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Breaking down the barriers: fMRI applications in pain, analgesia and analgesics

David Borsook12* and Lino R Becerra1

Author Affiliations

1 P.A.I.N. Group, Brain Imaging Center, Department of Psychiatry, McLean Hospital, Belmont, MA, USA

2 Athinoula Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA

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Molecular Pain 2006, 2:30  doi:10.1186/1744-8069-2-30

The electronic version of this article is the complete one and can be found online at: http://www.molecularpain.com/content/2/1/30


Received:26 July 2006
Accepted:18 September 2006
Published:18 September 2006

© 2006 Borsook and Becerra; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

This review summarizes functional magnetic resonance imaging (fMRI) findings that have informed our current understanding of pain, analgesia and related phenomena, and discusses the potential role of fMRI in improved therapeutic approaches to pain. It is divided into 3 main sections: (1) fMRI studies of acute and chronic pain. Physiological studies of pain have found numerous regions of the brain to be involved in the interpretation of the 'pain experience'; studies in chronic pain conditions have identified a significant CNS component; and fMRI studies of surrogate models of chronic pain are also being used to further this understanding. (2) fMRI studies of endogenous pain processing including placebo, empathy, attention or cognitive modulation of pain. (3) The use of fMRI to evaluate the effects of analgesics on brain function in acute and chronic pain. fMRI has already provided novel insights into the neurobiology of pain. These insights should significantly advance therapeutic approaches to chronic pain.

Background: 'O (Chronic) Pain Miserum'

At least two major hurdles remain in the treatment of chronic pain. The first is that no objective test for pain currently exists. A blood test, genetic marker or psychophysical measure would greatly improve diagnosis of chronic pain. The second is the lack of an "antibiotic equivalent" (i.e., drugs with high sensitivity and specificity) for the treatment of chronic pain subtypes (e.g., neuropathic pain). Controlled trials of drug efficacy indicate that, on average, the most effective drugs of different classes have similar efficacy (around 30% greater than placebo) across neuropathic conditions [1-3]. Analgesic use is dictated by both efficacy and adverse side effects and side effects can sometimes take precedence over efficacy [4]. A lack of controlled trials for other methods of pain treatment (interventional, psychological, physical therapy) makes it difficult for physicians to evaluate these possible therapies. As a result, chronic pain treatment is difficult, and physicians and patients often resort to using multiple treatments simultaneously or sequentially in the effort to achieve pain relief. Unfortunately, even a combined therapeutic approach frequently offers little benefit (Figure 1).

thumbnailFigure 1. The problem with chronic pain. Therapy for acute pain (e.g., acute inflammation, trauma, post-surgical pain) is overall excellent. However, in chronic pain (e.g., neuropathic pain, fibromyalgia, complex regional pain syndrome), therapy is poor. This group thus falls into a zone (circles) of "therapeutic failure" or "therapeutic impasse" where multiple therapies are tried with overall little success. Functional imaging appears poised to open up new approaches to the understanding of chronic pain conditions. An improved basic understanding of the mechanisms underlying chronic pain is likely to suggest new avenues for the development of novel pharmacotherapies.

Recent advances in functional imaging have revolutionized our concept of central process of pain. Indeed, it seems that we are on the verge of using this technology to reach a fundamental new understanding of clinical pain, particularly chronic pain (defined as pain lasting for more than 6 months). Subdivision of chronic pain syndromes into chronic neuropathic pain (e.g., phantom pain, post-herpetic neuralgia), chronic nociceptive pain (e.g., arthritis, migraine), and a group comprising very poorly understood categories of pain (e.g., fibromyalgia, depression-induced pain, or complex regional pain syndrome) has not clarified mechanistic processes. Even classification of chronic pain types based on clinical disease (e.g., cancer pain, diabetic pain) has not proved very helpful in understanding the mechanisms underlying chronic pain. Recently a mechanistic approach to defining pain has been suggested in which specific pain phenotypes such as shooting pain, burning pain, and allodynia can be applied across pain types such as neuropathic pain. [5]. However, this approach is based primarily on an understanding of peripheral nerve and spinal cord processing. Functional imaging has already redefined chronic pain as a degenerative disease, and has shed some light on complex diseases such as fibromyalgia [6]. Since brain responses are the final common pathway in behavioral responses to pain (unconscious and conscious), we believe that the application of functional imaging will allow us to categorize pain conditions in an objective manner and to better understand the underlying circuitry and identify targets for a new generation of analgesics [7,8].

fMRI measures neural activity by an indirect evaluation of changes in blood flow in capillary beds [9]. A number of approaches including block design [10], event-related [11], and percept-related. [12] paradigms, have been applied to fMRI studies of physiological, clinical and pharmacological aspects of pain and analgesia. Application of baseline measures of spontaneous pain have allowed the "basal state" to be evaluated.) [13]. Issues pertaining to the validity of fMRI in pain and analgesic measures have been presented elsewhere [14].

"To consider only the sensory features of pain, and ignore its motivational and affective properties, is to look at only part of the problem, not even the most important part at that." This statement of Melzack and Casey's [15] was an early recognition of these aspects of pain, but their importance is now widely accepted. The ability to use fMRI to image the whole brain at the same time and to use powerful algorithms to segregate functional circuits allows us to begin to elucidate the CNS processes underlying affective and motivational components of pain. It also allows a broader window to observe potential CNS sites of drug action. Our understanding of 'difficult' disease states (e.g., fibromyalgia or depression-related pain), the placebo response, emotional responses (e.g., empathy), and acupuncture will clearly be influenced by new insights into how emotional circuitry in the brain functions in pain states and in responses to analgesics. [16]. In this paper, we review the contribution of fMRI to the understanding of acute and chronic pain, its use in surrogate models and for evaluation of endogenous pain systems including the placebo response, and its potential use as an objective measure of analgesic efficacy. The approach we have taken to summarize the new advances has been to provide an overview for each domain (e.g., Acute and Chronic pain, Endogenous Systems etc.) and summary tables that focus on specific areas within each domain (e.g., Chronic pain: Neuropathic, Fibromyalgia etc.). Studies listed are predominantly from peer-reviewed journals (Data Sources: Medline) or data from our own lab presented at Society for Neuroscience and/or in press. We attempted to include primary examples on specific entities of CNS processing as defined with fMRI that are related to pain, analgesia and analgesics.

