The International Association for the Study of Pain (IASP) defines chronic pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" 1. Pain is considered chronic after 6 months of onset. However, the majority of pain studies set the minimum time at 3 months for pain to be considered chronic. Nevertheless, pain can be considered chronic when it does not resolve in the expected time frame after an acute injury, and does not respond to analgesic treatments. Chronic pain is a common and persistent problem in adult populations worldwide 23. A recent multi-national survey study (N = 42,249) reported a prevalence of 37.3% – 41.1% for chronic pain conditions. Chronic pain of moderate and severe intensity can have serious deleterious effects on the mental health, employment status, sleep and personal relationships of affected individuals 34.

Our understanding of the effect of chronic pain on cortical, subcortical and brainstem neural networks has been greatly advanced with the introduction of non-invasive neuroimaging techniques. Pain is a subjective experience that is not only or necessarily determined by the intensity of the noxious stimulus 5, but also by a variety of biological and psychosocial factors, such as sex hormones, emotions, memories, or social expectations. It is therefore not surprising that the associated structural and functional changes are widespread and can be observed in brain areas not directly implicated in 'classic' pain processing. Neuroimaging findings have fundamentally altered the way in which we should evaluate and probably treat pain: as a disease rather than a symptom 6 and a disease predominantly affecting the brain 7.

Brain imaging studies of chronic pain in pediatric populations offer unique opportunities to understand changes in the young brain. Aside from providing novel insights into CNS processing of pain in children, these studies allow investigation of the disease from both a developmental and neuroplastic perspective. In the pediatric population, the brain is undergoing rapid changes, is more plastic, and may have an increased ability to recover after injury. Currently, the long-term effects of early pain on neural systems are not well understood, but findings of early traumatic experiences (e.g., surgery, immunization, etc) resulting in persistent changes in CNS have been reported 8,. Ideally, the use of non-invasive imaging methods to objectively evaluate changes in the brain in pediatric patients will lead to new treatment approaches that could potentially limit the development of long-term consequences.

Several non-invasive imaging techniques have been applied in research to investigate the brain areas involved in processing of acute and chronic pain, as well as the long term structural and functional changes occurring in the brain of chronic pain sufferers. Most functional imaging studies have been performed in adult volunteers or patients. Despite the heterogeneity of the clinical pain syndromes, a "central pain matrix" composed of primary nociceptive areas commonly activated by painful stimuli has been described 9. Furthermore, additional brain areas are involved in processing the emotional 10 and cognitive 11 aspects of the pain experience, and their activation is dependent on the particular set of circumstances for each individual 6.

Imaging studies in adults have also helped uncover the central modulation of pain systems. By using distraction during painful stimulation, for example, Bantick and colleagues 12 showed that many areas involved in pain processing displayed reduced activation, supporting the behavioral observations of reduced pain perception. Studies of the placebo effect also provide evidence that the experience of pain can be altered by cortical mechanisms 13, suggesting that the sensory experience can be shaped by one's attitudes and beliefs 13. The anterior cingulate and frontal cortices are part of a descending pain modulatory system that exerts top-down influences on the periaqueductal grey (PAG) and posterior thalamus to gate pain modulation 14. Other regions, including the nucleus cuneiformis (NCF), have also been shown to be involved in modulation of pain in human imaging studies 615. If an individual can learn to control the activation of these cortical areas through biofeedback, this might provide a different approach to treating disease. Biofeedback using real-time magnetic resonance imaging has been successfully applied in a group of chronic pain patients 16. Subjects successfully learned to control the activation of the anterior cingulate cortex, and this process led to significant reductions in the magnitude of experienced chronic pain 16. Finally, brain networks activated by empathetic pain (observing pain in a close friend or loved one) are similar to those activated by pain resulting from somatic inputs in the same individual 17.

Imaging research has also contributed to our understanding of the changes that occur in the brain of adult chronic pain sufferers. The brain in chronic pain is not simply processing heightened pain information; rather, neuronal networks of pain-transmitting areas undergo plasticity that results in long-term functional and structural reorganization, and ultimately influence the sensory, affective, and cognitive perceptions related to pain 618. The role of the brain mechanisms in maintenance of chronic pain is apparent in some conditions such as chronic regional pain syndrome or fibromyalgia, in which the pain appears to result from abnormalities of central pain processing leading to hyperalgesia (i.e., increased response to normal painful stimuli) and allodynia (i.e., pain in response to normally non-painful stimuli), rather than from damage of peripheral structures 19. In addition, structural imaging studies have shown that significant atrophy is associated with chronic pain 20, raising the possibility that chronic pain could also be considered a degenerative disease.

Together, these studies inform our approach to therapy. Most drugs that are currently used in the treatment of chronic pain (opioids, antidepressants and anticonvulsivants) are not able to control the pain in most patients, and in controlled clinical trials they have a ceiling effect of approximately 30% efficacy level 20 in pooled patient sets. In this context, neuroprotective drugs or drugs targeting sensory and emotional brain circuits might prove beneficial. Brain imaging techniques may be useful in monitoring the disease process and progress and the responses to specific analgesia and experimental pain 7.

Compared to the wealth of data from adult studies, the research investigating brain changes in children with chronic pain is still in its infancy. While numerous studies have documented the increased prevalence in children of chronic pain conditions, such as headache, abdominal, limb and back pain 212223, as well as the long-term physical, psychological and social consequences of childhood pain (see below), very few studies have addressed the question of brain changes in pediatric pain populations. These studies are necessary in order to understand the effects of pain on brain maturation and plasticity processes. Indeed, many early experiences resulting in psychosocial or physical trauma in early childhood may eventually unfold in the form of generalized pain symptoms similar to those observed in depressed patients 24, patients with fibromyalgia 25 or in patients with post-traumatic stress disorder 26.

