# Influence of different transcranial magnetic stimulation current directions on the corticomotor control of lumbar erector spinae muscles during a static task

Mikaël Desmons, Antoine Rohel, Amélie Desgagnés, Catherine Mercier, Hugo Massé-Alarie

► To cite this version:

Mikaël Desmons, Antoine Rohel, Amélie Desgagnés, Catherine Mercier, Hugo Massé-Alarie. Influence of different transcranial magnetic stimulation current directions on the corticomotor control of lumbar erector spinae muscles during a static task. Journal of Neurophysiology, 2021, 126 (4), pp.1276-1288. 10.1152/jn.00137.2021. hal-05149810

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RESEARCH ARTICLE

Control of Movement

# Influence of different transcranial magnetic stimulation current directions on the corticomotor control of lumbar erector spinae muscles during a static task

Mikaël Desmons,¹ Antoine Rohel,¹ Amélie Desgagnés,¹ Catherine Mercier,¹,² and Hugo Massé-Alarie¹,²

¹CIRRIS Research Centre, Université Laval, Quebec City, Quebec, Canada and ²Rehabilitation Unit, Université Laval, Quebec City, Quebec, Canada

## Abstract

Different directions of transcranial magnetic stimulation (TMS) can activate different neuronal circuits. Whereas posteroanterior current (PA-TMS) depolarizes mainly interneurons in primary motor cortex (M1), an anteroposterior current (AP-TMS) has been suggested to activate different M1 circuits and perhaps axons from the premotor regions. Although M1 is also involved in the control of axial muscles, no study has explored whether different current directions activate different M1 circuits that may have distinct functional roles. The aim of the study was to compare the effect of different current directions (PA- and AP-TMS) on the corticomotor control and spatial cortical organization of the lumbar erector spinae muscle (LES). Thirty-four healthy participants were recruited for two independent experiments, and LES motor-evoked potentials (MEPs) were recorded. In experiment 1 (n = 17), active motor threshold (AMT), MEP latencies, recruitment curve (90% to 160% AMT), and excitatory and inhibitory intracortical mechanisms by paired-pulse TMS (80% followed by 120% AMT stimuli at 2-, 3-, 10-, and 15-ms interstimulus intervals) were tested with a double-cone (n = 12) and a figure-of-eight (n = 5) coil. In experiment 2 (n = 17), LES cortical representations were tested with PA- and AP-TMS. AMT was higher for AP- compared with PA-TMS (P = 0.002). Longer latencies with AP-TMS were present compared with PA-TMS (P = 0.017). AP-TMS produced more inhibition compared with PA-TMS at 2 ms and 3 ms (P = 0.010), but no difference was observed for longer intervals. No difference was found for recruitment curve and mapping. These findings suggest that PA- and AP-TMS may activate different cortical circuits controlling low back muscles, as proposed for hand muscles.

**NEW & NOTEWORTHY** For the first time, anteroposterior and posteroanterior induced electric currents in the brain were compared when targeting back muscle representation with transcranial magnetic stimulation. The use of the anteroposterior current resulted in later response latency, larger inhibition probed by paired-pulse stimulation, and higher motor threshold. These important differences between current directions suggest that each of the current directions may recruit specific cortical circuits involved in the control of back muscles, similar to that for hand muscles.

low back muscle; mapping; paired pulse; recruitment curve; transcranial magnetic stimulation

## INTRODUCTION

The primary motor cortex (M1) is essential for motor control. It is known to be involved in voluntary movement execution but also in motor preparation by integrating inputs from multiple regions of the central nervous system (1). Despite an increasing knowledge of M1's role, neuronal circuits involved in motor control remain poorly understood (2). M1 neuronal circuit excitability and function are influenced by resting and activity-

dependent interactions of neurons within (intrahemispheric) and between (interhemispheric) M1 and also between M1 and other regions (interregional, e.g., between premotor and M1) (1).

Transcranial magnetic stimulation (TMS) is a useful tool to probe the function and excitability of neuronal circuits involved in corticomotor control (3). TMS is a painless stimulation technique that activates corticocortical and corticospinal neurons to evoke a motor output recorded by electromyography (EMG) and called the motor-evoked potential (MEP). The
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MEP represents the excitability of the corticospinal tract, i.e., of cortical elements depolarized by the induced current and of the neural elements downstream on this pathway (e.g., spinal networks influencing α-motoneuron excitability), at the time of stimulation (1). TMS is based on the principle of electromagnetic induction, as discovered by Michael Faraday in 1838. A brief electric current passing through a coil produces a magnetic field perpendicular to the coil that flows through the scalp and the skull without attenuation (3). The magnetic field induces an electrical current in the cortex parallel to the coil electrical current but flowing in the opposite direction. An axon is depolarized if there is a difference of electrical potential between two points along its length. The axon depolarization happens either 1) when the induced current flow is nearly parallel to an axon and then curves away to cross its membrane (4) or 2) when an axon is bent and the induced current crosses the membrane (5). Thus, modifying the orientation of the coil changes the direction of the electric current flowing in the brain and which axons are preferentially activated (2).

A posteroanterior current orientation (PA-TMS) is used in most TMS studies. For studies focusing on hand muscles, MEPs have been shown to be composed of a series of descending volleys with epidural recordings. At low intensities of stimulation, PA-TMS produces early indirect waves (I waves) followed by late I waves (6). At higher intensities of stimulation, a direct wave (D wave) is produced at the earliest latency, followed by I waves (early and late). When anteroposterior current (AP-TMS) with a low intensity of stimulation is used, the late I waves are preferentially recruited (7). Although the D wave is believed to originate from direct excitation of the axons of corticospinal neurons in the subcortical white matter, there is much more uncertainty about the origin of the I waves. Some authors have suggested that they represent the activation of different intracortical neuronal circuits (2). Based on these observations, it has been hypothesized that AP- and PA-TMS currents could recruit distinct circuits (8, 9). These hypotheses are supported by a greater activation of inhibitory intracortical circuits (10, 11), longer MEP latencies (12, 13), and higher motor thresholds (8, 12, 14) with AP-TMS compared with PA-TMS. However, the possibility to generalize these results remains limited, as most studies have focused on hand muscles. Indeed, exploration of proximal and axial muscle cortical motor control remains limited, even though M1 appears involved in this control. For example, some studies demonstrated that paired-pulse TMS paradigms could be used to probe excitatory and inhibitory intracortical circuits of axial muscles including those influencing the corticospinal projections to low back muscles (15-17). However, it remains unexplored whether corticospinal modulation of low back muscles depends on the current direction and then if it may also recruit intracortical different circuits.

