Distilling the source of Transcranial evoked potentials: Test Plan

One method of analysis of the effects and neurological mechanisms of TMS is

transcranial evoked potential (TEP) analysis. TEPs are most commonly recorded by
EEG over many trials, then averaged over to increase the signal to noise ratio. Some
limitations of EEG include poor spatial resolution and limited bandwidth (~1-50 Hz).
TMS-ECoG (or iEEG) allows for an improved signal to noise ratio, increased spatial
resolution, and improved bandwidth (~0-200 Hz).

The similarities between TEPs from TMS protocols and somatosensory sham
stimulations have sparked a discussion in the scientific community [1], [2]. Conde et al.
[1] argue that the amplitude, timing, and spatial distributions of active TMS compared
to sham TMS are similar using amplitude correlation analysis. Belardinelli et al. [2] have
responded by pointing out that the study [1] used a smaller coil (outer winding
diameter 45 mm vs 70-90mm) which activated a smaller cortical volume given an
equivalent E-field. Also, the study [1] used a cephalic common reference as opposed to
an average reference which Belardinelli et al. argue caused an attenuation in the
measurement of earlier TEP components. Conde et al.’s findings are not congruent with
previous studies (e.g. [3]), this highlights the need to share data and use consistent
study parameters.

Some TEPs components are at least partially contributed to by somatosensory or

auditory responses. The P30 and P55 TEP components, exhibiting frontal positivity, are
contributed by the auditory sensation of the coil click [4]. An auditory N1-P2 complex is
also seen, corresponding closely to N100 and P180 components [5]. These are
contributed by the air and bone-conducted sound of the coil [4]. Sensory evoked
potentials through the trigeminal nerve occurs first at 70 ms [5]. Trigeminal
somatosensory stimulation is another effect of TMS. The largest peak-to-peak
amplitudes (<4 μV) of trigeminal SEPs occur in the first 80 ms with weaker amplitudes
in later components [5]. Belardinelli et al.’s criticism of [1] implies that the largest effect
of TMS occurs in earlier latencies (<70 ms). However, further work needs to be done to
characterize the contributions to each component spatially distributed TEPs from
auditory and somatosensory responses during TMS, that incorporates the feedback
from [2] to use consistent protocols with other research groups.

TMS has been shown to modulate brain behavior as opposed to sham stimulation
through other analyses including power, connectivity, and complexity analyses. Using
these analyses, which often use long time-samples after stimulation, the effects of active
TMS are often more easily explicitly decoupled from the sham condition than in TEP
amplitude analysis. Using TMS-ECoG may make this analysis easier due to its ability to
locate signals more accurately with high temporal resolution, thus being able to observe
the propagation of signals through space.

The first proposed test is to use existing data to compare sham and active stimulation.
This will give us a glimpse into the data and help develop future controlled
experiments.

First Test:
Using the data from 0.5 Hz stimulation in various locations on many patients, we
propose a TEP analysis of active with respect to sham stimulation across the brain. The
current data (March 2019) available includes nine patients, of which four patients
received DLPFC stimulation, five patients received Parietal stimulation, four patients
received STG stimulation, and one patient received stimulation at the precuneus. There
is overlap of patients between these groups. An amplitude analysis will compare global
mean field and local amplitudes of sham vs. active stimulation to EEG data published in
the literature. Time-frequency analysis can also provide more information on
differences at higher frequencies (>80Hz). Sham conditions used and the stimulation
parameters will be noted to determine equivalency to other studies.

This exploratory test will use amplitude correlation analysis to compare the TEPs from
sham and active protocols. The null hypothesis is that the active and sham stimulations
are very similar across all areas of the brain. A paired t-test can be used to test the Fisher
z-transformed correlation coefficients from various electrode locations. One challenge
will be finding electrodes with consistent locations across patients, and global fields
may also need to be considered.

Questions for University of Iowa:

What are the coil size and distance parameters in the active stimulation protocol?

What was the nature of the sham protocol?

[1] V. Conde et al., “The non-transcranial TMS-evoked potential is an inherent source

of ambiguity in TMS-EEG studies,” Neuroimage, 2019.
[2] P. Belardinelli et al., “Reproducibility in TMS–EEG studies: A call for data sharing,
standard procedures and effective experimental control,” Brain Stimul., vol. 12,
no. 3, pp. 787–790, 2019.
[3] M. Rosanova, A. Casali, V. Bellina, F. Resta, M. Mariotti, and M. Massimini,
“Natural Frequencies of Human Corticothalamic Circuits,” J. Neurosci., vol. 29, no.
24, pp. 7679–7685, 2009.
[4] S. Komssi and S. Kähkönen, “The novelty value of the combined use of
electroencephalography and transcranial magnetic stimulation for neuroscience
research,” Brain Res. Rev., vol. 52, no. 1, pp. 183–192, 2006.
[5] V. Nikouline, J. Ruohonen, and R. J. Ilmoniemi, “The role of the coil click in TMS
assessed with simultaneous EEG,” Clin. Neurophysiol., 1999.