided almost exclusively in the visual system. Defining the baseline state of an area in this manner attaches meaning to a group of areas that consistently exhibit decreases from this baseline, during a wide variety of goal-directed behaviors monitored with positron-emission tomography and functional MRI. These decreases suggest the existence of an organized, baseline default mode of brain function that is suspended during specific goal-directed behaviors.

10,708 citations

"Central mechanisms of pain revealed..." refers background in this paper

  • ...In a follow-up study of the same patients, this group (Napadow et al. 2012) found that DMN connectivity with the insula was reduced proportionally to the reduction of their pain....

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  • ...For example, we and others have found that the DMN is suppressed by both cognitive load and acute pain (Seminowicz and Davis 2007b) and disrupted in chronic pain (Baliki et al. 2008)....

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  • ...In the context of chronic pain, two recent studies have identified abnormal DMN connectivity....

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  • ...Furthermore, the mPFC, as part of the DMN, is deactivated (an abnormal response) during task performance in chronic pain (Baliki et al. 2008), including temporomandibular disorder (Weissman-Fogel et al. 2011)....

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  • ...The first network shown to have functional connectivity was deemed to represent a default mode of the brain (the DMN) (Raichle et al. 2001; Gusnard et al. 2001; Mazoyer et al. 2001) and includes the posterior cingulate, precuneus, medial PFC (mPFC) and lateral parietal cortices....

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Journal Article•DOI•
Voxel-Based Morphometry—The Methods

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John Ashburner1, Karl J. Friston1•
Queen's University1
01 Jun 2000-NeuroImage
TL;DR: In this paper, the authors describe the steps involved in VBM, with particular emphasis on segmenting gray matter from MR images with non-uniformity artifact and provide evaluations of the assumptions that underpin the method, including the accuracy of the segmentation and the assumptions made about the statistical distribution of the data.

8,049 citations

"Central mechanisms of pain revealed..." refers methods in this paper

  • ...A complementary method to VBM is called cortical thickness analysis (CTA) which measures scalar values of cortical thickness....

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  • ...Gray matter volume and cortical thickness Gray matter is often measured with the technique of voxelbased morphometry (VBM) (Ashburner and Friston 2000)....

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  • ...Gray matter is often measured with the technique of voxelbased morphometry (VBM) (Ashburner and Friston 2000)....

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Journal Article•DOI•
The human brain is intrinsically organized into dynamic, anticorrelated functional networks

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Michael D. Fox1, Abraham Z. Snyder1, Justin L. Vincent1, Maurizio Corbetta1, David C. Van Essen1, Marcus E. Raichle1 •
Washington University in St. Louis1
05 Jul 2005-Proceedings of the National Academy of Sciences of the United States of America
TL;DR: It is suggested that both task-driven neuronal responses and behavior are reflections of this dynamic, ongoing, functional organization of the brain, featuring the presence of anticorrelated networks in the absence of overt task performance.
Abstract: During performance of attention-demanding cognitive tasks, certain regions of the brain routinely increase activity, whereas others routinely decrease activity. In this study, we investigate the extent to which this task-related dichotomy is represented intrinsically in the resting human brain through examination of spontaneous fluctuations in the functional MRI blood oxygen level-dependent signal. We identify two diametrically opposed, widely distributed brain networks on the basis of both spontaneous correlations within each network and anticorrelations between networks. One network consists of regions routinely exhibiting task-related activations and the other of regions routinely exhibiting task-related deactivations. This intrinsic organization, featuring the presence of anticorrelated networks in the absence of overt task performance, provides a critical context in which to understand brain function. We suggest that both task-driven neuronal responses and behavior are reflections of this dynamic, ongoing, functional organization of the brain.

7,741 citations

"Central mechanisms of pain revealed..." refers background in this paper

  • ...Other functionally connected networks that become active during a task can show anti-correlated activity to the default mode network (Fox et al. 2005)....

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  • ...For example, several intrinsic resting state networks have been identified (Fox et al. 2005; De Luca et al. 2006; Weissman-Fogel et al. 2010) that may serve salience, executive control, sensorimotor, cognitive and emotional functions....

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Journal Article•DOI•
The Pain Catastrophizing Scale: Development and validation.