Advancing our Understanding of CNS Mechanisms in Acute and Chronic Pain through fMRI

fMRI of Physiological Pain – a new understanding of brain regionsinvolved in pain processing in humans

Much of the work in fMRI of pain has utilized thermal stimuli (contact peltier thermodes or laser) to activate pain circuits. Other types of stimuli, including electrical and mechanical (pressure) have not been as extensively used either in the intact system or where sensitization has been experimentally induced (see Table 3). The accumulation of data has begun to identify brain regions involved in pain processing – from peripheral ganglia to central limbic and brainstem structures previously only implicated in animal studies in the preclinical literature (see Table 1).

Table 3. Examples fMRI Studies of Surrogate Models of Pain

Table 1. Examples of Contributions by fMRI on the understanding Brain Regions activated by Acute Pain

Some of these regions are part of well-defined pain circuits (e.g., PAG, parabrachial nuclei) while for others such as the nucleus accumbens, their specific role in pain processing is not well understood [17,18]. Studies have reported specificity of somatotopic organization of structures outside of the primary somatosensory cortex involved in pain processing in humans; these such as the insula [19] and the trigeminal system [14,20]. Indeed, the results of human imaging help focus attention on specific regions, including the nucleus accumbens (involved in emotional salience), the insula (involved in specific interpretation of noxious stimuli) or the amygdala (involved in fear), opening new vistas for understanding how the human brain evaluates pain. The ability to evaluate activity and organize active regions into neural circuits that subserve specific pain/analgesia functions (i.e., sensory, emotional, autonomic, endogenous analgesic circuits) is a step forward. A number of studies have already begun this task including segregation of function within a structure (e.g., PAG [17] and NAc [18]), defining analgesia as a rewarding process [21], and functional differentiation of activation sites within a particular brain region (e.g., cognitive and affective regions within the anterior cingulate [17]).

What is needed now is to further evaluate these brain areas, some of whose role is newly defined in pain processing in humans, at a functional level. Several new fMRI approaches will aid this effort including techniques that allow definition of large scale systems organization [22]; techniques that define circuits/functional connectivity [23]; and automated parcellation of brain structures [24,25] including the thalamus [26]. Imaging studies have not only unveiled new regions involved in pain processing, but have also contributed new insights into the functioning of these regions in experimental pain. For example, the hippocampus, classically associated with memory, has been shown to be involved in pain-induced anxiety [27-29].

fMRI of Chronic Pain

Imaging clinical conditions is fraught with issues that make it more challenging, including the fact that it is difficult to assemble a cohort with similar symptoms, duration of disease, medication history, age distribution, etc. Among clinical conditions, chronic pain has a particularly wide spectrum of patient presentations and medical histories. However, studies have begun to evaluate CNS changes that occur in patients with chronic pain (see review by Apkarian and colleagues [30]), including those with neuropathic pain, fibromyalgia, complex regional pain syndrome and visceral pain (Table 2).

Table 2. Examples of Contributions of fMRI to the understanding of CNS circuitry underlying Chronic Pain

A number of important issues are emerging in the evaluation of chronic pain conditions as fMRI and associated imaging technologies become more sophisticated. Chronic pain produces changes that become manifest as alterations in the central nervous system. One may term this "centralization of hyperalgesia" or "centralization of pain". This has been evaluated across diseases including fibromyalgia [6], chronic back pain [31], and irritable bowel syndrome [32]. During functional imaging of fibromyalgia and chronic back pain, enhanced responses to thermal or mechanical stimuli that are applied heterotopically (i.e., away from the actual location of the pain) are present in a number of CNS regions, including non-sensory regions. Differences in specific responses to brush, heat and cold in affected vs. intact regions in patients with neuropathic pain have also been reported [33]. One feature that seems to be of in common with chronic pain patients is significantly greater frontal lobe activation in chronic pain sufferers [30]. This feature, suggests that in chronic pain CNS activity in regions involved in cognitive processing differs between acute and chronic pain. These insights are further complicated by the new and revolutionary recognition that, in chronic pain, neuronal loss occurs in significant pain pathways including the thalamus and the lateral prefrontal cortex [34]. The role of this neurodegeneration in producing either the altered CNS responses or the pain state is not understood.

Maladaptative changes in non-sensory circuits may contribute to the psychological states, including depression, anxiety and amotivation that are often seen in these patients. Thus the study of specific brain regions such as the nucleus accumbens (involved in probability assessments and reward evaluation), the amygdala (involved in orientating to and the memory of motivationally salient stimuli), the hippocampus (involved in evaluating the expectancy of an unknown condition), the prefrontal cortex (involved in cognitive and planning functions around emotional stimuli or regarding rewarding or aversive outcomes) and the anterior cingulated cortex (involved in the rank ordering of the value or salience of the stimulus) may provide new insights into brain functioning in these co-morbid conditions. Such insights should provide immediate benefits to the understanding of the calcitrant nature of chronic pain to therapeutic interventions.

