e40 Society Proceedings / Clinical Neurophysiology 124 (2013) e39–e187
IS 3. TMS field modelling-status and next steps—A. Thielscher
(Copenhagen University Hospital Hvidovre, Danish Research
Center for Magnetic Resonance, Copenhagen, Denmark, Technical
University of Denmark, Kgs. Lyngby, Denmark, Max-Planck-
Institute for Biological Cybernetics, Tübingen, Germany)
In the recent years, an increasing number of studies used geomet-
rically accurate head models and finite element (FEM) or finite
difference methods (FDM) to estimate the electric field induced by
non-invasive neurostimulation techniques such as transcranial mag-
netic stimulation (TMS) or transcranial weak current stimulation
(tCS; e.g., Datta et al., 2010; Thielscher et al., 2011). A general out-
come was that the field estimates based on these more realistic
models differ substantially from the results obtained with simpler
head models. This suggests that the former models are indeed
needed to realistically capture the field distribution in the brain.
However, it is unclear how accurate even these more advanced mod-
els are and, in particular, to which extent they allow predicting the
physiological outcome of stimulation. An experimental validation
of the novel methods for field calculation is thus necessary.
Focusing on motor cortex stimulation by TMS, our goal is to
explore to which extent the field estimates based on advanced mod-
els correlate with the physiological stimulation effects. For example,
we aim at testing whether interindividual differences in the field
estimates are also reflected in differences in the MEP responses. This
would indicate that the field calculations accurately capture the
impact of individual macroanatomical features of the head and brain
on the induced field distribution, in turn strongly supporting their
plausibility.
Our approach is based on the SimNIBS software pipeline
(www.simnibs.de) that allows for the automatic creation of accurate
head models from structural and diffusion-weighted magnetic reso-
nance images (MRI) (Windhoff et al., 2011). This enables us to perform
field calculations for multiple subjects, as required in neuroscientific
studies. We substantially improved the software in order to improve
its usability in a group analysis. At the moment, we are performing
field calculations and are acquiring motor mapping data in a group
of subjects for a systematic comparison of both data sets.
I will give an overview on the status of the SimNIBS project. I will
start by summarizing the key findings on how the individual brain
anatomy shapes the electric field induced by TMS (Thielscher
et al., 2011; Opitz, 2011). The putative link between the modeling
results and basic physiological TMS effects is highlighted. I will then
introduce the novel features of SimNIBS that include the import of
coil positions from neuronavigation systems, improved support for
diffusion-weighted MRI and transformation of the estimated fields
into MNI space for group analysis. Preliminary results on the com-
parison between field estimates and motor mapping data will be
presented.
To summarize, field estimates based on accurate head models
have already proven highly useful for a better understanding of
the biophysics of non-invasive brain stimulation. The improved soft-
ware tools now allow for systematic tests of the links between the
estimated fields and the physiological effects in multi-subject stud-
ies. This will give the knowledge needed, e.g., for a more accurate
spatial targeting of specific brain areas by TMS.
References
Datta A, Bikson M, Fregni F. Transcranial direct current stimulation in patients with
skull defects and skull plates: high-resolution computational FEM study of factors
altering cortical current flow. Neuroimage 2010;52(4):1268–78.
Thielscher A, Opitz A, Windhoff M. Impact of the gyral geometry on the electric field
induced by transcranial magnetic stimulation. Neuroimage 2011;54(1):234–43.
Windhoff, M., A. Opitz, and A. Thielscher, Field calculations in brain stimulation based
on finite elements: An optimized processing pipeline for the generation and usage
of accurate individual head models. Human Brain Mapping, 2011. epub.
Opitz A et al. How the brain tissue shapes the electric field induced by transcranial
magnetic stimulation. Neuroimage 2011;58(3):849–59.
doi:10.1016/j.clinph.2013.04.022
IS 4. Modelling TBS—Y.-Z. Huang (Chang Gung University, Taipei,
Taiwan)
Theta burst stimulation, a form of repetitive transcranial mag-
netic stimulation, can induce lasting changes in corticospinal excit-
ability through plasticity-like mechanisms on cortical synapses.
Interestingly, the direction of the effect on synaptic efficiency
depends on whether the bursts are delivered continuously (cTBS,
producing long-term depression (LTD)-like effects) or intermittently
(iTBS, producing long-term potentiation (LTP)-like effects). We
firstly built a simple phenomenological model based on knowledge
of calcium-dependent mechanisms of post-synaptic plasticity to suc-
cessfully explain this by postulating (1) that burst stimulation
induces a mixture of excitatory and inhibitory effects, (2) those
effects may cascade to produce long-lasting effects and (3) the final
effect of TBS (potentiation or depression) depends on the summation
of these two effects.
