¹⁸F-FDG PET/MRI Can Be Used to Identify Injured Peripheral Nerves in a Model of Neuropathic Pain

Abstract

We demonstrated increased 18 F-FDG uptake in injured peripheral nerves in a model of neuropathic pain using small-animal PET/MRI. Methods: A neuropathic pain model in rats was created by spared-nerve injury of the left sciatic nerve. Shamoperated rats without nerve injury were used as a control. The presence of pain was confirmed by testing for allodynia. Sequential small-animal 18 F-FDG PET and MRI scans of the thighs were obtained and coregistered. Autoradiography was performed on harvested nerves and muscle. Results: The group with spared-nerve injury showed the development of allodynia in the operated limb (P , 0.001). Increased 18 F-FDG uptake was observed on both PET/MRI (P , 0.001) and autoradiography (P , 0.005) in the operated nerve in this group. 18 F-FDG uptake in the nerves correlated well with allodynia (r 5 20.59; P , 0.024). Conclusion: Animals with neuropathic pain show increased 18 F-FDG uptake in the affected nerve. Smallanimal PET/MRI can be effectively used to localize 18 F-FDG uptake in peripheral nerves. Increasedspont aneous activity (1) and metabolic changes (2,3) are known to occur in injured nerves and are largely attributed to the symptoms of neuropathic pain. Neuronal activity is dependent on glucose metabolism (4). Isolated cases of increased 18 F-FDG uptake in peripheral nerves have been reported in noncancerous cases of peripheral neuropathy and neural inflammation (5,6). Little is known about glucose metabolism in the peripheral nervous system using 18 F-FDG in the setting of noncancerous nerve injury. To our knowledge, this study was the first systematic study of 18 F-FDG uptake in the peripheral nerves in a noncancerous setting, specifically in a rat model of neuropathic pain. Furthermore, we demonstrated the utility of coregistered MRI in localizing metabolic activity in peripheral nerves. MATERIALS AND METHODS Neuropathic Pain ModelAnimal experiments were approved by the institutional animal care and use committee. Two groups of male adult SpragueDawley rats weighing 200-250 g were used. The first was the spared-nerve injury group (n 5 3), which underwent a left spared-nerve injury procedure that creates a well-characterized neuropathic pain model (7). Briefly, under aseptic surgical techniques and inhalational 2%-3% isoflurane anesthesia, the left sciatic nerve and its 3 terminal branches were surgically accessed. A ligation and axotomy of the tibial and common peroneal nerves was performed, sparing the sural nerve. The second group was a control group (n 5 3), which was subjected to a sham operation similar to that used on the spared-nerve injury animals but without the nerve injury. Animals were permitted to heal for 4 wk after the surgery. Pain Behavior AssessmentAllodynia, a common feature of neuropathic pain, is pain that results from a stimulus that would normally not provoke pain. Development of mechanical allodynia was evaluated during the third week after surgery using von Frey hair filaments. Animals were acclimatized on a raised wire-mesh platform for 2 h/d for 4 d...

Noninvasive Imaging of Peripheral Nerves

“…Most of the current PET research in the peripheral nervous system involves evaluating peripheral nerve sheath tumors with very limited use in assessing injured peripheral nerves [Ferner et al, 2008; Lucas et al, 1998; Behera et al, 2011; Ferner et al, 2000]. PET imaging has shown significant utility in detecting nerve sheath tumors as well as in other fields, and its value in evaluating peripheral nerve metabolism and nerve injury warrants further investigation [Behera et al, 2011; Tatsumi et al, 2011; Osborn, and Jaffer, 2009]. The primary marker of nerve injury in 18 F-FDG-PET is the increased uptake of 18 F-FDG by damaged nerves, which corresponds with higher levels of metabolic activity.…”

“…The primary marker of nerve injury in 18 F-FDG-PET is the increased uptake of 18 F-FDG by damaged nerves, which corresponds with higher levels of metabolic activity. As injured neurons maintain higher rates of neuron firing, the difference in the γ photon emissions between injured and uninjured nerves can provide opportunities to locate and assess injured nerves [Behera et al, 2011]. Although current PET imaging of peripheral nerves uses metabolism to characterize injury, future research should seek to develop agents other than 18 F-FDG that specifically target injured nerves rather than only tissues with high metabolism.…”

“…Although current PET imaging of peripheral nerves uses metabolism to characterize injury, future research should seek to develop agents other than 18 F-FDG that specifically target injured nerves rather than only tissues with high metabolism. As PET has a low spatial resolution, the co-registration of PET with a spatial imaging technique such as MRI or CT allows for improved anatomic localization of the 18 F-FDG uptake [Behera et al, 2011; Tatsumi et al, 2011]. …”

Potential of PET-MRI for imaging of non-oncologic musculoskeletal disease

“…PET/MRI offers to combine molecular information to localize neuropathic pain with MRI which is able to provide high-resolution visualization of anatomical abnormalities (107). MRI in non-oncologic musculoskeletal applications.…”

“…FDG PET imaging can image the increased glucose metabolism utilized by inflamed or overactive neurons as a marker of neural activity. Studies in a rat model that used unilateral injury to induce neuropathic limb pain showed increased FDG uptake in injured nerves, but no increase in FDG uptake in the contralateral limb or in control asymptomatic animals ( Figure 4) (107). Additionally, in a human subject presenting with progressive difficulty walking, increased FDG uptake was observed in his lower spinal cord and sciatic nerves (108).…”