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Alterations in the structure, function, and microcirculation of the thalamus, a key brain region involved in pain pathways, have previously been demonstrated in patients with painless and painful diabetic peripheral neuropathy (DPN). However, thalamic neurotransmitter levels including γ-aminobutyric acid (GABA) (inhibitory neurotransmitter) and glutamate (excitatory neurotransmitter) in different DPN phenotypes are not known. We performed a magnetic resonance spectroscopy study and quantified GABA and glutamate levels within the thalamus, in a carefully characterized cohort of participants with painless and painful DPN. Participants with DPN (painful and painless combined) had a significantly lower GABA:H2O ratio compared with those without DPN (healthy volunteers [HV] and participants with diabetes without DPN [no DPN]). Participants with painless DPN had the lowest GABA:H2O ratio, which reached significance compared with HV and no DPN, but not painful DPN. There was no difference in GABA:H2O in painful DPN compared with all other groups. A significant correlation with GABA:H2O and neuropathy severity was also seen. This study demonstrates that lower levels of thalamic GABA in participants with painless DPN may reflect neuroplasticity due to reduced afferent pain impulses, whereas partially preserved levels of GABA in painful DPN may indicate that central GABAergic pathways are involved in the mechanisms of neuropathic pain in diabetes. Article Highlights: The thalamus has been shown to play a key role in the cerebral mechanisms of diabetic peripheral neuropathy (DPN), but neurotransmitter levels have not been explored. We sought to determine the levels of excitatory (glutamate) and inhibitory (γ-aminobutyric acid [GABA]) neurotransmitter levels in the thalamus in participants with painful and painless DPN. Thalamic GABA levels were reduced in participants with painless DPN, with partially preserved levels seen in painful DPN. Alterations of thalamic GABAergic pathways could be involved in the central mechanisms of both painful and painless DPN. [ABSTRACT FROM AUTHOR]

Purpose Of Review: The prevalence of diabetes mellitus and its chronic complications are increasing to epidemic proportions. This will unfortunately result in massive increases in diabetic distal symmetrical polyneuropathy (DPN) and its troublesome sequelae, including disabling neuropathic pain (painful-DPN), which affects around 25% of patients with diabetes. Why these patients develop neuropathic pain, while others with a similar degree of neuropathy do not, is not clearly understood. This review will look at recent advances that may shed some light on the differences between painful and painless-DPN.Recent Findings: Gender, clinical pain phenotyping, serum biomarkers, brain imaging, genetics, and skin biopsy findings have been reported to differentiate painful- from painless-DPN. Painful-DPN seems to be associated with female gender and small fiber dysfunction. Moreover, recent brain imaging studies have found neuropathic pain signatures within the central nervous system; however, whether this is the cause or effect of the pain is yet to be determined. Further research is urgently required to develop our understanding of the pathogenesis of pain in DPN in order to develop new and effective mechanistic treatments for painful-DPN. [ABSTRACT FROM AUTHOR]

Diabetic 'peripheral' neuropathy (DPN) is one of the common sequelae to the development of both type-1 and type-2 diabetes mellitus. Neuropathy has a major negative impact on quality of life. Abnormalities in both peripheral vasculature and nerve function are well documented and, in addition, evidence is emerging regarding changes within the central nervous system (CNS) that are concomitant with the presence of DPN. The often-resistant nature of DPN to medical treatment highlights the need to understand the role of the CNS in neuropathic symptomatology and progression, as this may modulate therapeutic approaches. Advanced neuroimaging techniques, especially those that can provide quantitative measures of structure and function, can provide objective markers of CNS status. With that comes great potential for not only furthering our understanding of involvement of the CNS in neuropathic etiology but also most importantly aiding the development of new and more effective, targeted, analgesic interventions. [ABSTRACT FROM AUTHOR]

Objective: We have previously reported increased thalamic vascularity in painful diabetic peripheral neuropathy (PDPN) but the microvascular perfusion characteristics of the other pain processing areas of the brain (Pain Matrix - PM) with or without pain at the time of scanning have not been assessed. The aim thus was to measure the cerebral perfusion of the PM areas using MR-Dynamic Susceptibility Contrast (MR-DSC). Methods: 55 T1DM subjects (20 PDPN, 23 painless-DPN, 13 no-DPN) and 19 healthy volunteers (HV) underwent clinical, neurophysiological and MR-DSC of the passage of IV-gadolinium-chelate through the cerebral vascular bed (3-Tesla, Philips, Netherlands) at rest. The PDPN group was further divided into those that had neuropathic pain during scan - P+ and no pain - P-) and the intensity of pain at the time of scanning was recorded. The Mean Transit Time -MTT and the time-to-peak -TTP concentrations of gadolinium in PM areas (Thalamus, Insular Cortex - IC, Anterior Cingulate Cortex - ACC) were measured. Results: Subjects experiencing spontaneous neuropathic pain (P+, n=10, VAS score≥4) during scanning had shorter mean TTP at the Right-Thalamus: P+ vs. painless-DPN p=0.017, P+ vs. HV p=0.033; Right-IC: P+ vs. painless-DPN p=0.048; and POWM: P+ vs. P- p=0.009, P+ vs. painless-DPN p=0.034, P+ vs. HV p=0.011. The MTT at the Right-Thalamus: P+ vs. HV p=0.043 and at the Left-IC: HV vs. No-DPN p=036, were also significant. Conclusion: This is the first study to show there is altered cerebral perfusion in the pain processing areas of of the brain, with shorter TTP during spontaneous pain at the time of scanning. This seems to be related to a bolus dispersal factor as MTT, and CBF do not match the TTP and the control area is also affected. However, whether this altered perfusion is primary or secondary to the experience of pain is yet to be determined. This novel finding may serve as objective marker of spontaneous neuropathic pain, and a target for the development of novel treatments. Disclosure: M. Greig: None. G. P. Sloan: None. P. Shillo: None. D. Selvarajah: None. I. D. Wilkinson: None. S. Tesfaye: Advisory Panel; Self; Angellini, Bayer AG, Eva Pharma, Wörwag Pharma, Speaker's Bureau; Self; Abbott, AstraZeneca, Grunenthal Group, MSD Corporation, Novo Nordisk, Pfizer Inc. Funding: European Foundation for the Study of Diabetes [ABSTRACT FROM AUTHOR]