Recent neurophysiological and computational studies suggest that AP-TMS could activate axons of neurons of the premotor cortex projecting to the corticospinal cells (18-21), in addition to direct M1 activation. Considering 1) that the premotor cortex plays an important role in motor preparation (22) and 2) that the excitability of the corticospinal projections to low back muscles is reduced during motor preparation of rapid flexion movement (low back muscles control the spine and maintain balance during this task)

(23), AP-TMS may become an additional technique to test the involvement of the premotor cortex during functional motor tasks and to identify the cortical circuits that may explain alteration in motor control in different clinical populations [e.g., low back pain (24, 25) or stroke (26)]. Beforehand, identifying whether PA- and AP-TMS potentially recruit different circuits/cortical areas is the first step before understanding the functional role of these circuits. TMS recruitment curve and mapping techniques may help to determine whether PA- and AP-TMS recruit cortical areas that have different spatial organizations.

The present study aims 1) to compare the effect of different current directions (PA- vs. AP-TMS) on corticomotor control in a postural static task and 2) to compare the lumbar erector spinae (LES) muscle cortical representation in M1 induced by each current direction. We hypothesized that, similar to hand muscles, single- and paired-pulse paradigms will display differences such as later MEP latencies and larger inhibition following AP- compared with PA-TMS. We also hypothesized that the cortical representation of low back muscle will be more anterior for AP- compared with PA-TMS, considering the potential recruitment of neurons of the premotor cortex.

# METHODS

## Ethical Approval

The study was approved by the Ethics Committee of the Center Intégré Universitaire de Santé et de Services Sociaux de la Capitale-Nationale—Institut de Réadaptation en Déficience Physique de Québec (Project No. #2020-1799), in accordance with the latest Declaration of Helsinki, and all participants provided their written informed consent before participation.

## Participants: All Experiments

A total of 29 different healthy adults [mean (SD) age: 27.1 (6.2) yr; 28 right-handed, 14 women] were recruited by community advertisement to participate in one of the three experiments. Five participated in two different experiments [age: 28.0 (3.67) yr; 5 right-handed, 1 woman]. All participants were free of low back pain at the time of testing and were excluded if they had any contraindications to TMS (e.g., any history of epilepsy, pregnancy, metal in head or jaw, medication reducing seizure threshold) (27) or if they had any major neurological, respiratory, orthopedic, or circulatory disorders.

## EMG Activity Recording and MVC: Experiments 1 and 2

Electromyography (EMG) was recorded from the right LES with pairs of surface Ag/AgCl electrodes (Kendall Medi-trace 200, Covidien, Dublin, Ireland) on the belly of the LES at L₃-L₄ level, according to SENIAM recommendations (28). The ground electrode (9160 F; 3M, St. Paul, MN) was overlapping the right iliac crest and anterosuperior iliac spine. EMG raw signals were amplified (1000×), band-pass filtered between 10 and 500 Hz with a D360 EMG amplifier (Digitimer Ltd, Welwyn Garden City, UK), and digitized at a sampling rate of 1,000 Hz with a Power 1401 Data Acquisition System with Spike2 software (Cambridge Electronic Design, Cambridge, UK).
To evaluate the maximal voluntary contraction (MVC), participants made three 3-s maximal resisted trunk extensions or maximal pelvic anteversions in the seated position. Maximal resisted trunk extension and maximal pelvic tilt were tested once for each participant. The motor task that produced the largest LES EMG activity was used, and three more repetitions were performed to determine the MVC. Breaks of 45 s were taken between trials. Verbal encourage- ments from the experimenters were provided to maximize the MVC. The maximal peak value obtained over the three trials was considered MVC. The peak value of each MVC trial was measured as the root mean square (rms) EMG activity over a 100-ms window around the peak amplitude.

**Transcranial Magnetic Stimulation: Experiments 1 and 2**

Considering that MEPs of LES muscles with transcranial magnetic stimulation (TMS) are difficult to obtain at rest (29), all TMS measurements were obtained while partici- pants were maintaining a slight LES muscle contraction (15 ± 5% MVC) (23). During TMS testing, rms EMG activity (time windows = 1 s) was displayed on a screen in front of the par- ticipants to help them maintain the targeted muscle activa- tion. This task also stabilized the subject's attention. For two participants, it was difficult to evoke consistent MEPs at 15% MVC. Muscle activation was then increased to 20% MVC, and consistent MEPs were obtained throughout the experiment.

A monophasic Magstim BiStim² stimulator (Magstim Co., Whitland, UK) connected to a double cone (126-mm diameter per wing; Magstim Co., Whitland, UK) was used to deliver TMS. Coil orientation and position were guided with a stereo- taxic neuro-navigation system (Brainsight, Rogue Research, Montreal, QC, Canada). The double-cone coil was also used for TMS mapping. Although it is not common, our decision was guided by methodological issues arising from the use of the figure-of-eight coil to map the erector spinae cortical rep- resentation. Almost all studies using the figure of eight mapped at 100% of the maximal stimulator output (MSO) without adjusting to the AMT (30–34). Since the motor threshold of the erector spinae is often high and close to 100% MSO with a figure-of-eight coil, stimulation at 100% MSO is often used to produce a LES map for every partici- pant. However, this technique does not allow the use of an intensity of stimulation relative to AMT for mapping. Thus, using such a methodology would have produced a severe bias in the present study because of the expected large differ- ence in motor threshold between PA- and AP-TMS (14). Even though a double-cone coil stimulates a larger cortical area compared with the figure-of-eight coil, it allows the use of an intensity relative to the AMT. This technique substantially reduces the interindividual differences in %MSO between the stimulation intensity and the AMT comparatively to the use of a figure-of-eight mapping technique at 100% MSO. However, in some participants, the use of the double-cone coil produced map distortions and the impossibility of stim- ulating the most anterior points of the grid (see RESULTS for details).

