Sensorimotor mu-alpha power is positively related to corticospinal excitability

Accepted Manuscript Sensorimotor mu-power is positively related to corticospinal excitability Miriam Thies, Christoph Zrenner, Ulf Ziemann, Til Ole Bergmann PII:

S1935-861X(18)30198-0

DOI:

10.1016/j.brs.2018.06.006

Reference:

BRS 1271

To appear in:

Brain Stimulation

Received Date: 28 February 2018 Revised Date:

18 May 2018

Accepted Date: 15 June 2018

Please cite this article as: Thies M, Zrenner C, Ziemann U, Bergmann TO, Sensorimotor mu-power is positively related to corticospinal excitability, Brain Stimulation (2018), doi: 10.1016/j.brs.2018.06.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Sensorimotor mu-power is positively related to corticospinal excitability

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Miriam Thies1, Christoph Zrenner1, Ulf Ziemann1 & Til Ole Bergmann1,2

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University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany

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Tübingen, Otfried-Müller-Straße 25, 72076 Tübingen, Germany

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Institute for Medical Psychology and Behavioral Neurobiology, Eberhard Karls University of

Article type: Short Communication

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Department of Neurology & Stroke, and Hertie Institute for Clinical Brain Research, Eberhard Karls

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Corresponding author: Til Ole Bergmann, [email protected]

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Keywords: real-time EEG-TMS, alpha oscillation, motor cortex, transcranial magnetic stimulation

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(TMS), motor evoked potential (MEP)

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ACCEPTED MANUSCRIPT Abstract

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Background: Alpha (8-14 Hz) oscillatory power is linked to cortical excitability and corresponding

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modulations of sensory evoked potentials and perceptual detection performance. In somatosensory

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cortex (S1), negative linear and inverted U-shape relationships exist, whereas its effect on the

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primary motor cortex (M1) is hardly known.

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Objective: We used real-time EEG-triggered transcranial magnetic stimulation (TMS) of M1 to

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characterize the relationship between spontaneous sensorimotor mu-alpha power fluctuations at

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rest and corticospinal excitability.

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Methods: In 16 subjects, mu-power was continuously monitored over the left sensorimotor cortex,

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and each 10%-percentile bin of the individual mu-power distribution was repeatedly targeted in

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pseudorandomized order by single-pulse TMS of left M1, measuring motor evoked potentials (MEP)

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in the contralateral hand.

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Results: We found a weak positive relationship between mu-power and MEP amplitude.

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Conclusion: Sensorimotor mu-power may reflect a net facilitation or disinhibition of M1, possibly

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resulting from mu-based suppression of excitatory and inhibitory input from S1.

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ACCEPTED MANUSCRIPT Introduction

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The pulsed inhibition hypothesis [1, 2] assumes that alpha band (8-14 Hz) oscillations rhythmically

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suppress neuronal processing and, due to their asymmetry [3], produce stronger inhibition with

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increasing amplitude. Alpha oscillations are expressed not only in visual, but also somatosensory (S1)

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and motor cortex (M1) [4, 5], where they are known as sensorimotor mu-rhythm. Alpha power has

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been repeatedly linked to cortical excitability and corresponding modulations of sensory evoked

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potentials and perceptual detection performance. In visual cortex, perception of transcranial

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magnetic stimulation (TMS) induced phosphenes [6] and peri-threshold visual stimuli [7, 8] is

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facilitated by lower pre-stimulus alpha power. In S1, mu-power expresses both negative linear [9, 10]

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and inverted U-shape relationships [10-13] with tactile stimulus detection performance and the

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related N1 component of the somatosensory evoked potential (SEP), as well as positive linear

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relationships with the supposedly inhibitory [14, 15] P1 component [10, 16]. In M1, previous studies

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reported either no relationship with corticospinal excitability, i.e., motor evoked potentials (MEP)

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amplitudes [17], or found a negative relationship using near-threshold stimulation and post-hoc trial

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sorting in very small samples (N = 4 [18]; N = 6 [19]). Here we used EEG mu-power-triggered TMS of

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M1 to systematically measure MEPs during ten a priori defined percentile bins covering the entire

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individual mu-power distribution.

