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2018
Modulation of motor cortical excitability with auditory stimulation
Löfberg, Olli
American Physiological Society
Tieteelliset aikakauslehtiartikkelit
© The American Physiological Society All rights reserved
http://dx.doi.org/10.1152/jn.00186.2017
https://erepo.uef.fi/handle/123456789/7027
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MODULATION OF MOTOR CORTICAL EXCITABILITY WITH AUDITORY STIMULATION 1
Olli Löfberga, Petro Julkunena,b, Elisa Kallioniemia,c, Ari Pääkkönena, and Jari Karhud,e 2
3
aDepartment of Clinical Neurophysiology, Kuopio University Hospital, Kuopio, Finland 4
bDepartment of Applied Physics, University of Eastern Finland, Kuopio, Finland 5
cDepartment of Clinical Radiology, Kuopio University Hospital, Kuopio, Finland 6
dNexstim Plc, Helsinki, Finland 7
eDepartment of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland 8
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Submitted to Journal of Neurophysiology as a Research Article 10
Running title: Auditory modulation of motor cortical excitability 11
Word count: 4827 (Abstract – Figure legends) 12
Corresponding author:
13
Olli Löfberg 14
Department of Clinical Neurophysiology 15
Kuopio University Hospital 16
POB 100 17
FI-70029 KYS, Kuopio, Finland 18
e-mail:olli.lofberg@gmail.com 19
tel.: +358405389077 20
21
Abstract 22
23
Loud sounds have been demonstrated to increase motor cortex excitability when transcranial 24
magnetic stimulation (TMS) is synchronized with auditory evoked N100 potential measured from 25
electroencephalography (EEG). The N100 potential is generated by an afferent response to sound 26
onset and feature analysis, and upon novel sound it is also related to the arousal reaction. Arousal 27
reaction is known to originate from the ascending reticular activating system of the brainstem and to 28
modulate neuronal activity throughout the central nervous system. In this study we investigated the 29
difference of motor evoked potentials (MEPs) when deviant and novelty stimuli were randomly 30
interspersed in a train of standard tones. Twelve healthy subjects participated in this study. Three 31
types of sound stimuli were used: 1) standard stimuli (800Hz), 2) deviant stimuli (560Hz) and 32
novelty stimuli (12 different sounds). In each stimulus sequence 600 stimuli were given. Of these, 33
90 were deviant stimuli randomly placed between the standard stimuli. Each of 12 novel sounds 34
was presented once in pseudo-randomized order. TMS was randomly mixed with the sound stimuli 35
so that it was either synchronized with the individual N100 or trailed the sound onset by 200 ms.
36
All sounds elicited an increase in motor cortex excitability. The type of the sound had no significant 37
effect. We also demonstrated that TMS timed at 200 ms interval caused a significant increment of 38
MEPs. This contradicted our hypothesis that MEP amplitudes to TMS synchronized with N100 39
would be greater than to TMS at 200 ms after a sound, and remains unexplained.
40 41
Keywords: Transcranial magnetic stimulation; neurophysiology; arousal; evoked potentials; auditory 42
43
New & Noteworthy 44
We demonstrated modulation of motor cortical excitability with parallel auditory stimulus by 45
combining navigated transcranial magnetic stimulation (TMS) with auditory stimuli. TMS was 46
synchronized with auditory evoked potentials considered to be generated by unconscious attention 47
call process in the auditory system.
48 49 50 51 52 53 54 55 56
1. Introduction 57
When a sudden roar from the dark reaches our auditory cortices the brain starts to evaluate if the 58
sound is important enough for conscious analysis. This process is executed simultaneously in 59
different areas of the central nervous system (CNS) processing the physical aspects of the sensory 60
stimulus and can be observed in the electroencephalography (EEG) as an auditory response N100.