Since there is no evidence that handedness influences TMS outcomes for back muscles (23, 25, 30, 35, 36), all TMS paradigms were performed with PA-TMS and AP-TMS over

the left hemisphere. The optimal stimulation site on the scalp (hotspot) was defined as the location that elicits the largest MEP amplitude at a given intensity in the contralat- eral LES. The active motor threshold (AMT) corresponded to the lowest stimulation intensity required to evoke at least three MEPs out of six stimulations that were clearly discerni- ble from background EMG activity and at a physiological la- tency (~14 ms) (37). TMS pulses were triggered automatically at a random interval between 5 and 8 s for every block of stimulation with a custom-made script in Spike2. Hotspot and AMT were defined for each current direction. Methods were reported in accordance with the TMS-specific check- list developed by Chipchase et al. (38) (score: 30/30; Supplemental Table S1, available at https://doi.org/10.5683/SP3/EHL63E).

**Study Design**

For all experiments, participants were seated comfortably on a height-adjustable chair, with arms along the body and knees at ~90°.

**Experiment 1: recruitment curve and paired-pulse TMS.**

Twelve subjects [mean (SD) age: 27.0 (6.6) yr; 11 right- handed, 7 women] participated in a 3-h experiment.

**TMS: experiment 1.**

Recruitment curve and paired-pulse paradigms were per- formed with both current directions (PA- and AP-TMS). Testing order was randomized with three hierarchical levels: 1) direction of current, 2) TMS paradigms (recruitment curve, paired-pulse TMS), and 3) parameters of stimulation [inten- sity of stimulation for the recruitment curve and interstimu- lus interval (ISI) for paired-pulse TMS]. Figure 1 represents the different levels of randomization from left to right and details the experimental protocol.

Paired-pulse TMS paradigms were applied over the hot- spot to probe intracortical facilitation and inhibition. Two- and three-milliscond ISIs were tested for short-interval intracortical inhibition (SICI) (39) and 10- and 15-ms ISIs for intracortical facilitation (ICF) (40). The conditioning stimu- lus was set at 80% AMT and the test stimulus at 120% AMT for all ISIs (15, 17). MEP test was set at 120% AMT because of the difficulty of using a predefined MEP test amplitude for back muscles (e.g., 1 mV as for TMS hand studies) (15). Ten single-pulse (120% AMT, MEP test) and ten paired-pulse (conditioned MEP) TMSs were delivered for each ISI (2, 3, 10, and 15 ms).

For the recruitment curve, five single-pulse TMSs were performed per intensity of stimulation tested (steps of 10% from 90% AMT to 160% AMT) (41).

**Validation experiment.**

Considering that the double-cone coil was never used to compare results from AP- and PA-TMS, a validation study was performed on a subset of participants from the main study. Five participants [mean (SD) age: 27.00 (3.67) yr, 5 right-handed, 1 woman] participated in a 2-h experiment in which both AP- and PA-TMS were tested with a 70-mm fig- ure-of-eight coil (Magstim Co., Whitland, UK). The handle of the coil pointed posteriorly for PA-TMS and anteriorly for AP-TMS. The same study design was used as described for
<figure><img src="image_3.png" /><figcaption>**Figure 1.** Schematic illustration of the experimental protocol. AMT, active motor threshold; AP, anteroposterior; ISI, interstimulus interval; PA, posteroanterior; TMS, transcranial magnetic stimulation.</figcaption></figure>

**experiment 1.** However, only the SICI paradigm (2 and 3 ms) and single TMSs at intensities of 120%, 130%, and 140% AMT were tested. These specific paradigms were tested because they were different between current directions with the double-cone coil (see RESULTS).

**Experiment 2: TMS mapping.**

Seventeen [age: 27.1 (6.0) yr; 17 right-handed, 7 women] subjects were recruited for mapping the LES cortical representation in both current directions.

**TMS: experiment 2.**

Four single TMSs were triggered at each point of a predefined grid (42) at an intensity of 110% AMT. A 36-point grid of 4 × 9 sites, located at 1-cm intervals, was aligned on the vertex (0–3 cm lateral and from 4 cm anterior to 4 cm posterior to the vertex; Fig. 1). The position of the vertex was determined with the International 10-20 System and was marked with a pencil on the scalp (30, 32–34). TMS mapping was guided with the neuro-navigation Brainsight system. Mapping started at the vertex, and the coil was moved 1 cm per 1 cm. At each point of the grid, a target was created by the Brainsight system that was used to move to the next point. When the map of the first current direction was done, we used the already defined targets for the map with the other current direction.

**Data Analysis**

**Experiment 1.**

Data analysis of raw EMG was performed with a custom-made script in Spike2 (version 9.06a, Cambridge Electronic Design, Cambridge, UK). Peak-to-peak amplitude was measured for each MEP recorded. For the recruitment curve, peak-to-peak MEP amplitudes were averaged for each

intensity of stimulation and normalized to the average amplitude of the five greatest MEP amplitudes across all intensities and current directions. The use of the mean amplitude of the five largest MEP amplitudes across all intensities and current directions limits the likelihood that an extreme value biases the result.

$$ \text{normalized MEP amplitude} = \left( \frac{\text{average MEP per stimulation intensity}}{\text{average of 5 largest MEPs}} \right) \times 100 $$

MEPs from paired-pulse TMS were expressed as a percentage of change from the MEP test.

$$ \% \text{ change} = \left( \frac{\text{conditioned MEP} - \text{MEP test}}{\text{MEP test}} \right) \times 100 $$

The MEP onset was visually determined from the rectified and averaged EMG signal for most stimulation intensities of the recruitment curve (5 trials, 120% to 160% AMT). Latencies at 90%, 100%, and 110% were not measured, considering that MEP onset was more difficult to identify at these intensities. The MEP onset was identified visually on the rectified and averaged EMG signal. Indeed, this technique was used to facilitate the identification of the LES MEP onsets that are sometimes of small amplitude and polyspheric with a low signal-to-noise ratio (29).

**Experiment 2.**

A custom-made MATLAB script (The MathWorks Inc., Natick, MA) was used to compute TMS maps. For each point of the grid, an average of the four peak-to-peak MEP amplitudes was computed and then normalized to the largest scalp site average MEP amplitude across the two current directions. The use of the largest mean MEP amplitude across current directions (rather than the largest mean MEP
amplitude of each current direction) to normalize allows detection of real differences in mean normalized MEP amplitude between currents, if any. For example, if large differences in absolute mean MEP amplitude were present between current directions, a normalization using the largest mean MEP amplitude of each current direction would have washed out these differences. If the normalized MEP amplitude was inferior to 25%, the value was removed and considered as null (34), to reduce the impact of these values on map characteristics. The normalized MEP amplitude of each site was superimposed onto a topographical map to produce a visual representation of the LES cortical representation.

