Recent developments and challenges in positron emission tomography imaging of gliosis in chronic neuropathic pain.

ABSTRACT: Understanding the mechanisms that underpin the transition from acute to chronic pain is critical for the development of more effective and targeted treatments. There is growing interest in the contribution of glial cells to this process, with cross-sectional preclinical studies demonstrating specific changes in these cell types capturing targeted timepoints from the acute phase and the chronic phase. In vivo longitudinal assessment of the development and evolution of these changes in experimental animals and humans has presented a significant challenge. Recent technological advances in preclinical and clinical positron emission tomography, including the development of specific radiotracers for gliosis, offer great promise for the field. These advances now permit tracking of glial changes over time and provide the ability to relate these changes to pain-relevant symptomology, comorbid psychiatric conditions, and treatment outcomes at both a group and an individual level. In this article, we summarize evidence for gliosis in the transition from acute to chronic pain and provide an overview of the specific radiotracers available to measure this process, highlighting their potential, particularly when combined with ex vivo/in vitro techniques, to understand the pathophysiology of chronic neuropathic pain. These complementary investigations can be used to bridge the existing gap in the field concerning the contribution of gliosis to neuropathic pain and identify potential targets for interventions.

Infraorbital nerve injury triggers sex-specific neuroimmune responses in the peripheral trigeminal pathway and common pain behaviours.

Trigeminal neuropathic pain is emotionally distressing and disabling. It presents with allodynia, hyperalgesia and dysaesthesia. In preclinical models it has been assumed that cephalic nerve constriction injury shows identical molecular, cellular, and sex dependent neuroimmune changes as observed in extra-cephalic injury models. This study sought empirical evidence for such assumptions using the infraorbital nerve chronic constriction model (ION-CCI). We compared the behavioural consequences of nerve constriction with: (i) the temporal patterns of recruitment of macrophages and T-lymphocytes at the site of nerve injury and in the trigeminal ganglion; and (ii) the degree of demyelination and axonal reorganisation in the injured nerve. Our data demonstrated that simply testing for allodynia and hyperalgesia as is done in extra-cephalic neuropathic pain models does not provide access to the range of injury-specific nociceptive responses and behaviours reflective of the experience of trigeminal neuropathic pain. Similarly, trigeminal neuroimmune changes evoked by nerve injury are not the same as those identified in models of extra-cephalic neuropathy. Specifically, the timing, magnitude, and pattern of ION-CCI evoked macrophage and T-lymphocyte activity differs between the sexes.

Performance evaluation of a PET insert for preclinical MRI in stand-alone PET and simultaneous PET-MRI modes.

BACKGROUND: This study aimed to evaluate the performance of a preclinical PET insert in three configurations: as a stand-alone unit outside the MRI bore, inside the bore of a cryogen-free 3T MRI and, finally, while performing simultaneous PET/MRI studies. METHODS: The PET insert consists of two rings of six detectors, each detector comprising 8 × 12 SiPMs reading out dual offset layers of pixelated LYSO crystals with a 1.4-mm pitch. The inner diameter is 60 mm, transaxial field of view (FoV) 40 mm and axial FoV 98 mm. Evaluation was based on NEMA NU 4-2008 guidelines with appropriate modifications. Spatial resolution and sensitivity were measured inside and outside the MR bore. Image quality, count rate and quantitative performance were measured in all three configurations. The effect of temperature stability on PET sensitivity during fast spin echo sequences was also evaluated. B0 field homogeneity and T1 and T2 relaxation times were measured using a water-filled phantom, with and without simultaneous PET operation. Finally, PET and MRI scans of a mouse injected with 10 MBq [18F]NaF and a mouse injected with 16 MBq [18F]FDG were performed in sequential and simultaneous modes. RESULTS: Peak absolute sensitivity was 10.15% with an energy window of 250-750 keV. Absolute sensitivity values outside and inside the MR bore with MR idle agreed to within 0.1%. Outside the MR bore, spatial resolution was 1.21/1.59 mm FWHM (radial/tangential) 5 mm from the centre of the FoV which compared well with 1.19/1.26 mm FWHM inside the MR bore. There were no substantial differences between all three scan configurations in terms of peak NEC rate (175 kcps at 17 MBq), scatter or random fractions. Uniformity and recovery coefficients were also consistent between scanning modes. B0 field homogeneity and T1 and T2 relaxation times were unaltered by the presence of the PET insert. No significant differences were observed between sequential and simultaneous scans of the animals. CONCLUSIONS: We conclude that the performance of the PET insert and MRI system is not significantly affected by the scanning mode.

PET-ABC: fully Bayesian likelihood-free inference for kinetic models.

Aims.We describe an intuitive, easy to use method called PET-ABC that enables full Bayesian statistical inference from single subject dynamic PET data. The performance of PET-ABC was compared with weighted non-linear least squares (WNLS) in terms of reliability of kinetic parameter estimation and statistical power for model selection.Methods.Dynamic PET data based on 1-tissue and 2-tissue compartmental models were simulated with 2 noise models and 3 noise levels. PET-ABC was used to evaluate the reliability of parameter estimates under each condition. It was also used to perform model selection for a simulated noisy dataset composed of a mixture of 1- and 2-tissue compartment kinetics. Finally, PET-ABC was used to analyze a non-steady state dynamic [11C] raclopride study performed on a fully conscious rat administered either 2 mg.kg-1amphetamine or saline 20 min after tracer injection.Results.PET-ABC yielded posterior point estimates for model parameters with smaller variance than WNLS, as well as probability density functions indicating confidence intervals for those estimates. It successfully identified the superiority of a 2-tissue compartment model to fit the simulated mixed model data. For the drug challenge study, the post observation probability of striatal displacement of the PET signal was 0.9 for amphetamine and approximately 0 for saline, indicating a high probability of amphetamine-induced endogenous dopamine release in the striatum. PET-ABC also demonstrated superior statistical power to WNLS (0.87 versus 0.09) for selecting the correct model in a simulated ligand displacement study.Conclusions.PET-ABC is a simple and intuitive method that provides complete Bayesian statistical analysis of single subject dynamic PET data, including the extent to which model parameter estimates and model choice are supported by the data. Software for PET-ABC is freely available as part of thePETabcpackagehttps://github.com/cgrazian/PETabc.