Our increased recognition that multiple neural systems are involved in pain processing and affect pain perception (reward/aversion circuitry, the role of anticipation, neural systems interpreting different pain types albeit at the same intensity, opponent systems and drug effects) suggests that multiple neural circuitries are likely affected in chronic pain. Results published thus far indicate that: (1) Pain intensity is probably not a good marker for changes in chronic pain state. Neural imaging may be able to define a correlation between CNS activation and patient answers to a simple subjective questionnaire that assesses emotional and other components of pain and suffering; (2) Neural systems interpreting components of the pain response (e.g., emotional, empathy, anticipation etc.) are clearly complex, and we still have no understanding of how these may change in the chronic pain condition; and (3) Standards will need to be applied across imaging facilities in order to interpret and compare data across studies.

fMRI of Human Surrogate Pain Models

Defining valid surrogate models has been a problem in both animal and human models of pain [35-37]. In human studies, mechanical (heat) or chemical (capsaicin) sensitization of skin and testing in primary and secondary regions affected has been used as a surrogate for neuropathic pain (hyperalgesia/allodynia to thermal and mechanical stimuli) [38]. Recently fMRI has been used to evaluate the capsaicin – induced hyperalgesia model (see Table 3). While many of these studies report increased activation in a number of brain regions, some of the more recent studies begin to define the utility of fMRI in dissecting mechanistic changes or insights using this model [39-41]. These studies demonstrate differences in brain activation in response to stimuli of equivalent pain intensity delivered in sensitized vs. non-sensitized state, providing further evidence that pain intensity by itself is probably not a useful measure of the status of the underlying pain processing circuitry [41]. An alternate explanation may be that there are mechanistic differences between these two states. Changes in perceived pain intensity may reflect acute changes in CNS sensory pathways but may not correlate with changes in CNS emotional pathways which may be relevant to an individuals' overall response to pain and may predict future pain conditions. Eventually, fMRI should allow the direct comparison of activation in specific CNS regions in experimental models with the activation seen in patients with neuropathic pain. Comparing such objective measures should allow us to determine where the model differs from the disease and to assess the validity of such models for evaluating potential therapies.

fMRI studies of Endogenous Analgesia

Endogenous modulatory networks can either facilitate or inhibit pain[42,43]. Endogenous analgesia refers to systems that produce the latter. These systems involve a network that includes higher cortical (e.g., anterior cingulate cortex) and subcortical regions (e.g., the amygdala, hypothalamus) that project to brainstem nuclei (periaqueductal gray and raphe nuclei) that send projections to the dorsal horn [44] These systems can be modulated by a number of factors including stress, pain and the placebo response [42].

A number of studies have used fMRI to investigate endogenous modulation of pain (Table 4) and map circuits involved in CNS systems that can alter decrease or increase pain [45-47]. Most of these studies involved attention or distraction to modulate circuits. In addition, closely linked with this are studies of placebo response, evaluation of the effects of attention and expectancy, of empathetic reactions to pain in others, to producing "trickery" of the brain by sensory inputs [48].

Table 4. Examples of Contributions of fMRI on Endogenous Mechanisms of Pain or Analgesia

Perhaps of greatest importance are studies of the placebo effect since there has been a significant literature in this domain from psychophysical studies [49,50]. A neurobiology and neurocircuitry were predicted for the placebo effect based on its effects on analgesia. [51]. Indeed the general circuitry of the placebo response can be applied to non-painful stimuli. These and other studies have enhanced our knowledge of the interaction of physiological pain circuits and cognitive/emotional circuits [52]. The use of imaging has now clearly established how some of these endogenous systems operate. This understanding coupled with an objective method of evaluating placebo should provide novel insights into drug development as well as the treatment of patients with acute and chronic pain.

Complementary with fMRI studies on placebo, the use of fMRI has identified neural systems involved in anxiety and fear related to pain. These two reactions to pain are important both from a neuroscience aspect. [16] as well as from practical applications of treating patients. While fear and anxiety have been considered to have different effects on neural processing [53], recent fMRI studies have begun to explore this issue [54].

The innate nature of the pain experience is clearly indicated by studies showing that activations in non-sensory CNS systems in an observer experiencing empathetic pain, are similar to those produced in a subject by noxious stimuli. The study of endogenous analgesia highlights the opponent systems operating in pain. In addition, fMRI studies reveal that in addition to the sensory pathways activated in endogenous analgesia and pain processing, reward/aversion circuitry is activated, with reward related to pain relief and aversion related to pain. [21]. The balance between these opponent systems may be crucial in determining the overall sensory and emotional experience of pain in chronic pain states.

fMRI has also been applied to exploring the neurobiology of acupuncture, which is believed to activate endogenous analgesic mechanisms [55]. Such studies have predominantly been in healthy subjects using experimental pain. The evidence for the benefit of acupuncture for clinical studies has been mixed. For example, recent studies in migraine patients has indicated that acupuncture may be no more effective than sham acupuncture in reducing migraine headaches, although both are more effective than no intervention. Such studies need to be repeated, but raise questions as to how acupuncture works (for example, through activation of diffuse noxious inhibitory controls or activation of endogenous systems through expectancy etc.) [56]. In carefully devised studies, defining brain circuits involved in expectancy, treatment etc. may help provide a more objective evaluation of such interventions.

fMRI Studies of Analgesics

fMRI is also being applied to the evaluation of analgesics (pharmacological MRI or phMRI). [57]. Examples are provided in Table 5.

Table 5. Examples of Contributions of fMRI on Analgesics

Analgesic effects on brain systems or neural circuits (stimulus independent) – Many analgesics have direct CNS effects, and very little is known about how they act on the human brain. Such studies are most often performed in healthy volunteers. Here the direct effect of administration of a drug is observed without any stimulus paradigm. These types of studies allow for the interrogation of effects that may not be obvious (e.g., subcortical, subconscious), for integration of how drugs may have a role on intact brain systems that still may be the case in the chronic pain state, and for the evaluation of potential side effects of drugs. Our naloxone and morphine studies (see Table 4; [58,59]) have taken this approach and indicate the ability to evaluate direct drug effects even when there are no obvious psychophysical effects (naloxone) or well-described side effect profiles (morphine) that can be evaluated based on circuit activation (e.g., reward, sedation or analgesic circuits). [59]. The ability to define specific differences

    across
classes of drugs (e.g., antidepressants, membrane stabilizers, opioids) may not only help focus on common areas of potential mechanisms but also provide information
    within
different drug classes (e.g., antidepressants – tricyclics vs. serotonin norepinehprine reuptake inhibitors). Advances in this domain should lead to use of standardized fMRI trials for early phase evaluation of pharmacotherapies for pain [60].