The map volume, which is a measure of the total excitability of the cortical representation (43), was calculated as the sum of the normalized MEP amplitude recorded across all scalp sites for each current direction independently. The center of gravity (CoG) was defined as the amplitude-weighted center of the map (34, 43); its coordinates were calculated with the formula

$$CoG = \frac{\Sigma(V_i \times X_i)}{\Sigma V_i}, \quad \frac{\Sigma(V_i \times Y_i)}{\Sigma V_i}$$

where $V_i$ = mean MEP amplitude at each site with the coordinates $X_i$ and $Y_i$.

For all experiments, the rms EMG activity (100-ms time window) before each TMS pulse was measured to verify the stability of the EMG background level throughout the experiment.

## Statistical Analysis

The mean (standard deviation) is reported in RESULTS throughout the text and figures. The threshold for statistical significance was set at $P < 0.05$. Normal distribution of the data was tested with the Shapiro-Wilk test. Since most of the data did not follow a normal distribution and no transformation normalized the distribution, nonparametric tests were used. For factorial design, nonparametric analyses of variance for longitudinal data (nparLDs) were used. nparLD is a robust method for factorial designs with small and inequivalent samples, is also robust with missing data, and does not require normality of distributions and homoscedasticity (44). Statistical tests were performed with IBM SPSS statistics software (v25) except for nparLD tests, which were performed with the R Studio (version 1.3.1093, RStudio: Integrated Development Environment for R, PBC, Boston, MA) using the nparLD package (44).

### Experiment 1.

To determine whether different TMS current directions influenced LES corticomotor control, multiple TMS outcomes were measured: 1) AMT, 2) latency and 3) MEP amplitude at multiple intensities of stimulation, and 4) conditioned MEP amplitude at multiple ISIs. Wilcoxon's signed-rank tests compared AMT obtained with PA- and AP-TMS (for all experiments). nparLD tests using the factors current direction (PA- vs. AP-TMS) and stimulation intensity (90% to 160% AMT), and their interaction, were used to determine whether different current directions evoked different MEP amplitudes. nparLD tests using the factors current direction and stimulation intensity (120% to 160% AMT), and their interaction, were computed to

determine whether different current directions differently influenced MEP latencies. nparLD tests using the factors current direction and ISI, and their interaction, were used to determine the effect of different current directions on conditioned MEP amplitude. These models were run independently on ISIs considered as inhibitory (2 and 3 ms) and excitatory (10 and 15 ms). This was done to reduce the large variability introduced in the model by opposite ISI-dependent conditioning effect. For nparLD, pairwise comparisons were conducted by one-factor nparLD test.

We undertook a supplementary analysis to determine whether PA and AP induced significant inhibition/facilitation at each specific ISI. One-sample Wilcoxon-signed-rank tests were used on the % change-conditioned MEP, using a hypothesized median of 0.

### Experiment 2.

To determine whether different TMS current directions induced different LES map characteristics, multiple map outcomes were measured. Wilcoxon's signed-rank tests compared volume, CoG X, and CoG Y between current directions.

To ensure that prestimulus LES EMG activity was constant throughout the experiment (i.e., stable motoneuro nal excitability), nparLD tests using the factors current direction and stimulation intensity (120% to 160% AMT, experiment 1-recruitment curve) or ISI-Baseline (Baseline, 2, 3, 10, and 15 ms, experiment 1-paired-pulse TMS) or point coordinate (experiment 2-mapping), and their inter action, were computed.

# RESULTS

## Missing Data

In experiment 1, it was not possible to stimulate at all pre-defined intensities of stimulation of the recruitment curve relative to AMT for some participants (PA: $n = 2$; AP: $n = 5$). Indeed, considering that a high AMT was present for these participants, the intensity of stimulation exceeded the MSO at some stimulation intensities relative to AMT [PA: at 160% ($n = 2$); AP: at 140% ($n = 1$), 150% ($n = 2$), and 160% ($n = 5$)]. Moreover, it was difficult to identify the MEP onset in one participant because of the polyphasic shape of the MEP. Thus, his data were excluded from the MEP latency analysis ($n = 11$).

In the validation experiment (figure of eight), AMT exceeded 100% MSO for four of five participants using AP-TMS. It was possible to obtain MEPS using 113% MSO. Indeed, using both 200² stimulators connected by the BiStim module at 100% MSO produced a stronger magnetic field corresponding to 113% MSO of a single Magstim 200² (45). For three participants, six MEPS out of six stimulations were obtained at 113% MSO but none at 100% MSO. For one partic ipant, only two MEPS out of six stimulations were obtained at 100% MSO. For these four participants, 100% MSO was considered AMT. Thus, AMT was too high to perform TMS paradigms in AP-TMS. In PA-TMS, AMT was low enough to perform SICI and recruitment curve in only two participants. In this additional experiment, it was therefore only possible to test the effect of current direction on AMT.
<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /><figcaption>**Figure 2.** Individual active motor thresholds [AMTs; expressed as % of maximal stimulator output (MSO)] with posteroanterior (PA)- and anteroposterior (AP)-transcranial magnetic stimulation (TMS) for *experiment 1* (A; *n* = 12), for the subset of participants in the validation experiment (B; *n* = 5) and for *experiment 3* (C; *n* = 16). Wilcoxon's signed-rank tests compared AMT obtained with PA- and AP-TMS for each experimentation. \* *P* < 0.05.</figcaption></figure>

In *experiment 2*, it was impossible to evoke MEPs in AP for one participant, and technical limitations of the mapping technique impeded performance of the experiment or use of the data collected for four participants. First, it was impossible to stimulate the most anterior points of the grid because the coil contacted the Brainsight system's glasses (*n* = 1). The shape and size of the skull of some participants made the anterior points of the grid converge, creating a grid deformation (*n* = 4). Thus, AMTs of 16 participants were entered in the analysis, whereas the data of 12 participants were available for mapping outcomes.

## Active Motor Threshold

Figure 2 demonstrates that a higher intensity of stimulation was needed to obtain AMT in AP- compared with PA-TMS for all experiments. In *experiment 1*, the mean AMT in PA was 40.8% (6.5) compared with 52.7% (10.1) MSO for AP (Z = -3.1, P = 0.002) with a double-cone coil. In the validation experiment, the mean AMT in PA was 81.6% (12.3) compared with 99.8% (0.5) MSO for AP (Z = -2.0, P = 0.043) with a figure-of-eight coil. In *experiment 2*, the mean AMT in PA was 46.1% (6.7) compared with 51.8% (7.9) MSO in AP (Z = -2.8, P = 0.005).

