The best magazine
What MRI Has Taught Us About Chronic Pain
Keeping the CNS in Perspective: How Pain (as Nociceptive Information) Gets to the Brain
Pain processing typically involves transmission and modulation of nociceptive signals along a predictable pathway. Noxious stimuli trigger signals in the peripheral nerves. A-delta nerve fibers transmit the 'first-pain' signals, the pricking, sharp sensations felt immediately after the painful stimulus is applied. C fibers transmit 'second-pain' signals, the dull, aching and throbbing pain felt after a 1–2-s delay. These peripheral nerve fibers synapse in the dorsal horn of the spinal cord, where interneurons cause inhibitory/excitatory modulation. Secondary spinal projection neurons then transmit the information to two areas of the brainstem – the rostral ventral medulla and periaqueductal gray, where they are further modulated and relayed first to the thalamus and then to the somatosensory cortex in the cerebrum, where they are interpreted as pain (for review).
In chronic pain states, inflammatory factors and sensitized receptors in the skin are thought to cause an abnormal increase in the transmission of nociceptive signals from the periphery as well as either a lack of inhibition or increased excitation, or both, at the spinal cord, brainstem or cortical levels, called 'central sensitization'.
Specific Brain & Brainstem Regions Implicated in Chronic Pain
Neuroimaging provides a means of noninvasively studying altered activity levels in the CNS. Specifically, neuroimaging can be used to study the brain, brainstem and spinal cord, where central sensitization and pain modulation occur and contribute to the ongoing experience of chronic pain and related symptoms. Much of neuroimaging research has focused on identifying the brain regions that demonstrate altered structure and activity in chronic pain states. A major goal of this research is to identify specific brain regions as future targets for chronic pain therapy.
Several key brain regions have been identified as potentially playing a role in chronic pain. These regions are primarily implicated in sensory and affective components of pain processing and perception, motor function and higher order brain processing and integration, as reviewed below.
Structural Changes
Differences in brain structure have been widely assessed in individuals with chronic pain, typically using voxel-based morphology and cortical thickness analysis. Regional increases and decreases in cortical thickness and gray matter density have been observed across several types of chronic pain, including CRPS, fibromyalgia, migraine, temporomandibular disorders (TMD) and cLBP and in visceral pain states, such as irritable bowel syndrome (IBS). One study demonstrated these changes simultaneously among different chronic pain syndromes, including CRPS, knee osteoarthritis and cLBP. These studies indicate that the key areas of observed gray matter change include regions within the insular, somatosensory, motor and associated cortices; in subcortical structures, including the thalamus and basal ganglia, and parietal cortices; in regions within the prefrontal cortex; and in structures implicated in memory and emotion regulation, such as the hippocampus and amygdala, respectively.
It was initially thought that changes in gray matter, primarily decreased gray matter density, were associated with increased rates of age-related gray matter atrophy. However, this theory is being questioned because several chronic pain studies have shown a mixture of regional increases and decreases in gray matter density, as well as reversal of gray matter change following effective therapy. The exact nature and cause of these changes are currently unknown. Moreover, we do not know whether the observed changes represent existing differences in brain structure that predispose individuals to chronic pain, whether they occur as a result of the presence of chronic pain (e.g., due to additional stress and pain experience itself), or whether they are functionally linked to the maintenance of chronic pain. In addition, it is unclear whether these detected differences in gray matter structure are specifically due to chronic pain, or whether they are more complex in nature and result from multiple factors linked to chronic pain (such as depression or the medications that the patient is taking for pain). For example, a meta-analysis of several studies of structural brain changes in patients with FM indicated that the depression score accounted for most, if not all, of the changes in gray matter structure in individuals with FM as compared with healthy volunteers. However, gray matter changes have also been shown to occur in patients with cLBP with little to no emotional distress.
Connections between brain regions are now under study as well. Diffusion tensor imaging and fractional anisotropy have been used to investigate differences in white matter structure seen in various chronic pain states, including TMD, and IBS. Changes in brain structure have also been observed using combined voxel-based morphology and diffusion tensor imaging to analyze interactions between regions of gray matter change and white matter change in patients with CRPS and FM.
Functional Changes
Alterations in brain function have been demonstrated in multiple chronic pain syndromes, and many of the identified regions of functional change overlap with regions of structural change. Investigations of brain function in the presence of chronic pain typically involve protocols to assess brain function in response to pain evoked by noxious or innocuous stimulation, in the presence of emotional or cognitive tasks or stress, or while patients rate their ongoing chronic pain symptoms. Ultimately, no one region within the brain, brainstem or spinal cord is singularly responsible for chronic pain: all neuroimaging studies have shown that chronic pain and its comorbid symptoms cause neurological changes across several brain regions. Moreover, these studies repeatedly demonstrate altered function in several key regions within the CNS, as described below.
Altered activity within the primary somatosensory cortex and posterior insular cortex has been observed when noxious stimuli are applied in individuals with cLBP, FM, CPP and CRPS. These are regions typically associated with intensity coding (which measures how painful a stimulus is), and these functional alterations suggest altered intensity processing of pain in chronic pain states. Similarly, the secondary somatosensory cortex (SII) is a region of higher order sensory processing and integration, and has shown both structural and functional alterations.
The primary motor cortex, premotor cortex and supplementary motor areas also play a role in chronic pain. Alterations within these motor regions may be related to the changes seen within the cerebellum, which have been historically reported, yet minimally discussed, in the literature. Currently, however, insights into cerebellar changes in chronic pain are accumulating and may add to the known function of the cerebellum and how it coordinates with altered sensory motor and emotional processing in the presence of chronic pain.
