Elsevier

The Lancet Neurology

Volume 5, Issue 12, December 2006, Pages 1033-1044
The Lancet Neurology

Review
Brain imaging of clinical pain states: a critical review and strategies for future studies

https://doi.org/10.1016/S1474-4422(06)70624-XGet rights and content

Summary

Research into brain imaging of pain is largely dominated by experimental acute-pain studies. Applied study paradigms have evolved a lot over past years and the ensuing results have furthered enormously our understanding of acute-pain processing. In sharp contrast, published work on brain-imaging in chronic pain remains scant. Furthermore, the results of these studies are highly incongruent, which could be explained by the fact that patient populations studied varied largely in terms of pain history, pain distribution, cause of pain, and psychological set-up. To circumvent these problems, several investigators have used surrogate models of neuropathic pain, but the validity of these models is highly questionable. In this Review we critically discuss the problems and shortcomings of most published reports on chronic pain and we propose some strategies for future studies. We argue that the post-operative pain model is highly appealing since it opens perspectives for prospective longitudinal studies with repeated assessments and it enables control for many confounding factors, which hamper the interpretation of most current studies. We also plead for a multimodal imaging approach in which classic brain-activation studies are supplemented with genetic, neurochemistry, brain morphometry, and transcranial magnetic stimulation studies.

Introduction

Modern brain-imaging studies such as PET, functional MRI, and, more recently, magnetoencephalography (MEG) have opened exciting new avenues for non-invasive exploration of brain mechanisms implicated in acute and chronic-pain processing. The physiological signals measured by these three techniques are different and the question of which technique to use is co-determined by the particular neurophysiological question that is being addressed (panel 1, figure 1, table). Most pain-imaging studies have investigated forms of acute nociceptive pain. Few brain-imaging studies have been devoted to the mechanisms associated with chronic pain and the results of these studies are often inconclusive with some arguing that there are no differences in the processing of acute and chronic pain and others concluding the opposite. This discrepancy might be explained, at least in part, by the fact that most studies investigating non-experimental forms of pain are based on relatively small samples of patients, include patients with different pain pathologies, or lack appropriate controls.

The aim of this Review is to critically discuss brain-imaging studies of clinical pain. We will not cover the published work on visceral pain and chronic forms of pain with unknown pathophysiology, such as chronic low-back pain, fibromyalgia, irritable bowel syndrome, etc. We will also discuss important methodological issues that have not been or have insufficiently been addressed by the brain-imaging community and will propose strategies for future brain-imaging studies, focusing on longitudinal studies investigating the transition from acute to chronic pain.

Section snippets

Imaging of acute, experimental pain

The pain system is divided into a lateral and a medial system.1 The lateral pain system consists of spinothalamic tract neurons projecting from the ventrobasal nucleus of the thalamus to the primary and secondary somatosensory cortex, parietal operculum, and the insula. By contrast, the medial pain system includes the spinothalamic tract neurons projecting to the intralaminar and medial thalamic nuclei and further to the anterior cingulate cortex, the amygdala, the hippocampus, and the

Imaging of clinical pain

Compared with the vast published research on brain imaging related to the processing of acute experimental pain and the psychological processes associated with its top-down modulation, the research on clinical pain processing is rather sparse. Additionally, methodological difficulties make the results of most studies difficult to interpret or to generalise to a larger population. Three approaches have been followed in the study of brain processes underlying chronic pain. In the first approach,

Measurement of the brain's response to clinical pain

Although PET, fMRI, and MEG have provided important and novel information about the role of the human cerebral cortex in pain processing, they also have important limitations. For instance, excitatory and inhibitory activities are difficult to differentiate with these techniques, although use of sophisticated fMRI approaches can overcome this difficulty.74 Additionally, they are non-specific with respect to the underlying neurochemical changes. Third, we do not know whether the same association

Study of non-experimental forms of pain

From a methodological point of view, the study of non-experimental forms of pain poses far greater challenges. We will address some of these issues in more detail (panel 2).

Post-operative pain as an alternative pain model

The only way to circumvent most of the problems outlined above is to use repeated-measure, prospective-study designs in which homogeneous groups of patients are investigated before and after a standard and well-described surgical intervention. This approach should include detailed quantitative sensory testing, genetic assessment of risk factors for the development of chronic pain, assessment of psychological functioning, and brain-imaging responses to painful stimulation (figure 3). Of course,

Conclusion

Brain-imaging studies of experimental pain have changed substantially over the past decade. Whereas the first studies tried to do an inventory of the areas activated by a noxious stimulus, recent studies used sophisticated study designs aimed at answering hypothesis-driven questions. In this Review we have pointed out that the specialty of brain imaging of pathological pain still awaits such a renaissance. Interpretation of the results of most of the published reports is hampered by the use of

Search strategy and selection criteria

References for this review were identified from the authors own files and by searches of PubMed, HubMed, and Scopus with search terms “brain imaging”, “PET”, “fMRI”, “MEG”, “chronic pain”, “postoperative pain”, “neuropathic pain”, “migraine”, and “headache”. Only original research and review papers published in English have been included. There were no date limitations, and the last search was done in August, 2006.

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