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Materials and Methods

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Sixteen healthy, right-handed volunteers (25 ± 3.6 years; 12 females) participated after providing

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written informed consent. The study was approved by the local ethics committee of the University

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Hospital Tübingen. Subjects were recruited based on (i) a clear mu-frequency peak (i.e., a distinct

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spectral peak between 8 and 14 Hz with an amplitude of at least twice the background 1/f noise was

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visually identified in the power spectrum estimated by a 3 s window Hanning tapered FFT from a 3

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min resting-state EEG measurement with eyes open obtained at the beginning of the session) to

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ensure sufficient signal-to-noise-ratio for real-time power targeting, and (ii) a resting motor threshold

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ACCEPTED MANUSCRIPT (RMT) ≤ 70% maximum stimulator output (MSO) to ensure sufficiently long stimulation periods

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without coil overheating. 64-channel EEG (EasyCap) and 2-channel EMG were recorded in DC mode

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with 1000 Hz low-pass filter and digitized at 5kHz using a TMS-compatible amplifier (NeurOne Tesla

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with Digital-Out Option). EMG was recorded from relaxed right abductor pollicis brevis (APB) and first

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dorsal interosseus (FDI) muscle in belly-tendon montage. TMS was applied to left M1 via two

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Magstim 200² stimulators, connected to a single 70 mm figure-of-eight coil via the Magstim 4-into-1-

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module to allow inter-trial intervals (ITI) below 4 s (recharge time). Coil position was determined to

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produce maximal MEPs in the target muscle (right FDI; APB in 2 subjects) and maintained using

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neuronavigation (Localite). Monophasic stimuli induced a posterolateral-to-anteromedial current in

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the brain tissue. Stimulation intensity (SI) was set to elicit half maximum MEP amplitude

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(57 ± 11% MSO), as determined from individual input-output-curves (SIs from 35% to 90% MSO in 5%

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steps), to allow bidirectional MEP modulation (this procedure revealed SIs very similar to the more

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commonly used 1 mV MEP SI, which was 56 ± 11 %MSO in this sample). Experimental sessions

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consisted of 4 blocks à 250 trials and 20 ± 3 min duration, separated by ~10 min breaks for coil

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cooling and relaxation. Per block ten percentile bins (1-10%, …, 91-100%) from the individual mu-

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power distribution were targeted 25 times each in pseudorandomized order (i.e., concatenating

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randomized sequences of the 10 power conditions), resulting in 100 trials per condition. The real-

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time EEG-TMS system is described elsewhere in detail [20]. Briefly, a Simulink Real-Time (R2016a,

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Mathworks) model processed the EEG data at 1 kHz and triggered TMS whenever the respective

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power criteria were met. Real-time EEG processing involved (i) downsampling to 1 kHz, (ii) spatial

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filtering with a C3-centered Hjorth-montage (C3 – mean(CP1, CP5, FC1, FC5)) [21], (iii) calculating a

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sliding Hanning-windowed FFT of the last 512 ms, (iv) extracting the frequency bin including

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individual mu-peak frequency (M±SD: 11.4 ± 0.9 Hz as determined before from 3 min resting-sate

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EEG with eyes open), (v) updating a sliding distribution of mu-power values based on the last 60 s of

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clean data, thus excluding 1.5 s intervals post-TMS, to account for mu-power drifts over time [22],

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(vi) calculating the respective percentile of the current mu-power value and comparing it to the

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ACCEPTED MANUSCRIPT percentile bin targeted in the current trial, and (vii) triggering TMS if criteria were met. The individual

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mu-power distribution at any time point consisted of the mu-power values that were sampled from

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the repeated (every 10 ms) recalculation of the windowed FFT for the last 60 s of unstimulated data,

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sorted in ascending order. A certain power percentile thus represented the power value that cut off a

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given percentage to the left. Being adjusted relative to a dynamically adapting power distribution,

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slow power drifts over time were compensated, and all relative power bins could be targeted in

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comparable numbers. Processing time per real-time cycle and trigger delays accumulated to < 1 ms.

