# The influence of experimental low back pain on neural networks involved in the control of lumbar erector spinae muscles

Antoine Rohel, Mikaël Desmons, Guillaume Léonard, Amélie Desgagnés, Rubens da Silva, Martin Simoneau, Catherine Mercier, Hugo Massé-Alarie

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## To cite this version:

Antoine Rohel, Mikaël Desmons, Guillaume Léonard, Amélie Desgagnés, Rubens da Silva, et al.. The influence of experimental low back pain on neural networks involved in the control of lumbar erector spinae muscles. Journal of Neurophysiology, 2022, 127 (6), pp.1593-1605. 10.1152/jn.00030.2022. hal-05149875

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Submitted on 8 Jul 2025

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RESEARCH ARTICLE

Control of Movement

# The influence of experimental low back pain on neural networks involved in the control of lumbar erector spinae muscles

Antoine Rohel,¹,² Mikaël Desmons,¹,² Guillaume Léonard,³ Amélie Desgagnés,¹,² Rubens da Silva,⁴
Martin Simoneau,¹,² Catherine Mercier,¹,² and Hugo Massé-Alarie¹,²

¹Cirris Research Centre, Centre Intégré Universitaire de Santé et Services Sociaux (CIUSSS) de la Capitale-Nationale, Quebec City, Quebec, Canada; ²Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada; ³Research Center on Aging, CIUSSS de l'Estrie—CHUS, Sherbrooke, Quebec, Canada; and ⁴BioNR Research Lab, Université du Québec à Chicoutimi, Chicoutimi, Quebec, Canada

## Abstract

Low back pain (LBP) often modifies spine motor control, but the neural origin of these motor control changes remains largely unexplored. This study aimed to determine the impact of experimental low back pain on the excitability of cortical, subcortical, and spinal networks involved in the control of back muscles. Thirty healthy subjects were recruited and allocated to pain (capsaicin and heat) or control (heat) groups. Corticospinal excitability (motor-evoked potential; MEP) and intracortical networks were assessed by single- and paired-pulse transcranial magnetic stimulation, respectively. Electrical vestibular stimulation was applied to assess vestibulospinal excitability (vestibular MEP; VMEP) and the stretch reflex for excitability of the spinal or supraspinal loop (R1 and R2, respectively). Evoked back motor responses were measured before, during, and after pain induction. Nonparametric rank-based ANOVA determined if pain modulated motor neural networks. A decrease of R1 amplitude was present after the pain disappearance (P = 0.01) whereas an increase was observed in the control group (P = 0.03) compared with the R1 amplitude measured at prepain and preheat period, respectively (group × time interaction, P < 0.001). No difference in MEP and VMEP amplitude was present during and after pain (P > 0.05). During experimental LBP, no change in cortical, subcortical, or spinal networks was observed. After pain disappearance, the reduction of the R1 amplitude without modification of MEP and VMEP amplitude suggests a reduction in spinal excitability potentially combined with an increase in descending drives. The absence of effect during pain needs to be further explored.

**NEW & NOTEWORTHY** In the presence of experimental low back pain, spinal, subcortical, and cortical motor networks involved in the control of back muscles were not modified. However, once the pain disappeared, a reduction in motoneuronal excitability was observed without change in corticospinal and vestibulospinal excitability, suggesting a reduction in descending drive. Experimental low back pain may elicit long-term plasticity even after pain extinction.

electrical vestibular stimulation; erector spinae; low back pain; stretch reflex; transcranial magnetic stimulation

## INTRODUCTION

The spine motor system seems particularly impacted by low back pain (LBP). For example, some individuals present atrophy of lumbar multifidus (1, 2) or observable differences in spine movement during various motor tasks compared with pain-free individuals such as a reduction in the range of motion and movement velocity during a spine flexion (3). These differences can also be less obvious such as “in phase” movement of the pelvis and the thorax during walking (4) or

differences in motor patterns of trunk muscles during postural tasks (5, 6) and are sometimes associated with psycho-logical factors such as fear of movement (7–9).

It has been suggested that some of these differences are the results of a reorganization of motor networks controlling the trunk muscles within the central nervous system (CNS) (10). In contrast to hand muscles, trunk muscles control results from the contribution of multiple neural networks and descending pathways [e.g., corticospinal (11, 12) and ventromedial system (13, 14) tracts] that can each be impacted
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by LBP. The corticospinal tract excitability and the primary motor cortex (M1) can be probed by transcranial magnetic stimulation (TMS). Indeed, TMS studies showed that the function of intracortical networks (15, 16) and M1 organization of motor maps (17, 18) of trunk muscles are different in chronic LBP (CLBP) compared with pain-free controls. This suggests that, for some individuals, LBP may modify the organization of M1 networks involved in trunk motor control. However, the latter results (15–18) come from case-control studies that were not designed to determine causality. Thus, to delineate the causal effects of pain on motor networks involved in the control of trunk muscles, experimental pain models are used. Different experimental LBP models exist such as hypertonic saline injection (3, 19–21) or a combination of capsaicin and heat (22). In addition to being noninvasive, the latter model reproduces many LBP characteristics such as motor symptoms (22), allodynia, central sensitization, and hyperalgesia (23–25). Systematic reviews with meta-analysis provided evidence that experimental pain applied to various body regions decreases corticospinal excitability (26, 27). However, in the only TMS study of back muscles, Tsao et al. (21) showed that an injection of hypertonic saline solution in the lumbar interspinous ligament rather increased the corticospinal excitability of lumbar erector spinae (LES). In line, in TMS studies targeting quadriceps muscles (vastus lateralis and vastus medialis), an increase in corticospinal excitability was observed during experimental knee pain elicited by hypertonic solution injection (28, 29). Moreover, a recent systematic review with meta-analysis demonstrated that the effect of experimental pain applied to various body sites on motoneuronal excitability measured by H-reflex amplitude was heterogeneous (30). For experimental LBP, Zedka et al. (3) observed that cu-taneous pain (electrical or pressure) did not influence the LES short-latency stretch reflex (SR) response (R1: representing spinal excitability) but only the long-latency SR (increase in R2 amplitude). This suggests no influence of pain on motoneuronal excitability but an influence on supraspinal networks considering that R2 represents the transcortical/ supraspinal processing of SR (3). Importantly, none of these studies (3, 21) measured cortical and spinal excitability simultaneously to better assess the origin of motor changes induced by LBP. Recent TMS studies of back muscles did not report any change in cortical networks and excitability of corticospinal projections to back muscles following neurostimulation (31) or motor training (32) of back muscles despite improvement in motor performance, suggesting that other networks/pathways could be at the origin of these behavioral changes. These authors hypothesized that brainstem neural networks could be at the origin of these changes.

