To the Editor:
Imagine yourself waiting at a red light to make a left turn behind another car. Both your blinker and the left-turn light in front of you flash rapidly, and, for a brief moment every 15 to 20 s they align before falling back out of sync. This phenomenon, called “beats,” has been elegantly exploited to propose an exciting technology. In a study recently published in Cell by Grossman and colleagues, entitled “Noninvasive Deep Brain Stimulation via Temporally Interfering Electric Fields,”1 a technique is described for selectively depolarizing small populations of neurons deep in the brain using sets of spatially overlapping oscillating electrical fields. The resistance and capacitance of neuronal cell walls make them impervious to oscillating electrical fields at frequencies above 2 kHz. However, like the blinker example, 2 high-frequency oscillating electrical fields (eg, rapidly flashing) can align at a much lower frequency. By constraining the region of overlap of 2 fields, Grossman and colleagues could induce focused lower frequency (∼10 Hz) deep brain stimulation, leaving the remainder of the brain unperturbed. This technique, which we call “temporal interference” deep brain stimulation (abbreviated ‘TI DBS’), was illustrated in a mouse brain. The authors could steerably evoke different effects in freely behaving mice by oscillating electrical fields induced via a set of electrodes fixed to the skull. In addition to the practical illustration in a mouse model, the authors validated the technique in phantom structures and mathematical models. These authors should be lauded for their ingenuity and practicality in attempting to optimize transcranial electrical stimulation for deep structures. Because of familiarity in targeting deep brain structures for stereotactic procedures, we believe a familiar-yet-novel application of TI DBS could be rapidly and intuitively deployed into the clinical arena. Nevertheless, TI DBS remains a leap from current surgical approaches for stimulation, which at present either impact superficial areas close to the primary stimulation site or require stereotactic implantation to achieve focality deep in the brain.2-4
The need for such a noninvasive option for our patients is paramount, particularly because many patients deemed suitable for DBS remain reluctant to undergo surgery.5 Of course, a noninvasive or minimally invasive (subgaleal superficial skull screw) option, if effective, would be optimal as we continue to explore novel indications in potentially vulnerable patient populations.6-9 The stimulation paradigm utilized was entirely novel but, at its core, grounded in a repurposing of otherwise well-described transcranial electrical stimulation approaches.10 What is particularly impactful is that the proposed methodology appeared capable of delivering a predictable current density to a deep target while sparing the rest of the head. The proposed steering TI methodology is thus thought to overcome 4 critical barriers of current transcranial electrical stimulation techniques: (1) inconsistent dosage precision, (2) lack of focus, (3) depth restriction, and (4) rigid targeting. We do expect the importance of skull impedance calibration for individual patients to vary considerably and remain an important factor in delivering TI DBS as it is for current techniques.11
The present study limited its steerable probing to 2 pairs of fixed electrodes. The authors astutely indicated the need for future studies using larger numbers of electrodes and multiple sets of interfering fields to pinpoint even smaller and deeper regions of the brain. Notably, the fundamentals of the approach by Grossman and colleagues have already been introduced for clinical use in the context of electronarcosis for surgical operations in the Russian literature in the 1960s.12 This method, at that time called “interference currents,” was introduced to minimize pain and unpleasant sensations at the site of the electrode placement and to reduce side effects caused by stimulation of nontarget brain regions.12 The successful use of interference currents for electronarcosis in 100 patients provides further hope that this approach may finally be used for the stimulation of deep structures as suggested by Grossman and colleagues.
To date, computational studies modeling optimization of current injection patterns have revealed that greater electrode density improves focality, directionality, and intensity parameters.13 This capability will likely be more critical as smaller volumes are targeted, particularly due to inhomogeneities of tissue throughout the brain.14 Indeed, optimized electrode configurations for classical transcranial electrical stimulation have already been examined for predefined targets and robust improvements were found in focus size and current dose delivery, though these findings were limited to cortical areas.15 Using the topography of electroencephalography, others have attempted to select locations for transcranial electrical stimulation using cortical dipoles for targeting and the needed current applied to each electrode.16,17
An additional consideration for Grossman and colleagues is that the targeted “deep” structure was the murine hippocampus, less than 1.5 mm deep from the mouse brain surface. While the overlying cortex did not exhibit activation, what does remain to be tested and/or demonstrated is whether TI can selectively and accurately target deep structures like the subthalamic nucleus or nucleus accumbens; in a mouse brain they are approximately 4 mm deeper than the hippocampus, and in a human brain they can be as much as 6 to 8 cm from the brain surface. Moreover, can the tunable steering capability provide anatomic specificity and achieve the spatial resolution needed to envelop the sensorimotor region of the subthalamic nucleus or the shell subregion of the nucleus accumbens? Given these targets are surrounded by other critical structures with different, sometimes opposing functions, optimal precision will almost certainly require dense electrode configurations and thorough, individualized computational analyses before human testing can be initiated.
