DOI: 10.5061/dryad.qz612jmsh
title: Data for: Kilohertz Transcranial Magnetic Perturbation (kTMP): A new non-invasive method to modulate cortical excitability

description: Non-invasive brain stimulation (NIBS) provides a method for safely
 perturbing brain activity and has been employed in basic research to test
 hypotheses concerning brain-behavior relationships with increasing
 translational applications. We introduce and evaluate a novel subthreshold
 NIBS method: kilohertz transcranial magnetic perturbation (kTMP). kTMP is
 a magnetic induction method that delivers continuous kHz-frequency
 cortical electric fields (E-fields) which may be amplitude-modulated to
 potentially mimic electrical activity at endogenous frequencies. We used
 TMS to compare the amplitude of motor-evoked potentials (MEPs) in a hand
 muscle before and after kTMP. In Experiment 1, we applied kTMP for 10 min
 over the motor cortex to induce an E-field amplitude of approximately 2.0
 V/m, comparing the effects of waveforms at frequencies of 2.0, 3.5, or 5.0
 kHz. In Experiments 2 and 3, we used two forms of amplitude-modulated kTMP
 with a carrier frequency at 3.5 kHz and modulation frequencies of either
 20 or 140 Hz. The only percept associated with kTMP was an auditory tone,
 making kTMP amenable to double-blind experimentation. Relative to sham
 stimulation, non-modulated kTMP at 2.0 and 3.5 kHz resulted in an increase
 in cortical excitability, with Experiments 2 and 3 providing a replication
 of this effect for the 3.5 kHz condition. Although amplitude-modulated
 kTMP increased MEP amplitude compared to sham, no enhancement was found
 compared to non-modulated kTMP. kTMP opens a new experimental NIBS space,
 inducing relatively large amplitude subthreshold E-fields able to increase
 cortical excitability with minimal sensation.
description: # Data for: Kilohertz Transcranial Magnetic Perturbation (kTMP): A new
 non-invasive method to modulate cortical excitability Dataset DOI:
 [10.5061/dryad.qz612jmsh](10.5061/dryad.qz612jmsh) ## Description of the
 data and file structure **Apparatus** The **kilohertz transcranial
 magnetic perturbation (kTMP)** system consists of a high-amplitude current
 source, a TMS coil, and a control system. The same TMS coil may be
 connected to either the kTMP current source or to a commercial TMS pulse
 generator (MagVenture MagPro R30 with MagOption), permitting interleaved
 kTMP-TMS experiments and ensuring identical kTMP and TMS E-field
 distributions up to an amplitude scaling factor. The kTMP amplifier (AE
 Techron Model 7794) is a voltage-controlled current source capable of
 delivering up to 200 A to the coil. We used an actively-liquid-cooled
 figure-of-eight coil (MagVenture Cool-B65; inner and outer loop diameters
 of 35 mm and 75 mm, respectively). The kTMP control system consists of a
 personal computer (PC), an input/output PCI card, and a custom interface
 to read the coil’s built-in temperature sensor. Using a data acquisition
 toolbox (Mathworks R2018a), the PCI card was programmed to deliver analog
 input to the amplifier, thus specifying the temporal waveform of the
 E-field. The input waveform can either be at a fixed-amplitude sinusoidal
 frequency (non-modulated) or amplitude modulated. Bench testing indicated
 that the system, when running in kTMP mode, did not produce marked changes
 in coil temperature. As an added safeguard, the PCI card was set up to
 receive an analog input from the coil’s temperature sensor and create an
 automatic shutdown if the coil temperature exceeded 41° C, which is within
 the guidelines established by the International Electrotechnical
 Commission (IEC). In practice, for E-fields up to 2 V/m used in the
 present experiments, the coil temperature never rose above 32 °C during
 system operation. ## Procedure To evaluate the kTMP system as a new tool
 to modulate neuronal excitability, we measured the impact of kTMP on
 corticospinal excitability using suprathreshold TMS stimulation over the
 motor cortex. In brief, kTMP stimulation was preceded by two 4–7 min probe
 blocks and followed by three such blocks. In Exps 1 and 2, each block
 consisted of single-pulse TMS and two paired-pulse protocols, short
 intracortical inhibition and intracortical facilitation. In Exp 3, only
 the single-pulse TMS protocol was employed. ### kTMP For each carrier
 frequency, the current amplitude was selected to achieve a peak E-field
 amplitude of 2.0 V/m at a distance of 14 mm perpendicular to the coil
