Overview of pain imaging studies- adults
A recent meta-analysis of human studies of acute pain described a neural network composed of several areas that are consistently activated during pain perception. This network, sometimes termed the "pain matrix", included the thalamus, primary (S1) and secondary (S2) somatosensory cortices, insula, anterior cingulate cortex (ACC) and the prefrontal cortex (PFC) [
89]. The activity of the pain matrix decreases during pharmacologically induced analgesia [
90]. These areas perform parallel processing of the different aspects of pain. While thalamus, S1, S2 and parts of insula process the sensory-discriminative features of the painful stimulus (i.e., stimulus localization and intensity), the ACC and anterior insula process the affective-motivational aspects (emotion, arousal, selective attention) and the PFC responds to the cognitive aspects of pain (attention, memory, stimulus evaluation) [
91,
92].
The signature of chronic pain on the brain is partially distinct, and includes not only the pain matrix, but also brain regions critical for cognitive and emotional processing, such as the medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex (DLPFC), parietal association cortex, amygdala, ventral striatum, and hippocampus [
93,
94]. Imaging studies have shown that reorganization occurs in several brain areas involved in sensory and affective processing of pain, such as the thalamus and the cortex. One study investigating patients with chronic back pain (lasting more than 6 months) showed regionally specific decreased gray matter volume in bilateral dorso-lateral prefrontal cortex (DLPFC) and right thalamus [
95] suggesting that the pathophysiology of chronic pain includes thalamo-cortical processes. Both DLPFC and thalamus are involved in perception of pain, and DLPFC has been hypothesized to inhibit the orbitofrontal cortex (OFC), therefore decreasing the intensity of perceived pain [
96]. The thalamus is an important relay in the nociceptive and sensory pathways from the spinal cord to the cortex and decreased thalamic gray matter may be related to the generalized sensory abnormalities associated with chronic pain [
97]. One recent study [
93] has shown that chronic spontaneous pain is associated with increased activation of the mPFC, a region involved in detection of unfavorable outcomes and processing negative emotions and response conflict [
98]. Other studies also described reduced gray matter in brain areas related to pain sensation, memory, and associated emotional processing, such as the anterior cingulate cortex (ACC), anterior and posterior insula, orbito-frontal cortex, and parahippocampus [
20,
99,
100]. Taken together, these studies support the idea that chronic pain may lead to structural changes in cortical and subcortical brain areas.
Further evidence for pain-related changes in the brain is provided by studies investigating brain chemistry. N-acetyl aspartate (NAA) is a neuronal marker involved in synaptic processes [
50]. Decreased levels of NAA in the brain may reflect neuronal loss and degeneration, as well as long-term neurotransmitter changes. Grachev and colleagues [
101,
102] showed decreased levels of NAA in the DLPFC in patients with chronic low back pain or CRPS. Similarly, Sorensen and colleagues [
103] found that patients with neuropathic diabetic pain have reduced NAA levels in the thalamus compared to diabetic patients without pain.
Results from functional studies using positron-emission tomography (PET) or fMRI suggest that brain function may be affected by chronic pain. Von-Frey stimulation of the affected limb in adult patients with CRPS evoked pinprick hyperalgesia and produced greater contralateral activation than identical stimulation of the unaffected limb in primary (S1) and secondary (S2) sensory cortex, insula, anterior cingulate cortex, and frontal cortices [
104,
105]. Mechanical allodynia evoked by brushing the affected limb was reported to correspond with activation of motor (M1) and cognitive regions (frontal regions), areas involved in emotional processing (e.g., anterior and posterior cingulate cortex, temporal lobe), parietal association cortices, as well as pain sensory regions (e.g., S1, insula) [
104]. Of note was the significant negative activation in visual, posterior insular, and temporal cortices in response to brushing that evoked allodynia. In a recent study using magnetic source imaging, cortical reorganization was reported in the contralateral S1 cortex in patients with CRPS [
105]. The reorganization involved parts of the body (lips and fingers) that did not have pain, but exchanged representations following recovery from CRPS. Functional cortical reorganization has also been described after limb amputation in primary somatosensory and motor cortices [
106], and it has been related to phantom limb pain, rather than referred phantom sensations [
18]. Cortical reorganization in patients with phantom limb pain also occurs in brain areas involved in processing affective-motivational aspects of pain, such as the insula, anterior cingulated cortex, and frontal cortices [
107]. Taken collectively, these studies suggest that cortical plasticity in adults suffering from chronic pain is intrinsically maladaptive, particularly with respect to sensory-motor processing and that such changes are an essential feature underlying the pathophysiology of the disease.
During performance of cognitive tasks, the RSN shows functional reorganization and at least three canonical networks emerge. The "default-mode network" (DMN) is composed of brain regions that show decreases in activation and includes the ventromedial prefrontal cortex (VMPFC) and posterior cingulate cortex (PCC) [
45,
46,
108]. Other emerging networks typically show increases in activation during cognitive tasks, including the central-executive network, which includes the DLPFC and posterior parietal cortex (PPC), and the salience network, which includes the ventrolateral prefrontal cortex (VLPFC), anterior insula, and the anterior cingulate cortex (ACC) [
109,
110]. Baliki and colleagues [
46] showed that the functional connectivity within the DMN is altered in patients that had suffered from chronic back pain for an average of 6 years. Compared to healthy control subjects, patients with chronic back pain exhibited decreased deactivation in the mPFC, amygdala, and PCC during performance of an attention task. The extent of the mPFC deactivation was correlated with the number of years of pain suffering. In this study, performance on the attention task was similar between chronic pain and control subjects, suggesting that the differences in DMN connectivity were not related to the ability to complete the task. This study supports the idea that chronic pain has a widespread effect on brain function, affecting cortical circuits beyond those involved in perception. A second study investigated RSNs in female patients with complex regional pain syndrome and found increased connectivity between nodes of the salience network, including the bilateral insula and temporal pole, the bilateral cerebellum, and the left sensory-motor cortex; no changes were found in the vision-related network or the DMN between patients and healthy controls [
111]. In this study, the pain severity was correlated with bilateral insular and temporal pole connectivity, whereas the duration of pain was correlated with dorsal anterior cingulate and hypothalamus/thalamus connectivity, suggesting that the brain changes are a consequence, rather than a cause of the increased nociceptive perception [
111]. While these two studies report contradictory results in relation to the changes in DMN in chronic pain, it is important to note that brain reorganization is a plastic, time-dependent process that is initially driven by peripheral and spinal cord events, and subsequently by higher processing related to coping strategies [
46]. Therefore, it is likely that the extent and the pattern of functional alteration in the DMN are related to the duration of chronic pain, as well as other pain characteristics (intensity and type of pain, presence of depression or anxiety).
In summary, findings from structural and functional imaging studies in humans suggest that the brain in chronic pain is not simply processing heightened pain information. The network of pain-transmitting areas within the central nervous system undergoes functional and structural reorganization in patients with chronic pain, and this central plasticity could in turn influence the sensory, affective, and cognitive perceptions related to pain.