Analgesic effects on acute or chronic pain (stimulus-dependent) – In this group, the effect of the drug is evaluated in subjects usually following an applied painful stimulus. A few examples of this type of approach include the studies of cyclooxygenase (cox) inhibitors [61] and amitriptyline [62] in chronic pain conditions and the effects of drugs on capsaicin-induced hyperalgesia (see Table 5). These approaches show that pharmacological evaluation of the CNS effects of drugs is possible, suggesting that fMRI can be used for objective assessments of drug efficacy; until now, all assessments of analgesic efficacy relied on subjective psychophysical measures.

Conclusion

A revolution in the application of a relatively new technology, fMRI, to the field of pain and analgesia is upon us. Within the next half decade, we should begin to see direct benefits in the clinical setting that could range from (a) use of fMRI to evaluate/diagnose a pain condition; (b) use of fMRI to evaluate drug efficacy in responders vs. non-responders; (c) use of fMRI to evaluate novel drug efficacy (the latter will be driven predominantly by the pharmaceutical industry) and (d) use of fMRI to provide new insights into the mechanisms of endogenous 'pain systems'. We believe there is good reason to expect that the contribution of this technology together with advances in other neurosciences will help transition the state of current pain therapy from 'o me miserum!' ('o woe is me!') to more optimistic states for both patient and clinician 'semper aliqud novii' ('always something new' .... and better/useful). We believe there is good reason to expect that the contribution of this technology together with advances in other neurosciences will significantly advance therapies for chronic pain and alleviate physical and emotional suffering for the many individuals living with this disease.

Abbreviation List

aCG – anterior cingulated cortex; CNS – central nervous system; CRPS – complex regional pain syndrome; DNIC – Diffuse noxious inhibitory Controls; GOb – Orbitorfrontal cortex; Hi – Hippocampus; I – Insula; IBS – irritable bowel syndrome; NAc – nucleus accumbens; nCF – cuneiform nucleus; P – putamen; PAG – periaqueductal gray; pCG – posterior cingulated cortex; Rx – treatment; SCI – Spinal cord injury; SI – primary somatosensory cortex; SII – secondary somatosensory cortex; SLEA – sublenticular extended amygdala; SMP – sympathetically maintained pain; TG – trigeminal ganglion; TN – trigeminal nucleus; VAS – visual analogue scale; VMpo – ventromedial nucleus;

Acknowledgements

This work was supported by a Grant to DB from NINDS (NS042721). We would like to thank Sadie Cole, B.A., for her help with the preparation of the manuscript.

References

  1. Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L: Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial.[see comment].

    JAMA 1998, 280(21):1837-1842. PubMed Abstract | Publisher Full Text OpenURL

  2. Lesser H, Sharma U, LaMoreaux L, Poole RM: Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial.

    Neurology 2004, 63(11):2104-2110. PubMed Abstract OpenURL

  3. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL: Morphine, gabapentin, or their combination for neuropathic pain.

    N Engl J Med 2005, 352(13):1324-1334. PubMed Abstract | Publisher Full Text OpenURL

  4. Gilron I, Max MB: Combination pharmacotherapy for neuropathic pain: current evidence and future directions.

    Expert Rev Neurother 2005, 5(6):823-830. PubMed Abstract | Publisher Full Text OpenURL

  5. Woolf CJ, Borsook D, Koltzenburg M: Mechanism-based classifications of pain and analgesic drug discovery. In Pain: Current Understanding, Emerging Therpaies, and Novel Approaches to Drug Discovery. Edited by C. Bountra RMWKS. New York , Marcel Dekker, Inc.; 2004:1-8. OpenURL

  6. Gracely RH, Geisser ME, Giesecke T, Grant MA, Petzke F, Williams DA, Clauw DJ: Pain catastrophizing and neural responses to pain among persons with fibromyalgia.

    Brain 2004, 127(Pt 4):835-843. PubMed Abstract | Publisher Full Text OpenURL

  7. Tracey I: Prospects for human pharmacological functional magnetic resonance imaging (phMRI).

    J Clin Pharmacol 2001, Suppl:21S-28S. PubMed Abstract OpenURL

  8. Borsook D, Ploghaus A, Becerra L: Utilizing brain imaging for analgesic drug development.

    Curr Opin Investig Drugs 2002, 3(9):1342-1347. PubMed Abstract OpenURL

  9. Logothetis NK: The neural basis of the blood-oxygen-level-dependent functional magnetic resonance imaging signal.

    Philos Trans R Soc Lond B Biol Sci 2002, 357(1424):1003-1037. PubMed Abstract | Publisher Full Text OpenURL

  10. Becerra LR, Breiter HC, Stojanovic M, Fishman S, Edwards A, Comite AR, Gonzalez RG, Borsook D: Human brain activation under controlled thermal stimulation and habituation to noxious heat: an fMRI study.

    Magn Reson Med 1999, 41(5):1044-1057. PubMed Abstract | Publisher Full Text OpenURL

  11. Davis KD, Kwan CL, Crawley AP, Mikulis DJ: Event-related fMRI of pain: entering a new era in imaging pain.

    Neuroreport 1998, 9(13):3019-3023. PubMed Abstract OpenURL

  12. Davis KD, Pope GE, Crawley AP, Mikulis DJ: Neural correlates of prickle sensation: a percept-related fMRI study.

    Nat Neurosci 2002, 5(11):1121-1122. PubMed Abstract | Publisher Full Text OpenURL

  13. Foss JM, Apkarian AV, Chialvo DR: Dynamics of pain: fractal dimension of temporal variability of spontaneous pain differentiates between pain States.

