Digitizing Non-Invasive Neuromodulation Trials: Scoping Review, Process Mapping, and Recommendations from a Delphi Panel

Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided. Device appraisal showed moderate digitalization readiness, with high safety and possibility of trial implementation, but low connectivity. Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; although they reached no consensus about aspects regarding methodological biases. We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials.Funding Information: This work received no specific funding from any source.Declaration of Interests: AD, RCK, ER, F. Frohlich, KH, KS, MB, PF: have equity in a company. F. Frohlich, FP, MG, MB, MN, PF, RCK, S. Laureys, WP: are members of the Scientific Advisory Board of a company. AA, F. Frohlich, FP, KMS, MB, MN, RCK, S. Laureys, UP: received honoraria of a company. CB, CL, DD, FP, KMS, S. Laureys, TR, WP: received in-kind support of a company; MC, received financial support by the Italian Ministry of Health (Ricerca Corrente); AD, RCK, ER, F. Frohlich, KS, CP: has a chief role in a company. EMNP: Scientific consulting for a company. AD, KS, MB, PF, RCK, WP: have patents related to a company. ARB receives scholarships and support from FAPESP, the Brazilian National Council of Scientific Development (CNPq-1B), University of São Paulo Medical School (FMUSP), the UK Academy of Medical Sciences (Newton Advanced Fellowship), and the International Health Cohort Consortium (IHCC). HE is supported by the Laureate Institute for Brain Research (LIBR), Warren K. Family Foundation, Oklahoma Center for Advancement of Science and Technologies (OCAST, #HR18-139) and Brain and Behavior Foundation (NARSAD Young Investigator Award #27305). AA is supported by the VW Foundation German 2018 - Israeli Cooperation in Biological and Life Sciences, Medicine (A128416) and by the BMBF (Stimcode, 01FP2124B). TKR has received research support from Brain Canada, Brain and Behavior Research Foundation, BrightFocus Foundation, Canada Foundation for Innovation, Canada Research Chair, Canadian Institutes of Health Research, Centre for Aging 16 and Brain Health Innovation, National Institutes of Health, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute. TKR also received for an investigator-initiated study in-kind equipment support from Newronika, and in-kind research online accounts from Scientific Brain Training Pro, and participated in 2021 in an advisory board for Biogen Canada Inc. TKR is also an inventor on the United States Provisional Patent No. 17/396,030 that describes cell-based assays and kits for assessing serum cholinergic receptor activity. JL receives scholarship and support from the Portuguese Foundation for Science and Technology (FCT), co-funded through COMPETE 2020 – PO Competitividade e Internacionalização/Portugal 2020/European Union, FEDER (Fundos Europeus Estruturais e de Investimento – FEEI) under the number: PTDC/PSI-ESP/30280/2017. SC receives scholarship and support from the Portuguese Foundation for Science and Technology (FCT), co-funded through COMPETE 2020 – PO Competitividade e Internacionalização/Portugal 2020/European Union, FEDER (Fundos Europeus Estruturais e de Investimento – FEEI) under the number:PTDC/PSI ESP/29701/2017. CL has received research funding from the Australian National Health and Medical Research Council and Stanley Medical Research Foundation. GV (Ganesan Venkatasubramanian) is supported by the Department of Biotechnology - Wellcome Trust India Alliance (IA/CRC/19/1/610005) and Department of Biotechnology, Government of India (BT/HRD-NBA-NWB/38/2019-20(6)). LBR has received support from FAPESP (grant 2019/07256-7). MB has received support from NIH (grant 1R01NS112996 and 1R01NS101362). IRV received funding from thr BBSRC (Ref: BB/S008314/1). AHO has received scholarships (Process 13/10187-0 and 14/10134-7) and support from FAPESP (CEPID/BRAINN - The Brazilian Institute of Neuroscience and Neurotechnology Process: 13/07559–3), and the Brazilian National Council of Scientific Development (CNPq 479000/2012-3; 487361/2013-0; PQ-2). LC has received support from the NIH grants NIH 1R01NS112996-01A, R21NS101712-0), US Department of Defense (grant W81XWH-17-1-0320), VA Healthcare (GRANT13010404), and National MS Society (RG-1803-30492). KPB has received support from the Spaulding Research Institute (Spaulding Research Accelerator Program). All other authors have nothing to declare.