Noninvasive Temporal Interference Electrical Stimulation for Spinal Cord Rehabilitation

Summary

This study proposes a TI stimulation protocol for spinal cord injury that optimizes electrode placement for specific regions and efficiently implements this optimized strategy in clinical application.

Abstract

Spinal cord injury (SCI) can lead to permanent loss of motor, sensory, and autonomic functions, presenting a significant clinical challenge for rehabilitation. In addition to conventional rehabilitation approaches, epidural spinal cord stimulation (eSCI) is often used to enhance recovery. However, the invasive nature of eSCI limits patient acceptance and widespread application. Compared to traditional spinal cord stimulation, temporal interference (TI) stimulation offers a noninvasive approach to stimulate deep spinal cord regions, making it a promising technique for SCI treatment. A critical factor in achieving effective TI stimulation for SCI rehabilitation is the accurate placement of two electrode pairs on the skin surface to generate a high electric field envelope within the targeted spinal cord area. We propose a unique protocol that utilizes electric field simulations and parameter optimization to determine the optimal electrode placement for specific SCI regions. Additionally, this protocol provides a systematic description of how to efficiently implement the optimized electrode placement strategy in clinical TI stimulation.

Introduction

Spinal cord injury (SCI) is a debilitating central nervous system disorder that can result in the permanent loss of motor, sensory, and autonomic functions below the level of injury^1,2. Consequently, the treatment and rehabilitation of SCI patients have become a focal point of both scientific research and clinical practice. Traditional treatment approaches, including pharmacological and physical therapies, have certain limitations in promoting functional recovery^3,4,5,6. Among physical therapies, spinal cord electrical stimulation has emerged as an effective strategy for SCI rehabilitation, which can be categorized into invasive and noninvasive modalities^7,8. Invasive spinal cord electrical stimulation, such as epidural spinal cord stimulation (eSCI), delivers direct electrical stimulation via implanted electrodes but carries risks of infection and scar tissue formation^9,10. In contrast, noninvasive techniques, such as transcutaneous electrical nerve stimulation (TENS), are limited in their ability to effectively reach deep spinal structures, thereby compromising therapeutic efficacy^11,12.

Temporal interference (TI) stimulation is an emerging neuromodulation technology that enables noninvasive stimulation of deep tissues through a specific mode of electrical current delivery^13,14. This technique involves placing two pairs of electrodes on the skin surface to deliver electrical currents at slightly different kilohertz frequencies. Based on the principle of interference, this setup generates a unique low-frequency envelope (ranging from a few hertz to several tens of hertz) within deep tissues, thereby enabling targeted neuromodulation. This distinct working mechanism allows TI stimulation to overcome the depth limitations of conventional neuromodulation techniques, providing an effective intervention for deep neural structures without invasive procedures. Unlike TENS, TI achieves deeper penetration with high spatial specificity, and unlike eSCI, it avoids surgical risks, offering a safer, more accessible alternative for SCI neuromodulation. TI stimulation has been investigated for the treatment of various diseases, such as movement disorders and depression. In incomplete SCI, as some neural pathways remain intact, TI stimulation is highly likely to enhance the activity of remaining neural circuits, thereby promoting neuroplasticity and functional recovery^15,16. Thus, TI stimulation holds significant promise as a neuromodulation strategy for SCI treatment¹⁷.

However, current TI stimulation hardware systems are primarily designed for transcranial applications, and there is a lack of TI systems specifically developed for spinal cord stimulation. Due to anatomical and electrophysiological differences between the head and the torso, existing TI stimulation devices designed for the head are not fully applicable to spinal stimulation, leading to challenges in output parameter optimization and electrode placement. When performing TI stimulation on the head, a fixed leadfield coordinate system (such as the 10-10 system) is often used to facilitate electrode positioning on the head. However, this system is not applicable to the torso. Furthermore, because TI stimulation generates low-frequency envelopes deep within biological tissues, it is difficult to predict the resulting electric field distribution based solely on manual electrode placement. Instead, computational simulations are typically required to visualize and optimize the internal electric field distribution. At present, however, there is no established workflow for electric field simulation and parameter optimization for spinal TI stimulation, which poses significant challenges for its clinical application. Parameters such as electrode placement, stimulation frequencies, and current amplitude directly influence the electric field distribution and the amplitude of the low-frequency envelope, modulating neural activity and promoting neuroplasticity^13,17.

