To the editor
We recently conducted a study examining whether transcranial electrical
stimulation (TES) motor threshold (MT), reverse-calculation transcranial direct
current stimulation (tDCS) electric field modeling, or both could potentially be
used as methods of individualizing tDCS doses(1). We found that TES MT significantly
correlates with a reverse-calculated tDCS dosage in the motor cortex and were
intrigued by the possibility of using TES MT as an MRI-free method of individually
dosing tDCS(1). A limitation of this previous work was that we did not test the
utility of TES MT to estimate reverse-calculation tDCS doses outside of the motor
cortex. Here we extend this research by assessing whether TES MT correlates with
reverse-calculation electric field models of prefrontal stimulation in a common
F3-F4 electrode montage that has been used in depression [2], drug craving [3], working
memory [4], and many other
conditions.
In this study we used the same dataset as in Ref. [1], in which we acquired transcranial
magnetic
stimulation (TMS) MT, TES MT, and anatomical T1w MRI scans for 29 healthy adults (15
women, mean age = 26.9, SD = 9.1). We previously described the two-visit study
protocol in depth in Ref. [1] but briefly
describe it here. In Visit 1, we placed a plastic cap on each participant’s
head and used a closed-loop TMS-motor evoked potential (MEP) acquisition setup using
single pulses of TMS (Magstim BiStim machine with 70mm figure-of-eight Remote Coil;
Whitland, Wales, UK) over the left motor hotspot and electromyography (EMG)
electrodes over the contralateral right hand [5]. We defined a positive MEP as having
a peak-to-peak amplitude of
≥0.05mV, and used PEST software (https://www.clinicalresearcher.org/software.htm)
to determine the
next stimulation intensity for MT acquisition [6]. After determining the TMS MT, we
cut through the plastic cap to
place a 35 × 20mm electrode (Natus Neurology Inc., Pleasanton, CA, USA) on
the head at the left motor hotspot and placed a 55 × 42mm electrode (Natus
Neurology Inc., Pleasanton, CA, USA) on the left deltoid. We used a Digitimer DS7A
(Letchworth Garden City, England, UK) to send single pulses of electrical
stimulation through the electrodes, with a pulse width of 200 ms, maximum voltage
of
400V, and initial stimulation intensity of 58.0mA. Using this left M1-left deltoid
electrode configuration and these stimulation parameters, TES was safe, tolerable,
and relatively pain-free for each participant (****See Supplemental Materials
S1 in Ref. [1] for tolerability and
pain ratings). In addition, a modified PEST algorithm allowed our determination of
a
TES MT for each participant with just 5 TES pulses [1].
In Visit 2, we acquired anatomical T1w MRI scans for each participant to be
used for electric field modeling. To segment each person’s MRI scan we used
headreco (https://simnibs.github.io/simnibs/build/html/documentation/command_line/headreco.html),
a command that calls SPM12 (https://www.fil.ion.ucl.ac.uk/spm/) and CAT12 (http://www.neuro.uni-jena.de/cat/)
and converts
NIFTI to MSH files [7]. Using previously
published methods, we used visual inspection and a Z-score analysis to evaluate the
quality of tissue segmentation of grey matter, white matter, and cerebrospinal fluid
(CSF) [1]. We did not identify any improper
segmentations in these data.
To perform electric field modeling, we used SimNIBS 3.1.1 (https://simnibs.github.io/simnibs/build/html/index.html)
[8] as it can be used to perform region of
interest (ROI) analyses and has been validated against ROAST [9]. We placed rectangular
70 × 50mm electrodes
over each participant’s F3 and F4, with the longer axis running left/right on
the head (Fig. 1A) and 2.0mA of current input
into F3 (anode) and −2.0mA for F4 (cathode). We extracted 10mm radius
spherical ROIs at MNI coordinates for the cortical projections underneath the
electrodes at F3 and F4. This method has previously been used to determine the MNI
coordinates of ROIs at the cortical level that underlie TMS coils placed on the
scalp(10)(Fig. 1A). We further measured an
ROI at the cortical projection midway between the two electrodes underneath Fz
[10]. Under each ROI, an average electric
field was computed using a grey matter mask. We then reverse-calculated the tDCS
dose at the scalp that would be required to produce the group average electric field
for each person using the cross-multiplication method detailed in Fig. 1B and regressed
the dose against the TES MT for each
person in SPSS 25.0 (Armonk, NY, USA: IBM Corp.).
The group average reverse-calculation doses were 2.045mA for the ROI
underneath F3 (range = 1.444–2.515mA, SD = 0.320mA), 2.036mA for the ROI
underneath F4 (range = 1.426–2.764mA, SD = 0.280mA), and 2.053mA for the ROI
underneath Fz (range = 1.545–2.445mA, SD = 0.351mA). TES MT significantly
correlated with the reverse-calculation dose based on the ROIs underneath F3, F(1,
27) = 12.03, R2 = 0.31, p = 0.002 and F4, F(1,27) = 6.55, R2 =
0.20, p = 0.016 and trended toward significance at the ROI underneath Fz, F(1, 27)
=
3.60, R2 = 0.12, p = 0.068 (Fig.
1C-E). We did not evaluate if TMS MT
correlates with prefrontal reverse-calculation doses as we previously found that TMS
MT did not correlate with reverse-calculation tDCS doses over the motor hotspot and
also that TMS MT only has a trending relationship with TES MT [1].
In sum, we conducted a complementary study to Ref. [1], finding that TES MT acquired
over the motor cortex
could help to estimate ROI-based reverse-calculation tDCS doses in the prefrontal
cortex. With further evaluation in larger sample sizes and in different populations
and disease states, TES MT holds promise as an MRI-free technique to individually
dose tDCS over not just motor areas [1] but
also for prefrontal stimulation. Evaluating MRI-free approaches to individualize
tDCS dosage would help to reduce the resources and cost that are required for
reverse-calculation tDCS modeling.
It is unclear why the reverse-calculation tDCS electric fields underneath F3
correlated more strongly with TES MT than underneath F4 or Fz. It may be due to the
TES MT being acquired over the same left hemisphere as the ROI underneath F3, rather
than between hemispheres (Fz) or in the right hemisphere (F4). The Fz location
between hemispheres may be particularly prone to variability since it could contain
a lower and more variable number of voxels between participants. Reverse-calculation
modeling and TES MT acquisition should be further refined and evaluated as methods
of individually dosing tDCS. Further research should investigate the use of
reverse-calculation tDCS modeling, TES MT, or both to prospectively dose tDCS.