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Neuropathic Pain Mechanisms and Imaging Ka-Wah Tung, MD1
Deepak Behera, DNB1
Sandip Biswal, MD2
1 Department of Radiology, Stanford University School of Medicine,
Stanford, California 2 Division of Musculoskeletal Radiology, Stanford University School of Medicine, Stanford, California
Address for correspondence Sandip Biswal, MD, Division of Musculoskeletal Radiology, Department of Radiology, Stanford University School of Medicine, 300 Pasteur Drive S-068B, Stanford, CA 94305 (e-mail:
[email protected]).
Semin Musculoskelet Radiol 2015;19:103–111.
Abstract
Keywords
► neuropathic pain ► biological markers ► musculoskeletal imaging ► molecular imaging
Molecular and cellular imaging of neuropathic pain, utilizing the myriad of receptors and inflammatory mediators involved in nociceptive activity, is a promising approach toward objectively identifying peripheral pain generators. Neuropathic conditions arise from injured and inflamed nerves, which have been shown to elaborate several molecular and cellular elements that give rise to the neuropathic phenotype and can be exploited for imaging purposes. As such, in vivo approaches to image neuropathic pain mechanisms include imaging voltage-gated sodium channels with radiolabeled saxitoxin, calcium signaling with manganese-enhanced magnetic resonance imaging, and inflammatory changes and nerve metabolism with 18F-fluorodeoxyglucose. Imaging approaches exploiting other mediators of nociceptive activity, such as substance P (neurokinin-1) receptor, sigma-1 receptor, and macrophages, have shown promising early advances in animal models. By combining the sensitivity and specificity of molecular imaging with the high anatomical, spatial and contrast resolution afforded by computed tomography and MRI, radiologists can potentially identify sites of nerve injury or neuroinflammation that are implicated as peripheral pain drivers with greater accuracy and confidence. In addition to guiding therapy, these approaches will aid in new drug designs for analgesia and more individualized treatment options.
This article provides an overview of molecular and cellular approaches toward imaging of neuropathic pain pathophysiology. It includes in vivo imaging techniques of the peripheral tissues involved in nociception. We hope to demonstrate the advantage of complementing current conventional imaging techniques with molecular and cellular-based functioning imaging methods in elucidating pain syndromes. In the United States, pain is the most common reason for patients to seek medical attention. At least 116 million people in the United States suffer from acute and chronic pain every year, including up to 80% of the elderly population, affecting more American adults than heart disease, diabetes, and cancer combined.1 The national annual economic cost associated with chronic pain is estimated to be $560 to $635 billion (or $2,000 for each American), spent on medical treatment ($260–300 billion) and in lost productivity ($297–336 billion). In 2008, 14% of all federal Medicare expenditures were spent on pain management. Chronic
Issue Theme Advanced Imaging of Peripheral Nerves; Guest Editor, Avneesh Chhabra, MD
pain is often associated with other comorbidities such as depression, decreased appetite, and sleep disturbances, further adding to the costs. Unfortunately, diagnosis and characterization of pain remains a clinical challenge. A clinician’s assessment of pain continues to rely heavily on a patient’s self-reporting, which can be highly subjective. Current conventional clinical imaging methodology using computed tomography (CT) and MRI are based on finding anatomical abnormalities that may cause pain. However, these modalities offer only low sensitivity and specificity for the detection of pain-generating pathology. MR abnormalities can be found in up to 80% of asymptomatic patients, and the prevalence of anatomical abnormalities in asymptomatic and symptomatic patients is very similar.2–4 Such data question the accuracy of these imaging modalities in detecting causative pathologic abnormalities. A meta-analysis on imaging strategies for lower back pain concluded that imaging performed on patients without indications for serious underlying conditions
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1547371. ISSN 1089-7860.
