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Pain is a subjective experience with a definite physical basis. The physical indices associated with pain may not correlate well with the subjective experience, such as measurable degenerative changes in the lumbar spine and self-reported intensity of low back pain. Other physical indices, such as the gating mechanism in the spine that modulates the degree of pain ascending to the brain, are well studied but not objectively measurable in any routine clinical test. Newer neuroimaging methods may finally bridge the gap between subjective experience and objective findings. This article illustrates some of these newer methods and the possibilities for objective measures of pain on the horizon.

Computerized tomography (CT) is essentially a three-dimensional x-ray. The technique can readily identify bone fractures, bleeding in tissues, and gross abnormalities in bodily organs and structures. CT scanners are almost universally available in health care settings and relatively inexpensive. CT is highly sensitive to movement artifacts or the presence of metals that can displace electrons and distort the image. Magnetic resonance imagery (MRI) requires a shielded location for a massive electromagnet, is common but not universally available, and more expensive. As the magnet turns on (very briefly), elements such as the hydrogen in water rapidly align themselves in the magnetic field, and heavier elements such as the calcium in bone do not move as rapidly. Sophisticated software can differentiate tissues and structure densities with greater precision and definition than in CT. The resulting reconstructed image can often reproduce bodily structures with uncanny clarity. Images are weighted in different analyses to create contrasts designed to better identify common disease patterns and medical conditions. The CT and MRI are essentially structural methods, which identify physical abnormalities in tissues and structures.

Another set of neuroimaging procedures are often termed functional, that is, they measure active functional activity within the brain or other bodily organs. One of the more common techniques is the electromyogram and nerve conduction velocity (EMG/NCV) test. Often done as a combined test, the former assesses the responsiveness of muscles to nerve stimulation. The latter assesses the integrative integrity of the major peripheral nerve pathways. The test is typically used to confirm conditions such as carpal tunnel syndrome or radiculopathy caused by compression of a nerve root in the neck or back. Such a test has a better correlation with subjective pain than would structural imaging, but that relationship is still not perfect. The most common functional imaging of the brain is the electroencephalogram (EEG). Systematically placed surface electrodes measure the nature and intensity of brain activity. It is sensitive to many seizure conditions, gross abnormalities in consciousness, and can identify some components of migraine. The technique lacks sensitivity.

“Newer neuroimaging methods may finally bridge the gap between subjective experience and objective findings."

Biofeedback is not a neuroimaging technique per se, but can assess the nature and intensity of physiological aspects of physical functioning impacted by pain conditions. Surface measures of skin conductance, muscle tension, peripheral skin temperature, heart rate, respiration rate and pattern, quantitative EEG, and other measures can identify functional changes relative to normal in persons with localized injury or the generalized effects of pain through the autonomic nervous system. The limitations of biofeedback are lack of a universal standardized assessment procedure, the susceptibility of measures to some medications, caffeine and other substances, and variability in how the methods are used. Measures may quantify and substantiate subjective complaints. Biofeedback is best used as a relative quantitative measure of an individual’s response to pain treatment.

Newer and exciting neuroimaging techniques are often blends of the structural and functional approaches, but are usually limited in availability and require highly specialized equipment, analysis software and trained professionals to interpret the results. The methods are very expensive and often denied by insurers. Thus, the Official Disability Guidelines consider these methods as potentially useful but not recommended because the scientific body of evidence is still insufficient. Cousins (2007) offers a succinct description of the mechanisms involved in the pain response. There are a variety of neural and chemical responses at the location of a physical injury. In the context of persistent pain, nerves can become sensitized and over time adapt their function to the existing trauma. In the presence of persistent pain, modulating neurons at the level of the spinal cord can “wind up” in response to a chronic pain signal, thus amplifying peripheral signals not processed as “painful” prior to an injury, such as touch or temperature change. Through a shift in the balance of neurochemical activity, loss of inhibitory control, and brain plasticity, changes can also take place at the brain level that make pain chronic and enduring, regardless of the nature and extent of the original injury. Psychological factors, genetics, and other physical characteristics have a modulating effect on these neurological processes. The chronic stress on the nervous system can also lead to cell death, tissue shrinkage, and other enduring structural changes that make pain far more difficult to regulate. Woolf and Salter (2000) provide an even richer and comprehensible description of the neural changes at all levels of the nervous system in response to persistent pain.