61
N100 is an event-related potential (ERP) with a peak latency between 50 and 150 ms depending on 62
the individual (Näätänen and Picton 1987; Näätänen et al. 2011). A separate auditory response 63
called mismatch negativity (MMN) can occur right after the N100 and is generated by cortical 64
mechanisms comparing the sound with previous sounds (Näätänen et al. 2011). MMN can be 65
generated when a deviant sound follows a train of 2-3 standard sounds (Cowan et al. 1993), but it 66
can also be generated from violations in so complex sound patterns that the listener cannot 67
consciously point out the violation or even the pattern (Paavilainen et al. 2007). If the activated 68
unconscious attention call process is strong enough, the attention is drawn to the stimulus and 69
conscious analysis of the sound begins. The auditory response P3 (P3a and P3b) (Sutton et al. 1965) 70
has a peak latency at about 300 ms and is considered to be generated by novelty detection 71
mechanisms and top-down attention modulation (Sergent et al. 2005). Smaller negative potential 72
between N1 and P3 is called N2 and it can be divided into two subcomponents N2b and N2c.
73
Previously used term “N2a” has been replaced by MMN (Folstein and Van Petten 2008). N2 is 74
suggested to be elicited by cognition control and detection of mismatch of stimuli (Folstein and Van 75
Petten 2008).
76
Transcranial magnetic stimulation (TMS) is a non-invasive method for studying the excitability and 77
neural connections of the CNS (Barker et al. 1985). TMS mainly activates small pyramidal neurons 78
which activate the pyramidal tract via transsynaptic connections (indirect waves, I-waves) 79
(Amassian et al. 1987; Day et al. 1989; Di Lazzaro et al. 2004). Thus, the changes in motor evoked 80
potentials (MEPs) measured from a peripheral muscle reflect the transient changes in cortical 81
excitability. Previously, paired parallel stimulation targeted to the motor and sensory systems has 82
been shown to affect cortical excitability in the somatomotor system (Raij et al. 2008; Laaksonen et 83
al. 2012) demonstrating interaction between these two networks. Peripheral nerve stimulation 84
preceding TMS causes attenuation of MEPs with both short latencies of approximately 20 ms (short 85
afferent inhibition, SAI) (Tokimura et al. 2000) and longer latencies of 100-1000 ms (long afferent 86
inhibition, LAI) (Chen et al. 1999). The primary motor cortex (M1) is modulated by somatosensory 87
feedback relayed through thalamus (Iriki et al. 1991), but recently also short cortico-cortical 88
connections (U-shaped tracts) between sensory and motor cortices have been identified (Catani et 89
al. 2012). Raij et al. (2008) demonstrated that TMS targeted on the second somatosensory cortex 90
speeded up reaction times (RTs) suggesting that parallel input facilitates cortico-cortical 91
connections.
92
Distracting auditory stimuli have also been demonstrated to speed up RTs (Bidet-Caulet et al.
93
2015). Because auditory cortices and cortical motor areas are likely not connected via direct 94
cortico-cortical connections (Cammoun et al. 2014) this bottom-top modulation of motor system is 95
most likely induced by arousal reaction caused by a strong and sudden auditory stimulus (Moruzzi 96
and Magoun 1949; Whyte 1992; Fuller et al. 2011). A loud sound preceding TMS by 30–50 ms has 97
been shown to suppress MEPs in the hand muscles (Furubayashi et al. 2000). However, TMS 98
studies of hand centered peripersonal space (PPS) have demonstrated that the MEPs measured from 99
the hand muscles are facilitated when sound source’s distance from hand is less than 60 cm and the 100
sound precedes TMS by 50 ms (Serino et al. 2009; Finisguerra et al. 2015). This contradiction is 101
most likely caused by difference in sound intensity, as PPS studies have used low sound intensity of 102
70 dB to avoid startle reaction (Serino et al. 2009; Finisguerra et al. 2015). In our previous study we 103
demonstrated that TMS synchronized with the auditory N100 evokes significantly larger MEPs 104
when compared with TMS without a preceding sound (Löfberg et al. 2014). We concluded that the 105
sensory neuronal activity at the time of N100 overlaps the general arousal reaction, is capable of 106
increasing motor system excitability and has a relatively short time window for modulating the 107
motor system. In approximately 20 ms after the observed peak activation level in the auditory 108
sensory cortex the enhancement of motor excitability was already fading.