    J Neurophysiol 2006, 95(2):730-736. PubMed Abstract | Publisher Full Text OpenURL

  14. Borsook D, Becerra L: Functional imaging of pain and analgesia--a valid diagnostic tool?

    Pain 2005, 117(3):247-250. PubMed Abstract | Publisher Full Text OpenURL

  15. Melzack R, Casey KL: Sensory, motivational, and central control determinants of pain. In The Skin Senses. Edited by Kenshalo DR. Springfield, IL , Thomas; 1968:423-439. OpenURL

  16. Borsook D, Becerra L, Carlezon W, Shaw M, Renshaw P, Elman I, Levine JA: Reward-aversion circuitry in analgesia and pain: Implications for psychiatric disorders.

    European Journal of Pain 2005, In press . OpenURL

  17. Becerra L, Breiter HC, Wise R, Gonzalez RG, Borsook D: Reward circuitry activation by noxious thermal stimuli.

    Neuron 2001, 32(5):927-946. PubMed Abstract | Publisher Full Text OpenURL

  18. Aharon I, Becerraa L, Chabris CF, Borsooka D: Noxious heat induces fMRI activation in two anatomically distinct clusters within the nucleus accumbens.

    Neurosci Lett 2006, 392(3):159-164. PubMed Abstract | Publisher Full Text OpenURL

  19. Brooks JC, Zambreanu L, Godinez A, Craig AD, Tracey I: Somatotopic organisation of the human insula to painful heat studied with high resolution functional imaging.

    Neuroimage 2005, 27(1):201-209. PubMed Abstract | Publisher Full Text OpenURL

  20. DaSilva AF, Becerra L, Makris N, Strassman AM, Gonzalez RG, Geatrakis N, Borsook D: Somatotopic activation in the human trigeminal pain pathway.

    J Neurosci 2002, 22(18):8183-8192. PubMed Abstract OpenURL

  21. Seymour B, O'Doherty JP, Koltzenburg M, Wiech K, Frackowiak R, Friston K, Dolan R: Opponent appetitive-aversive neural processes underlie predictive learning of pain relief.

    Nat Neurosci 2005, 8(9):1234-1240. PubMed Abstract | Publisher Full Text OpenURL

  22. Salvador R, Suckling J, Coleman MR, Pickard JD, Menon D, Bullmore E: Neurophysiological architecture of functional magnetic resonance images of human brain.

    Cereb Cortex 2005, 15(9):1332-1342. PubMed Abstract | Publisher Full Text OpenURL

  23. Horwitz B, Warner B, Fitzer J, Tagamets MA, Husain FT, Long TW: Investigating the neural basis for functional and effective connectivity. Application to fMRI.

    Philos Trans R Soc Lond B Biol Sci 2005, 360(1457):1093-1108. PubMed Abstract | Publisher Full Text OpenURL

  24. Thirion B, Flandin G, Pinel P, Roche A, Ciuciu P, Poline JB: Dealing with the shortcomings of spatial normalization: Multi-subject parcellation of fMRI datasets.

    Hum Brain Mapp 2005, 678-693. OpenURL

  25. Woldorff MG, Hazlett CJ, Fichtenholtz HM, Weissman DH, Dale AM, Song AW: Functional parcellation of attentional control regions of the brain.

    J Cogn Neurosci 2004, 16(1):149-165. PubMed Abstract | Publisher Full Text OpenURL

  26. Johansen-Berg H, Behrens TE, Sillery E, Ciccarelli O, Thompson AJ, Smith SM, Matthews PM: Functional-anatomical validation and individual variation of diffusion tractography-based segmentation of the human thalamus.

    Cereb Cortex 2005, 15(1):31-39. PubMed Abstract | Publisher Full Text OpenURL

  27. Ploghaus A, Tracey I, Gati JS, Clare S, Menon RS, Matthews PM, Rawlins JN: Dissociating pain from its anticipation in the human brain.

    Science 1999, 284(5422):1979-1981. PubMed Abstract | Publisher Full Text OpenURL

  28. Ploghaus A, Narain C, Beckmann CF, Clare S, Bantick S, Wise R, Matthews PM, Rawlins JN, Tracey I: Exacerbation of pain by anxiety is associated with activity in a hippocampal network.

    J Neurosci 2001, 21(24):9896-9903. PubMed Abstract OpenURL

  29. Ploghaus A, Becerra L, Borras C, Borsook D: Neural circuitry underlying pain modulation: expectation, hypnosis, placebo.

    Trends Cogn Sci 2003, 7(5):197-200. PubMed Abstract | Publisher Full Text OpenURL

  30. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK: Human brain mechanisms of pain perception and regulation in health and disease.

    Eur J Pain 2005, 9(4):463-484. PubMed Abstract | Publisher Full Text OpenURL

  31. Giesecke T, Gracely RH, Grant MA, Nachemson A, Petzke F, Williams DA, Clauw DJ: Evidence of augmented central pain processing in idiopathic chronic low back pain.

    Arthritis Rheum 2004, 50(2):613-623. PubMed Abstract | Publisher Full Text OpenURL

  32. Verne GN, Himes NC, Robinson ME, Gopinath KS, Briggs RW, Crosson B, Price DD: Central representation of visceral and cutaneous hypersensitivity in the irritable bowel syndrome.

    Pain 2003, 103(1-2):99-110. PubMed Abstract | Publisher Full Text OpenURL

  33. Becerra L, Pendse G, Korn J, Shaw M, Gostic JM, Sherman S, Gostic R, Borsook D: Dissecting drug efficacy for neuropathic pain in healthy subjects.: November.

    2005.

  34. Apkarian AV, Sosa Y, Sonty S, Levy RM, Harden RN, Parrish TB, Gitelman DR: Chronic back pain is associated with decreased prefrontal and thalamic gray matter density.