The objective of this study is to develop a convenient and effective workflow for TI electric field simulation and parameter optimization, along with a TI hardware system tailored for spinal cord injury treatment. Through electric field simulation and parameter optimization, we aim to determine electrode placement configurations that maximize the envelope field amplitude of TI at specific SCI target regions, thereby enhancing therapeutic efficacy. Additionally, to facilitate the practical implementation of optimized electrode configurations, we have designed a new electrode coordinate positioning method for spinal cord TI stimulation based on the original TI hardware system for the head. This system is intended to simplify electrode positioning and improve operational feasibility in clinical settings.

Protocol

This study involves human subjects and was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the Institutional Review Board of Zhejiang University. Written informed consent was obtained from all participants prior to their inclusion, ensuring they were fully informed of the study's purpose, procedures, potential risks, and their right to withdraw at any time without penalty. The reagents and the equipment used in this study are listed in the Table of Materials.

Contraindications and special considerations
SCI patients are assessed for eligibility using a medical history questionnaire and physical examination to identify conditions affecting participation:
Inclusion criteria: (1) Age between 18 and 80 years (male or female); (2) Incomplete SCI graded as ASIA B, C, or D, with onset of 1-6 months; (3) No changes in ASIA assessment within the past week; (4) Stable medication regimen throughout the study period; (5) Willingness to comply with all study requirements, including participation in all required training sessions and rehabilitation assessments.
Exclusion criteria¹⁷: (1) Motor function limitations due to neurological disorders (e.g., stroke, multiple sclerosis, traumatic brain injury); (2) Presence of any unstable or severe medical conditions (e.g., uncontrolled hypertension, heart failure); (3) History of epilepsy; (4) Contraindications to electrical stimulation (e.g., implanted electronic devices, pacemakers, metallic implants).

1. Materials

1. Verify the completeness of required materials (see Table of Materials).
2. Evaluate SCI patients using magnetic resonance imaging (MRI) or computed tomography (CT) scans.
3. Open electromagnetic simulation software to perform electric field simulations (all steps are implemented within the software, eliminating the need to switch to other software or use additional scripts). Before conducting electric field simulations, ensure that the electromagnetic simulation software contains human models (male or female).
   1. If these models are not available, select Model/Phantom - Humans in the ribbon, then download the human model. Once the download is complete, import the model into the current project for subsequent simulations.
4. Press the power button to turn on the TI stimulator before each stimulation session, then connect the electrode adapter using the designated connection cables (Figure 1). Check the battery status on the device screen. Charge the device immediately if the battery level is below 20%, using the designated power adapter plugged into a standard electrical outlet.
   NOTE: Incompatible adapters may damage the battery or cause irregularities in the TI stimulator's output.
5. Inspect each Ag/AgCl electrode visually for cracks, discoloration, or residue. Clean the electrodes with isopropyl alcohol and a soft cloth to remove contaminants. Then apply a thin and even 1 mm layer of conductive gel to the electrode surface to reduce contact impedance and prevent skin irritation during stimulation.
   1. Additionally, ensure to have precise information regarding the dimensions of the electrodes, including their diameter and thickness, as these parameters play a critical role in subsequent electric field simulations.
6. Connect the two pairs of electrode cables to the electrode adapter by matching the cable connectors to the labeled ports.

2. Electric field simulation and parameter optimization

NOTE: The overall workflow of the electric field simulation consists of three main steps: constructing the geometric model (including the human model and electrodes), defining simulation conditions (material properties, boundary conditions, and mesh generation), and finally performing computations to visualize the electric field distribution in the target region of spinal cord (Figure 2). Parameter optimization involves simulating electric fields for various candidate electrode pair configurations, calculating the average electric field intensity in the target region, and identifying the configuration that maximizes this intensity. The specific steps are as follows:

1. Launch the electromagnetic simulation software on a computer with at least 16 GB of RAM and a multi-core processor. Create a new project by selecting File - New Project in the ribbon.
2. Geometric model construction
   1. Click on the Model tab in the ribbon and import a human model by selecting Model/Phantom - Humans and choosing a male or female static model (Figure 3).
   2. Identify the vertebral location closest to the SCI site using anatomical landmarks (e.g., C5 is approximately 2-3 cm below the C7 spinous process, palpable as a prominent bony protrusion at the base of the neck). Set the coordinate of the skin surface directly above the central region of the selected vertebra as the origin (Sketch - Point). Define the horizontal and vertical axes as the x- and y-axes, respectively (Figure 4).
      NOTE: In the demonstration of the protocol, we select the spinal cord region wrapped by the C5 vertebra as the stimulation target. This is not a fixed choice, but it was made for the convenience of demonstration. When applying the protocol in practice, any specified spinal cord target area can be arbitrarily selected.
   3. For each electrode pair configuration, place the four electrodes symmetrically about the origin (Figure 4), with one pair on each side of the spine. Define positions by the horizontal distance (d₁) and vertical distance (d₂) from the origin, such that the coordinates of the four electrodes in each configuration are (d₁, d₂), (d₁, -d₂), (-d₁, d₂), and (-d₁, -d₂).
      NOTE: In this demonstration, 25 electrode pair configurations are evaluated, with adjacent electrodes in each quadrant spaced 1 mm apart horizontally and 5 mm apart vertically, which allows the candidate electrodes to be distributed within a suitable range relative to the target area. The specific electrode placement procedure is as follows. Using the first quadrant as an example:
      1. Create a cylindrical electrode by clicking on Solids - Cylinder in the ribbon with dimensions corresponding to the actual electrodes used in the clinical treatment. The thickness may be slightly increased to account for minor intersections with the skin surface in the simulation model.
         NOTE: In this demonstration, the electrode diameter was set to 10 mm, and the thickness to 5 mm.
      2. Click on Move in the ribbon to place the cylinder on the posterior skin surface with slight embedding. Adjust its center to (10 mm, 10 mm), representing a horizontal and vertical distance of 10 mm from the origin.
      3. Duplicate the cylinder in the Model explorer and shift it rightward by 11 mm to position the second electrode at (21 mm, 10 mm). Repeat this process to create additional electrodes at (32 mm, 10 mm), (43 mm, 10 mm), and (54 mm, 10 mm).
      4. Copy the first electrode and shift it upward by 15 mm to position the second electrode at (10 mm, 25 mm). Repeat this process to generate electrodes at (10 mm, 40 mm), (10 mm, 55 mm), and (10 mm, 70 mm).
      5. Repeat this process, generate 25 electrodes (5 rows × 5 columns) within the first quadrant.
         NOTE: Each TI stimulation configuration uses four electrodes (two pairs) to deliver two kilohertz-frequency currents that interfere to create a low-frequency envelope in the spinal cord. To optimize placement, 25 configurations, each with four electrodes, are tested using a 5 x 5 grid of positions per quadrant, totaling 100 electrodes across all simulations. The size of the electrodes and the distance between electrodes in different groups are specified according to actual conditions, and this demonstration only provides an example.
   4. For the placement procedure of the second, third, and fourth quadrants, follow the same process. Upon completion, all 25 electrode pair configurations (a total of 100 electrodes) are arranged as shown in Figure 4.
   5. Rename electrodes systematically by right-clicking on the corresponding electrode in the Model explorer (e.g., "ROn" for first quadrant, "LOn" for second, "LBn" for third, "RBn" for fourth, where n is the group number from 1 to 25).
   6. Inspect electrode placement visually in the 3D model view. Adjust positions using the Move to ensure each electrode embeds slightly (0.5 mm) into the skin surface without gaps.
3. Simulation conditions setting
   1. Click on the Simulation tab and create a new simulation by clicking on New - EM LF Electro - Ohmic Quasi-Stat in the ribbon. Right click and rename it "LF-R1". Since TI stimulation operates at low frequencies, use "Ohmic Quasi-Stat" solver to consider only the quasi-static approximation.
   2. Click on the Setup panel under Simulation explorer, set the frequency to 1040 Hz.
   3. Drag the human model from the Multi-Tree into LF-R1 - Materials, which will automatically assign tissue-specific conductivity values at 1040 Hz (Table 1).
   4. In Boundary Conditions, modify the default Boundary settings to Flux by selecting Boundary Type and choosing Flux from the dropdown menu. Then, create two new "Boundary settings" by clicking on new setting and assign input voltages of +1 V and 0 V ( Figure 5).
      1. Assign the electrodes "RO1" and "RB1" to these settings by dragging them into the respective "Boundary Settings", respectively, indicating that "RO1" outputs +1 V while "RB1" serves as the return path.
   5. Retain the default settings for "Sensors" and adjust the Grid by setting Maximum Step to 1 mm and Geometry resolution to 1 mm, based on computational resources.
   6. Create a new simulation "LF-L1" by duplicating "LF-R1", set the frequency to 1000 Hz, and assign the electrodes "LB1" and "LO1" to the +1 V and 0 V "Boundary settings".
      NOTE: This setup mirrors "LF-R1" but with the opposite electrode configuration, generating the interference effect. All other settings remain unchanged. This completes the first electrode pair simulation setup .
   7. Duplicate LF-R1 and LF-L1, rename them as LF-R2 and LF-L2, and modify the Boundary settings to assign the corresponding electrodes. Remove prior electrodes from "Grid" and "Voxels" and add the new set for each pair. Repeat for all 25 groups.
   8. Once all simulations are configured, select all simulations in the Simulation tab, click on Auto Grid Update in the ribbon (Click on the Task Manager in the lower right corner. If the window indicates that the grid has been constructed, this confirms that the steps are proceeding normally), and then select Run - Batch Run to run all simulations simultaneously.
      NOTE: The frequencies of 1040 Hz (LF-R1) and 1000 Hz (LF-L1) are chosen to produce a low-frequency envelope of 40 Hz (1040 Hz - 1000 Hz) through interference, which is the effective stimulation frequency in the target spinal cord region for neuromodulation¹⁷.
4. Perform statistical analysis
   1. Click on the Analysis tab, select LF-R1 - Overall Field - Sensor Extractor, and click on Overall Field to generate an Overall Field .
   2. Click on Overall Field - EM E(x,y,z,f0) - Field Data Tools - Field Scaling to convert the electric field distribution from an input voltage of 1V to an input current of 1mA. The scale factor is determined as follows (Figure 6):
      1. In the Model tab, create a cubic volume (Block RO1) enclosing electrode RO1 by selecting Solids - Block in the ribbon and setting dimensions to fully encompass the electrode (e.g., 12 mm × 12 mm × 7 mm).
      2. Drag Block RO1 from the Multi-tree into the Analysis panel, generating two identical "Block RO1" modules.
      3. Select Overall Field under LF-R1 and the first Block RO1 in the Model explorer, then click on Surface and EM E(x,y,z,f0) simultaneously. Click on Flux Evaluator - List Viewer to display the "Total Flux" value. Compute the scale factor by dividing 0.001 by the Total Flux value.
   3. Repeat the same process for "LF-L1" .
   4. Multi-select LF-R1 and LF-L1 under Field Scaling in the Analysis explorer, then click on Max Modulation in the ribbon to couple the electric field distributions from the two electrode pairs. Set "Weight A" and "Weight B" to 2 to reflect 2 mA output per electrode pair (Figure 7).
   5. Extract the average electric field intensity in the target region of the spinal cord:
      1. Apply a "Mask Filter" by selecting Field Data Tools - Mask Filter in the ribbon to retain only the "Spinal Cord" region.
      2. Click on LF-R1 in the Analysis explorer and click on Field Data Tools - Crop in the ribbon to isolate the target spinal cord region (Figure 8).
      3. Click on Statistics - Table Viewer in the ribbon to display the average electric field intensity for the cropped region (Normal value range: 0.1-2 V/m).
   6. Repeat the process for all 25 electrode pair configurations and acquire the average electric field intensity at the target of all 25 groups .
   7. Compare the average electric field intensity for each configuration and identify the configuration with the highest intensity as the optimal setup.

