Pain and the Brain
Pain is a complex biopsychosocial process that impacts millions of Americans each year and results in human suffering and significant costs to society via health care expenditures and lost productivity.1,2 With the advent of functional magnetic resonance imaging (fMRI), our understanding of the underlying physiological/anatomical mechanisms of pain, as well as the impact of proven interventions for the treatment of pain, can be more fully understood. This new technology provides the ability to identify a variety of cortical and subcortical structures involved in the cerebral response to nociceptive stimuli in humans. This article aims to synthesize and summarize the current literature on what has been learned about pain through fMRI.
Basic Description of fMRI
There are several different brain imaging techniques that can be used for the study of pain: positron emission tomography (PET),3 single photon emission computerized tomography (SPECT),4,5 Magnetoencephalography (MEG),6 functional magnetic resonance imaging (fMRI),7 and others.8 The advantage of using brain imaging tools is that they are non-invasive, and can be applied to both normal and abnormal subjects to study dynamic brain activities. Among these tools, fMRI is currently the most widely used.
The fMRI was developed on the basis of MRI—a discovery by Felix Bloch and Edward Mills Purcell, who were awarded the Nobel Prize in Physics in 1952 for this discovery. The principle of MRI is that atomic nuclei will rotate with a frequency that is dependent on the strength of the magnetic field. In the absence of a strong magnetic field, hydrogen nuclei (protons) are randomly aligned. When the strong magnetic field is applied, the hydrogen nuclei wobble or precess about the direction of the field. Therefore, when a human body is placed in a large magnetic field, many of the free hydrogen nuclei align themselves with the direction of the magnetic field. A radio-frequency (RF) pulse is then delivered whose energy can be increased if they absorb radio waves with the same frequency (resonance). When the RF pulse stops, the nuclei return to equilibrium or relaxed state and the nuclei realign themselves at their net magnetic moment. When the atomic nuclei return to their previous energy level, radio waves are emitted to be measured, processed, and reconstructed to obtain 3D grey-scale MR images. Paul C. Lauterbur and Peter Mansfield pioneered the application of MRI in medical imaging and led to their Nobel Prize in Physiology and Medicine in 2003.
To enhance the signal, intravenous injection of gadolinium was first used in the fMRI as a contrast agent in the visual cortex and evoked by flashing light.7 However, it was soon realized that the body has its own natural contrast agent—deoxygenated hemoglobin.9-11 Most fMRIs now rely on the blood oxygenation level dependent (BOLD) effect, which is based on the increased neuronal firing in response to a stimulus that will induce hemodynamic changes and ultimately modify the magnetic field to increase the MRI signals.12 It is thought that an increased metabolic demand, due to increased neuronal activity, results in an increase in blood flow beyond metabolic needs, such that the final ratio of deoxyHb/oxyHb actually is reduced. It is the reduction in deoxyHb that alters the magnetic field properties and produces the increased MRI signal.13 On the other hand, by using visual system circuitry to elicit synaptic activity, a strong correlation was observed between local field potentials and change in brain oxygen concentration without generation of action potentials.14 The advantages of fMRI include its non-invasiveness, good spatial (down to 1 to 2 mm) and temporal (100s of ms is possible) resolution. However, fMRI has its limitations such as expense, availability due to time-sharing on a clinical scanner, restriction to only those having no metallic devices in their bodies, and loud noise.
As will be reviewed in greater detail later in this article, fMRI has been conducted to investigate brain mechanisms underlying both chronic and acute pain. The fMRI has been used to study stimulus-related responses, such as noxious electrical stimulation of the skin or peripheral nerve,15-17 noxious heat or cold,18-23 mechanical,24 chemical,25,26 or visceral27 stimuli. The fMRI has also been used to image allodynia in complex regional pain syndrome,28 and patients suffering from neuropathic pain.29 Several brain areas can be activated. They include the SI, SII, anterior insula, ACC, thalamus, and cerebellum.
The relationship and interaction of pain, attention, and anticipation has been demonstrated to activate slightly different areas of the brain.15,22 For example, anticipation of pain activated the anterior ACC, whereas the pain itself activated the posterior ACC. Further dissection on this line demonstrated that the posterior insula/secondary somatosensory cortex, the sensorimotor cortex (SI/MI), and the caudal ACC were specific to receiving pain, whereas the anterior insula and rostral ACC activation correlated with individual empathy scores when the subjects watched their loved ones receiving pain stimuli.30 It was suggested that the modulatory effect of expectation on pain transmission might involve activation of descending modulatory systems.31 On the other hand, with the combination of psychophysical assessment and fMRI, pain-related activations have been obtained in parallel psychophysical sessions,18 or during the imaging sessions,15,23,26 in order to separate those activations due to the mere presence of a stimulus (due to attention) from those related to the subjects’ actual sensory experiences.
Despite the technical advantages of the fMRI, the notion of whether fMRI is a modern phrenology is under debate.32-34 One should be cautious of its potential abuse,35,36 especially when it is used in dissecting the cognitive and emotional mechanisms, because cognitive function is a “moving target.” “Ask a person a question once, and it is a different person to whom you repeat that question the next minute or the next day.” A good fMRI study is difficult to design, conduct, analyze, and interpret; special expertise is needed to design a methodologically-sound study.
Brief Overview of the Physiology of Pain
Prior to a discussion of more specific fMRI findings, a review of what was known about the physiology of pain prior to the advent of fMRI is warranted. At the level of the peripheral nervous system, myelinated Aδ fibers play a significant role in the transmission of sharp pain, while slower, unmyelinated C-fibers transmit dull or burning pain sensations. Pain signals travel along a combination of these fibers and enter the central nervous system at the dorsal horn of the spinal column.37 Within the dorsal horn of the spinal column, pain signals are modified before ascending to different brain regions.38