    J Neurosci 2004, 24(46):10410-10415. PubMed Abstract | Publisher Full Text OpenURL

  35. Klein T, Magerl W, Rolke R, Treede RD: Human surrogate models of neuropathic pain.

    Pain 2005, 115(3):227-233. PubMed Abstract OpenURL

  36. Blackburn-Munro G: Pain-like behaviours in animals - how human are they?

    Trends Pharmacol Sci 2004, 25(6):299-305. PubMed Abstract | Publisher Full Text OpenURL

  37. Mogil JS, Crager SE: What should we be measuring in behavioral studies of chronic pain in animals?

    Pain 2004, 112(1-2):12-15. PubMed Abstract | Publisher Full Text OpenURL

  38. LaMotte RH, Lundberg LE, Torebjork HE: Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin.

    J Physiol 1992, 448:749-764. PubMed Abstract | PubMed Central Full Text OpenURL

  39. Maihofner C, Handwerker HO, Neundorfer B, Birklein F: Cortical reorganization during recovery from complex regional pain syndrome.

    Neurology 2004, 63(4):693-701. PubMed Abstract OpenURL

  40. Maihofner C, Handwerker HO: Differential coding of hyperalgesia in the human brain: a functional MRI study.

    Neuroimage 2005, 28(4):996-1006. PubMed Abstract | Publisher Full Text OpenURL

  41. Iannetti GD, Zambreanu L, Wise RG, Buchanan TJ, Huggins JP, Smart TS, Vennart W, Tracey I: Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans.

    Proc Natl Acad Sci U S A 2005, 102(50):18195-18200. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  42. Fields HL: Pain modulation: expectation, opioid analgesia and virtual pain.

    Prog Brain Res 2000, 122:245-253. PubMed Abstract OpenURL

  43. Suzuki R, Rygh LJ, Dickenson AH: Bad news from the brain: descending 5-HT pathways that control spinal pain processing.

    Trends Pharmacol Sci 2004, 25(12):613-617. PubMed Abstract | Publisher Full Text OpenURL

  44. Millan MJ: Descending control of pain.

    Prog Neurobiol 2002, 66(6):355-474. PubMed Abstract | Publisher Full Text OpenURL

  45. Keltner JR, Furst A, Fan C, Redfern R, Inglis B, Fields HL: Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study.

    J Neurosci 2006, 26(16):4437-4443. PubMed Abstract | Publisher Full Text OpenURL

  46. Tracey I, Ploghaus A, Gati JS, Clare S, Smith S, Menon RS, Matthews PM: Imaging attentional modulation of pain in the periaqueductal gray in humans.

    J Neurosci 2002, 22(7):2748-2752. PubMed Abstract OpenURL

  47. Valet M, Sprenger T, Boecker H, Willoch F, Rummeny E, Conrad B, Erhard P, Tolle TR: Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain--an fMRI analysis.

    Pain 2004, 109(3):399-408. PubMed Abstract | Publisher Full Text OpenURL

  48. Davis KD, Pope GE, Crawley AP, Mikulis DJ: Perceptual illusion of "paradoxical heat" engages the insular cortex.

    J Neurophysiol 2004, 92(2):1248-1251. PubMed Abstract | Publisher Full Text OpenURL

  49. Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen JD: Placebo-induced changes in FMRI in the anticipation and experience of pain.

    Science 2004, 303(5661):1162-1167. PubMed Abstract | Publisher Full Text OpenURL

  50. Lorenz J, Hauck M, Paur RC, Nakamura Y, Zimmermann R, Bromm B, Engel AK: Cortical correlates of false expectations during pain intensity judgments--a possible manifestation of placebo/nocebo cognitions.

    Brain Behav Immun 2005, 19(4):283-295. PubMed Abstract | Publisher Full Text OpenURL

  51. Fields HL, Levine JD: Biology of placebo analgesia.

    Am J Med 1981, 70(4):745-746. PubMed Abstract | Publisher Full Text OpenURL

  52. Kong J, White NS, Kwong KK, Vangel MG, Rosman IS, Gracely RH, Gollub RL: Using fMRI to dissociate sensory encoding from cognitive evaluation of heat pain intensity.

    Hum Brain Mapp 2005, 715-721. OpenURL

  53. Gray JAMNN: The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-Hippocampal System. In Oxford Psychology Series. Volume 33. 2nd edition. Edited by N.J. Mackintosh TSATJLMGDSLW. Oxford , Oxford University Press; 2000::424. OpenURL

  54. Ochsner KN, Ludlow DH, Knierim K, Hanelin J, Ramachandran T, Glover GC, Mackey SC: Neural correlates of individual differences in pain-related fear and anxiety.

    Pain 2006, 120(1-2):69-77. PubMed Abstract | Publisher Full Text OpenURL

  55. Ma SX: Neurobiology of Acupuncture: Toward CAM.

    Evid Based Complement Alternat Med 2004, 1(1):41-47. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  56. Sandkuhler J: The organization and function of endogenous antinociceptive systems.

    Prog Neurobiol 1996, 50(1):49-81. PubMed Abstract | Publisher Full Text OpenURL

  57. Honey G, Bullmore E: Human pharmacological MRI.

    Trends Pharmacol Sci 2004, 25(7):366-374. PubMed Abstract | Publisher Full Text OpenURL

  58. Becerra L, Harter K, Gonzalez RG, Borsook D: Functional magnetic resonance imaging measures of the effects of morphine on central nervous system circuitry in opioid-naive healthy volunteers.

    Anesth Analg 2006, 103(1):208-16, table of contents. PubMed Abstract | Publisher Full Text OpenURL

  59. Borras MC, Becerra L, Ploghaus A, Gostic JM, DaSilva A, Gonzalez RG, Borsook D: fMRI measurement of CNS responses to naloxone infusion and subsequent mild noxious thermal stimuli in healthy volunteers.

    J Neurophysiol 2004, 91(6):2723-2733. PubMed Abstract | Publisher Full Text OpenURL

  60. Borsook D, Becerra L, Hargreaves RA: I spy fMRI: To be or not to be in drug development.

    Nature Reviews Drug Discovery

    under review

    PubMed Abstract OpenURL

  61. Baliki M, Katz J, Chialvo DR, Apkarian AV: Single subject pharmacological-MRI (phMRI) study: modulation of brain activity of psoriatic arthritis pain by cyclooxygenase-2 inhibitor.