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did not improve clinical outcomes, and that clinicians should refrain from routine immediate lumbar imaging in these patients.5 In fact, the authors warned that imaging can be harmful due to radiation exposure and the risk for labeling patients with an anatomical diagnosis that may not correlate with the actual cause of pain and give rise to unnecessary surgeries without clearly favorable outcomes.6,7
Current Challenges in Neuropathic Pain Imaging In cases of chronic musculoskeletal joint or nerve pain, it can be difficult to determine if inflammatory or degenerative changes seen on imaging represent active and symptomatically relevant changes of a disease process or simply part of the normal aging process. In the cervical and lumbar spine, abnormal processes include changes in disk signal, disk displacement, nerve root compression, and facet arthropathy. Unfortunately, these changes can be seen in 64 to 89% of asymptomatic patients.8,9 Similarly, shoulder MR imaging of asymptomatic volunteers has shown abnormalities such as partial- or fullthickness rotator cuff tears and acromioclavicular osteoarthritic changes, findings typically seen in symptomatic patients.10–12 The frequency of these abnormalities increases with age and may represent senescent changes rather than clinically relevant disease. The value of such findings in patients with clinical pain is doubtful at best. In addition, in patients with multiple imaging abnormalities, such as multiple bulging, desiccated disks, and multilevel facet arthropathy, it can be difficult to determine which, if any, of these abnormalities are the source of pain. Because therapeutic decisions are influenced by imaging, this lack of specificity in diagnosis can indirectly or directly contribute to delayed, ineffective, or even unnecessary treatment regimens. The need for imaging a molecular biomarker specific to pain-generating pathology cannot be stressed enough. Molecular imaging relies on identifying abnormal biological processes even in the presence of apparently normal-appearing anatomical structures. However, due to the large number and complexity of biochemical pathways involved in the mechanism of pain, identifying a common molecular pathway for chronic pain is a daunting, if not impossible, task. Adding to the challenge is the fact that etiologies of pain (e.g., inflammatory versus neuropathic) arise from unique physiologic and biomolecular changes. For example, patients with knee osteoarthritis tend to respond favorably to cyclooxygenase-2 (COX-2) inhibitors, but those with pain from a spinal cord injury do not, indicating that although COX-2 plays an important role in inflammatory pain, it has a significantly lesser role in neuropathic pain. Therefore, a labeled radiotracer designed to identify elevated COX-2 levels may pinpoint sources of inflammatory pain only. Technical limitations of molecular imaging techniques have thus far precluded their routine clinical use in identifying tissues of interest in neuropathic pain. Small structures of interest such as dorsal root ganglia and peripheral nerves, for instance, may simply get volume averaged out in positron emission tomography (PET) imaging and are highly subject to Seminars in Musculoskeletal Radiology
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patient motion artifact. 18F-fluorodeoxyglucose (18F-FDG) is a metabolic marker used for PET imaging. Background tissue activity of 18F-FDG in PET may overwhelm uptake in areas of interest such as neural and perineural structures. Even with modern PET scanners, it is nearly impossible to ascribe any abnormality confidently to an anatomical structure without the aid of anatomical imaging. The addition of CT scans in PET/CT helps to some extent, especially in spinal imaging. However, it is the superior soft tissue contrast of MRI that allows the radiologist to pinpoint abnormalities seen in PET to a distinct type of soft tissue, such as nerves or dorsal root ganglia. Therefore, the advent of PET/MRI as a hybrid functional-anatomical imaging modality has opened up avenues that were previously nonexistent. Additionally, radiation doses, which are nontrivial with PET/CT, are substantially lower with PET/MRI due to the absence of the CT radiation and can decline further as PET detectors improve and administered radiotracer doses decrease. Perhaps one of the main challenges to “image pain” is that pain is a complex subjective experience and that the experience of pain can differ from patient to patient, and vary according to affective factors. In this regard, one way to perhaps ascribe more specificity to an imaging approach would be to develop whole-body imaging assays to study simultaneously both the central and peripheral nervous system in toto so a complete individualized picture of pain can be studied from a more detailed and global perspective. Understanding the areas of increased activity throughout the entire system as conveyed by imaging biomarkers will give us insight into personalized pain experiences.