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A minimal ITI of 3 s was maintained to avoid corruption of power estimates by TMS-related activity

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or artifacts from the previous trial. MEP peak-to-peak amplitudes were normalized block-wise as

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percent change from block average (across all power bins) and then averaged across blocks. EEG

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preprocessing included re-referencing to common average, segmentation (-1000 to -20 ms) relative

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to TMS, rejection of trials with EMG pre-innervation (amplitude > 50 µV) or EEG artifacts in C3-Hjorth

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(z-normalized signal > 5 SDs), zero-padding 1 s into the post-TMS interval, and ICA to remove eye

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movements and muscle noise [23]. Medium power bins were originally associated with shorter ITIs

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than extreme values (F9,135 = 11.8, p < 0.0001), presumably because they occur twice per cycle during

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spontaneous power fluctuations, i.e., during both periods of rising and falling power. Not to

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confound MEP amplitude [24], power conditions were thus stratified for ITI in each subject by

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iteratively removing trials with longest ITI from conditions with longest average ITI until an rmANOVA

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across conditions reached p ≥ 0.2. Average ITI across conditions (M ± SD) was 4.7 ± 0.99 s (ranging

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from 3.95 s (41-50 %) to 5.20 (1-10 %) and 7.33 s (91-100 %)) before stratification and 3.8 ± 0.03 s (M

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± SD; ranging from 3.79 s (41-50 %) to 3.88 (1-10 %) and 3.85 s (91-100 %)) after stratification. After

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bad trial rejection and stratification 76 ± 16 trials remained per condition.

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Differences in normalized MEP amplitude between mu-power percentile bins (Figure 1A)

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were tested with a one-factorial repeated-measures ANOVA (10 power bins) and post-hoc two-sided

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paired t-tests comparing pairs of neighboring bins (Figure 1A). Slopes of individually fitted regression

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lines (Figure 1A) were tested for consistency across subjects using a two-sided one-sample t-test 5

ACCEPTED MANUSCRIPT against zero. Successful targeting of mu-power bins was tested with a one-factorial repeated-

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measures ANOVA (10 power bins) and post-hoc two-sided paired t-tests comparing pairs of

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neighboring bins (Figure 1B). Per subject, single-trial correlations were calculated between pre-TMS

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mu- and beta-power, and partial correlations were calculated between single-trial mu-power/beta-

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power and MEP amplitude, while controlling for the influence of the respective other frequency.

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Subject-wise correlation values were then tested for consistency across subjects using two-sided

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one-sample t-tests against zero.

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Results

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MEP amplitude was modulated as a function of pre-TMS mu-power bin as indicated by the significant

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ANOVA (F9,135 = 2.67, p = 0.007), but MEP amplitudes did not differ significantly for directly

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neighboring power bins (all t-test p > 0.05). Regression lines fitted per subject across power-bins

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indicated on average a positive slope (t15 = 2.20, p < 0.05; Fig. 1A). The positive relationship with MEP

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amplitude in both analyses was dependent on the 91-100% power bin (all p > 0.1 if removed) and on

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ITI stratification (all p > 0.1 if not stratified). Pre-TMS mu- and beta-power were positively correlated

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across trials (ravg = 0.28, t15 = 7.44, p < 0.00001), which may be partially be driven by both beta as

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harmonic of the arch-shaped mu-alpha rhythm and the natural covariation of two independently

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generated rhythms [14, 25]. Trial-wise partial correlations, however, revealed a weak positive

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correlation of MEP amplitude only with mu-power (ravg = 0.05, t15 = 2.44, p = 0.028) but not beta-

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power (ravg = 0.02, t15 = 1.60, p = 0.13). Local sensorimotor mu-power bins were successfully targeted,

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as confirmed by offline power analyses (F9,135 = 748.0, p < 0.00001; neighboring pairs differ with all

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p < 0.000001; Fig. 1B-C), as well as their time-frequency (Fig. 1D) and topographical representations

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(Fig. 1E).

