Notes on Human Trials of Transcranial Direct Current Stimulation between 1960 and 1998

Abstract

Background: Transcranial direct current stimulation (tDCS) is investigated to modulate neuronal function including cognitive neuroscience and neuropsychiatric therapies. While cases of human stimulation with rudimentary batteries date back more than 200 years, clinical trials with current controlled stimulation were published intermittently since the 1960s. The modern era of tDCS only started after 1998.Objectives: To review methods and outcomes of tDCS studies from old literature (between 1960 and 1998) with intention of providing new insight for ongoing tDCS trials and development of tDCS protocols especially for the purpose of treatment.Methods: Articles were identified through a search in PubMed and through the reference list from its selected articles. We included only non-invasive human studies that provided controlled direct current and were written in English, French, Spanish or Portuguese before the year of 1998, the date in which modern stimulation paradigms were implemented.Results: Fifteen articles met our criteria. The majority were small-randomized controlled clinical trials that enrolled a mean of approximately 26 subjects (Phase II studies). Most of the studies (around 83%) assessed the role of tDCS in the treatment of psychiatric conditions, in which the main outcomes were measured by means of behavioral scales and clinical observation, but the diagnostic precision and the quality of outcome monitoring, including adverse events, were deficient by modern standards. Compared to modern tDCS dose, the stimulation intensities used (0.1–1 mA) were lower, however as the electrodes were typically smaller (e.g., 1.26 cm2), the average electrode current density (0.2 mA/cm2) was approximately 4× higher. The number of sessions ranged from one to 120 (median 14). Notably, the stimulation session durations of several minutes to 11 h (median 4.5 h) could markedly exceed modern tDCS protocols. Twelve studies out of 15 showed positive results. Only mild side effects were reported, with headache and skin alterations the most common.Conclusion: Most of the studies identified were for psychiatric indications, especially in patients with depression and/or schizophrenia and majority indicated some positive results. Variability in outcome is noted across trials and within trials across subjects, but overall results were reported as encouraging, and consistent with modern efforts, given some responders and mild side effects. The significant difference with modern dose, low current with smaller electrode size and interestingly much longer stimulation duration may worth considering.

Immediate neurophysiological effects of transcranial electrical stimulation

“…However, rodent studies typically use ten-fold stronger current intensities compared to human studies 66 . Across the 28 rodent experiments reviewed 67 (Supplementary Table 2), the induced intracranial fields averaged 6.8 ± 3.8 V/m ( n = 11, ten epicranial and 1 subdural studies), compared to < 1 V/m measured in conventional human TES studies 19 , 68 , 69 .…”

How to consider animal data in tDCS safety standards

“…tDCS protocols in humans circa 1970 used relatively low current intensities but with smaller electrodes and longer durations than are common today, resulting in cases of electrode charge density >100 kC/m 2 , with no reports of lasting side-effects [8]. It would be unreasonable to apply only electrode charge density-safety threshold values from rodent studies (using small epicranial electrodes) as evidence these tDCS protocols were in fact injurious.…”

Adaptive current tDCS up to 4 mA

“…In 16 healthy participants 3 mA tDCS, with topical anesthetic cream, was tolerated and produced intensity-specific neuromodulation [8]. A review of early evaluations of tDCS circa 1960 identified a single instance of 3 mA, with local anesthetic used [9]. High-definition tDCS (HD-tDCS) was tolerated at 3 mA [10] in a sample of older adults.…”