Pathophysiology of Pain Persons with neuropathic pain often experience hypersensitivity to a stimulus that clinically manifests as allodynia (pain from a noninjurious stimulus) and hyperalgesia (heightened and prolonged pain sensation to a painful stimulus). The central manifestations of neuropathic pain are beyond the scope of this section but mentioned very briefly here. The pain matrix of the brain primarily includes the insula, anterior cingulate cortex, primary and secondary somatosensory cortices, and secondarily includes other regions of the brain such as the posterior parietal and prefrontal cortices, motor-related regions such as the cerebellum and striatum, as well as periaqueductal gray matter.13,14 These centers in the brain and spinal cord undergo maladaptive changes including central sensitization, microglial cell activation, and synaptic plasticity, creating an environment for heightened sensitivity for painful sensations.15 Peripheral nociception is the translation of harmful mechanical, chemical, and thermal stimuli into an electrochemical signal that results in afferent activity in the peripheral and central nervous system (CNS).16 Neuropathic pain is defined as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system,”16 and although pain typically is the result of harmful stimuli, neuropathic pain can occur in the absence of a stimulus or substantially lower nociceptive thresholds.17 Neuropathic pain is
Neuropathic Pain Mechanisms and Imaging increasingly thought of as a syndrome derived from a pathologic interaction between the neurons themselves, the glial cells (microglia, astrocytes, Schwann cells, satellite glia) that surround them, and the peripheral immune system. Excitability of the nociceptive nerve is influenced by the action of these neuroimmune mediators, inflammatory mediators, ion channel dysregulation, interactions with macrophages, and several other modulatory events. At the sites of tissue damage, inflammatory mediators, such as neurotrophic growth factor, prostaglandin E2, bradykinin, cytokines, and chemokines are released, stimulating the ends of peripheral neurons and activating inflammatory cells such as mast cells. These inflammatory mediators interact with neural cell receptors or ion channels, resulting in intracellular kinase activations that in turn cause phosphorylation of target proteins, changing activation thresholds and producing an effect, such as increased synaptic transmission efficiency between the primary afferent neurons and the secondary dorsal horn neurons. This can ultimately result in a sensory effect such as pain.17 To identify and image neuropathic pain objectively or, more accurately stated, to image nociceptive activity, several functional, molecular, and cellular-based imaging approaches are currently being developed and used. These approaches take advantage of heightened metabolic, hemodynamic, mediator, and cellular changes that are associated with increased nociceptive activity. The goal of molecular imaging of nociception is to detect abnormal physiologic activity anywhere along the nociceptive pathway in the peripheral nervous system and CNS, to allow for novel and target-specific analgesic therapy.
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The molecular mechanisms explored for imaging of the painful neuropathic nerve can be broadly divided into four categories (►Fig. 1): cellular response, inflammatory mediators and receptors, ion channel expression, and metabolic response. Specific imaging strategies using these mechanisms are reviewed in the following sections.
Cellular Response Early in the course of nerve damage or neuropathy, several types of cells respond with the aim of limiting and repairing the damage. Monocytic derivatives, namely glial cells and macrophages, are involved in modulating chronic pain but are also implicated in the maintenance of neuropathic pain conditions. Schwann cells respond to nerve damage by proliferating rapidly, cleaning up the dead tissue and laying groundwork for axonal regeneration; activated macrophages are recruited from blood to aid in the repair process soon thereafter. Further, activated microglial cells and astrocytes play a significant role in the maladaptive plasticity of the nervous system that is observed in the neuropathic pain phenotype.18 Molecular imaging techniques can be used to interrogate the response of these cell types in the vicinity of the nerve injury as well as in the CNS upstream to the injury.