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Discussion

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The weak positive relationship observed between sensorimotor mu-power and corticospinal

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excitability appears at first sight to be incompatible with the pulsed inhibition hypothesis [1, 2], 6

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ACCEPTED MANUSCRIPT which predicts a negative relationship, as observed in the visual cortex [6-8]. However, the

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relationship between mu-rhythm power and both S1 [9-13, 16] and M1 [18, 19] excitability appears

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to be more complex, and our data do not allow strong conclusions regarding the neuronal

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mechanisms underlying the observed weak positive relationship in M1. Notably, the EEG C3-Hjorth

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montage is most sensitive to radial sources and presumably picks up the mu-rhythm predominantly

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from S1 (crown of postcentral gyrus) rather than M1 (anterior bank of central sulcus), which is in

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accordance with its proposed post-central origin [26, 27]. Since S1 and M1 are tightly interconnected

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[28], and somatosensory inputs into M1 are not only excitatory but also evoke feedforward inhibition

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[29, 30], large mu-power in S1 may indeed be inhibitory, but with each pulse of inhibition cause as a

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net effect a weak and transient local disinhibition of corticospinal neurons in M1. However, this

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interpretation remains speculative until future work can show a phase-dependent facilitation of M1

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clearly originating in S1.

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Figure 1. Effects of somatosensory mu-rhythm power on corticospinal excitability. (A) Positive

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linear relationship between targeted pre-TMS mu-power percentile bin and normalized MEP

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amplitudes. MEP amplitudes differed significantly from each other (p = 0.007), with regression lines

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showing on average a positive slope (p < 0.05). (B) Average pre-TMS mu-power values for all targeted

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percentile bins as determined offline (Hanning-windowed FFT of 512 ms pre-TMS, zero-padded to

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1 s, 1 Hz resolution). Individual mu-power values differed significantly between all targeted mu-

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power bins (p < 0.000001). (C) Average z-normalized FFT power spectrum (hence showing positive

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and negative deflections from zero mean) demonstrates that power differences were most

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pronounced at mu-frequency with a less pronounced co-modulation of beta power. Mu- and beta-

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power were positively correlated across trials (ravg = 0.28, t15 = 7.44, p < 0.00001). However,

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individual trial-by-trial partial correlations between MEP amplitude and pre-TMS power, controlling

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for the respective other frequency, revealed a very weak but significant correlation only for mu7

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ACCEPTED MANUSCRIPT power (ravg = 0.05, p < 0.05) but not beta-power (ravg = 0.02, p > 0.1). (D) Z-normalized time-frequency

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representations (hence showing positive and negative deflections from zero mean) of the 0.5 s pre-

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TMS interval reveal that transient mu-power fluctuations were targeted. Note that the apparent

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decrease of the modulation shortly before the TMS-pulse (at 0 s) is due to zero-padding of the post-

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TMS interval to prevent corruption of pre-TMS interval by overlapping of the sliding window (length:

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3 cycles per frequency) with TMS-related activity artifacts. (E) The topographical distribution of z-

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normalized pre-TMS mu-power (time window [-0.3 -0.1] from D) reveals that a very local power

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increase over left sensorimotor regions was targeted, and estimates were not driven by parieto-

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occipital alpha oscillations. Note that C3-centered activation is not seen for the middle two power

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bins only because of their z-normalization across power bins.

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Competing financial interests

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The authors declare no competing financial interests.

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Author contributions

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T.O.B., M.A.T., C.Z., and U.Z. created concept and design of the study; C.Z. and T.O.B. developed the

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real-time software; M.A.T. performed the experiments; T.O.B. designed the experimental set-up,

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analyzed the data, and created the figures. T.O.B., M.A.T., C.Z., and U.Z. wrote the manuscript.

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Acknowledgements

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This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)

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– grant no. 362546008 to T.O.B..

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References

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Relationship of sensorimotor mu-alpha (8-14Hz) power and corticospinal excitability Real-time EEG-triggered TMS of M1 targeted ten power bins of sensorimotor mu-rhythm Motor evoked potential (MEP) amplitude was increased for larger mu-rhythm power Results suggest differential function of mu-power in somatosensory and motor cortex

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ACCEPTED MANUSCRIPT Highlights

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Relationship of sensorimotor mu-alpha (8-14Hz) power and corticospinal excitability Real-time EEG-triggered TMS of M1 targeted ten power bins of sensorimotor mu-rhythm Motor evoked potential (MEP) amplitude was increased for larger mu-rhythm power Results suggest differential function of mu-power in somatosensory and motor cortex

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