### Experiment 1: Paired-Pulse TMS

Figure 3 is an example of one participant's MEPs for the different paired-pulse TMS paradigms. For the inhibitory paradigms (ISI = 2 and 3 ms), the conditioned MEP amplitude (% change) was smaller in AP [-35.2% (31.3)]- compared with PA [-9.4% (27.5)]; main effect: current direction; F = 6.7, P = 0.010; Fig. 4]-TMS. ISI at 3 ms [-26.33% (30.48)] produced smaller conditioned MEPs compared with 2 ms [-18.33% (33.43)]; main effect: ISI; F = 8.0, P = 0.005]. No interaction was detected (F = 0.6; P = 0.421). For the facilitation paradigms (ISI = 10 and 15 ms), no main effect of current direction (F = 0.0; P = 0.909) or ISI (F = 2.3; P = 0.129) or interaction was observed (F = 1.2; P = 0.265).

Conditioned MEP amplitude at 2 [-32.4% (34.1); P = 0.015]- and 3 [-38.0% (29.5); P = 0.010]-ms ISI induced by AP-TMS induced significant inhibition (different from 0). No other paired-pulse paradigms significantly conditioned the MEP amplitude (all *P* values reported in Table 1).

No main effect of current direction (F = 1.1; P = 0.296) or ISI/baseline (F = 0.5; P = 0.652) and interaction (F = 0.2; P = 0.871) was detected for prestimulus rms EMG for paired-pulse paradigms.

### Experiment 1: Recruitment Curve

Figure 5 is an example of MEP observed for a participant for the intensities of the recruitment curve.

No main effect of current direction (F = 3.2, P = 0.074) and intensity (F = 1.0, P = 0.401) or interaction (F = 1.1, P = 0.361) was observed for prestimulus rms EMG for the recruitment curve.

#### Modulation of MEP latencies.

The nparLD revealed shorter latencies for PA [13.9 (2.4) ms]- compared with AP [14.8 (3.1) ms]-TMS (main effect: current direction; F = 5.7, P = 0.017; Fig. 6). No significant main effect of stimulation intensity (F = 2.3, P = 0.075) or interaction (F = 0.4, P = 0.732) was observed.

#### Modulation of MEP amplitudes.

The nparLD test showed a main effect of stimulation intensity (F = 79.5, P < 0.001) on normalized MEP amplitude but did not detect any difference for current direction (F = 1.8, P = 0.185) or interaction (F = 0.8, P = 0.501). Table 2 reports amplitudes for each stimulation intensity in PA- and AP-TMS.

### Experiment 2: Mapping

Table 3 shows the map characteristics for each current direction. No difference in the map volume (Z = -0.8, P = 0.937) or in CoG coordinates (X: Z = -0.6, P = 0.583; Y: Z = -1.4, P = 0.158) was observed across current directions.

No main effect of current direction (F = 0.8, P = 0.373) or coordinates (F = 1.131, P = 0.340) or interaction (F = 0.745, P = 0.636) was observed for prestimulus rms EMG for the LES maps.

## DISCUSSION

The present study investigated the influence of PA- and AP-current orientation on the corticomotor control of low back muscles assessed with multiple TMS paradigms. The two experiments performed led to three main findings. First,
<figure><img src="image_6.png" /><figcaption>**Figure 3.** Examples of average motor-evoked potential (MEP) observed for the different single-pulse and paired-pulse transcranial magnetic stimulation (TMS) paradigms for 1 participant. Left: MEP average with posteroanterior (PA)-TMS. Right: MEP average with anteroposterior (AP)-TMS. From top to bottom: Test is single pulse unconditioned MEP elicited at ~120% active motor threshold (AMT) followed by conditioned MEP obtained with interstimulus interval (ISI) of 2 and 3 ms and 10 and 15 ms. Arrow indicates stimulation artifacts for each of the single- and paired-pulse stimulus. cs, Conditioning stimulus; ts, test stimulus.</figcaption></figure>

our results revealed a higher AMT with AP- compared with PA-TMS. Second, PA-MEP latencies were significantly shorter than AP-MEP latencies. Third, a greater inhibition was present with paired-pulse TMS (2–3 ms) in AP- compared with PA-TMS. These findings are compatible with the hypothesis that each current direction (PA and AP) activates different cortical circuits controlling low back muscles, as proposed for hand muscles (2, 46, 47). Moreover, results

from the validation experiment confirm, in a subset of participants, a similar higher AMT in AP-TMS with a conventional figure-of-eight coil. Also, these results highlight the difficulty of probing the intracortical and corticospinal excitability of the LES M1 representation with a figure-of-eight coil.

## Potential Circuits Recruited by PA and AP

Although the corticospinal projections to intrinsic hand muscles differ from those projecting to proximal and axial muscles (48), our results are fairly consistent with what has been previously reported for hand muscles. First, those TMS studies consistently reported lower MT with PA- compared with AP-TMS (8–12, 14, 19). Second, shorter latencies in PA than AP MEP have been reported for hand muscles (12–14, 19, 49). Third, two recent studies showed stronger effect of SICI with AP- compared with PA-TMS (10, 11) in hand muscles. Considering the similarities between TMS hand studies and the present results, we suggest that similar circuits could be at play to modulate the excitability of the corticospinal cells for both distal and axial corticomotor representations. Our hypotheses are based on TMS methodologies performed on hand muscles that have not been tested (e.g., pharmaco-TMS) or that are not possible to test (e.g., epidural recording) for low back muscles. Thus, the hypotheses presented remain speculative and based on results coming from TMS studies of hand muscles.