PET Imaging of Activated Glial Cells and Macrophages In the setting of chronic or neuropathic pain, activated microglia and macrophages have been found to be intimately associated with sites of neuronal injury and
Fig. 1 Four main mechanisms of neuropathic pain imaging: (1) Cellular response to neuropathy: Schwann cell and macrophage imaging by sigma1 receptor positron emission tomography (PET) and iron oxide MRI, respectively; (2) inflammatory mediator and receptor using radiolabeled neuropeptides and cyclooxygenase-2 tracers; (3) ion channel expression by utilizing radiolabeled saxitoxins that are specific to the voltage-gated sodium channels and calcium channel imaging by manganese-enhanced MRI; and (4) studying metabolic response by monitoring increased fluorodeoxyglucose utilization by 18F-fluorodeoxyglucose PET/MRI. Seminars in Musculoskeletal Radiology
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neuroinflammation paradoxically promoting nociceptive activity and pain symptoms.19–22 Identification of the location of activated microglia and macrophages is now possible by the fact that these cells express translocator proteins (TSPOs) that are significantly upregulated in activated microglia and macrophages under pathologic conditions.23,24 Thus radioligands to TSPO have the potential to define areas of increased microglial/macrophage activation. This, in turn, will help objectively identify areas of increased peripheral and central neuroinflammation and sensitization as it relates to enhanced nociceptive activity. Several TSPO radioligands are currently available and have been utilized in a variety of studies of humans with a various inflammatory and neurodegenerative conditions. These include 11C-PK11195, 18FDPA-714, 11C-PBR28, and 11C-DAA1106, to name a few.25–28 Preclinical studies of neuropathic pain have recently showed 11 C-PK11195 PET uptake in the spinal cord increased of animals that experienced partial sciatic nerve ligation. Increased radiotracer uptake correlated to increased microglial cell activation, suggesting a possible for a role of this tracer in clinical patients experiencing neuropathic pain.29
Inflammatory Mediators and Receptors
Imaging of Sigma-1 Receptors The sigma-1 receptor, once thought to be a subtype of opioid receptor, is a transmembrane protein particularly concentrated in certain regions of the CNS, and it has an established role in the development and maintenance of chronic pain.30 These receptors are abundantly expressed in Schwann cells as well as in macrophages that proliferate during neural damage and are involved in repair and neural inflammation.31,32 Proinflammatory mediators released by Schwann cells, macrophages, and other immune cells contribute to spontaneous nociceptive activity and central sensitization.33 This combination of Schwann cell proliferation and the recruitment of macrophages to the sites of nerve inflammation, along with a possible cellular upregulation of sigma-1 receptor expression, leads to a substantial increase in sigma-1 receptor density. Radiotracers aimed at the detection of the sigma-1 receptor can therefore help pinpoint sites of nerve inflammation. In a neuropathic pain animal model, 18F-FTC146, a highly specific radiolabeled sigma-1 receptor ligand, was shown to demonstrate increased uptake in a neuroma caused by nerve injury. The increased tracer uptake correlated with sigma-1 receptor expression and Schwann cell proliferation, as seen with immunohistochemistry.34,35 Identifying sites of neural damage using specific radiotracers can aid in identifying sources of posttraumatic pain, postsurgical pain, complex regional pain syndrome, and necroinflammatory chronic pain disorders that result from nerve injury.
MRI of Macrophage Trafficking Macrophages and microglia play a critical role in the nerve damage repair process. However, inflammatory mediators released by these cells add to the pathogenesis of chronic pain by potentiating and maintaining heightened sensitivity of pain-sensing neurons. Localization of these pro-nociceptive cells near neural structures of interest may elucidate potential pain generators. Seminars in Musculoskeletal Radiology
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Iron nanoparticle–labeled macrophage tracking with MRI has been explored as a method of localizing inflammation during the nerve repair process. After intravenous injection of iron oxide nanoparticles, macrophages engulf and incorporate these particles, allowing MR imaging to track their migration, given the superparamagnetic properties of iron. Ghanouni et al utilized ultrasmall superparamagnetic iron oxide (USPIO) MRI to demonstrate that macrophages did indeed traffic to the sites of nerve injury in a neuropathic pain model, with USPIO-injected rats showing reduced T2-weighted signal at the sites of nerve injury. Administration of minocycline, which inhibits macrophage and microglial activity, reduced the recruitment of macrophages to the neuroma, resulting in decreased pain behaviors.36 When combined with the excellent anatomical resolution of MRI, USPIO-laden macrophages can be used to pinpoint foci of macrophage infiltration along nociceptive pathways. Furthermore, this method can be used to localize chronic pain generators and perhaps aid in the development of more specific macrophage inhibitors as novel targeted analgesics.