    Mol Pain 2005, 1:32. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  62. Morgan V, Pickens D, Gautam S, Kessler R, Mertz H: Amitriptyline reduces rectal pain related activation of the anterior cingulate cortex in patients with irritable bowel syndrome.

    Gut 2005, 54(5):601-607. PubMed Abstract | Publisher Full Text OpenURL

  63. Borsook D, DaSilva AF, Ploghaus A, Becerra L: Specific and somatotopic functional magnetic resonance imaging activation in the trigeminal ganglion by brush and noxious heat.

    J Neurosci 2003, 23(21):7897-7903. PubMed Abstract OpenURL

  64. Fulbright RK, Troche CJ, Skudlarski P, Gore JC, Wexler BE: Functional MR imaging of regional brain activation associated with the affective experience of pain.

    AJR Am J Roentgenol 2001, 177(5):1205-1210. PubMed Abstract OpenURL

  65. Dunckley P, Wise RG, Fairhurst M, Hobden P, Aziz Q, Chang L, Tracey I: A comparison of visceral and somatic pain processing in the human brainstem using functional magnetic resonance imaging.

    J Neurosci 2005, 25(32):7333-7341. PubMed Abstract | Publisher Full Text OpenURL

  66. Bingel U, Glascher J, Weiller C, Buchel C: Somatotopic representation of nociceptive information in the putamen: an event-related fMRI study.

    Cereb Cortex 2004, 14(12):1340-1345. PubMed Abstract | Publisher Full Text OpenURL

  67. Ploghaus A, Tracey I, Clare S, Gati JS, Rawlins JN, Matthews PM: Learning about pain: the neural substrate of the prediction error for aversive events.

    Proc Natl Acad Sci U S A 2000, 97(16):9281-9286. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  68. Rolls ET, O'Doherty J, Kringelbach ML, Francis S, Bowtell R, McGlone F: Representations of pleasant and painful touch in the human orbitofrontal and cingulate cortices.

    Cereb Cortex 2003, 13(3):308-317. PubMed Abstract | Publisher Full Text OpenURL

  69. Peyron R, Schneider F, Faillenot I, Convers P, Barral FG, Garcia-Larrea L, Laurent B: An fMRI study of cortical representation of mechanical allodynia in patients with neuropathic pain.

    Neurology 2004, 63(10):1838-1846. PubMed Abstract OpenURL

  70. Becerra L, Morris S, Bazes S, Gostic R, Sherman S, Gostic J, Pendse G, Moulton E, Scrivani S, Keith D, Chizh B, Borsook D: Trigeminal Neuropathic Pain Alters Responses in CNS Circuits to Mechanical (brush) and Thermal (cold and heat) Stimuli.

    J Neurosci 2006, in press. OpenURL

  71. Nicotra A, Critchley HD, Mathias CJ, Dolan RJ: Emotional and autonomic consequences of spinal cord injury explored using functional brain imaging.

    Brain 2005. PubMed Abstract OpenURL

  72. Villemure C, Wassimi S, Bennett GJ, Shir Y, Bushnell MC: Unpleasant odors increase pain processing in a patient with neuropathic pain: Psychophysical and fMRI investigation.

    Pain 2006, 120(1-2):213-220. PubMed Abstract | Publisher Full Text OpenURL

  73. Lebel A, Becerra L, Waring M, Morris S, Pendse G, Grant E, Moulton E, Berde C, Borsook D: fMRI of mechanical allodynia in children with complex regional (leg) pain syndrome (CRPS).

    Soc Neuroscience 2005. OpenURL

  74. Apkarian AV, Thomas PS, Krauss BR, Szeverenyi NM: Prefrontal cortical hyperactivity in patients with sympathetically mediated chronic pain.

    Neurosci Lett 2001, 311(3):193-197. PubMed Abstract | Publisher Full Text OpenURL

  75. Cook DB, Lange G, Ciccone DS, Liu WC, Steffener J, Natelson BH: Functional imaging of pain in patients with primary fibromyalgia.

    J Rheumatol 2004, 31(2):364-378. PubMed Abstract OpenURL

  76. Kwan CL, Diamant NE, Pope G, Mikula K, Mikulis DJ, Davis KD: Abnormal forebrain activity in functional bowel disorder patients with chronic pain.

    Neurology 2005, 65(8):1268-1277. PubMed Abstract | Publisher Full Text OpenURL

  77. Wilder-Smith CH, Schindler D, Lovblad K, Redmond SM, Nirkko A: Brain functional magnetic resonance imaging of rectal pain and activation of endogenous inhibitory mechanisms in irritable bowel syndrome patient subgroups and healthy controls.

    Gut 2004, 53(11):1595-1601. PubMed Abstract | Publisher Full Text OpenURL

  78. Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, Kessler R: Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention.

    Gastroenterology 2000, 118(5):842-848. PubMed Abstract | Publisher Full Text OpenURL

  79. Bonaz B, Baciu M, Papillon E, Bost R, Gueddah N, Le Bas JF, Fournet J, Segebarth C: Central processing of rectal pain in patients with irritable bowel syndrome: an fMRI study.

    Am J Gastroenterol 2002, 97(3):654-661. PubMed Abstract | Publisher Full Text OpenURL

  80. Pukall CF, Strigo IA, Binik YM, Amsel R, Khalife S, Bushnell MC: Neural correlates of painful genital touch in women with vulvar vestibulitis syndrome.

    Pain 2005, 115(1-2):118-127. PubMed Abstract | Publisher Full Text OpenURL

  81. Baron R, Baron Y, Disbrow E, Roberts TP: Brain processing of capsaicin-induced secondary hyperalgesia: a functional MRI study.

