Rationale and Objectives
To assess differences in excitatory (glutamate/glutamine or Glx) and inhibitory (γ-Aminobutyric acid or GABA) neurotransmitter levels using MR spectroscopy in pain processing regions of the brain in patients diabetic neuropathy (DN) and positive sensory symptoms and age-matched healthy control (HC) subjects.
Materials and Methods
Seven diabetic patients (5 males, 2 females, mean age = 57.0 ± 8.5 years) with confirmed DN and positive sensory symptoms and 7 age and sex matched HC subjects (mean age = 57.7 ± 3.2 years) underwent 3 Tesla MR spectroscopy. Glx and GABA levels were quantified in the right anterior and posterior insula, anterior cingulate cortex and right thalamus.
Results
Mean Glx levels were significantly higher and mean GABA levels were significantly lower within the posterior insula in the DN patients compared to HC ( P = 0.005 and 0.012 respectively).
Conclusions
This pilot data demonstrates an excitatory/inhibitory neurotransmitter imbalance in the brain of in patients with DN and positive sensory symptoms compared to pain free HC subjects.
Summary
Diabetic neuropathy (DN) is a common complication of diabetes, affecting approximately 50% of diabetic patients and in at least half of these patients the neuropathy is associated with tingling, allodynia, hyperalgesia or frank pain. DN is traditionally considered a disease of the peripheral nervous system; however, there is emerging evidence for significant central nervous system modulation of symptoms of DN and painful DN in particular. Advanced neuroimaging methods provide a unique opportunity to study central nervous system factors in the setting of diabetic neuropathy, noninvasively and under physiologic conditions. Magnetic resonance (MR) spectroscopy in particular can provide important information regarding brain biochemistry. Alterations in N-acetyl aspartate within the thalamus have been reported in the context of diabetic neuropathy using conventional MR spectroscopy methods.
Glutamatergic (excitatory) and γ-aminobutyric acid (GABA)ergic (inhibitory) neurotransmission are thought to play a significant role within the pain processing pathways of the central nervous system. Glutamine (Glx) levels (combined glutamate and glutamine) can be measured using conventional MR techniques. GABA quantification using MR spectroscopy is not possible using conventional techniques because of signal overlap and low signal intensity. Elevated Glx levels within pain processing regions of the brain have been demonstrated in other chronic pain conditions such as fibromyalgia and migraine headaches. Until recently, there were no reports of brain GABA quantification in the setting of chronic pain; our group recently published the first report of GABA MR spectroscopy in fibromyalgia patients showing lower levels of GABA in the anterior insula in this patient population. Glx or GABA levels in the context of DN with or without associated pain have not been described in the literature. Our study provides the first report of Glx and GABA quantification in the brain of DN patients with positive sensory symptoms including pain at rest and reveals elevated Glx and reduced GABA levels in the insula, similar to previously reported findings in other chronic pain states.
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Research design and methods
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MRS
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Postprocessing of MRS Data
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Statistical Analysis
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Results
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Table 1
NAA, Glx, and GABA Levels as well as Glx/GABA Ratios in Brain Regions within the Pain Processing Network for DN Subjects with Positive Sensory Symptoms and Age- and Gender-matched HC
DN (n = 7) HC (n = 7)P Value Right anterior insula Mean NAA (SD) 6.69 (0.65) 7.15 (0.30) .14 Mean Glx (SD) 9.39 (1.26) 8.75 (1.77) .49 Mean GABA (SD) 1.20 (0.21) 1.26 (31) .69 Mean Glx/GABA (SD) 8.21 (2.35) 7.58 (2.80) .68 Right posterior insula Mean NAA (SD) 6.87 (0.57) 6.99 (0.36) .69Mean Glx (SD)10.45 ( 1.90)7.40 ( 1.17).005Mean GABA (SD)1.21 ( 0.11)1.50 ( 0.09).012Mean Glx/GABA (SD)8.64 ( 1.55)5.12 ( 1.83).002 Right thalamus Mean NAA (SD) 7.40 (1.32) 7.62 (0.59) .74 Mean Glx (SD) 8.92 (2.70) 7.56 (2.26) .39 Mean GABA (SD) 1.38 (0.54) 1.84 (0.54) .19 Mean Glx/GABA (SD) 7.64 (3.48) 4.20 (1.14) .06 Anterior cingulate cortex Mean NAA (SD) 7.49 (1.1) 7.59 (0.44) .84 Mean Glx (SD) 7.62 (2.57) 8.26 (4.0) .74 Mean GABA (SD) 1.33 (0.34) 1.26 (0.30) .70 Mean Glx/GABA (SD) 6.12 (2.49) 7.19 (3.62) .56
GABA, γ-aminobutyric acid; Glx, glutamine; NAA, N-acetylaspartate; SD, standard deviation.