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Nerve damage and inflammation involves a myriad of mediators originating from inflammatory cells as well as nerve cells and Schwann cells. Attempting to locate increased inflammatory response by radiolabeling such mediators is an intuitive way to recognize neuropathic nerves. Several neuropeptide analogs and other compounds related to inflammation and pain have been radiolabeled. These compounds hold promise in neuropathic pain imaging.
Labeled Neuropeptides and Analogs A diverse group of cell receptors have been identified as expressed in increased quantities in nociception, leading to increased sensitization and spontaneous activation of the nociceptive axis. Substance P and its receptor, substance P receptor (neurokinin-1 receptor), have been studied extensively in a variety of animal pain models, and upregulation of these receptors are thought to play a major role in the development of hypersensitivity in the pain pathway, serving as a transition from acute to persistent pain states. Substance P receptor upregulation in the dorsal root ganglion and dorsal horn of the spinal cord has been demonstrated in persistent pain models such as the complete Freund adjuvant model.37–40 Radiolabeled neuropeptides may be used to identify sources of receptor mediators of chronic pain. Substance P and some of its analogs have been radiolabeled using 111 In-DTPAArg1 in animal models and been shown to localize to normal substance P receptor–positive tissues such as the salivary gland, as well as to arthritic joints.41,42 A substance P antagonist, SPA-RQ, has been radiolabeled with 18F and been shown in preliminary PET imaging of the brain in healthy volunteers in its expected striatal localization in a dosedependent fashion.42,43 This antagonist to the substance P receptor is specifically selective to the neurokinin 1 (NK1) receptor and may serve as a marker for inflammatory changes
Neuropathic Pain Mechanisms and Imaging because NK1 receptors are expressed in increased amounts in inflammatory (and thus painful) tissue. Other ligand receptor systems that are generally increased in inflammatory pain include calcitonin gene–related peptide, serotonin, bradykinin, brain-derived neurotrophic factor, vanilloid receptor VR1, N-methyl-D-aspartate, tyrosine kinase B, neurotensin, and cholecystokinin, and they may play a role in modulating pain.44 Radiolabeled opioids have also been the subject of study. For example, PET imaging with 11 C-diphrenorphine has shown that in patients with central poststroke pain, reduced regional binding is seen in the neural structures associated with nociceptive processing. This suggests that an imbalance between excitatory and inhibitory mechanisms of pain may be a cause of this pain syndrome.45 Studies with this tracer and other radiolabeled opioids, such as 6-O-(2-[18F]fluoroethyl)-6-O-desmethyldiprenorphine and 11C-carfentanil, [6-O-[11C]methyl]buprenorphine, may provide another avenue of research in comprehending more central mechanisms of pain.46,47
COX-2 Tracers Many inflammatory mediators are important in the development of chronic pain syndromes. COX-2 enzyme is considered a major facilitator of tissue inflammation due to its role in prostacyclin production, by metabolizing arachidonic acid into prostaglandin H, a precursor for prostaglandin E2. The success of COX-2 inhibitors in treating chronic pain is evidence of its importance in the inflammatory cascade. Radiolabeled COX-2 inhibitors can potentially be useful in imaging the type of inflammation characterized by increased COX-2 enzyme. To date, these tracers include 99mTc-celebrex, 18 F-SC51825, and 18F-desbromo-DuP-697. Unfortunately, use of COX-2 as a potential marker target has not been verified because successful localization in inflammation models has not yet been reported. Imaging with 18F-desbromo-DuP-697 in an animal paw inflammation model was met with little success, in part due to the relatively low level of COX-2 enzyme generated in this model.48–50
Ion Channel Expression Ion channels, such as calcium and sodium channels, are responsible for the maintenance of resting membrane potential in neurons, generation of action potential, and propagation of signal along the nerve. In neuropathy and pain, increased calcium and sodium flux across the membrane results in an altered excitation threshold that leads to abnormal action potential and continuous firing of the nerves. Targeting ion channel expression or activity provides another way of imaging foci of abnormal neural activity.