Epidural recordings from the cervical cord showed that MEP is a signal composed of a series of descending corticospinal volleys (50). This includes the direct (D) wave representing the direct activation of corticospinal cell axon and the indirect (I) wave divided into early $I_1$ wave (reflecting monosynaptic excitatory projections to corticospinal cells) and late I wave (reflecting a more complex circuit composed of both excitatory and inhibitory neurons; for a review see Ref. 2). It has been demonstrated that high intensity of TMS above motor threshold with PA-TMS may evoke D waves (51). However, our results do not support the activation of D waves since the MEP latency was not significantly earlier at higher intensity of stimulation. Also, wave patterns differ

<figure><img src="image_7.png" /><figcaption>**Figure 4.** Individual short-interval intracortical inhibition (SICI) ($n = 12$) for both posteroanterior (PA)- and anteroposterior (AP)-transcranial magnetic stimulation (TMS) current directions with interstimulus intervals (ISIs; 2 and 3 ms) averaged. Nonparametric analysis of variance for longitudinal data (nparLD) tests using factors current direction and ISI and their interaction were used to determine the effect of different current directions on conditioned motor-evoked potential (MEP) amplitude. \*P < 0.05.</figcaption></figure>
<table><caption>**Table 1.** Modulation of MEP amplitude using different paired-pulse TMS paradigms for both current directions</caption><thead><tr><th rowspan="2"></th><th colspan="4">PA</th><th colspan="4">AP</th></tr><tr><th>Uncond<br>MEP, mV</th><th>Cond<br>MEP (mV)</th><th>Cond MEP, %<br>change</th><th>P value, difference<br>from 0</th><th>Uncond<br>MEP, mV</th><th>Cond<br>MEP, mV</th><th>Cond MEP, %<br>change</th><th>P value, difference<br>from 0</th></tr></thead><tbody><tr><td>Test</td><td>0.30 (0.19)</td><td></td><td></td><td></td><td>0.32 (0.15)</td><td></td><td></td><td></td></tr><tr><td>2 ms</td><td></td><td>0.26 (0.11)</td><td>-4.2 (27.2)</td><td>0.583</td><td></td><td>0.20 (0.12)</td><td>-32.4 (34.1)</td><td><strong>0.015</strong></td></tr><tr><td>3 ms</td><td></td><td>0.24 (0.16)</td><td>-14.7 (27.9)</td><td>0.099</td><td></td><td>0.18 (0.10)</td><td>-38.0 (29.5)</td><td><strong>0.010</strong></td></tr><tr><td>10 ms</td><td></td><td>0.30 (0.24)</td><td>-1.5 (35.4)</td><td>0.433</td><td></td><td>0.31 (0.18)</td><td>-1.2 (28.2)</td><td>0.875</td></tr><tr><td>15 ms</td><td></td><td>0.33 (0.24)</td><td>13.2 (38.6)</td><td>0.388</td><td></td><td>0.31 (0.17)</td><td>2.0 (43.1)</td><td>1.000</td></tr></tbody></table>

AP, anteroposterior; Cond, conditioned; MEP, motor-evoked potential; PA, posteroanterior; TMS, transcranial magnetic stimulation; Uncond, unconditioned. Significant *P* values are in bold.

between current directions. PA-TMS recruits $I_1$ wave followed by the later I waves numbered in the order of appearance ($I_2$, $I_3$...). In contrast, AP-TMS recruits first a $I_3$-like wave followed by other volleys whose origins remain unclear (1, 2). The latter AP volleys (including the $I_3$-like) are delayed by 2-3 ms compared with the PA late I waves (Refs. 12-14, 50; AP delayed I wave). The difference observed between PA- and AP-MEP latencies [0.9 ms; PA: 13.9 (2.4) ms, AP: 14.8 (3.1) ms] is shorter than those reported for hand muscles (2-3 ms) (50). However, the difference is in the same direction with shorter latency for PA-TMS compared with AP-TMS that could suggest that different TMS current directions over LES representation may recruit different volleys and potentially different intracortical circuits (50). Future studies are necessary to determine whether the smaller difference in latencies between PA- and AP-TMS is physiologically relevant.

For hand muscles, PA-SICI paradigms are proposed to moderately suppress $I_3$ waves but do not affect $I_1$ waves (52). In contrast, AP current (above MT) recruits delayed I wave circuits, which have been suggested to be different from the I waves evoked by PA-TMS (50). The large difference in the SICI level between PA- and AP-TMS supports the hypothesis of two different circuits recruited by the different current directions. The absence of significant inhibition in PA-TMS could come from our small sample of participants, since

previous TMS studies on back muscles reported inhibition with similar PA-SICI paradigms (25, 36). In addition, this absence of SICI was especially obvious at 2-ms ISI. This may be caused by the intensity of the conditioning stimulus (CS), which influences the level of inhibition. Indeed, Ortu et al. (53) reported more inhibition at 70% AMT compared with 80% and 90% AMT when the hand muscles were active during TMS positioned in anteromedial direction. However, Sale et al. (10) reported more SICI with AP-TMS when the CS was set at 80% with an ISI of 3 ms, and Cirillio and Byblow (11) observed more SICI with a CS of 80% or 90% for both AP- and PA-TMS. In the present study, the CS was set at 80% AMT, whereas 70% AMT was used in TMS studies of back muscles (15, 16, 36). It is possible that 70% AMT is more efficient at 2-ms ISI to produce inhibition, although it has never been tested for trunk muscles. It remains unclear whether the lack of SICI with PA-TMS was due to the selection of non-optimal parameters. For hand muscles, SICI probes the excitability of local γ-aminobutyric acid (GABA)Aergic inhibitory circuits in M1 (52). Since GABA is the principal inhibitory neurotransmitter in the brain, our results suggest the involvement of similar GABAergic inhibitory circuits modulating corticospinal projections to LES. However, pharmacoc-TMS is necessary to confirm this hypothesis. Intracortical excitatory circuits are less understood (1, 6). Muscle

<figure><img src="image_8.png" /><figcaption>**Figure 5.** Examples of averaged motor-evoked potential (MEP) observed across transcranial magnetic stimulation (TMS) intensities of the recruitment curve for 1 participant. Dashed lines indicate the test stimulus. AP, anteroposterior; PA, posteroanterior.</figcaption></figure>
<figure><img src="image_9.png" /><figcaption>**Figure 6.** Individual average latency (all stimulation intensities averaged) (n = 11) for posteroanterior (PA)- and anteroposterior (AP)-transcranial magnetic stimulation (TMS). Nonparametric analysis of variance for longitudinal data (nparLD) tests using factors current direction and stimulation intensity [120–160% active motor threshold (AMT)], and their interaction, were computed to determine whether different current directions differently influenced motor-evoked potential (MEP) latencies. \*P < 0.05.</figcaption></figure>

activation during TMS abolishes the facilitation in TMS hand studies (40). This might explain why significant ICF has been rarely reported for back muscles, given that these muscles are generally tested during activity (15) because of the difficulty of obtaining MEP at rest (29). Lack of facilitation during active muscle contraction could be due to a saturation of the ICF circuit.

