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Research paper
Altered cerebral blood flow in the anterior cingulate cortex is associated with neuropathic pain
  1. Keisuke Watanabe1,
  2. Shigeki Hirano1,
  3. Kazuho Kojima1,
  4. Kengo Nagashima2,
  5. Hiroki Mukai3,
  6. Takatoshi Sato2,
  7. Minoru Takemoto4,
  8. Koji Matsumoto5,
  9. Takashi Iimori5,
  10. Sagiri Isose1,
  11. Shigeki Omori1,
  12. Kazumoto Shibuya1,
  13. Yukari Sekiguchi1,
  14. Minako Beppu1,
  15. Hiroshi Amino1,
  16. Tomoki Suichi1,
  17. Koutaro Yokote4,
  18. Takashi Uno3,
  19. Satoshi Kuwabara1,
  20. Sonoko Misawa1
  1. 1 Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
  2. 2 Clinical Research Center, Chiba University Hospital, Chiba, Japan
  3. 3 Diagnostic Radiology and Radiation Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
  4. 4 Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, Chiba, Japan
  5. 5 Department of Radiology, Chiba University Hospital, Chiba, Japan
  1. Correspondence to Dr Satoshi Kuwabara, Department of Neurology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; kuwabara-s{at}


Objective To assess the cerebral blood flow (CBF) in patients with diabetic neuropathic pain, and its changes after duloxetine therapy.

Methods Using iodine-123-N-isopropyl-p-iodoamphetamine single-photon emission computed tomography (IMP-SPECT), we performed a cross-sectional study of 44 patients with diabetes, and compared CBF in those with (n = 24) and without neuropathic pain (n = 20). In patients with neuropathic pain, we also longitudinally assessed changes in CBF 3 months after treatment with duloxetine.

Results IMP-SPECT with voxel-based analyses showed a significant increase in cerebral blood flow in the right anterior cingulate cortex and a decrease in the left ventral striatum in patients with neuropathic pain, compared with those without pain. After duloxetine treatment, volume of interest analyses revealed a decrease in cerebral blood flow in the anterior cingulate cortex in patients with significant pain relief but not in non-responders. Furthermore, voxel-based whole brain correlation analyses demonstrated that greater baseline CBF in the anterior cingulate cortex was associated with better pain relief on the numerical rating scale.

Conclusions Our results suggest that the development of neuropathic pain is associated with increased activity in the anterior cingulate cortex, and greater baseline activation of this region may predict treatment responsiveness to pharmacological intervention.

Trial registration number UMIN000017130;Results.

  • cerebral blood flow
  • diabetic neuropathy

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  • Contributors KW and SM designed the study. SI, SO, KS, YS, MB, HA, TaS, ToS, KY and MT collected clinical and electrophysiological data. KM and TI collected IMP-SPECT and MRI data. KK and HM analysed MRI images. SH analysed and interpreted the data. KN supervised statistical analyses. KW and SH drafted the manuscript. SM, TS, TU supervised this study.

  • Funding This study is funded by Shionogi & Co., Ltd and by a Research Grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (SM, Kakenhi- 25461308: SK, Kakenhi- 26461305). The sponsors played no role in the design and management of the study, collection and analysis of data, interpretation of the results or the writing of the writing of the report.

  • Competing interests SM received lecture and consultation fee from Shionogi & Co., Ltd and Pfizer Inc. SK serves as a Deputy Editor of “Journal of Neurology, Neurosurgery, and Psychiatry” and Editorial Board member of the “Journal of the Neurological Sciences”.

  • Patient consent Obtained.

  • Ethics approval The Institutional Review Board and Ethical Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.