“Biofeedback is not a neuroimaging technique per se, but can assess the nature and intensity of physiological aspects of physical functioning impacted by pain conditions.”

Pain is the most dynamic of the human senses (Watkins and Maier, 2003). There is no scientific doubt that pain experience is physical and genuine. Its complexity is only beginning to be appreciated. Pain is “in one’s head” only because it is experienced in the brain. Treating pain effectively and as early as possible in the course of an injury is paramount to minimize these neural changes. Appropriate pain treatment at any time may attenuate negative experience and utilize the same plasticity principles to shift pain modulation in a positive direction. Neuroimaging can be useful to capture these functional processes and subtle but important structural brain changes.

Borrowing a simple analog model of the brain from Siegel (2007), make a fist with the right hand (works with the left but from the opposite point of view) and tuck the thumb under the curled fingers. This is a lateral view of the brain from the left side. The model needs an extra thumb on the outside for the right temporal lobe to be a more complete brain model. The curled fingers represent the frontal lobes (executive functions), the thumb the temporal lobe (sequential or contextual processing and memory), the top knuckles the central sulcus (fold) separating the frontal lobe before it from the parietal lobe (integrated sensory processing) behind it. The occipital lobes (visual processing) would be represented by the base of the back of the hand before the wrist. Assuming the right hand to model the brain from the left hemisphere, an important structure for all sensory processing is the cingulated gyrus (a raised section of brain tissue). This is central to the brain and wraps itself under the middle and ring fingers and underside of palm. The cingulate is activated when new sensory information comes in and serves as a wake up to various areas of the brain to process the information and to ready the brain for action. Sticking the left index finger into the center of the palm, the model now includes: 1) the top of the finger as the diencephalon (thalamus, hypothalamus, and pituitary which relay and modulate all sensory input and direct hormones, “drives,” and other internal functions, pain included), 2) the midbrain (between 2nd and 3rd knuckles—knuckle one joins the finger to the hand), which contains the brain’s primary chemical factories and the center of which includes the periaqueductal gray (essential area for pain modulation), 3) the pons (between knuckles one and two), which coordinates and regulates movement and sensation with multiple connections to the cerebellum (heel of hand), and 4) the medulla (left knuckle one), which regulates all the basic functions of the body including control over the intensity of the body’s stress response. This simple brain model can provide relative reference points for regions of the brain as they are discussed.

“There is no scientific doubt that pain experience is physical and genuine. Its complexity is only beginning to be appreciated. Pain is “in one’s head” only because it is experienced in the brain.”

Traditional MRI can identify structural brain changes attributed to chronic pain, but the technology must use high-speed resolution techniques and focus on regional volumes instead of the usual clinical inspection of image slices. May (2008) reviewed two methods applied to brain changes associated with chronic back pain, migraine and tension headache, fibromyalgia, and irritable bowel syndrome. These methods are voxel-based morphometry (VBM) and diffuse tensor imaging (DTI). More detailed general descriptions of these and other imaging techniques can be found at en.wikipedia.org. VBM focuses on tissue volume in selected brain areas of interest and DTI creates three-dimensional gradients based on tissue volume. Gray matter tissue loss in multiple chronic pain conditions has been found in the cingulate gyrus, orbital frontal cortex (knuckle three to finger tip of middle and ring fingers in the hand model above), and insula (inner side of bent thumb closer to joint