As for SICI and latencies, MT differences between current directions could represent the recruitment of different circuits. Pharmaco-TMS studies suggest that MT reflects the excitability of axons membrane rather than that of cell bodies of cortical neurons (54). The set of axons preferentially oriented to be depolarized by PA-TMS may have a lower threshold of activation than the second set of axons oriented to be preferentially activated by AP-TMS (6). Another possibility would be that the difference in MT reflects fewer axons preferentially oriented to AP-TMS. However, it seems unlikely since the recruitment curve and the map volume did not differ between current directions. When the threshold is reached, MEP amplitude represents a transsynaptic activation of excitatory networks controlled by inhibitory interneurons (54); therefore, a similar density of neurons may be depolarized for both current directions, as suggested by similar MEP amplitude and map volume. Within this pool of recruited neurons, AP-TMS may have recruited a larger population of inhibitory circuits, as suggested by a larger level of SICI in AP- compared with PA-TMS.

## AP MEP: Connection from Premotor?

Some authors have suggested that AP current in the brain could recruit cortical circuits connected or belonging to the premotor area (7). Importantly, strong connections have been reported between the premotor area and M1 in macaques (55) and to some extent in humans (56). Current evidence points toward a potential recruitment of the premotor cortex with AP-TMS. First, modeling studies suggested that AP stimulation may excite premotor regions (18, 20). Second, corticocortical afferents from premotor cortices and somatosensory

cortex seem to be oriented largely along the AP axis (6, 7). Third, a study tested PA- and AP-TMS in addition to the functional connectivity of cortical motor areas with magnetic resonance imaging during an isometric hand task; a strong positive correlation between the MEP latency following AP-TMS and the functional connectivity between M1 and the premotor cortex was observed (19). However, although a later MEP latency following AP-TMS was observed and concurs with results from TMS hand studies, no difference in the CoG of the LES cortical representation was observed across current directions. This could be explained because AP-TMS depolarizes corticocortical axons coming from the premotor cortex within the M1 and not the cell bodies located in the premotor cortex (or axons of interneurons within the premotor cortex; see, e.g., Ref. 57), making it more difficult to show CoG difference.

## LES Cortical Representation

The cortical representation of the LES is typically mapped at 100% MSO with a figure-of-eight coil (30–34). All published studies reported the localization of the CoG more anterior than ours, i.e., between 0.8 and 3 cm anterior to the vertex. We observed a more posterior CoG than previous studies [−0.61 (0.86) cm in PA and −0.91(0.46) in AP, i.e., posterior to the vertex (Fig. 7)]. Although one recent study used a double-cone coil to map the cortical representation of thoracic longissimus pars lumborum at the level of L₁, it was not possible to determine the position of the CoG in relation to the vertex (58). Another study used a double-cone coil to map the cortical representation of lower limb muscles (59). They reported an average CoG localization on, or slightly posterior to, the vertex [from −0.1 (0.8) cm to −0.2 (0.9) cm posterior to the vertex] (59), in contrast with previous mapping studies of quadriceps muscles, which reported more anterior localization of CoG with a figure-of-eight coil [from 0.45 (0.45) cm to 3.8 (1.5) cm anterior to the vertex] (60–64). It is suggested that a portion of the cortical representation may be inaccessible to the figure-of-eight coil but not to the double-cone coil. Consequently, the resulting map may appear more complex, reflecting anatomical complexity. Moreover, a double-cone coil may also excite neuronal elements remote from the stimulation sites because of a less focal stimulation compared with the figure-of-eight coil (65) that may modify the location of the CoG. Furthermore, Tsao et al. (66) mapped the MEP amplitude of the transversus abdominis (TrA) on a mediolateral single line from the vertex

<table><caption>**Table 2.** Normalized average amplitude (% max MEP) for both current directions at each intensity of stimulation</caption><thead><tr><th>Intensity, % AMT</th><th>PA, amplitude (% max MEP)</th><th>AP, amplitude (% max MEP)</th></tr></thead><tbody><tr><td>90</td><td>17.6 (9.9)</td><td>17.9 (6.9)</td></tr><tr><td>100</td><td>24.9 (10.4)</td><td>21.6 (10.8)</td></tr><tr><td>110</td><td>35.0 (16.6)</td><td>32.4 (7.8)</td></tr><tr><td>120</td><td>50.1 (10.5)</td><td>43.1 (12.7)</td></tr><tr><td>130</td><td>53.5 (13.1)</td><td>49.8 (12.5)</td></tr><tr><td>140</td><td>58.7 (12.2)</td><td>62.6 (12.4)</td></tr><tr><td>150</td><td>72.8 (11.0)</td><td>67.7 (8.8)</td></tr><tr><td>160</td><td>77.3 (12.0)</td><td>67.6 (7.1)</td></tr><tr><td>Mean (SD)</td><td>48.5 (23.0)</td><td>43.6 (20.8)</td></tr></tbody></table>