The questions that this research opens up are legion. What kind of electrode array would be required to target a truly deep region, one where potentially dangerous adverse effects can be seen if stimulation is not tuned optimally? Would such an array require embedded implantation in the skull, or perhaps this would be a future application for wearable technology? Even though neuronal activation was not detected superficially to the hippocampus in mice, is it possible the 2 kHz induced deactivation, a change from baseline that an assay like c-Fos immunohistochemistry would miss? The authors attempted to deliver 10 Hz stimulation via a TI protocol, but this is not a frequency currently used in the clinical arena—this begs the question of what would happen at more conventional, higher frequencies, and whether novel stimulation paradigms could be administered?
Certainly, there is much further work to be done, but the authors are credited with providing this vision of a promising approach to an already fundamentally available technology that may lead to the development of a noninvasive technique for focused electrical modulation of brain circuitry.
The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
1. Grossman N, Bono D, Dedic N, et al. Noninvasive deep brain stimulation via temporally interfering electric fields. Cell. 2017;169(6):1029-1041.
2. Boggio PS, Ferrucci R, Rigonatti SP, et al. Effects of transcranial direct current stimulation on working memory in patients with Parkinson's disease. J Neurol Sci. 2006;249(1):31-38.
3. de Hemptinne C, Swann NC, Ostrem JL, et al. Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson's disease. Nat Neurosci. 2015;18(5):779-786.
4. Keeser D, Meindl T, Bor J, et al. Prefrontal transcranial direct current stimulation changes connectivity of resting-state networks during fMRI. J Neurosci. 2011;31(43):15284-15293.
5. Wachter T, Minguez-Castellanos A, Valldeoriola F, Herzog J, Stoevelaar H. A tool to improve pre-selection for deep brain stimulation in patients with Parkinson's disease. J Neurol. 2011;258(4):641-646.
6. Ali R, DiFrancesco MF, Ho AL, Kampman KM, Caplan AL, Halpern CH. Attitudes toward treating addiction with deep brain stimulation.Brain Stimul. 2016;9(3):466-468.
7. Dougherty DD, Rezai AR, Carpenter LL, et al. A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression. Biol Psychiatry. 2015;78(4):240-248.
8. Halpern CH, Tekriwal A, Santollo J, et al. Amelioration of binge eating by nucleus accumbens shell deep brain stimulation in mice involves D2 receptor modulation. J Neurosci. 2013;33(17):7122-7129.
9. Riva-Posse P, Choi KS, Holtzheimer PE, et al. A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression. Mol Psychiatry. 2017.
10. Price AR, McAdams H, Grossman M, Hamilton RH. A meta-analysis of transcranial direct current stimulation studies examining the reliability of effects on language measures.Brain Stimul. 2015;8(6):1093-1100.
11. Fernández-Corazza M, Beltrachini L, von Ellenrieder N, Muravchik CH. Analysis of parametric estimation of head tissue conductivities using electrical impedance tomography.Biomed Signal Proces. 2013;8(6):830-837.
12. Sachkov VI, Livenstev NM, Kuzin MI, Zhukovskii VD. Experiences with combined electronarcosis with interference currents in clinical surgery In: Wageneder FM, et al, eds. Electrotherapeutic Sleep and Electroanesthesia. The Hague, Netherlands: Excerpta Medica; 1967:321-326.
13. Fernandez-Corazza M, Turovets S, Luu P, Anderson E, Tucker D. Transcranial electrical neuromodulation based on the reciprocity principle.Front Psychiatry. 2016;7:87.
14. Rudko DA, Klassen LM, de Chickera SN, Gati JS, Dekaban GA, Menon RS. Origins of R2* orientation dependence in gray and white matter. Proc Natl Acad Sci U S A. 2014;111(1):E159-E167.
15. Dmochowski JP, Datta A, Bikson M, Su Y, Parra LC. Optimized multi-electrode stimulation increases focality and intensity at target. J Neural Eng. 2011;8(4):046011.
16. Cancelli A, Cottone C, Tecchio F, Truong DQ, Dmochowski J, Bikson M. A simple method for EEG guided transcranial electrical stimulation without models. J Neural Eng. 2016;13(3):036022.
17. Woods AJ, Hamilton RH, Kranjec A, et al. Space, time, and causality in the human brain. Neuroimage. 2014;92:285-297.