109
The aim of the present study was to investigate if deviant or novel sounds in a long train of standard 110
tones modulate the motor cortical system by activating early feature detectors (N100, MMN) or 111
later novelty detection processes (N2-P3a) mentioned earlier. We hypothesized that at the N100 112
time frame different tones would cause no difference in the MEPs but at the 200 ms the pre- 113
attentive feature analysis of the stimulus might cause a difference between the MEPs following a 114
standard or a deviant tone. Later ERPs respond to deviances or unexpected events in the 115
environment (El Karoui et al. 2015) so we selected time-point of 200 ms after the tone and targeted 116
the N2-P3a complex (Snyder and Hillyard 1976).
117 118 119 120
121
2. Experimental Procedures 122
Subjects 123
Twelve healthy right-handed volunteers (5 female, age range 22 – 35 year) were recruited. The 124
study was conducted in accordance with the Declaration of Helsinki and all procedures were 125
conducted with the informed consent of the subjects (permission 78/2014, Kuopio University 126
Hospital).
127 128
Stimulation protocol 129
Prior to the measurement session, the subjects underwent T1-weighted 3D magnetic resonance 130
imaging with a Siemens Magnetom Avanto (Erlangen, Germany). Individual MR data were used 131
for navigated TMS (nTMS). Measurement session began by measuring hearing threshold of the 132
subjects by gradually decreasing the sound intensity of the 800-Hz tone stimulus until the subject 133
could not hear the stimulus (Löfberg et al. 2014). The duration of the tone was 84 ms including 7 134
ms rise and fall times and the inter-trial interval (ITI) between the tones was 1 s. Subsequently, we 135
measured the cortical N100 responses in the EEG using the same tones and ITI of 1 s. The tones 136
were delivered to the right ear of the subject at 60 dB above the hearing threshold (85 dB being 137
minimal intensity for the sound stimulus).Neuroscan Stim Audio System P/N 1105 (Compumedics 138
Neurocan, El Paso, Texas, USA) was used for auditory stimulation. From the cortical responses, we 139
measured the N100 latency from the vertex electrode (Cz, Fig. 1) used later in the study. The 140
cortical responses to auditory stimuli were recorded with a 64-channel EEG amplifier (BrainAmp 141
DC, Brain Products GmbH, Gilching, Germany) at 5000 Hz. The EEG electrodes were referenced 142
to an electrode placed on the right mastoid. For online analysis, the EEG was bandpass filtered 143
between 1-40 Hz. During nTMS, electromyography (EMG) was recorded from the first dorsal 144
interosseous (FDI) muscle by using pre-gelled disposable Ag/AgCl surface electrodes and 145
integrated EMG device. The EMG was recorded with a 3 kHz sampling rate and band-pass filtered 146
to 10–500 Hz. The MEPs were measured from the resting muscle EMG as peak-to-peak responses.
147
The primary motor cortex area was then mapped using navigated TMS (eXimia 3.2.2, Nexstim Plc, 148
Helsinki, Finland) to locate the cortical representation area of right hand FDI. The mapping was 149
performed with a figure-of-eight coil (outer winding diameter of 70mm) and biphasic stimulation 150
waveform. During the mapping, the direction of the maximum induced current was perpendicular to 151
the nearest sulcus. The resting motor threshold (rMT) intensity was determined at the mapped target 152
using Motor Threshold Assessment Tool (MTAT 2.0) with 20 stimuli (Awiszus and Borckardt 153
2012). Threshold for an acceptable MEP amplitude in both mapping and rMT calculation was 50 154
µV. ITI of 5–7 s was used between the TMS-stimuli. Baseline MEPs were measured using 30 TMS 155
stimuli focused on the optimal stimulation target of the right hand FDI muscle with a randomized 156
ITI between 2.5 and 6 s to resemble the interval between TMS stimuli in the following stimulation 157
sequence.
158
Three types of sound stimuli were used: 1) standard (800Hz), 2) deviant (560Hz) and novelty (12 159
different sounds were varied). In each sound sequence 600 stimuli were given. Majority of the 160
stimuli were of standard type, while 90 were deviant randomly placed between the standard stimuli.