AMT, active motor threshold; AP, anteroposterior; MEP, motor-evoked potential; PA, posteroanterior; SD, standard deviation.
<table><caption>**Table 3.** M1 map characteristics in each current direction</caption><thead><tr><th rowspan="2">Subjects</th><th colspan="3">PA</th><th colspan="3">AP</th></tr><tr><th>Volume, sum%</th><th>CoG X, cm</th><th>CoG Y, cm</th><th>Volume, sum%</th><th>CoG X, cm</th><th>CoG Y, cm</th></tr></thead><tbody><tr><td>1</td><td>1,143.7</td><td>1.6</td><td>-0.8</td><td>1,829.8</td><td>1.6</td><td>-0.8</td></tr><tr><td>2</td><td>1,340.8</td><td>1.5</td><td>-1.8</td><td>212.1</td><td>1.7</td><td>-1.4</td></tr><tr><td>3</td><td>1,302.6</td><td>1.4</td><td>-0.2</td><td>2,651.1</td><td>1.4</td><td>-0.2</td></tr><tr><td>4</td><td>1,492.4</td><td>1.8</td><td>-0.2</td><td>1,787.1</td><td>1.4</td><td>-0.9</td></tr><tr><td>5</td><td>2,138.7</td><td>1.7</td><td>-0.4</td><td>708.5</td><td>2.0</td><td>-0.8</td></tr><tr><td>6</td><td>1,436.7</td><td>1.5</td><td>-0.1</td><td>1,354.7</td><td>1.6</td><td>-1.5</td></tr><tr><td>7</td><td>1,612.3</td><td>1.6</td><td>0.4</td><td>982.0</td><td>1.9</td><td>-0.6</td></tr><tr><td>8</td><td>1,936.2</td><td>1.5</td><td>-0.9</td><td>2,035.7</td><td>1.5</td><td>-0.8</td></tr><tr><td>9</td><td>634.8</td><td>1.9</td><td>-1.3</td><td>1,205.9</td><td>1.4</td><td>-1.4</td></tr><tr><td>10</td><td>1,469.3</td><td>1.5</td><td>0.8</td><td>2367.1</td><td>1.6</td><td>-0.4</td></tr><tr><td>11</td><td>2,217.9</td><td>1.6</td><td>-0.4</td><td>1,614.7</td><td>1.6</td><td>-0.6</td></tr><tr><td>12</td><td>964.6</td><td>1.4</td><td>-2.3</td><td>584.0</td><td>1.3</td><td>-1.6</td></tr><tr><td>Mean (SD)</td><td>1,474.2 (462.2)</td><td>1.6 (0.1)</td><td>-0.6 (0.9)</td><td>1,444.4 (740.5)</td><td>1.6 (0.2)</td><td>-0.9 (0.5)</td></tr></tbody></table>

AP, anteroposterior; CoG, center of gravity; M1, primary motor cortex; PA, posteroanterior; SD, standard deviation.

to 5 cm lateral to the midline. They showed the largest MEP amplitude at 2 cm lateral from the vertex, which is similar to our results when considering this single medio-lateral line. In the present study, the average PA map (Fig. 7) suggests that points lateral to 3 cm could evoke LES MEP. Unfortunately, because of the double-cone shape, stimulating lateral to 3 cm was technically difficult. It is possible that stimulating more laterally might have influenced the CoG in PA-TMS.

## Comparison with TMS Studies Targeting Back Muscles

AMTs with PA current reported in this study (PA 40.8% MSO) are similar to previous studies on lumbar back muscles using a double-cone coil and similar methodology (i.e., 36 to 51% MSO) (23, 25, 37, 67). A study using AP-TMS reported lower AMT [43.5% MSO (15)]. These differences could be explained by differences in methodology (e.g., fine-wire electrode recording of the deep multifidus muscles and lying

<figure><img src="image_10.png" /><figcaption>**Figure 7.** Average lumbar erector spinae (LES) map (n = 12) for posteroanterior (PA; A)- and anteroposterior (AP; B)-transcranial magnetic stimulation (TMS). The circle represents the mean center of gravity (CoG) with error bars; the cross represents the vertex. Scale: % of motor evoked potential (MEP) max.</figcaption></figure>
prone position with hip leg extension during TMS). PA-MEP latencies in the present study (13.9 ms) were similar (i.e., ~12–20 ms) (16, 30, 37). As mentioned above, some studies tested the paired-pulse TMS in lower back muscles, but current direction was rarely reported. In PA-TMS, inhibition of the MEP test amplitude with SICI paradigms (2 or 3 ms) ranged between approximately –53% (36) and approximately –17% (67), which is more than the present study [approximately –4.2% (2 ms) and approximately –14.7% (3 ms)]. This may be caused by testing SICI at the thoracic level ($T_{12}$) rather than the lumbar level in the present study. In AP-TMS, one study tested a range of ISIs (from 1 to 12 ms) using AP-TMS over the cortical representation of deep multifidus [$L_4$–$L_5$: MEP amplitude was significantly inhibited at ISI of 1, 3, 4, and 12 ms (15)]. Overall, our results are similar to the available literature in the field.

## Limitations

This study was the first to investigate the effect of current direction with a double-cone coil and for back muscles. Trunk muscles remain challenging to test using TMS with a conventional figure-of-eight coil. Although AMT was higher for AP-TMS compared with PA-TMS, it is uncertain whether the double-cone coil recruits the cortical neurons in the same way as the figure-of-eight coil. However, the more focal figure-of-eight coil lacks power to recruit reliably cortical neurons controlling back muscles. The small sample size potentially increased the probability of presenting type II errors. The mere reversal of the coil underestimates the complexity of $M1$. A more selective approach of the motor cortex nonuniform orientation may be more appropriate even though more technically challenging (68). The use of a double-cone coil limits the possible size of the map grid for two reasons: 1) the double cone does not always fit the shape of each skull and 2) the most anterior points of the grid were sometimes impossible to map. However, the use of this technique allows comparison of the two current directions. Also, the reliability of the TMS outcomes of the back muscles is not known.

## Conclusions

The present study aimed to investigate the effect of current direction on the corticomotor control of the erector spinae muscles. Our findings showed higher motor threshold, longer latencies, and larger inhibition for AP-TMS compared with PA-TMS. We propose that these differences could represent the recruitment of distinct cortical circuits depending on the current direction, similarly as for hand muscles. The functional role of these distinct motor circuits may be tested in future studies in addition to their potential involvement in clinical populations presenting with alteration in the control of trunk muscles (e.g., low back pain and stroke). Future work is essential to confirm these hypotheses.

## SUPPLEMENTAL DATA

Supplemental Table S1: https://doi.org/10.5683/SP3/EHL63E.

## GRANTS

This work was funded by a Discovery grant from the Natural Sciences and Engineering Research Council of Canada (RGPIN-

2019-06529). H.M.-A. and C.M. are supported by research scholarships from Fonds de recherche du Québec-Santé (respectively #281961 and #251649). M.D. and A.D. are supported by scholarships from the CIRRIS. A.R. is supported by a scholarship from Fonds de recherche du Québec-Santé (#289953). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

## DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

## AUTHOR CONTRIBUTIONS

M.D., C.M., and H.M.-A. conceived and designed research; M.D., A.R., A.D., and H.M.-A. performed experiments; M.D. and H.M.-A. analyzed data; M.D., C.M., and H.M.-A, interpreted results of experiments; M.D. and H.M.-A, prepared figures; M.D. and H.M.-A. drafted manuscript; M.D., A.R., A.D., C.M., and H.M.-A. edited and revised manuscript; M.D., A.R., A.D., C.M., and H.M.-A. approved final version of manuscript.

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