Parameters showing significant differences between groups are marked in bold.
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Discussion
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Conclusion
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References
1. Galer B.S., Gianas A., Jensen M.P.: Painful diabetic polyneuropathy: epidemiology, pain description, and quality of life. Diabetes Res Clin Pract 2000; 47: pp. 123-128.
2. Stewart W.F., Ricci J.A., Chee E., et. al.: Lost productive time and costs due to diabetes and diabetic neuropathic pain in the US workforce. J Occup Environ Med 2007; 49: pp. 672-679.
3. Ritzwoller D.P., Ellis J.L., Korner E.J., et. al.: Comorbidities, healthcare service utilization and costs for patients identified with painful DPN in a managed-care setting. Curr Med Res Opin 2009; 25: pp. 1319-1328.
4. Selvarajah D., Wilkinson I.D., Emery C.J., et. al.: Thalamic neuronal dysfunction and chronic sensorimotor distal symmetrical polyneuropathy in patients with type 1 diabetes mellitus. Diabetologia 2008; 51: pp. 2088-2092.
5. Sorensen L., Siddall P.J., Trenell M.I., et. al.: Differences in metabolites in pain-processing brain regions in patients with diabetes and painful neuropathy. Diabetes Care 2008; 31: pp. 980-981.
6. Selvarajah D., Wilkinson I.D., Emery C.J., et. al.: Early involvement of the spinal cord in diabetic peripheral neuropathy. Diabetes Care 2006; 29: pp. 2664-2669.
7. Cauda F., Sacco K., Duca S., et. al.: Altered resting state in diabetic neuropathic pain. PLoS One 2009; 4: pp. e4542.
8. Harris R.E., Sundgren P.C., Craig A.D., et. al.: Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis Rheum 2009; 60: pp. 3146-3152.
9. Prescot A., Becerra L., Pendse G., et. al.: Excitatory neurotransmitters in brain regions in interictal migraine patients. Molel Pain 2009; 5: pp. 34.
10. Mescher M., Merkle H., Kirsch J., et. al.: Simultaneous in vivo spectral editing and water suppression. NMR Biomed 1998; 11: pp. 266-272.
11. Foerster B.R., Petrou M., Edden R.A., et. al.: Reduced insular gamma-aminobutyric acid in fibromyalgia. Arthritis Rheum 2012; 64: pp. 579-583.
12. Albers J.W., Herman W.H., Pop-Busui R., et. al.: Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Diabetes Care 2010; 33: pp. 1090-1096.
13. Apfel S.C., Asbury A.K., Bril V., et. al.: Positive neuropathic sensory symptoms as endpoints in diabetic neuropathy trials. J Neurol Sci 2001; 189: pp. 3-5.
14. Harris R.E., Sundgren P.C., Pang Y., et. al.: Dynamic levels of glutamate within the insula are associated with improvements in multiple pain domains in fibromyalgia. Arthritis Rheum 2008; 58: pp. 903-907.
15. Valdes M., Collado A., Bargallo N., et. al.: Increased glutamate/glutamine compounds in the brains of patients with fibromyalgia: a magnetic resonance spectroscopy study. Arthritis Rheum 2010; 62: pp. 1829-1836.
16. Fischer T.Z., Tan A.M., Waxman S.G.: Thalamic neuron hyperexcitability and enlarged receptive fields in the STZ model of diabetic pain. Brain Res 2009; 1268: pp. 154-161.
17. Wang X.L., Zhang Q., Zhang Y.Z., et. al.: Downregulation of GABAB receptors in the spinal cord dorsal horn in diabetic neuropathy. Neurosci Lett 2011; 490: pp. 112-115.
18. Hertz L., Dringen R., Schousboe A., et. al.: Astrocytes: glutamate producers for neurons. J Neurosci Res 1999; 57: pp. 417-428.
19. Sachdev P.S., McBride R., Loo C., et. al.: Effects of different frequencies of transcranial magnetic stimulation (TMS) on the forced swim test model of depression in rats. Biol Psychiatry 2002; 51: pp. 474-479.
20. Rothman D.L., Behar K.L., Hyder F., et. al.: In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: implications for brain function. Annu Rev Physiol 2003; 65: pp. 401-427.