161
There were also 12 randomly placed novelty stimuli within these sequences. Inter-trial interval 162
between the sounds was 800 ms. This sequence was ran once for control purposes. In the 163
subsequent sequences TMS was randomly mixed with the sound stimuli with a latency of either 164
individual N100 (Figure 1) or 200 ms. Within each MMN sequence of 600 sound stimuli, 20 TMS 165
stimuli were randomly placed after standard stimuli, 20 TMS stimuli after deviant stimuli and 6 166
after novelty sound stimuli. The TMS protocol was conducted twice with each ISI using separately 167
randomized protocols. Therefore, there were altogether 92 TMS stimuli given with both latencies.
168
During the entire experiment, the subjects were instructed to keep their hands in rest and not to 169
focus their attention on the stimulation or muscle contraction. During the experiment, the subjects 170
watched a muted video.
171 172
Statistical analysis 173
Linear mixed model was used to determine whether there was a difference between the MEP 174
amplitudes between the sequences with or without sound accounting. Subsequently, post-hoc 175
analysis was used to detect differences between the different sounds. Absolute MEP amplitudes 176
were used in the comparisons as dependent variable, while subject identifier was used as the 177
random factor. The fixed parameters were used as fixed factors. A linear mixed model was applied 178
to assess the sound effect sizes compared to condition without sound. In the model, sound/no sound 179
was set as a fixed factor. In the post-hoc comparisons, Sidak adjustment was applied to account for 180
multiple comparisons. Statistical analyses were performed using SPSS version 22 (IBM Corp.).
181
Estimation of the effect size was done using Cohen’s d.
182 183
3. Results 184
Group mean cortical responses to auditory stimuli are presented in Figure 1. We found that mixing 185
sound with TMS increased the MEP amplitudes from an average of 914 µV to 1298 – 1399 µV (F = 186
13.24, p = 0.001) demonstrating modulation of motor cortical excitability with parallel auditory 187
stimulation (Figure 2). In the post-hoc comparison between different sounds, we found that all the 188
sounds induced a significant increment to the MEP amplitudes (p ≤ 0.018) as opposed to no sound.
189
The standard stimulus independent of timing induced an average increment of 456 µV in the MEP 190
amplitudes compared to no sound (F = 7.20, p = 0.014, d = 0.48). Similarly, the deviant stimulus 191
induced an average increment of 428 µV in the MEP amplitudes compared to no sound (F = 6.58, p 192
= 0.018, d = 0.42). The novelty stimulus induced an average increment of 435 µV in the MEP 193
amplitudes compared to no sound (F = 8.47, p = 0.008, d = 0.45).
194
The types of sounds preceding TMS had no effect on the MEP amplitudes when compared with 195
each other (p > 0.999). The timing of the TMS pulse with respect to the sounds made no difference 196
to the increasing effect of sound to MEP amplitudes, since both timings increased the MEP 197
amplitudes with no difference between the sounds (p = 0.998); timing of TMS to N100 independent 198
of sound type induced an average increment of 432 µV in the MEP amplitudes compared to no 199
sound (F = 10.21, p = 0.003, d = 0.41), while timing of TMS to 200 ms induced an average 200
increment of 446 µV in the MEP amplitudes compared to no sound (F = 18.64, p < 0.001, d = 201
0.53). No interaction effects were observed. No clear difference was observed in the effect sizes 202
between the sounds or timing of TMS. Overall Cohen’s d indicated medium effect with sound 203
affecting MEP amplitudes.
204 205
Details of the measured parameters and demographics for all subjects are presented in Table 1.
206 207
4. Discussion 208
All loud sounds increased motor cortex excitability while the type of the auditory stimulus did not 209
make a difference in effect size. Our hypothesis, that any sound with similar loudness elicits similar 210
enhancement in motor cortical excitability overlapping the N100 potential, was confirmed.
211
Furthermore, we found that TMS timed at 200 ms after an auditory stimulus elicits stronger MEPs 212
compared with the control stimulation with no preceding sound. Our findings highlight the 213
interaction between the auditory and motor systems and show that a relatively long-lasting effect of 214
auditory stimulation on the motor cortex can be readily observed.