Furthermore, we went onto extend the model by including spike
timing dependent plasticity with detailed calcium dynamics based
on kinetic equations that mimic protein kinase interactions at the
cellular and molecular levels. However, the post-synaptic calcium
dependent plasticity model alone was not sufficient for describing
diverse plasticity effects aroused by different rTMS protocols. We
then further recruited the pre-synaptic mechanism for the extended
model, because we noticed that shot-term pre-synaptic depression
due to vesicle depletion could play a critical key in the regulation
of long-term plasticity in post-synaptic neurons. In results, the
new improved synaptic model has successfully simulated not only
the results of TBS but also those of conventional rTMS protocols.
doi:10.1016/j.clinph.2013.04.023
IS 5. Clinical efficacy of non-invasive transorbital alternating
current stimulation in optic neuropathy: A double-blind,
randomized, sham-controlled multi-center study—C. Gall a,
A. Federov a,b, A. Antal c, M. Schittkowski d, S. Kropf e, A. Mante f,
S. Schmidt f, B. Sabel a (a University of Magdeburg, Medical Fac-
ulty, Institute of Medical Psychology, Magdeburg, Germany, b EBS
Technologies GmbH, Kleinmachnow, Germany, c Georg-August
University Göttingen, Department of Clinical Neurophysiology,
Göttingen, Germany, d Georg-August University Göttingen,
Department of Ophthalmology, Göttingen, Germany, e University
of Magdeburg, Medical Faculty, Institute of Biometry and Medical
Informatics, Magdeburg, Germany, f Universitätsmedizin Charité,
Department of Neurology, Berlin, Germany)
Question: Non-invasive brain current stimulation enhances neuro-
nal plasticity in the visual system both in normal subjects and in
patients with visual field loss (Antal et al., 2012; Sabel et al.,
2011). In order to improve visual functions in patients with optic
nerve damage we have now validated the efficacy of repetitive trans-
orbital alternating current stimulation (rtACS) for the treatment of
optic nerve damage in a randomized, multi-center clinical trial.
Methods: A total of 98 patients were randomized in rtACS and
sham group using stratified block randomisation considering the
study center (3 levels) and the defect depth of visual fields at base-
line (2 levels) as a potential prognostic factor. Patients were stimu-
lated with 4 stimulation electrodes positioned near the closed eyes
on 2  5 consecutive weekdays for 25–40 min daily with square
 Society Proceedings / Clinical Neurophysiology 124 (2013) e39–e187
pulse rtACS at 125% of individual phosphene threshold based on a
preceding parameter optimization study (reported in an accompany-
ing abstract). The sham group received a “minimal dose” of short-
lasting single pulse phosphenes once per minute. Diagnostic sessions
assessing visual field parameters, reaction times, visual acuity, and
EEG were conducted 2 days before and after stimulation and at a
2-months follow-up. Eighty-two patients were finally included in
the analyses.
Results: The primary analysis was directed to the comparison of
percentage changes in detection rates in visual field diagnostics
using the high resolution perimetry method (HRP) between the
two treatment arms (rtACS vs. sham) with a significant difference
in favor of rtACS (p = 0.011; one-sided Mann–Whitney U). RtACS-
treated patients showed significant improvements after treatment
(Hodges–Lehmann estimator for median increase 6.4%, 95%–CI
(2.9%, 11.6%); p < 0.001 (Wilcoxon signed rank test one-sided). No
significant change was seen in the sham-group (median change
1.1%, 95%–CI ( 2.0%; 4.3%); p = 0.256. Due to a higher number of
responders in the rtACS-group the mean improvement of visual
fields was larger for visual field parameters after rtACS (23.96%)
compared to sham (2.53%). RtACS-induced visual field changes were
stable at a 2-months follow-up. Secondary perimetry measures con-
firmed this result, the most pronounced visual field changes being
located in the central 5°. Covariance analysis for the logarithms of
visual field change parameters did not reveal any significant differ-
ences between the study centers, neither as main factor nor as inter-
action with the treatment arm. EEG findings are reported in an
accompanying abstract.
Conclusions: RtACS treatment led to visual field improvement in
patients with optic neuropathy suggesting that it is a viable clinical
tool to improve visual fields in patients with long-lasting visual field
loss. Together with the changes in EEG power spectra this finding
supports the notion that visual system plasticity can be altered by
non-invasive alternating current stimulation.
Funding: The study was funded by EBS Technologies GmbH (Klein-
machnow, Germany) and the University of Magdeburg.
References
Antal A, Paulus W, Nitsche MA. Electrical stimulation and visual perception. Restor
Neurol Neurosci 2012;29:365–74.