Nuclear Imaging of Voltage-Gated Sodium Channels Voltage-gated sodium channels are critical in action potential generation and propagation of the electrical signal along the nociceptive pathway. In injured or inflamed nerves, the density of voltage-gated sodium channels is increased.51,52 The increased sodium channel density has been attributed to frequent and spontaneous depolarization associated with
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chronic pain. The mechanism of action of many commonly used analgesics, including lidocaine, is through voltage-gated sodium channel blockade. Saxitoxin, a well-known paralytic shellfish toxin, has been recently modified and radiolabeled with 18F, allowing binding to voltage-gated sodium channel with nanomolar affinity. A 40% increase in PET signal was seen in painful neuromas in a neuropathic pain model using 18 F-saxitoxin and PET/MRI.53
Manganese-enhanced Magnetic Resonance Imaging in Voltage-gated Calcium Channels Voltage-gated calcium channels also play an important role in action potential generation in nerves. During cellular depolarization, there is an initial influx of calcium, followed by an efflux of calcium to return the cell to its resting membrane potential. This electrical activity is increased in injured or chronically inflamed nerves. Manganese is a T1-shortening MRI contrast agent that physiologically follows calcium. In hyperactive cells, the rate of calcium (and manganese) efflux is very slow, resulting in the accumulation of manganese in the cell, generating imaging contrast. Manganese-enhanced MRI (MEMRI) can thus act as a surrogate method of estimating calcium fluxes in neuronal cells because cells that are more electrically active will accumulate manganese intracellularly over time. In a preclinical animal model study using orally administered manganese, MEMRI highlighted the lumbar plexus of a sciatic nerve injury model. T1-weighted signal-to-noise ratios in sciatic nerves within the pelvis correlated well with manganese content in the nerves measured by inductively coupled plasma spectrometry54 (►Fig. 2). Control uninjured animals demonstrated significantly less T1-weighted MEMRI signal than the neuropathic pain model.55 This also correlated with behavior scores and lower manganese content as measured by inductively coupled plasma spectrometry.
Metabolic Response Continuous neural activities as they occur in chronic pain as well as inflammatory processes are energy-demanding processes. Imaging the rate of energy utilization or metabolic activity is yet another way of detecting local abnormalities in the peripheral nervous system.
Nuclear Imaging of Glucose Metabolism 18
F-FDG is a well-known radiopharmaceutical PET marker that mimics glucose as it enters the cell and is trapped within the cell during the glycolytic cycle. Tissues involved in infectious, inflammatory, or malignant etiologies are hypermetabolic and demonstrate an increased uptake of glucose and FDG. In chronic pain syndromes, continuously or spontaneously firing neurons and their associated inflamed tissues are glucose avid. This phenomenon is exploited in 18F-FDG PET/ MRI to visualize increased neural metabolism. In a rat model, Behera et al were able to localize increased 18F-FDG uptake in injured nerves using PET/MRI. The 18F-FDG uptake correlated well with behavioral measurements of allodynia in the affected paw. In contrast, control nerves in the contralateral Seminars in Musculoskeletal Radiology
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Fig. 2 T1-weighted fast spin-echo manganese-enhanced MRI (MEMRI) of the lumbosacral plexus in two separate types of sciatic nerve injury pain models (spared nerve injury [SNI] and chronic constrictive injury [CCI]) and using two different contrast delivery routes. MEMRI signal is much more increased in lumbosacral plexus in pain models than controls. (a) (Top row) Axial slices of the pelvic spine in a SNI and uninjured control rat 48 hours after oral manganese. Arrow indicates sciatic nerves lying anterior to the sacrum. (Bottom row) Three-dimensional (3D) maximum intensity projection (MIP) of lumbosacral spinal cord and plexus in the same SNI and control rats. Increased color intensity of the lumbar plexus is noted compared with control, suggesting increased calcium influx in the pain model (Jacobs et al 54). (b) 3D MIP of lumbosacral spinal cord and plexus precontrast (baseline), and after intraperitoneal manganese injection in a model of CCI of the sciatic nerve and an uninjured control rat. Increased color intensity is noted in the CCI animal compared with control, again suggesting that the subject with pain undergoes more calcium metabolism and pain compared with the control. 55
normal limb of the subject and in control asymptomatic animals showed significantly less 18F-FDG uptake56 (►Fig. 3). 18 F-FDG avidity in peripheral nerves has also been observed in patients with pain. In a clinical case report, an 18F-FDG PET/CT scan showed 18F-FDG-avid lumbar spinal cord and sciatic nerves. On biopsy, these neural structures showed pathologic signs of chronic neuropathy.57 Preliminary work studying patients with sciatica has also shown increased 18F-FDG uptake in the neuroforamina of the lower lumbar spine ipsilateral to the site of symptoms (►Fig. 4). Additionally, increased muscle uptake is also seen in the proximal thigh of patients with sciatica, ipsilateral to the side of symptoms (►Fig. 4). Thus localizing sites of hypermetabolic neural tissues and neuroinflammation on imaging may be a strategy to identify chronic neuropathic pain generators. Although large prospective human studies have yet to be performed on painful peripheral nerve imaging, both 18 F-FDG and USPIOs are clinically approved agents and favorably poised for clinical investigations.
