Personalized High-Definition tDCS Protocols for Chronic Pain Treatment

Official title

Innovative Neuromodulation Treatments for Chronic Pain: Assessing and Predicting the Effects of Personalized High-Definition Protocols for Transcranial Direct Current Stimulation (HD-tDCS)

Overview

This study aims to examine the use of neurostimulation as a potential adjuvant treatment for chronic pain. Among neurostimulation techniques, transcranial direct current stimulation (tDCS) represents a promising, yet not fully exploited, option. Recent methodological advances allow for increased intensity and focality of its effects through personalized high-definition tDCS protocols (HD-tDCS), enabling targeted stimulation of specific brain regions involved in pain and analgesia processing, such as the dorsal anterior cingulate cortex (dACC). Based on this evidence, the specific objective of the study is to investigate the effect of an innovative HD-tDCS protocol (personalized using structural and functional magnetic resonance imaging (fMRI)), with stimulation applied to the dACC. The experimental design involves randomly assigning 144 patients with chronic pain to three groups, who will undergo an intensive treatment (five sessions in the same week) with cathodal, anodal, or sham (placebo) HD-tDCS. Patient recruitment and treatment will be equally distributed between sites located in Lombardy (IRCCS Maugeri-Pavia; University of Milano-Bicocca; n=72) and Palermo (IRCCS ISMETT-Palermo; University of Palermo; n=72). The effects of neurostimulation will be: a) evaluated using self-reported measures of physical and social functioning (Brief Pain Inventory, BPI; primary outcome) before and after treatment, and at follow-up assessments at 3 weeks and 3 months; b) interpreted in relation to underlying neurophysiological changes, as revealed by the high spatial and temporal resolution provided, respectively, by fMR) and by transcranial magnetic stimulation-evoked potentials combined with electroencephalographic recording (TMS-EEG) before and after treatment (secondary outcome).

Interventions

• Device Anodal High-Definition transcranial Direct Current Stimulation
  Participants will receive 5 stimulation sessions in a week, with the HD-tDCS setup including 6 electrodes (3 anode + 3 cathode electrodes) delivering a total current of 2mA. The spatial configuration of the six electrodes is aimed to induce the maximum intensity of stimulation at the target stereotactic coordinate, based on the modeling of estimated distribution of electric fields. The active stimulation lasts for 20 minutes.
• Device Cathodal High-Definition transcranial Direct Current Stimulation
  Participants will receive 5 stimulation sessions in a week, with the HD-tDCS setup including 6 electrodes (3 anode + 3 cathode electrodes) delivering a total current of 2mA. The spatial configuration of the six electrodes is aimed to induce the maximum intensity of stimulation at the target stereotactic coordinate, based on the modeling of estimated distribution of electric fields. The active stimulation lasts for 20 minutes. In cathodal sessions, polarity is reversed.
• Device Sham (No Treatment)
  Participants will receive 5 stimulation sessions in a week, with the HD-tDCS setup including 6 electrodes (3 anode + 3 cathode electrodes) delivering a total current of 2mA. The spatial configuration of the six electrodes is aimed to induce the maximum intensity of stimulation at the target stereotactic coordinate, based on the modeling of estimated distribution of electric fields. In sham sessions, the duration is also 20 minutes but participants are unaware that the stimulation intensity gradu

Primary outcome measures

• Reduction of perceived pain [Time frame: Baseline; Up to 3 weeks; After 3 months]

Secondary outcome measures (1)

• Change in pain-related neural sensitivity measured with fMRI and TMS-EEG [Time frame: Baseline; Up to 3 weeks]

Eligibility criteria

Inclusion criteria

• Diagnosis of chronic pain lasting for at least six months
• Pain scores equal to or greater than 4 on Numerical Rating Scale (NRS) 0-10 on most days for the last 3 months
• Pain unresponsive to conservative treatment such as pharmacological therapy and physiotherapy, and unresponsive to minimally invasive treatments such as peripheral nerve blocks or neuromodulation or steroid epidural injections, when appropriate
• Age between 18 and 75
• Stable pain levels and willingness not to modify any ongoing pain management therapies during the study period (1 week)

Exclusion criteria

• History of seizure disorders
• Active malignancy
• Implanted medical devices and/or metallic implants in the head or neck region
• Cranial abnormalities
• Severe cognitive impairment (Montreal Cognitive Assessment (MoCA)<15.5)
• Neurological or psychiatric conditions, or significant comorbidities, that may interfere with tDCS
• Pregnancy
• Incompatibility with MRI and/or TMS

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Italy · 4 centers

• University of Milano-Bicocca — Milan
• Irccs Ismett — Palermo
• University of Palermo — Palermo
• Istituti Clinici Scientifici Maugeri Spa Società Benefit — Pavia

Publications

• Roth, Y., Padberg, F., and Zangen, A. (2007). Transcranial magnetic stimulation of deep brain regions: principles and methods. ADVANCES IN BIOLOGICAL PSYCHIATRY-BASEL-, 23(R), 204.
• Garg, A., and Mago, V. (2021). Role of machine learning in medical research: A survey. Computer science review, 40, 100370.
• Xiong HY, Cao YQ, Du SH, Yang QH, He SY, Wang XQ. Effects of High-Definition Transcranial Direct Current Stimulation Targeting the Anterior Cingulate Cortex on the Pain Thresholds: A Randomized Controlled Trial. Pain Med. 2023 Jan 4;24(1):89-98. doi: 10.1093/pm/pnac135. PMID 36066447
• Xiao X, Ding M, Zhang YQ. Role of the Anterior Cingulate Cortex in Translational Pain Research. Neurosci Bull. 2021 Mar;37(3):405-422. doi: 10.1007/s12264-020-00615-2. Epub 2021 Feb 10. PMID 33566301
• Wertli MM, Eugster R, Held U, Steurer J, Kofmehl R, Weiser S. Catastrophizing-a prognostic factor for outcome in patients with low back pain: a systematic review. Spine J. 2014 Nov 1;14(11):2639-57. doi: 10.1016/j.spinee.2014.03.003. Epub 2014 Mar 7. PMID 24607845
• Varoli E, Pisoni A, Mattavelli GC, Vergallito A, Gallucci A, Mauro LD, Rosanova M, Bolognini N, Vallar G, Romero Lauro LJ. Tracking the Effect of Cathodal Transcranial Direct Current Stimulation on Cortical Excitability and Connectivity by Means of TMS-EEG. Front Neurosci. 2018 May 15;12:319. doi: 10.3389/fnins.2018.00319. eCollection 2018. PMID 29867330
• Van Ryckeghem DML, Crombez G, Goubert L, De Houwer J, Onraedt T, Van Damme S. The predictive value of attentional bias towards pain-related information in chronic pain patients: a diary study. Pain. 2013 Mar;154(3):468-475. doi: 10.1016/j.pain.2012.12.008. Epub 2012 Dec 28. PMID 23375161
• Truini A, Aleksovska K, Anderson CC, Attal N, Baron R, Bennett DL, Bouhassira D, Cruccu G, Eisenberg E, Enax-Krumova E, Davis KD, Di Stefano G, Finnerup NB, Garcia-Larrea L, Hanafi I, Haroutounian S, Karlsson P, Rakusa M, Rice ASC, Sachau J, Smith BH, Sommer C, Tolle T, Valls-Sole J, Veluchamy A. Joint European Academy of Neurology-European Pain Federation-Neuropathic Pain Special Interest Group o PMID 37253688

Identifiers

NCT: NCT07432841 · 37813/2024 · PNRR-MCNT2-2023-12378259

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