Prevalence rates of chronic pain in children reported in the literature are variable, depending on the definition, method of reporting and type of pain, as well as the characteristics of the study sample (age, gender, age of onset and duration of illness). For example, McGrath and colleagues 27 investigated chronic pain (defined as pain present for more than 3 months) in children with enuresis, cancer, and arthritis and found that the prevalence of chronic pain was 2.2% for enuresis, 12.5% for cancer, and 78% for arthritis. One epidemiologic study that investigated the prevalence of chronic pain regardless of etiology found that 25% of the 5336 children aged 4–18 years included in the study were affected by chronic pain 23. A survey that investigated four of the most frequent pains (headache, stomach, back and limb pain) in a sample of 2465 adolescents aged 12–15 years revealed that 16.5% complained of pain that occurred at least weekly; moreover, 6.5% of subjects reported having pain in more than one location 22. Van Dijk and colleagues 28 surveyed 495 schoolchildren aged 9 to 13 years and found that 57% of children experienced at least one recurrent pain (headache, stomach pain, muscle pain or growing pain). Six percent of the subjects were identified as having a history of chronic pain or having chronic pain at the time of the study 28. An even higher prevalence of chronic pain, 30.8% (defined as pain present for more than 6 months) has been reported in a survey of German children and adolescents aged 4–18 years 21. Despite treatment, a considerable proportion of children and adolescents continue to experience long-term pain. In a study of 254 children and adolescents aged 0–18 years with chronic pain, it was found that 48% of the subjects continued to experience pain one year after the original assessment, and 30% continued to have pain at a two year follow-up 29. There are several methodological factors that influence the outcome of prevalence studies in chronic pediatric pain, related to the definition of recurrent and chronic pain, sampling techniques and methods of data collection. Despite the variability in the reported prevalence rates, these studies indicate that chronic pain is a common complaint in childhood and adolescence.

Because chronic pain frequently results in higher use of medical services and medication, it is not only an individual patient concern, but also a public health concern. Chronic pain has a negative impact on the quality of life, performance and mood of the affected children, and adolescents and can cause social, emotional and financial consequences for the family 30. The severity of the pain-associated problems experienced by children and their families varies considerably depending on the clinical population studied. The effect of pain on psychological well being of children and adolescents can be substantial and a considerable number of studies have shown that symptoms of depression, anxiety (general and pain-specific) and stress are common complaints in children suffering from recurrent childhood pain of various etiologies, particularly when the pain is severe and causes disability 3031. The prevalence of depression in 13–18 year old adolescents that experience daily pain was three times higher (45%) than in the general population (16%) 3233. In addition to the pain intensity, depression can also be a predictor of functional disability 31 and interdisciplinary cognitive-behavioral treatment focusing on disability. Children and adolescents that experience pain are also at increased risk of missing school 32, and some have adjustment problems related to peer rejection and isolation 34. These problems have been linked to academic underachievement, involvement with antisocial peers and unemployment 35.

In addition to problems encountered during childhood, chronic pain predisposes an individual to somatic and psychosocial consequences that extend into adulthood, specifically, increased reports of pain, disability and psychiatric symptoms 3637. Infants who have major surgery in the first 3 months of life show greater pain responses and require more intra-operative pain management during subsequent operations 38. Even less noxious stimuli, such as heel prick, can result in increased sensitivity to mechanical stimulation lasting at least during the first year of life 39, suggesting that abnormal plasticity occurs in the pain pathways in the sensory connections in the dorsal horn, but possibly at higher levels in the spinal cord and even the brain. Several long-term follow-up studies of subjects that experienced recurrent pain during childhood found that they continue to experience pain during adulthood. For example, about 60% of children who experienced migraine headaches during childhood and early adolescence were still experiencing migraines 23 years later 40, and a relatively large percentage of adult daily headache sufferers report the initial onset of symptoms early in life 41. The relative higher impact on long-term functioning of chronic pain in childhood compared to adulthood is not surprising. The nervous system is more plastic during childhood to allow for developmental and maturational processes to follow their course. Abnormal stimuli such as recurrent pain may affect plasticity in the peripheral and central nervous systems and may lead to long-term pain-related effects influencing a wide range of functions, including nociceptive processing, emotional processing and coping behaviors 42. Pediatric patients that survive severe injuries have high incidence of post-traumatic stress disorder and depressive symptoms in the days, weeks and months following hospitalization, and these symptoms are associated with long-term functional impairment and diminished quality of life 43. Therefore, early therapeutic interventions are essential in learning adaptive rather than maladaptive coping strategies and prevention of long-term negative outcomes of childhood pain.

A schematic of the imaging techniques used in pain research is presented in Figure 1. Below we provide detailed descriptions of these techniques.

Magnetic resonance imaging is non-invasive and can be used repeatedly in children, therefore allowing longitudinal studies of the development of neural networks during childhood and adolescence, evolution of disease processes and treatment effects. Functional magnetic resonance imaging (fMRI) is a powerful tool that can be used to investigate neuronal networks involved in cognitive processing and the effects of disease states on brain functioning.

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) 9192.

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 9394. 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 2099100. 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 101102 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 104105. 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) 4546108. 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) 109110. 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.