215
The N100 is the index of sound detection before the conscious perception of the sound (Näätänen et 216
al. 2011). While the major generator of the auditory N100 is located in auditory cortex in superior 217
temporal gyrus (Vaughan and Ritter 1970; Alho et al. 1996), several other cortical processes are 218
considered to participate in generation of the N100 (Näätänen and Picton 1987) so N100’s effect on 219
cortical excitability even in the motor cortex was somewhat expected. The N100 is considered to be 220
part of the pre-attentive automatic processing of sound and serves as an attention call mechanism 221
before the activation of conscious perception and analyzation of the stimulus (Näätänen et al. 2011).
222
No difference in MEPs elicited by TMS timed at N100 following different sounds is congruent with 223
this model of preconscious auditory processing.
224
The mismatch negativity (MMN) responds to complex changes in stimulus patterns that may 225
remain unconscious (Paavilainen et al. 2007). In this study we did not find any significant 226
difference in MEP amplitudes after deviant or novelty stimuli were mixed in the train of standard 227
sounds. This suggests that complex mechanisms underlying MMN do not cause similar wide spread 228
modulation of cortical excitability as the more basic mechanisms contributing to N100 potential do.
229
The importance of differences between the sounds are evaluated later in the conscious phase of the 230
auditory analysis (Näätänen et al. 2011).
231
The significant enhancement of the MEPs induced by TMS timed at 200 ms interval was 232
unexpected because in our previous study (Löfberg et al. 2014) the MEPs induced by TMS timed at 233
120 ms interval were not significantly altered. Magnetoencephalography studies have demonstrated 234
that during wakefulness the auditory evoked responses after a tone with a higher frequencies than 235
250 Hz show greatest auditory evoked magnetic field (AEF) potentials in latencies of 100 ms 236
(M100) and 200 ms (M200) after the sound, but the M150 potential is significantly weaker (Naka et 237
al. 1999). The M100 is considered to a AEF equivalent of the N100, while M200 is considered as a 238
counterpart of P2 but it overlaps also N2 and partly MMN. This led us to hypothesize that cortical 239
excitability is modulated by activation of later cortical processes that analyze the sound, visualized 240
in the EEG by the P2, N2-P3a or P3 complexes (Goodin et al. 1978; Crowley and Colrain 2004).
241
The longer latency of 200 ms between the sound and TMS coincides in time with early processes of 242
N2-P3a complex and partly with MMN. (Figure 1).
243
Long latency intracortical inhibition (LICI) is a cortical phenomenon that can be studied using 244
paired pulse TMS (ppTMS). A conditioning TMS pulse causes inhibition of the MEPs elicited by a 245
subsequent TMS pulse at ISIs of 60-150ms (Valls-Solé et al. 1992). This inhibition of MEPs is 246
thought to reflect GABAB mediated cortical inhibition (Rogasch et al. 2013a). Many ppTMS studies 247
have used sham stimulation, i.e. electrical scalp stimulation or other ways to mimic the real TMS 248
stimulation, to differentiate the magnetic stimulation effect from other effects caused by the sound 249
or somatosensory sensation of the TMS. (Fitzgerald et al. 2007; Gagnon et al. 2011). These studies 250
have demonstrated a clear difference between real TMS stimulation and sham-stimulation, but even 251
sound of sham-stimulation has been demonstrated to affect cortical functions (Duecker and Sack 252
2013). Our study again demonstrates the need for sham controlled trials to exclude the modulatory 253
effects of the “click” sound caused by TMS (Nikouline et al. 1999). Using white noise to mask the 254
TMS clicks can be used in ppTMS studies (Manganotti et al. 2012; Rogasch et al. 2013b) but then 255
the task impairing effect of white noise must be considered (Herweg and Bunzeck 2015). Also 256
using ear-plugs might reduce the cortical effects caused by the TMS click. As a deviant stimulus, 257
the click can affect habituation of auditory evoked potentials (Näätänen and Picton 1987), but in our 258
study with several different auditory stimuli and long ISI between TMS stimuli we do not expect 259
this to have any significant effect on results.