One common combined functional-structural method is the functional MRI (fMRI). In addition to the structural and spatial layout of structures on a MRI, fMRI uses blood flow dynamics and rapid sequential images to create a temporal dimension that serves as an index of functional processes. Orme-Johnson and colleagues (2006) demonstrated the effect of meditation on brain function using fMRI. Healthy adults (average age in mid-50s) were subjected to conditions of the left hand being placed in warm water (43° C, 109° F) as a standard reference and the right hand placed in hot water (51° C, 124° F). Subjects who were experienced meditators were able to have a significantly lower pain response during the hot water experience than those who were not meditators. This was measured in several areas known to respond to such pain. The thalamus, which serves as the brain’s primary sensory relay station, was the most significant, with meditators having much less activation than nonmeditators. Nonmeditators were then taught a meditation technique and practiced it for 5 months. Activation in the long-term meditators did not change compared to the first time of measurement. New meditators had reduced activation (better pain modulation) at the follow up for the thalamus and the prefrontal cortex (2nd knuckles of curled right hand). There was also a trend in the small sample for reduced activation of the anterior cingulate gyrus (underside of index and ring fingers), which takes sensory information from the thalamus and activates the attentional aspect of the frontal lobes.

“Gray matter tissue loss in multiple chronic pain conditions has been found…”

Baliki and associates (2008) used fMRI to study information processing in a small group of healthy adults and those with chronic low back pain. They were particularly interested in brain areas associated with the default-mode network (DMN). The DMN paradigm involves brain areas that are activated or deactivated during particular tasks. Because the investigators were using a visual attention task, subjects were expected to deactivate: 1) the medial pre-frontal cortex (adjacent middle and ring fingers in the model), which is associated with behavioral and emotional calmness, 2) the posterior cingulate (mid-palm back from center), which would rest processing of sensations from the body, and 3) lateral parietal cortex (off-center portions of back of hand), which also would be associated with processing bodily sensations. This deactivation allocates more attention to areas involved in the target task, such as visual processing and judgment of line orientation. The visual attention task involved moving a finger joystick to continuously match a changing line image. Persons with chronic back pain performed the task as well as healthy controls, but areas expected to deactivate did not. Results suggested that chronic pain forces the brain to continuously process pain sensations and prevent normal resting activation.

Geha et al. (2008) used fMRI to study the effects of light touch, which is experienced as painful in patients with post-herpetic neuralgia. The virus-injured nerves in such persons create constant burning and other noxious sensations. Through mechanisms of sensitization, any touch, even clothing for some people, can be extremely painful. The task involved being touched with a light brush in the affected pain area. The investigators were able to determine time-sequenced activation of the multiple areas in brain stem and cortex that would process sensory pain information. Touch activated pain was objectively worse than any spontaneous pain. Treatment with lidocaine over two weeks seemed to help some individuals, but overall treatment effects were not significant based on aggregate fMRI data.

Using fMRI, Wrigley and colleagues (2008) were able to document brain reorganization and areas associated with neuropathic pain in persons with complete thoracic spinal cord injuries (SCI). Reorganization of somatosensory cortex (area on back of hand behind knuckles in the brain model) has been well-studied in persons with amputation, phantom pain, and stroke, but this study did the same for persons with SCI. Neuropathic pain was associated with zones of partial preservation of sensory function.

Wiech and associates (2008) utilized fMRI to demonstrate that decreased perceived pain while contemplating religious art was associated with reduced activation in the right ventrolateral prefrontal cortex (underside of right pinkie), which is a brain area associated with emotional regulation. Brown et al. (2008) utilized EEG and fMRI to demonstrate that prior emotional distress ratings in response to a painful stimulus (variable intensity laser shot to forearm) affected subsequent brain activation of the painful stimulus. Activation of the anterior insula was associated with greater pain anticipation. The hippocampus (inner thumb joint at knuckle two) is a key area for memory encoding and reconstruction and located just below the insula.

