• Divya Bharatkumar Adhia, Ramakrishnan Mani, ReynoldsJohn N JJNJDepartment of Anatomy and the Brain Health Research Centre, School of Biomedical Sciences, University of Otago, Dunedin, Otago, New Zealand., Matthew Hall, Sven Vanneste, and Dirk De Ridder.
• Department of Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin, Otago, New Zealand; Pain@Otago Research Theme, School of Physiotherapy, University of Otago, Dunedin, Otago, New Zealand. Electronic address: divya.adhia@otago.ac.nz.
• Neuromodulation. 2023 Jun 1; 26 (4): 788800788-800.

IntroductionPain can be regarded as an emergent property of multiple interacting, dynamically changing brain networks and thus needs a targeted treatment approach. A novel high-definition transcranial infraslow pink-noise stimulation (HD-tIPNS) technique was developed to modulate the key hubs of the three main nociceptive pathways simultaneously, ie, the pregenual anterior cingulate cortex (pgACC) (descending inhibitory pathway), the dorsal anterior cingulate cortex (dACC) (medial nociceptive pathway), and both somatosensory cortices (S1) (lateral nociceptive pathway). This study aimed to evaluate safety and verify whether a single session of HD-tIPNS may disrupt functional and effective connectivity between targeted cortical regions.Materials And MethodsA pilot double-blind randomized two-arm placebo-controlled parallel trial was conducted. Participants (N = 30) with chronic low back pain were equally randomized to receive a single session of either sham stimulation or HD-tIPNS (targeting the pgACC, dACC, and bilateral S1). Primary outcomes included safety and electroencephalographic measures, and secondary outcomes included pain measures, collected after treatment. A Mann-Whitney U test was used to compare between-group differences in percentage changes with baseline for each outcome measures. A Wilcoxon signed-rank test was used to identify difference in effective connectivity measure before and after HD-tIPNS.ResultsNo serious adverse events were reported. A significant decrease in instantaneous functional connectivity was noted between the pgACC and dACC (U = 47.0, Z = -2.72, p = 0.007) and the pgACC and left S1 (U = 41.0, Z = -2.97, p = 0.003) in the infraslow band after HD-tIPNS when compared with sham stimulation. A significant decrease in instantaneous effective connectivity was noted in the direction of the dACC to the pgACC (Z = -2.10, p = 0.035), in the infraslow band after HD-tIPNS when compared with baseline. No changes in clinical pain measures were detected.ConclusionsHD-tIPNS can safely modulate the functional and effective connectivity between targeted pain-related cortical hubs. Further studies are warranted to evaluate whether repeated exposures to HD-tIPNS can incur clinical benefits through inducing changes in functional and effective connectivity at targeted cortical regions.Clinical Trial RegistrationThe Clinicaltrials.gov registration number for the study is ACTRN12621001438842.Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.

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