 surface, a distance we took to represent the approximate depth of the
 motor cortex from the overlying scalp. The current amplitude needed to
 obtain the required E-field amplitude is estimated as follows. The E-field
 amplitude, *E*0 (units of V/m), is proportional to the frequency, *fc*
 (units of Hz), and amplitude *I* (units of A) of the current source
 according to:
 ![](https://prod--epp.elifesciences.org/iiif/2/92088%2Fv2%2Fcontent%2F465477v4_ueqn1.gif/full/max/0/default.jpg) For the MagVenture Cool-B65 coil used in the kTMP system, *E*0 = 185 V/m when *fc* = 3570 Hz (280 μs biphasic TMS pulse) and *I* = 6950 A. From these reference values, we estimate *k*: ![](https://prod--epp.elifesciences.org/iiif/2/92088%2Fv2%2Fcontent%2F465477v4_ueqn2.gif/full/max/0/default.jpg) where V, s, A, and m correspond to volts, seconds, amperes, and meters, respectively. We verified the accuracy of our estimates within a 5% error using E-field measurements obtained from a triangular probe following the method of Nieminen. ### Experiment 1. Non-Modulated kTMP We used a within-subjects design, testing each participant on each of four kTMP stimulation conditions, with the order counter-balanced across participants. For three of the conditions, the carrier frequency (2 kHz, 3.5 kHz, 5 kHz) was paired with an intensity to create an E-field at the superficial aspect of the hand area of the motor cortex of *E*0 = 2 V/m. We set the non-modulated E-field to be a sine wave with frequency *fc*: ![](https://prod--epp.elifesciences.org/iiif/2/92088%2Fv2%2Fcontent%2F465477v4_ueqn3.gif/full/max/0/default.jpg) Note that we did not adjust for individual differences in scalp-to-cortex distance. For the sham condition, we used a 3.5 kHz carrier frequency producing a 0.01 V/m E-field at the approximate distance of the cortical surface. ### Experiments 2 and 3. Amplitude-Modulated kTMP (AM kTMP) For Exps 2 and 3, we again used a within-subjects design, testing each participant in four sessions. Two of the conditions were repeated from Exp 1: the 3.5 kHz non-modulated kTMP condition at 2 V/m and the sham condition. For the other two conditions, the carrier frequency was set at 3.5 kHz, and the waveform was amplitude modulated (AM) at modulation frequencies of either 20 Hz or 140 Hz. The 3.5 kHz carrier frequency was chosen since we had obtained the largest effect size compared to sham at this frequency in Exp 1. We selected the 20 Hz modulation frequency, given the relevance of beta to motor function, and the 140 Hz modulation frequency based on literature concerning ripple effects at this frequency. The peak cortical E-field amplitude for the AM conditions was 2 V/m, identical to the non-modulated condition. Note that the inclusion of the 3.5 kHz non-modulated condition and sham for both experiments provides two replications of these conditions from Exp 1 as well as points of comparison for the AM kTMP conditions. Exps 2 and 3 differed in the form used for amplitude modulation. In general, an amplitude-modulated current can be written as ![](https://prod--epp.elifesciences.org/iiif/2/92088%2Fv2%2Fcontent%2F465477v4_ueqn4.gif/full/max/0/default.jpg) where *A*(*t*) is a time dependent amplitude modulation factor. A popular form used in communications systems is: ![](https://prod--epp.elifesciences.org/iiif/2/92088%2Fv2%2Fcontent%2F465477v4_ueqn5.gif/full/max/0/default.jpg) where *f*(*t*) is the signal one wishes to convey between two components of a system, and the ratio *m*⁄*a* is the modulation index. The modulation index is typically chosen to suit the proposed means of demodulation. In *Experiment 2,* we used *f*(*t*) = sin(2π*fmt*) and an infinite modulation index. Correspondingly, the E-field has a time dependence of the form: ![](https://prod--epp.elifesciences.org/iiif/2/92088%2Fv2%2Fcontent%2F465477v4_ueqn6.gif/full/max/0/default.jpg) where *fm* is the modulation frequency. In Experiment 3, we used *f*(*t*) = sin(2π*fmt*) and a modulation index of one. ![](https://prod--epp.elifesciences.org/iiif/2/92088%2Fv2%2Fcontent%2F465477v4_ueqn7.gif/full/max/0/default.jpg) Although the same modulation frequencies are used to calculate *EAM*1 and *EAM*2they differ with respect to the spectrum of their upper envelope, the frequency of which we refer to as the burst repetition frequency (*fb*). For *EAM*1, the burst repetition frequency is double that of the modulation frequency, whereas for *EAM*2, the burst repetition frequency and the modulation frequency are matched. The burst repetition frequency may be an important parameter in