Sabel BA, Fedorov AB, Naue N, Borrmann A, Herrmann C, Gall C. Non-invasive
alternating current stimulation improves vision in optic neuropathy. Restor
Neurol Neurosci 2011;29:493–505.
doi:10.1016/j.clinph.2013.04.024
IS 6. Trials in psychiatry—A.J. Fallgatter a, T. Dresler a, A.-C. Ehlis a,
P. Zwanzger b, C. Plewnia a (a University of Tuebingen, Dept. of
Psychiatry, Tuebingen, Germany, b University of Muenster, Dept.
of Psychiatry, Muenster, Germany)
Objectives: Psychiatric disorders like depression, anxiety and
schizophrenias are currently mainly treated with pharmacothera-
peutic and psychotherapeutic methods. The success measured as
improvement of symptoms under pharmacotherapeutic and psycho-
therapeutic treatment strategies is surprisingly good with high effect
sizes (>0.8) in randomized controlled trials. However, there is still
room and need for improvement.
Methods: Non-invasive brain stimulation methods like repetitive
transcranial magnetic stimulation (rTMS) and transcranial direct
current stimulation (tDCS) are increasingly applied (1) in combi-
nation with neuroimaging methods like fMRI, NIRS or EEG in
order to better understand the pathophysiological background of
the above-mentioned psychiatric disorders or disorder-related
e41
symptoms and (2) as an alternative or add-on therapeutic
approach.
Results: Evidence from multiple studies with rTMS and in the last
years also with tDCS points to a major role of a dysfunction of the
lateral prefrontal cortex in depression and anxiety and of the tempo-
ral cortex in auditory hallucinations in schizophrenic patients. Treat-
ment protocols with rTMS and tDCS focussing on a functional
improvement of these brain regions in the respective disorders pro-
vide first evidence for a therapeutic application.
Conclusion: Both rTMS and tDCS are of increasing importance as
methods for an improved understanding of the brain pathophysiol-
ogy underlying depression, anxiety and schizophrenias as well as
methods suitable for a direct therapeutic application in these
disorders.
doi:10.1016/j.clinph.2013.04.025
IS 7. News about short interval intracortical inhibition (SICI)—R.
Hanajima (University of Tokyo Hospital, Neurology, Tokyo, Japan)
Conditioned transcranial magnetic stimulation (TMS) techniques
have been proposed to reflex many intracortical inhibition or facili-
tation mechanisms of the primary motor cotex (M1). Conditioning
stimuli (CS) at intensity below threshold over M1 suppressed MEP
to test stimuli given through the same coil at interstimulus intervals
(ISIs) of 1–5 ms (Kujirai methods). The inhibition is called as short
interval intracortical inhibition (SICI) and has been considered as
one of basic tool to evaluate cortical excitability changes.
1. Physiological features of SICI: SICI was reported to be a cortical
inhibition, because neither H-waves nor MEPs to transcranial electri-
cal stimulation were affected. Only later I-waves, probably induced
though several synapses in M1, are suppressed by CS, but I1-waves
are not. Pharmacological studies showed that GABAA mediated
mechanisms could contribute to SICI. The GABAergic inhibition,
however, lasts longer than 5 ms even though SICI lasts 5 ms. The
GABAergic inhibition may not explain SICI at all 1–5 ms intervals.
Inhibition at 1 ms interval mainly reflects the refractory period.
Those at 2–5 ms intervals may be produced mainly by GABAergic
inhibition. Another point to mind is the mask of inhibition by some
facilitation mechanisms. The intracortical facilitation overlaps GAB-
Aergic inhibition at later intervals, which must mask the longer part
of inhibition. Even at short intervals, short intervals intracortical
facilitation (SICF) overlaps it when the CS intensity is too high.
When the amount of SICI is reduced in the experiment, we should
not simply conclude that the GABAergic inhibition is reduced and
consider contamination of these cofounding mechanisms. We should
consider the possibility that the MEP could are composed mainly by
D-waves or I1-waves and the possibility that the some enhanced
intracortical facilitation mask normal inhibition.
I will present some example. SICI test showed inhibition reduc-
tion in Parkinson’s disease (PD) with usual Kujirai methods. How-
ever, when CS was set at 80% RMT, the amount of SICI at an ISI of
3 ms in PD was similar to that in healthy volunteers. Moreover,
when using TMS pulse with AP directed currents, normal inhibition
was induced and it continued longer than 5 ms probably because AP
directed currents produces mainly I3-waves. These findings sug-
gested that M1 GABAergic inhibition is not affected in PD, but some
confounding factors may affect the results of SICI experiment.
2. SICI and cortical plasticity: Repetitive TMS (rTMS) noninvasively
induces long lasting effects on M1. The lasting effects are considered
to be a kind of synaptic plasticity induction in cortical neurons. SICI
is used to evaluate the M1 excitability state after these inductions.
Conventional rTMS at 5 Hz enhances MEP size and reduces the
amount of SICI. However, prolonged 5 Hz rTMS with 1800 pulses
does not affect SICI, even though MEP is still enlarged. On the other