Positron-emission tomography (PET) is a technique that involves injection of a radio-tagged sugar into the blood stream. A task is performed and the PET scan measures areas of brain activation. Kuehn (2005) summarized multiple studies that have examined actual brain changes in fMRI and PET that measured opiate-mediated response in prefrontal cortex, anterior cingulate and insula among other areas by use of placebo or manipulated expectations prior to pain stimulus. In research underway, Stanford University pain physician, Sean Mackey, and colleagues are studying the effects of real-time fMRI feedback and patient’s ability to regulate pain experience.

“Persons with chronic back pain performed the task as well as healthy controls, but areas expected to deactivate did not. Results suggested that chronic pain forces the brain to continuously process pain sensations and prevent normal resting activation.”

Although not a standard of practice, functional MRI and several other novel structural and functional neuroimaging techniques are on the horizon for clinical application that can objectify pain experience. Most scientific studies to date have utilized small samples, did not involve randomized controlled trials, and focused on applying specific models to evoke pain experience. However, the seminal research is consistently supporting known functional brain areas involved in the processing of pain sensation. The medical-legal realm must still rely on subjective pain reports and consistency with known pathology and behavioral manifestation. However, if pain is a significant contested fact, fMRI at a university-based facility studying pain might provide an option for a qualified or independent medical evaluation.

“Although not a standard of practice, functional MRI and several other novel structural and functional neuroimaging techniques are on the horizon for clinical application that can objectify pain experience.”

Michael Gilewski, PhD, ABPP (Rp, Cl)
Dept of Physical Medicine and Rehabilitation (Neuropsychology)
Loma Linda University Health Care
11406 Loma Linda Drive, Suite 105
Loma Linda, CA 92354-3711
Tel: (909) 558-6220
Fax: (909) 558-6278
Email: mgilewski@llu.edu  






References
Brown, CA, Seymour, B, El-Deredy, W., & Jones, A. K. P. (2009). Confidence in beliefs about pain predicts expectancy effects on pain perception and anticipatory processing in right anterior insula. Pain, 139, 324-332.

Cousins, M. J. (2007). Persistent pain: A disease entity. Journal of Pain and Symptom Management, 33, S4-10.

Geha, P. Y., Baliki, M. N., Wang, X., Harden, R. N., Paice, J. A., & Apkarian, A. V. (2008). Brain dynamics for perception of tactile allodynia (touch-induced pain) in postherpetic neuralgia. Pain, 138, 641-656.
Kuehn, B. M. (2005). Pain studies illuminate placebo effect. Journal of the American Medical Association, 294, 1750-1751.

May, A. (2008). Chronic pain may change the structure of the brain. Pain, 137, 7-15.

Orme-Johnson, D. W., Schneider, R. H., Son, Y. D., Nidich, S, & Cho, Z-H. (2006). Neuroimaging of the meditation’s effect on brain reactivity to pain. NeuroReport, 17, 1359-1363.

Siegel, D. J. (2007). The mindful brain: Reflection and attunement in the cultivation of well-being. NY: Norton.

Watkins, L. R., & Maier, S. F. (2003). When good pain turns bad. Current Directions in Psychological Science, 12, 232-235.

Wiech, K, Farias, M., Kahane, G., Shackel, N., Tiede, W., & Tracey, I. (2009). Pain, 139, 467-476.

Woolf, C. J., & Salter, M. W. (2000). Neural plasticity: Increasing the gain in pain. Science, 288, 1765-1768.

Wrigley, P. J., Press, S. R., Gustin, S. M., Macefield, V. G., Gandevia, S. C., Cousins, M. J., et al. (2009). Neuropathic pain and primary somatosensory cortex reorganization following spinal cord injury. Pain, 141, 52-59.

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> Reflections on Almaraz Guzman
> Pain & the Brain: Imaging Methods
> Functional Capacity Evaluation
> Defense Perspective: Mad as Hell
> Computer Corner: TextMap
> Editor's Rant: A Dog's Breakfast
Pain and the Brain – New Imaging
Methods to Objectify Experience
By Michael Gilewski, Ph.D, Neuropsychologist