3. Electrode positioning and device setup

1. Ask the SCI patient to sit comfortably on a chair with a backrest, ensuring their torso is upright and back exposed by removing or adjusting clothing.
2. Identify the vertebral level closest to the SCI site by palpating the spinous processes along the spine. Locate the C7 spinous process (prominent at the base of the neck) and count downward to the target vertebra (e.g., C5 is two vertebrae above C7). Mark the skin surface above the target vertebra's spinous process with a washable marker (58-7726, Crayola Inc.) to designate the origin¹⁸.
3. Based on the previously optimized electrode placement parameters (d₁, d₂), measure the four electrode positions using a flexible measuring tape. From the origin, measure d₁ horizontally (left and right) and d₂ vertically (up and down) to locate positions in the four quadrants: (d₁, d₂), (d₁, -d₂), (-d₁, d₂), (-d₁, -d₂). Mark each position with a washable marker.
4. Clean the skin at the marked electrode sites with alcohol wipes to remove oils and debris. Inspect the skin to ensure it is intact, with no cuts or abrasions. Apply 1.5 mL of conductive gel to each site using a syringe or applicator, spreading it evenly over a 10 mm diameter area.
5. Minimize tension on the electrode cables by securing excess cable length with tape. Suspend cables to hang naturally by attaching them to the chair or a nearby stand, reducing the risk of accidental detachment.
6. Attach the electrodes to the marked positions on the patient's back by pressing each Ag/AgCl electrode firmly onto the gel-covered skin. Secure each electrode with adhesive tape, covering the edges to prevent movement.
   NOTE: The right-side and left-side electrodes each form an electrode pair. Designate the right-side upper electrode as the anode and the lower electrode as the cathode. Designate the left-side upper electrode as the cathode and the lower electrode as the anode, forming a mirror-image configuration.
7. Once the electrodes are properly positioned and all connections are verified, power on the TI stimulator by pressing the power button. Click on Global Parameter Settings and configure the following stimulation parameters: Stimulation mode: tTIS, Stimulation type: Standard Stimulation, Total stimulation duration: 1200 s, Stimulation waveform: Sine wave by selecting the corresponding options in the menu.
8. Perform impedance measurement for the two selected stimulation channels. Click on Start Impedance Test to ensure that the impedance falls within the acceptable range (the stimulator will automatically stop output if the load impedance exceeds 12 kΩ). The optimal impedance range for effective stimulation is 6-8 kΩ.
9. Configure the stimulation frequency and output current amplitude for each channel. Channel 1: Frequency set to 1040 Hz, current amplitude set to 2 mA. Channel 2: Frequency set to 1000 Hz, current amplitude set to 2 mA¹⁵.