determining the neural effects of kTMP. ### TMS: Hotspot and Threshold Procedure (Session 1) Single-pulse TMS was applied over the left hemisphere primary motor cortex to determine the resting motor threshold (rMT) for the first dorsal interosseous muscle (FDI) in the right hand. We focused on FDI since it is relatively easy to isolate in all individuals, and threshold values are stable across test sessions. The TMS coil was placed tangentially on the scalp with the handle pointing backward and laterally at 45° from the midline. TMS was administered with a biphasic pulse waveform with a posterior–anterior direction of the second, dominant phase of the induced current. The stimulator intensity was initially set to 30% of maximal stimulator output, and single pulses were generated at 5 s intervals, with the experimenter visually monitoring the electromyography (EMG) output for MEPs. If no MEPs were detected after 2 or 3 pulses, the experimenter moved the coil a few mm. If a search over the candidate area failed to produce any MEPs, the stimulator output was increased (step size of 3%), with the location search repeated. Once MEPs were detected, a more focused search was conducted to identify the optimal location for eliciting MEPs. This location was registered in three-dimensional space relative to the subject’s head using the Brainsight neuronavigation system to ensure consistent coil position during and between experimental sessions. rMT was defined as the minimum TMS intensity required to evoke MEPs of at least 50 µV peak-to-peak amplitude on 5 of 10 consecutive trials. The mean threshold was 58% (SD = 11.3%), 63% (SD = 11.1%), and 56% (SD = 9.2%) of maximum stimulator output in Experiments 1, 2, and 3, respectively. We repeated the threshold procedure in each of the kTMP sessions to capture possible intra-individual baseline changes in the cortico-excitability of the participants. In practice, the individual’s threshold values remained very stable across days (SD = 2.4%). ### TMS Assays of Corticospinal Excitability (Sessions 2-5) For Exps 1 and 2, each of the five probe blocks (two pre-kTMP and three post-kTMP) included single-pulse TMS (SP), and two paired-pulse protocols: short intracortical inhibition (SICI) and intracortical facilitation (ICF). Similar to SP, paired pulse protocols were administered with biphasic pulse waveforms with a posterior–anterior direction of the second, dominant phase of the induced current. These three protocols have been widely used in prior studies designed to evaluate the efficacy of tES and rTMS methods in altering neural excitability. For SP, the stimulation level was set at 120% of rMT. For the paired-pulse assays, the suprathreshold pulse was preceded by a subthreshold conditioning stimulus set at 80% of rMT, with an interstimulus interval (ISI) of 3 ms or 10 ms for SICI and ICF, respectively. The probe block consisted of 90 trials, 30 for each of the three assays, with the order randomized within the block. For Exp 3, the five probe blocks consisted only of the single-pulse TMS assay. We made this decision after finding that kTMP had no effect on SICI or ICF in Exps 1 and 2. We lengthened the breaks between blocks in Exp 3 to match the timing of the three post blocks relative to kTMP stimulation in the first two experiments. We developed a system to read and record the spatial and angular position of the coil with respect to the hotspot in real time from Brainsight. This information was recorded at the time of each TMS pulse and used to exclude trials in which the coil was distant from the hotspot or the angle had changed from the optimal hotspot orientation. ### EMG EMG activity was recorded (Bagnoli-8 EMG System, Delsys Inc.) from surface electrodes placed over the right FDI muscles, with a reference electrode over the right elbow. The experimenter visually inspected the EMG traces on a monitor to ensure that the participant remained relaxed (i.e., negligible EMG background activity in FDI), to detect the presence or absence of MEPs in response to the TMS pulses, and, since kTMP is a novel brain stimulation modality, to monitor for safety by checking for after discharges or other features suggesting excessive increase in excitability that could evolve into a seizure. The EMG signal was amplified and bandpass filtered online between 20 and 450 Hz. The signals were digitized at 2000 Hz for offline analysis. All EMG measures were analyzed with custom scripts written in MATLAB 2018a. EMG was recorded continuously during the experiment. Offline, data were segmented based on a TTL pulse from the TMS system recorded by the EMG amplifier on an auxiliary channel. ### Brainsight Sessions were cancelled if we could not use Brainsight to target the located hotspot during TMS pulses and during kTMP. There were some technical issues where, for some sessions, Brainsight was working online, but we were not able to record the coordinates during the TMS pulses to analyze offline. These sessions were still included, but we could not clean the data based on the BrainSight coordinates for these sessions.  ### Files and variables #### File: Exp3.csv **Description:** Motor evoked potentials from single pulse TMS before and after 10 minutes of kTMP ##### Variables * sub - Refers to the subject number (e.g., P01) * session - Refers to the order of the session (e.g., 1 = first session, 2 = second session, etc) * condition - Refers to the kTMP condition that was run in the session.  * 3500 = Non-modulated kTMP at 3.5 kHz (e-Field = 2 V/m). * 20AM = Amplitude modulated kTMP at 20 Hz with a carrier frequency of 3.5 kHz (e-field = 2 V/m). * 140AM = Amplitude modulated kTMP at 140 Hz with a carrier frequency of 3.5 kHz (e-field = 2 V/m).  * Sham = Non-modulated kTMP at 3.5 kHz (e-Field = 0.01 V/m) * block - Refers to the block order * pre1 = first block before kTMP * pre2 = second block before kTMP * pst1 = first post block after kTMP * pst2 = second post block after kTMP * pst3 = third post block after kTMP * trial number - refers to the number in the current block * mep - refers to the peak-to-peak motor evoked potential amplitude of the current trial * emg_sd - refers to the standard deviation of the 100ms of EMG activity directly before the TMS pulse #### File: Exp2.csv **Description:**  ##### Variables * sub - Refers to the subject number (e.g., P01) * session - Refers to the order of the session (e.g., 1 = first session, 2 = second session, etc) * condition - Refers to the kTMP condition that was run in the session.  * 3500 = Non-modulated kTMP at 3.5 kHz (e-Field = 2 V/m). * 20AM = Amplitude modulated kTMP at 20 Hz with a carrier frequency of 3.5 kHz (e-field = 2 V/m). * 140AM = Amplitude modulated kTMP at 140 Hz with a carrier frequency of 3.5 kHz (e-field = 2 V/m).  * Sham = Non-modulated kTMP at 3.5 kHz (e-Field = 0.01 V/m) * block - Refers to the block order * pre1 = first block before kTMP * pre2 = second block before kTMP * pst1 = first post block after kTMP * pst2 = second post block after kTMP * pst3 = third post block after kTMP * trial number - refers to the number in the current block * tms_protocol - refers to the type of TMS pulse(s) **(ONLY FOR EXP1 and EXP2)** * 0 = single pulse TMS * 3 = paired pulse TMS with a 3 ms delay between the conditioning pulse and the test pulse * 10 = paired pulse TMS with a 10 ms delay between the conditioning pulse and the test pulse * mep - refers to the peak-to-peak motor evoked potential amplitude of the current trial * emg_sd - refers to the standard deviation of the 100ms of EMG activity directly before the TMS pulse Brainsight coordinates: Available for some datasets, but not all, due to some technical issues during the experiments.  * target error - The shortest distance from the coil to the marked hotspot (mm) * angular error - The tilt error of the tool with respect to the initial path to the target. * twist error - The rotation error of the tool with respect to the initial path to the target. * loc_x - X values of the location of the tracked tool at the time the sample was taken. * loc_y - Y values of the location of the tracked tool at the time the sample was taken. * loc_z - Z values of the location of the tracked tool at the time the sample was taken. * Disttotarget - The straight line distance from the coil reference point to the target. * r1 - Euler's angle 1 (rotation in X) * r2 - Euler's angle 2 (rotation in Y) * r3 - Euler's angle 3 (rotation in Z) #### File: Exp1.csv **Description:**  ##### Variables * sub - Refers to the subject number (e.g., P01) * session - Refers to the order of the session (e.g., 1 = first session, 2 = second session, etc) * condition - Refers to the kTMP condition that was run in the session.  * 3500 = Non-modulated kTMP at 3.5 kHz (e-Field = 2 V/m). * 20AM = Amplitude modulated kTMP at 20 Hz with a carrier frequency of 3.5 kHz (e-field = 2 V/m). * 140AM = Amplitude modulated kTMP at 140 Hz with a carrier frequency of 3.5 kHz (e-field = 2 V/m).  * Sham = Non-modulated kTMP at 3.5 kHz (e-Field = 0.01 V/m) * block - Refers to the block order * pre1 = first block before kTMP * pre2 = second block before kTMP * pst1 = first post block after kTMP * pst2 = second post block after kTMP * pst3 = third post block after kTMP * trial number - refers to the number in the current block * tms_protocol - refers to the type of TMS pulse(s) **(ONLY FOR EXP1 and EXP2)** * 0 = single pulse TMS * 3 = paired pulse TMS with a 3 ms delay between the conditioning pulse and the test pulse * 10 = paired pulse TMS with a 10 ms delay between the conditioning pulse and the test pulse * mep - refers to the peak-to-peak motor evoked potential amplitude of the current trial * emg_sd - refers to the standard deviation of the 100ms of EMG activity directly before the TMS pulse Brainsight coordinates: Available for some datasets, but not all, due to some technical issues during the experiments.  * target error - The shortest distance from the coil to the marked hotspot (mm) * angular error - The tilt error of the tool with respect to the initial path to the target. * twist error - The rotation error of the tool with respect to the initial path to the target. * loc_x - X values of the location of the tracked tool at the time the sample was taken. * loc_y - Y values of the location of the tracked tool at the time the sample was taken. * loc_z - Z values of the location of the tracked tool at the time the sample was taken. * Disttotarget - The straight line distance from the coil reference point to the target. * r1 - Euler's angle 1 (rotation in X) * r2 - Euler's angle 2 (rotation in Y) * r3 - Euler's angle 3 (rotation in Z) ## Code/software All EMG measures were analyzed with custom scripts written in MATLAB 2018a. EMG was recorded continuously during the experiment. Offline, data were segmented based on a TTL pulse from the TMS system recorded by the EMG amplifier on an auxiliary channel.  After the data was segmented custom Matlab scripts were used to perform analyses: Trials were excluded from the analysis based on the following criteria: 1) If the MEP amplitude was 2.5 standard deviations above or below the mean, with the mean and standard deviation calculated separately for each TMS assay (SP, ICF, SICI) for each probe block. 2) If the Brainsight recording indicated that the coil was more than 3 mm (Euclidean distance) from the optimal hotspot location or had an angular or twist error of more than 5° from the optimal trajectory angle. 3) If the noise in the EMG signal 100 ms before the TMS pulse exceeded 2.5 standard deviations of the mean EMG signal. On average, 10% (SD = 3%) of the trials were excluded per participant, with a range of 4.8% to 20%. After cleaning the MEP data, there were a minimum of 20 MEP measures per protocol in each assessment block for each individual, a sufficient number for performing the MEP analyses. Raw MEP amplitudes were log-transformed to normalize the distribution of MEP amplitudes. The average log-transformed MEP amplitude was then calculated for each of the three TMS protocols in each probe block on an individual basis. After averages were calculated, the data were exponentiated to get the MEPs back to an easily interpreted scale (i.e., mV). SICI and ICF measures were calculated by computing a ratio of the paired-pulse MEP average over the single-pulse MEP average for each block. For all three TMS assays, the effect of kTMP stimulation was operationalized as the average percent change post-kTMP relative to the two baseline blocks (averaged). For example, a value of 0% would indicate no change in single-pulse MEP amplitude from pre- to post-stimulation, whereas a value of 100% would indicate the single-pulse MEP amplitude doubled from pre- to post-stimulation. Thus, the main analysis focuses on the three post-kTMP stimulation probe blocks for each of the three TMS assays (SP, SICI, ICF). These custom analysis scripts, along with the code to reproduce Figures 4 and 5 from the paper, are publicly available at [https://github.com/cmerrick15/kTMP_MEP_Analysis](https://github.com/cmerrick15/kTMP_MEP_Analysis).  ## Access information N/A ## **Versions** **21-Aug-2025:** Corrected an error in the previous dataset. In experiment 3, participant 10 accidentally had condition 3500 labeled as the 140 Hz condition. This error occurred when unblinding the dataset to publicly post it, and is not what was analyzed in the paper. The next version has the correct labels for participant 10.  ## Human subjects data Participant data is coded as P01, P02 etc, no identifying information is contained within the datasets.