The Microvascular Perfusion Characteristics of the Pain Matrix of the Brain in subjects with Type 1 Diabetes and Painful Neuropathy

Background: Painful diabetic peripheral neuropathy (Painful-DPN) affects between 10-28% of those with diabetes, but treatments are not effective for all those with the condition. Our understanding of the risk factors that underlie the development of chronic neuropathic pain is limited. Increased thalamic vascularity has been reported in a pilot study of subjects with painful-DPN, but the microvascular perfusion characteristics of other pain processing areas of the brain (pain matrix) have not been assessed. It was hypothesised that quantification of perfusion, using dynamic susceptibility contrast magnetic resonance imaging, could be a biomarker for the perception of pain in the brain. The main aim of this study was to measure cerebral perfusion of the pain processing areas of the brain using Dynamic Susceptibility Contrast magnetic resonance imaging (DSC-MRI) at rest and during an experimental pain condition. The secondary aims of this study were to characterise participants using clinical, metabolic and psychological parameters to identify features that may be markers of painful diabetic peripheral neuropathy; to assess the reproducibility of four quantitative perfusion parameters: regional blood volume (RBV), regional blood flow (RBF), mean transit time (MTT), and Time-to-peak concentration (TTP) using quantitative dynamic susceptibility contrast magnetic resonance imaging; and to investigate if perfusion parameters and proton magnetic resonance spectroscopy (1H-MRS) neuronal metabolite ratios in the thalamus of subjects with painful diabetic peripheral neuropathy are associated. These parameters could be used to identify phenotypes to be targets for novel treatments and to monitor treatment response in trials of new agents. Methods: This was an observational, cross sectional cohort study of 54 subjects with type 1 diabetes mellitus: 19 with painful-DPN, 23 with painless-DPN, 13 with type 1 diabetes mellitus and no neuropathy (DM-NN) and 19 healthy non-diabetic volunteers (HV). Clinical examination, questionnaires and blood tests were performed. DSC-MRI measurements were made at baseline and during a painful thermal stimulus. The reproducibility was assessed by blinded comparison of measurements by two raters. Proton Magnetic resonance spectroscopy measurements (1H-MRS) were obtained at 3T and compared with perfusion measurements by DSC-MRI. Results: Time-to-peak (TTP)concentration of gadolinium, when adjusted for pain perception (Likert scale) and group interaction, was significantly longer for the painful-DPN group as compared with healthy volunteers, at the left and right thalamus, left and right insula cortex and the left and right primary sensory cortex. Mean transit time was shorter at baseline between healthy volunteers (HV) and all diabetes groups, with the greatest difference between HV and diabetes with no neuropathy (DM-NN). In a subgroup analysis subjects experiencing neuropathic pain at the time of scanning had an shorter TTP at baseline. Discriminant function analysis using measures of mood, and somatic focus significantly differentiated painful-DPN from other groups in this study. Additionally, there was a significant negative correlation between scores on measures of anxiety and depression and N-Acetyl Aspartarte/Creatine (NAA/Cr) ratio measured by 1H-MRS in the thalamus. Reproducibility of the perfusion technique was measured and TTP had an “excellent” intraclass correlation coefficient of 0.837, RBF =0.710 and MTT= 0.618, and fair for RBV=0.443. Conclusion: This is the first study to suggest that during a baseline state there may be hyper-perfusion in the cerebro-vascular bed, analogous to hyper-perfusion in the kidney and peripheral nerve, in subjects with diabetes and particularly diabetes with no neuropathy (DM-NN) which is reflected by a shorter mean transit time in the studied regions of interest. Additionally, this is the first study to our knowledge that describes a difference between painful-DPN and other groups using CNS microvascular perfusion measures and can link this perfusion change to the perception of neuropathic pain. Subgroup analysis of subjects with painful-DPN, who were experiencing neuropathic pain during the baseline scan, revealed that TTP and MTT is significantly shorter in this group, suggesting that peripheral pain is measurable centrally, and perfusion changes are secondary to pain perception rather than structural abnormalities. Therefore, pain at the time of the scan is an important parameter that must be accounted for in painful-DPN studies. We have reported the novel finding that dynamic pain response is altered in those with painful-DPN as compared to healthy volunteers. When experimental pain is applied TTP significantly lengthens for subjects with painful-DPN whilst healthy volunteers shorten their TTP, after adjustment for pain perception. Possibilities for the observation of this phenomena may be due to primed descending or ascending inhibition of pain in the painful-DPN group, or inappropriately sluggish response due to a failure of neurovascular coupling. This apparently paradoxical perfusion response to a pain stimulus may be key to understanding central nervous system contribution to symptoms of painful-DPN, and should be the focus of future studies as a promising biomarker of this condition. Future studies will be designed to interrogate perfusion responses at different levels of stimulus to understand inhibitory mechanisms that may be exploited to enhance symptom relief and develop perfusion response as a biomarker of painful-DPN. This is the first study to show somatic focus as a correlate of painful-DPN. The results show that negative psychological traits such as somatic focus, mood and pain catastrophising are strongly associated with, and can predict cases of painful-DPN. Finally, we report a novel finding describing a link between mood disorders and neuronal metabolites in the context of painful-DPN. NAA/Cr ratio is more strongly associated with measures of depression and anxiety than measures of perfusion or neuropathy. H1-MRS studies must be carefully characterised for depression and anxiety to minimise the confounding effect of mood disorders in studies of painful-DPN. This is a cross sectional study therefore the contribution of mood disorders to the development and persistence of painful-DPN requires further longitudinal study. In summary, this study found that there are unique perfusion states and responses of subjects with painful-DPN that are measurable with the quantifiable technique of DSC-MRI.