Summary Pain remains the most common reason for American patients to seek medical attention, affecting over 100 million, costing $560 to $635 billion annually, and is associated with Seminars in Musculoskeletal Radiology
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multiple comorbidities. Routine imaging diagnosis of pain is currently limited to the detection and identification of anatomical abnormalities, which has unfortunately been shown to be limited in both sensitivity and specificity. Molecular imaging of neuropathic pain utilizing the myriad of receptors and inflammatory mediators involved in nociceptive activity is a promising avenue of research in developing more accurate and objective tools in the diagnosis of pain, and potentially it open roads for more tailored and specific treatment options. Although research into peripheral nerve imaging for chronic neuropathic pain generators is promising, implementation remains challenging. Methods directed at ion channels can be potentially toxic. Other challenges include accounting for the subjective and affective components of pain, determining the accuracy of preclinical animal pain models when applied to the complex human pain experience, and imaging of small structures of interest such as the dorsal root ganglia and peripheral nerves. However, by combining the sensitivity and specificity of molecular markers, with the high anatomical spatial and contrast resolution afforded by CT and MRI, the diagnosis of sources of pain generators can lead to more intelligently guided therapy. Should successful imaging and identification of pain become a reality, this would have a
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Fig. 3 A 18F-fluorodeoxyglucose positron emission tomography (PET)/MRI of sciatic nerve in neuropathic pain model shows increased radiotracer uptake at the site of injury, confirmed with autoradiography of excised sciatic nerves. Normal, significantly lower uptake is seen in uninjured nerves on the opposite side in the same animal. (a) Transaxial MRI, PET, and fused PET/MR images in spared nerve injury (SNI) pain model, a model of neuropathic pain (top row), and control (bottom row). (b) Autoradiography of sciatic nerves excised from the SNI model (top row) and control (bottom row).
Fig. 4 A 18F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) of a 26-year-old man experiencing right-sided sciatica and a 26-year-old asymptomatic individual. (a) Axial PET/CT image through the L5–S1 neuroforamen shows increased 18 F-FDG uptake in the right neuroforamen (white arrows). (b) Axial image through the same patient’s anterior hip musculature (white arrows) also shows increased 18 F-FDG uptake. (c) By comparison, an asymptomatic 26-year-old man has essentially no 18 F-FDG uptake in both neuroformina on an axial image at L5–S1 and (d) normal low physiologic 18F-FDG uptake in the anterior musculature of the hips bilaterally.
tremendous impact in the field of medicine, benefiting millions of chronic pain sufferers.
Take-Home Points • Neuropathic pain remains a challenging diagnosis because anatomical abnormalities seen on conventional imaging do not always correspond to clinical presentation.
• Molecular imaging promises to bridge the gap between anatomical imaging and the clinical diagnosis of neuropathic pain. • Hybrid imaging techniques such as PET/MRI afford radiologists both functional and anatomical imaging information, allowing us to visualize both anatomical abnormalities and biological pathologic processes in studies that were seemingly normal on conventional imaging techniques. Seminars in Musculoskeletal Radiology
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• Molecular mechanisms explored for imaging of neuropathic nerves include: (1) cellular response, (2) inflammatory mediation and reception, (3) ion channel expression, and (4) metabolic response.
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