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Introduction: Pain 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 Methods: A 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., Results: No 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., Conclusions: HD-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 Registration: The Clinicaltrials.gov registration number for the study is ACTRN12621001438842., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Tinnitus has been linked to activity and connectivity changes in the auditory cortex (AC), parahippocampus (PHC), and posterior cingulate cortex (PCC). Although previous studies have targeted these areas individually, no study has yet modulated them simultaneously. Furthermore, novel stimulation designs may be superior to traditional alternating or direct current stimulation. This pilot study investigated the feasibility and safety of a novel brain stimulation technique (high-definition transcranial infraslow pink noise stimulation [HD-tIPNS]) for treating chronic tinnitus targeting the AC, PHC, and PCC., Materials and Methods: A pilot, double-blind, randomized two-arm placebo-controlled parallel trial was conducted, with clinical outcomes collected at baseline, three days, and ten days after treatment. Participants with chronic tinnitus (n = 20) received 12 sessions (three per week for four weeks) of either HD-tIPNS or acti-sham stimulation. Primary outcomes included feasibility, safety, and resting-state electroencephalography (rsEEG) measures, and secondary outcomes included tinnitus and quality of life questionnaires. Feasibility, safety, and secondary measures were assessed using descriptive statistics. rsEEG was analyzed using standard low-resolution electromagnetic brain tomography., Results: No long-term adverse events were reported. Mild side effects included headache and dizziness, indicating the safety of this stimulation. Participants were rapidly recruited and adhered to the study protocol with minimal difficulty. Drop-out rate was 13%, and the treatment approach was acceptable to participants, supporting the feasibility of the protocol. Tinnitus measures were similar between HD-tIPNS and acti-sham stimulation. rsEEG analyses revealed decreased beta-1 activity in PCC ten days after treatment for acti-sham. The HD-tIPNS group showed decreased beta-1 activity in inferior parietal lobule three days after treatment. Increased functional connectivity in the beta-1 frequency between left and right PHC was found in the HD-tIPNS group compared with the acti-sham group, three days after treatment., Conclusions: In conclusion, the novel approach is safe and feasible and revealed EEG changes unsupported by clinical benefit. Further research is essential to evaluate the potential of this multifocal network stimulation approach., Clinical Trial Registration: This study was registered with the Australia New Zealand Clinical Trial Registry (Registry number: ACTRN12621000151831; Universal Trial Number: U1111-1261-6945)., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)