260
We used different ITIs for the TMS baseline measurement (2.5 – 6.0 s) and the sound mixed 261
sequence (2.5 – 29.2 s) due to random placement of TMS pulses within the randomized set of 262
auditory stimuli. For controlling this effect, we conducted separate analyses also with ITIs between 263
3 s and 6 s and found that it did not affect the major results although it did increase the variance 264
especially in the MEPs induced in combination with novelty sound stimulus, since the total number 265
of analyzed responses was reduced. However, this confirmed that the variation in ITIs was not a 266
contributor to the finding that any type of sound stimulus preceding TMS at N100 or 200 ms 267
latency tends to increase the MEP amplitude.
268
Our results demonstrated that parallel stimulation of auditory and motor systems with latencies 269
longer than previously used (Furubayashi et al. 2000; Fisher et al. 2004; Löfberg et al. 2014) has an 270
modulatory effect on motor cortex excitability. In the future, exploring even longer latencies and 271
targeting individually measured P3 peak amplitudes could complement our knowledge of cortical 272
modulatory effects of conscious processing of sensory stimuli. Also the fact that in our previous 273
study the MEPs induced by TMS timed at 120 ms interval were not significantly greater than 274
baseline (Löfberg et al. 2014) urges for future studies that explore the effect of preceding sound on 275
motor excitability with ISIs ranging from 50 ms to longer ISIs, even 400 ms.
276 277
5. Conclusion 278
We confirmed modulation of motor cortical excitability with parallel auditory stimulus by 279
demonstrating that TMS overlapping auditory evoked N100 or timed at 200 ms after the sound 280
induced significantly greater MEPs compared with TMS with no preceding sound. There were no 281
significant differences in MEPs after standard or deviant sounds. This further adds evidence on the 282
interaction between motor system and top-down attentional mechanisms. Further studies are 283
required to determine the time-line of auditory-motor modulation, as the present study was unable 284
distinguish the time-line with the two latencies applied.
285
Conflict of interest
286
P.J. has received consulting fees from Nexstim Ltd. J.K. is employed part-time by Nexstim Ltd, 287
manufacturer of navigated TMS systems.
288 289
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Tables:
416
Table 1: Subject demographics 417
Id Gender Age
(years)
Hearing threshold (dB)
N100 latency (ms)
rMT (%-MSO)
1 F 30 25 93 45
2 M 29 35 99 38
3 M 25 30 99 48
4 F 35 35 94 46
5 M 34 25 100 36
6 M 25 20 99 31
7 F 28 20 102 38
8 M 28 25 105 40
9 M 25 30 101 37
10 F 27 20 98 44
11 F 22 25 101 41
12 M 34 35 107 43
Abbreviations: F= female, M=male, rMT = resting motor threshold, MSO = maximum stimulator 418
output 419
Figures 420
Figure 1: A) Mean (with standard error of the mean) baseline N100 response for standard stimulus.
421
The latency of the N100 peak was used as ISI in timing the TMS after an auditory stimulus. B) 422
Mean (with standard error of the mean) MMN response computed as a difference between cortical 423
responses between standard and deviant stimulus. The other timing of TMS after an auditory 424
stimulus was 200 ms timed approximately to the MMN peak. C) Mean (with standard errors of 425
mean) P3 response for novelty stimulus. Vertical line indicates the moment of auditory stimulus 426
(time = 0 ms).
427 428 429
Figure 2: MEP amplitudes normalized to individual mean MEP amplitudes at the baseline condition 430
(median and 95% confidence interval). Sound stimulus type or the interval between the sound 431
stimulus and TMS did not affect the MEP amplitudes. Any type of sound used (standard, deviant or 432
novelty) or either ISI induced an increment to MEP amplitudes compared to the baseline condition 433
where no sound stimuli to accompany TMS were used.
434
N100
0 100 200 300 400
-100 -200 0
-1 -2 -3 -4 -5 -6
1
Potential (µV)
Time (ms) A)
MMN (average, 198 ms)
0 100 200 300 400
-100 -200 0
-1 -2 -3 -4 -5 -6
1
Potential (µV)
Time (ms) B)
0 -3 -6
3
Potential (µV)
6 9 -9
0.5 1.0 1.5 2.0
2.5 N100 200ms
MEP amplitude normalizedto baselineMEP