Several investigators have examined the relationship between cognitive processes and chronic pain. These studies primarily identify functional changes in higher order regions within the prefrontal cortex (PFC), including the ventromedial PFC, dorsolateral PFC and orbitofrontal PFC. Regions within the parietal cortex, including the temporo-parietal junction, precuneus and posterior cingulate cortex, also demonstrate functional changes in individuals with chronic pain. These regions are involved in introspection, mind wandering and self-referential thought processes, which may be more highly integrated with pain processing and experience in chronic pain states.
Brain regions related to the affective aspects of pain processing (such as the level of unpleasantness, negative context), including the anterior insular cortex and anterior cingulate cortex, demonstrate altered function in chronic pain states. Studies investigating the psychological aspects of chronic pain, including altered fear and emotional processing, have identified scale-based correlations of altered emotion processing with altered brain structure and function in emotion and fear-processing regions, including the amygdala, and in memory-related processing regions including the hippocampus. While changes in the amygdala have been observed, fear avoidance (of movement) is not indicated as being responsible for these changes. Therefore, these alterations are more likely due to general changes in limbic and memory networks.
Altered function within subcortical, midbrain and brainstem regions suggests that chronic pain modifies brain circuits and modulation. Thalamic lesions have been implicated in central pain, and they frequently accompany altered activity and structure in other chronic pain states as well. Functional alterations within the basal ganglia suggest altered motor and general connectivity of the brain. Altered activity within midbrain regions, in particular in the ventral tegmental area, may signal that chronic pain disrupts the mechanisms of reward, punishment and dopamine function.
Altered activity within brainstem regions, especially involving the periaqueductal gray, may signify disrupted regulatory control of pain. However, further research is needed because the small size and highly complex, multifunctional heterogeneity of the brainstem has thus far limited study within this region.
Although invasive electrophysiology studies of chronic pain and chronic pain models have observed altered activity within the spinal cord, MRI imaging of the cervical spinal cord has to date been conducted only in healthy individuals. This technology is evolving and may soon be useful for the study of chronic pain. However, technological advances are necessary to improve the S/N in cervical spinal cord imaging, which is greatly diminished by local pulsation and physiological noise.
Brain Network-based Approach: Resting State fMRI
Recent methods of resting-state fMRI have focused on multiple regions in the brain, targeting inherent and altered measures of connectivity between regions and within brain 'networks'. Resting-state fMRI has the advantage of enabling neuroimaging data to be collected while individuals with chronic pain simply rest in the MRI scanner. Moreover, it provides information about the natural state of brain activity in chronic pain without having to apply any external sensory or cognitive stimulation. Resting-state fMRI methods investigate the degree of functional connectivity, seen as changes in correlation of low-frequency oscillations in neural activity between brain regions. These changes can provide information about altered resting-state brain activity in chronic pain states. Chronic pain has been noted to alter several networks, or groups, of individual brain regions with similar low-frequency oscillatory activity and an increase or decrease in the presence or absence of external stimulation. These primarily include the default-mode networks (DMN), which are more active at rest; salience and executive control networks, which are more active during stimulation of the senses or tasks; and sensory motor networks, which are related to sensory and motor processing. Notably, altered DMN function in chronic pain has also been demonstrated in a study using arterial spin labeling.
Decreased DMN connectivity, specifically within the medial PFC, posterior cingulate cortex and amygdala, has been observed in cLBP. Conversely, greater connectivity within the default mode and executive attention networks has been observed in FM. Greater connectivity between the DMN and insular cortex has also been observed, indicating that these regions function together differently in FM as compared with healthy states. Additional studies in FM have noted similar alterations between the insular cortex and other cortical regions. Low-frequency fluctuations within brain regions are also altered in chronic pain, specifically within the primary somatosensory cortex, supplementary motor area, dorsolateral prefrontal cortex and amygdala. Conversely, in CRPS, reduced resting-state functional connectivity has been observed within the DMN, and greater connectivity has been noted in the sensory and motor regions with other pain-processing-related regions. Altered resting state activity within sensory and motor network regions and within the DMN have been demonstrated in CPP. Several studies have shown that altered functional connectivity of the brainstem, basal ganglia and other regions within the frontal and temporal cortices may underlie chronic migraine. Diabetic neuropathic pain also shows similar alterations in resting state activity.
Longitudinal Changes & Limitations
The majority of investigations mentioned thus far are nonlongitudinal, and none of these observational studies track individuals before the onset and through the development of chronic pain. This is a major limitation for all neuroimaging studies of chronic pain: the observed functional and structural changes cannot specifically be determined to be caused by the presence of chronic pain. Typically, in order to gain some sense of the longitudinal progression of structural and functional brain changes in chronic pain, the observed alterations are assessed for correlations with the duration and intensity of pain within the studied population. However, more recently, a growing number of longitudinal investigations have been conducted, in particular for cLBP and IBS. A recent study that tracked patients who transitioned from subacute to cLBP noted changes in the structure of white matter. A few interesting studies have also shown that brain changes reverse when chronic pain is reduced by means of various effective therapies, including psychological therapy. This indicates that although CNS abnormalities are highly implicated in chronic pain states, they may not have to be permanent – the use of appropriate, effective therapy may be able to restore normal brain function, at least in part.
Source: ...