    Neurology 1999, 53(3):548-557. PubMed Abstract OpenURL

  82. Zambreanu L, Wise RG, Brooks JC, Iannetti GD, Tracey I: A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging.

    Pain 2005, 114(3):397-407. PubMed Abstract | Publisher Full Text OpenURL

  83. Wiech K, Seymour B, Kalisch R, Stephan KE, Koltzenburg M, Driver J, Dolan RJ: Modulation of pain processing in hyperalgesia by cognitive demand.

    Neuroimage 2005, 27(1):59-69. PubMed Abstract | Publisher Full Text OpenURL

  84. Petrovic P, Dietrich T, Fransson P, Andersson J, Carlsson K, Ingvar M: Placebo in emotional processing--induced expectations of anxiety relief activate a generalized modulatory network.

    Neuron 2005, 46(6):957-969. PubMed Abstract | Publisher Full Text OpenURL

  85. Bingel U, Lorenz J, Schoell E, Weiller C, Buchel C: Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network.

    Pain 2006, 120(1-2):8-15. PubMed Abstract | Publisher Full Text OpenURL

  86. Bantick SJ, Wise RG, Ploghaus A, Clare S, Smith SM, Tracey I: Imaging how attention modulates pain in humans using functional MRI.

    Brain 2002, 125(Pt 2):310-319. PubMed Abstract | Publisher Full Text OpenURL

  87. Hoffman HG, Richards TL, Coda B, Bills AR, Blough D, Richards AL, Sharar SR: Modulation of thermal pain-related brain activity with virtual reality: evidence from fMRI.

    Neuroreport 2004, 15(8):1245-1248. PubMed Abstract OpenURL

  88. Kulkarni B, Bentley DE, Elliott R, Youell P, Watson A, Derbyshire SW, Frackowiak RS, Friston KJ, Jones AK: Attention to pain localization and unpleasantness discriminates the functions of the medial and lateral pain systems.

    Eur J Neurosci 2005, 21(11):3133-3142. PubMed Abstract | Publisher Full Text OpenURL

  89. Singer T, Seymour B, O'Doherty J, Kaube H, Dolan RJ, Frith CD: Empathy for pain involves the affective but not sensory components of pain.

    Science 2004, 303(5661):1157-1162. PubMed Abstract | Publisher Full Text OpenURL

  90. Panksepp J: Neuroscience. Feeling the pain of social loss.

    Science 2003, 302(5643):237-239. PubMed Abstract | Publisher Full Text OpenURL

  91. Downar J, Mikulis DJ, Davis KD: Neural correlates of the prolonged salience of painful stimulation.

    Neuroimage 2003, 20(3):1540-1551. PubMed Abstract | Publisher Full Text OpenURL

  92. Sawamoto N, Honda M, Okada T, Hanakawa T, Kanda M, Fukuyama H, Konishi J, Shibasaki H: Expectation of pain enhances responses to nonpainful somatosensory stimulation in the anterior cingulate cortex and parietal operculum/posterior insula: an event-related functional magnetic resonance imaging study.

    J Neurosci 2000, 20(19):7438-7445. PubMed Abstract OpenURL

  93. Koyama T, McHaffie JG, Laurienti PJ, Coghill RC: The subjective experience of pain: where expectations become reality.

    Proc Natl Acad Sci U S A 2005, 102(36):12950-12955. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  94. Porro CA, Baraldi P, Pagnoni G, Serafini M, Facchin P, Maieron M, Nichelli P: Does anticipation of pain affect cortical nociceptive systems?

    J Neurosci 2002, 22(8):3206-3214. PubMed Abstract OpenURL

  95. Derbyshire SW, Whalley MG, Stenger VA, Oakley DA: Cerebral activation during hypnotically induced and imagined pain.

    Neuroimage 2004, 23(1):392-401. PubMed Abstract | Publisher Full Text OpenURL

  96. Mailis-Gagnon A, Giannoylis I, Downar J, Kwan CL, Mikulis DJ, Crawley AP, Nicholson K, Davis KD: Altered central somatosensory processing in chronic pain patients with "hysterical" anesthesia.

    Neurology 2003, 60(9):1501-1507. PubMed Abstract OpenURL

  97. Napadow V, Makris N, Liu J, Kettner NW, Kwong KK, Hui KK: Effects of electroacupuncture versus manual acupuncture on the human brain as measured by fMRI.

    Hum Brain Mapp 2005, 24(3):193-205. PubMed Abstract | Publisher Full Text OpenURL

  98. Liu WC, Feldman SC, Cook DB, Hung DL, Xu T, Kalnin AJ, Komisaruk BR: fMRI study of acupuncture-induced periaqueductal gray activity in humans.

    Neuroreport 2004, 15(12):1937-1940. PubMed Abstract | Publisher Full Text OpenURL

  99. Salomons TV, Johnstone T, Backonja MM, Davidson RJ: Perceived controllability modulates the neural response to pain.

    J Neurosci 2004, 24(32):7199-7203. PubMed Abstract | Publisher Full Text OpenURL

  100. deCharms RC, Maeda F, Glover GH, Ludlow D, Pauly JM, Soneji D, Gabrieli JD, Mackey SC: Control over brain activation and pain learned by using real-time functional MRI.

    Proc Natl Acad Sci U S A 2005, 102(51):18626-18631. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  101. Wise RG, Williams P, Tracey I: Using fMRI to quantify the time dependence of remifentanil analgesia in the human brain.

    Neuropsychopharmacology 2004, 29(3):626-635. PubMed Abstract | Publisher Full Text OpenURL

  102. Wise RG, Rogers R, Painter D, Bantick S, Ploghaus A, Williams P, Rapeport G, Tracey I: Combining fMRI with a pharmacokinetic model to determine which brain areas activated by painful stimulation are specifically modulated by remifentanil.

    Neuroimage 2002, 16(4):999-1014. PubMed Abstract | Publisher Full Text OpenURL