4. Stimulation

1. Ensure that the participant remains in a comfortable seated position throughout the procedure and remains fully conscious at all times.
2. Activate the stimulator by pressing the Start switch on the device's interface to initiate stimulation.
3. Monitor the patient's feedback during stimulation by asking them to report any sensations (e.g., tingling, discomfort). Reduce the current amplitude by 0.5 mA increments or pause stimulation immediately by pressing the Stop button if the patient reports significant discomfort or a strong stinging sensation.
   NOTE: Expect a mild tingling or itching sensation, which is a normal physiological response to transcutaneous electrical stimulation, as observed in this study and in prior research on similar techniques¹⁷. This sensation typically subsides within 2-3 min.

5. Postprocedural steps

1. After the stimulation session is completed, measure the impedance status again by selecting Start Impedance Test to assess changes post-stimulation. Record the values for comparison.
2. Verify the patient's physical stability by checking their balance and comfort while seated. Remove medical tape gently by peeling it slowly from the skin to avoid irritation. Detach electrodes carefully by lifting them from one edge.
3. Rinse electrodes with clean water under a faucet and air-dry them on a clean towel. Wipe the patient's skin at electrode sites with a damp paper towel to remove residual gel.
4. Administer a standardized questionnaire to the patient, asking about sensory changes (e.g., tingling, numbness), motor improvements, and adverse events (e.g., skin irritation, pain). Record responses for analysis¹⁹.

Results

When conducting TI simulations without errors, the average electric field intensity in the target spinal cord region stimulated by the current group of electrode pairs can be obtained. Taking Group 10 stimulating the C5 target area as an example (Figure 9), the "Volume Weighted Average" displayed in the interface is 0.50 V/m. Additionally, by clicking "Max Modulation - Mask Filter - Viewers - Surface Viewer", a 3D view of the electric field distribution on ...

Discussion

Critical steps

Setting up simulation conditions
When electrodes are placed on the surface of the human model's skin, the cylindrical electrodes are partially embedded into the skin to ensure there is no air gap between the electrodes and the skin. Otherwise, the current cannot pass through the air and into the human body. The distance from the electrode to the origin (d₁, d₂) is measured along the skin surface, as the skin is n...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
3T MRI or CT system	Siemens Healthineers	MAGNETOM Skyra (MRI) / SOMATOM X.cite (CT)
Adhesive Tape	3M	Durapore 1538-1
Alcohol Wipes	PDI Healthcare	S41125
Battery	Neurodome		Accessory of NervioX-1000
Computer	Dell Technologies	Precision 3660	16 GB RAM, multi-core processor
Electrically conductive gel	Soterix	HD-1AGE-12
Electrodes adapter	Neurodome		Accessory of NervioX-1000
Electromagnetic simulation software	ZMT Zurich MedTech AG	Sim4Life v8.0
Human simulation models	IT’IS Foundation	Virtual Population 3.0	Duke (Static) 3.0, Ella (Static) 3.0
Isopropyl Alcohol	Medline Industries	MDS098003Z
Measuring tape	Stanley Tools	33-725
Paper Towel	Kimberly-Clark	Kimwipes 34155
Syringe or Applicator	BD	305857
TI stimulator	Neurodome	NervioX-1000	Temporal Interference Stimulation Device
Two pairs of Ag/AgCl electrodes and cables	Shanhai Medical Ltd	SHTIS
Washable Marker	Crayola	58-7726