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Michael J. L. Sullivan1, Scott R. Bishop, Jayne Pivik•
Dalhousie University1
01 Jan 1995-Psychological Assessment
TL;DR: In this paper, the Pain Catastrophizing Scale (PCS) was administered to 425 undergraduates and a three component solution comprising (a) rumination, (b) magnification, and (c) helplessness.
Abstract: In Study 1, the Pain Catastrophizing Scale (PCS) was administered to 425 undergraduates. Analyses yielded a three component solution comprising (a) rumination, (b) magnification, and (c) helplessness. In Study 2, 30 undergraduate participants were classified as catastrophizers (n = 15) or noncatastrophizers (n = 15) on the basis of their PCS scores and participated in an cold pressor procedure. Catastrophizers reported significantly more negative pain-related thoughts, greater emotional distress, and greater pain intensity than noncatastrophizers. Study 3 examined the relation between PCS scores, negative pain-related thoughts, and distress in 28 individuals undergoing an aversive electrodiagnostic medical procedure. Catastrophizers reported more negative pain-related thoughts, more emotional distress, and more pain than noncatastrophizers. Study 4 examined the relation between the PCS and measures of depression, trait anxiety, negative affectivity, and fear of pain. Analyses revealed moderate correlations among these measures, but only the PCS contributed significant unique variance t o the prediction of pain intensity.

6,173 citations

"Central mechanisms of pain revealed..." refers background or methods in this paper

  • ...We have recently demonstrated that pain helplessness, a subscale of the Pain Catastrophizing Scale (Sullivan et al. 1995) is related to gray and white matter structure in temporomandibular disorder patients....

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  • ...2001), and can be assessed with the Pain Catastrophizing Scale (Sullivan et al. 1995)....

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  • ...…during actual or anticipated pain experience” (Keefe et al. 1989; Sullivan et al. 2001; Turk 2002), comprises rumination, magnification, and helplessness (Osman et al. 1997; Osman et al. 2000; Sullivan et al. 2001), and can be assessed with the Pain Catastrophizing Scale (Sullivan et al. 1995)....

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  • ...For example, pain catastrophizing, an “exaggerated negative mental set brought to bear during actual or anticipated pain experience” (Keefe et al. 1989; Sullivan et al. 2001; Turk 2002), comprises rumination, magnification, and helplessness (Osman et al. 1997; Osman et al. 2000; Sullivan et al. 2001), and can be assessed with the Pain Catastrophizing Scale (Sullivan et al. 1995)....

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Journal Article•DOI•
Functional connectivity in the resting brain: A network analysis of the default mode hypothesis

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Michael D. Greicius1, Ben Krasnow, Allan L. Reiss, Vinod Menon•
Stanford University1
07 Jan 2003-Proceedings of the National Academy of Sciences of the United States of America
TL;DR: This study constitutes, to the knowledge, the first resting-state connectivity analysis of the default mode and provides the most compelling evidence to date for the existence of a cohesive default mode network.
Abstract: Functional imaging studies have shown that certain brain regions, including posterior cingulate cortex (PCC) and ventral anterior cingulate cortex (vACC), consistently show greater activity during resting states than during cognitive tasks. This finding led to the hypothesis that these regions constitute a network supporting a default mode of brain function. In this study, we investigate three questions pertaining to this hypothesis: Does such a resting-state network exist in the human brain? Is it modulated during simple sensory processing? How is it modulated during cognitive processing? To address these questions, we defined PCC and vACC regions that showed decreased activity during a cognitive (working memory) task, then examined their functional connectivity during rest. PCC was strongly coupled with vACC and several other brain regions implicated in the default mode network. Next, we examined the functional connectivity of PCC and vACC during a visual processing task and show that the resultant connectivity maps are virtually identical to those obtained during rest. Last, we defined three lateral prefrontal regions showing increased activity during the cognitive task and examined their resting-state connectivity. We report significant inverse correlations among all three lateral prefrontal regions and PCC, suggesting a mechanism for attenuation of default mode network activity during cognitive processing. This study constitutes, to our knowledge, the first resting-state connectivity analysis of the default mode and provides the most compelling evidence to date for the existence of a cohesive default mode network. Our findings also provide insight into how this network is modulated by task demands and what functions it might subserve.

6,025 citations

"Central mechanisms of pain revealed..." refers background in this paper

  • ..., task-negative activity), hence the proposal that the network functions as an internal and external environmental monitor (Greicius et al. 2003; Greicius and Menon 2004; Fransson 2005)....

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  • ...…were active and showed functional connectivity in a task-free state, but were suppressed during a task (i.e., task-negative activity), hence the proposal that the network functions as an internal and external environmental monitor (Greicius et al. 2003; Greicius and Menon 2004; Fransson 2005)....

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Human brain mechanisms of pain perception and regulation in health and disease.

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Beyond Feeling: Chronic Pain Hurts the Brain, Disrupting the Default-Mode Network Dynamics

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