Abstract
Temporal interference stimulation (TIS) is a new form of transcranial electrical stimulation (tES) that has been proposed as a method for targeted, non-invasive stimulation of deep brain structures. While TIS holds promise for a variety of clinical and non-clinical applications, little data is yet available regarding its effects in humans. To inform the design and approval of experiments involving TIS, researchers require quantitative guidance regarding exposure limits and other safety concerns. To this end, we sought to delineate a safe range of exposure parameters (voltages and currents applied via external scalp electrodes) for TIS in humans through comparisons with well-established but related brain stimulation modalities. Specifically, we surveyed the literature for adverse events (AEs) associated with transcranial alternating/direct current stimulation (tACS/tDCS), deep brain stimulation (DBS), and TIS to establish known boundaries for safe operating conditions. Drawing on the biophysical mechanisms associated with the identified AEs, we determined appropriate exposure metrics for each stimulation modality. Using these metrics, we conducted an in silico comparison of various exposure scenarios for tACS, DBS, and TIS using multiphysics simulations in an anatomically detailed head model with realistic current strengths. By matching stimulation scenarios in terms of biophysical impact, we inferred the frequency-dependent TIS stimulation parameters that resulted in exposure magnitudes known to be safe for tACS and DBS. Based on the results of our simulations and existing knowledge regarding tES and DBS safety, we propose frequency-dependent thresholds below which TIS voltages and currents are unlikely to pose a risk to humans. Safety-related data from ongoing and future human studies are required to verify and refine the thresholds proposed here.
Competing Interest Statement
Esra Neufeld is a minority shareholder and a board member of TI Solutions AG. Niels Kuster is a shareholder of NF Technology Holdings AG, which is a minority shareholder of TI Solutions AG. He is also a board member of TI Solutions AG. Sabine Regel is the CEO of TI Solutions AG.
Footnotes
Added disclosure of competing interests for several authors.
† ICNIRP guidelines specify that, independent of contact area, currents of ≤1 mA for f ≤2.5 kHz and ≤0.4 x f mA (f in kHz) for f >2.5 and ≤100 kHz are safe for occupational exposure. Thus, extrapolated to a neurostimulation context, field exposures and stimulation currents with applied frequencies above 2.5 kHz would be safer than those of the same amplitude at lower frequencies. However, occupational safety guidelines are of limited applicability to electrical neuromodulation, where stimulation is applied intentionally under controlled conditions. By contrast, safety guidelines provide limits for unintended contact currents and accept non-hazardous sensations as benign side-effects84.
Acronyms
- AC
- Alternating current
- A-CalCAP
- California computerized assessment package
- ACC
- Anterior cingulate cortex
- AD
- Alzheimer’s disease
- AE
- Adverse event
- AF
- Activating function
- ALIC
- Anterior limb of the internal capsule
- ANT
- Anterior nucleus of the thalamus
- AP
- Action potential
- AUC
- Area under the curve
- BNST
- Bed nucleus of the stria terminalis
- CB
- Conduction blocking
- CMN
- Centromedian nucleus of the thalamus
- CM-PFc
- Centromedian-parafascicular thalamic complex
- CN
- Caudate nucleus
- CNS
- Central nervous system
- CSF
- Cerebral spinal fluid
- cZI
- Caudal zona incerta
- DBS
- Deep brain stimulation
- DC
- Direct current
- DTI
- Diffusion tensor imaging
- ECT
- Electroconvulsive therapy
- EM
- Electromagnetic
- ET
- Essential tremor
- FDA
- U.S. food and drug administration
- GABAB
- Gamma-aminobutyric acid
- GP
- Globus pallidus
- GPe
- External globus pallidus
- GPi
- Internal globus pallidus
- HD-tES
- High-density tES
- Hipp
- Hippocampus
- IPG
- Implanted pulse generator
- ISI
- Interspike interval
- ITP
- Inferior thalamic peduncle
- LTD
- Long-term depression
- LTP
- Long-term potentiation
- MAUDE
- Manufacturer and user facility device experience
- MD
- Major depression
- MFB
- Medial forebrain bundle
- mNSS
- Modified neurological severity score
- MoCA
- Montreal cognitive assessment
- MRI
- Magnetic resonance imaging
- NAcc
- Nucleus accumbens
- NBM
- Nucleus basalis of Meynert
- NIBS
- Non-invasive brain stimulation
- NMDA
- N-methyl-D-aspartate
- NSE
- Neuron-specific enolase
- OCD
- Obsessive-compulsive disorder
- PAG
- Periaqueductal grey matter
- PBE
- Pennes Bioheat Equation
- PD
- Parkinson’s disease
- pHr
- Posterior hypothalamic region
- PMA
- Premarket approval
- PMS
- Postmarket surveillance
- PNS
- Peripheral nervous system
- PPN
- Pedunculopontine nucleus
- PPT
- Purdue pegboard test
- PSA
- Posterior subthalamic area
- PSC
- Postsynaptic current
- PVG
- Periventricular grey matter
- RF
- Radiofrequency
- RMS
- Root mean square
- SAR
- Specific absorption rate
- SAS
- Self-assessment scale
- SAT
- Subcutaneous fat
- SD
- Standard deviation
- SCC
- Subcallosal cingulate cortex
- SCG
- Subgenual cingulate gyrus (=BA25=Cg25)
- SNpr
- Substantia nigra pars reticulata
- SNR
- Signal-to-noise ratio
- STN
- Subthalamic nucleus
- tACS
- Transcranial alternating current stimulation
- tDCS
- Transcranial direct current stimulation
- tES
- Transcranial electrical stimulation
- TI
- Temporal interference
- TIS
- Temporal interference stimulation
- TMS
- Transcranial magnetic stimulation
- TPLC
- Total product life cycle
- VAMS-R
- Visual analog mood scale
- VC
- Ventral capsule
- VIM
- Ventral intermedius nucleus of the thalamus
- VO
- Ventral oralis nucleus of the thalamus
- VPL
- Ventral posterior lateral nucleus
- VPM
- Ventral posterior medial nucleus
- VS
- Ventral striatum
- VTA
- Ventral tegmental area
- ZI
- Zona incerta