Seminal studies highlighted the importance of the ventromedial system, originating from the brainstem (e.g., vestibulospinal, reticulospinal tracts), in the control of trunk extensors muscles [e.g., a lesion prevented maintaining an upright spine posture (13, 14)]. In humans, the vestibular control of erector spinae can be studied using electrical vestibular stimulation (EVS) (33, 34). EVS depolarizes the vestibular system by modifying the firing rate of the vestibular afferents (otoliths and semicircular canals) (35, 36). Vestibular afferents travel via the vestibulospinal tract connecting directly (excitatory) or indirectly (excitatory or inhibitory) to the α-motoneurons of the

muscles acting to preserve balance [for review see Forbes et al. (37)]. In CLBP, muscle overactivation of erector spinae [i.e., higher muscle activity compared to pain-free participants (10, 38)] could be driven, in part, by changes in the excitability of the vestibulospinal tract, considering its involvement in the control of muscle tone of back muscles (13, 14, 39). Thus, considering the known influence of LBP on M1 networks and the involvement of the vestibulospinal tract in the control of back muscles, LBP may influence erector spinae motor responses to EVS.

The objective of this study was to determine the effect of experimental LBP on various neural networks and pathways involved in the control of back muscles. Three neurophysiological techniques (TMS, cortical networks and corticospinal excitability; EVS, vestibular reflex; muscle tap, spinal excitability) were used to test the impact of experimental LBP (pain group, combination of capsaicin cream and heat | control group, heat alone) on neural networks and pathways involved in the control of back muscles. We hypothesized that during pain, cortical excitability and vestibulospinal excitability would increase but not spinal excitability. These hypotheses are based on the absence of change in R1 amplitude (spinal excitability) and on the increase in R2 amplitude (transcortical loop) of back muscles during experimental LBP (3), and on the rationale that LBP may influence muscle activity of back muscles that are controlled, in part, by the vestibulospinal tract.

# METHODS

## Participants

Thirty pain-free adults [15 females; 27 right-handed; means ± SD, age: 27 ± 7 yr; height: 173 ± 10 cm; weight: 69 ± 10 kg; body mass index (BMI; weight/height²): 23 ± 2 kg/m²] were recruited using convenience sampling in the university population. Participants were excluded if they presented major neurological, cardiorespiratory, or circulatory conditions that may interfere with postural control, scoliosis, chilli pepper allergy (a component of capsaicin), and if they presented with contraindications to TMS (40–42). Participants gave written informed consent, and the study was approved by the Institutional Human Research Ethics Committee of the CIUSSS – Capitale-Nationale (#2020-1952) and was conducted following the Declaration of Helsinki.

## Experimental Design

Of note, this section is an overview of the experimental design and aims to briefly detail the different steps of the experiment. Methodological aspects of neurophysiological techniques used and of the pain model are provided in specific subsequent sections. This project has been conducted in one session (Fig. 1, A and B). Participants were allocated randomly to one of two groups: “pain” (combination of heat and capsaicin) or “control” (heat only) before the beginning of the session [see *Experimental pain model (pain group)* and *Heat model (control group)* for details]. The session consisted of three measurement periods: before (prepain/heat), during (during-pain/heat), and after pain/heat (postpain/heat). Within each period of measurements, three different neurostimulation techniques were used: i) TMS, ii) EVS, and iii) a direct
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<figure><img src="image_5.png" /><figcaption>**Figure 1.** Experimental designs for the pain (A) and control (B) groups. C: methodological schematization of the different types of stimulations and of the position of participants. EVS, electrical vestibular stimulation; LES, lumbar erector spinae; NPRS, numeric pain rating scale; SR, stretch reflex; TMS, transcranial magnetic stimulation.</figcaption></figure>

muscle tap to induce an SR. Each technique was used to test different neural motor networks. For all neurostimulation techniques, participants were seated on a stool with arms resting along the body to minimize the contraction of superficial trunk muscles (trapezius and latissimus dorsi) (33). Participants' head was either facing forward (for TMS and SR) or with a cervical rotation (for EVS – see *Electrical vestibular stimulation* for details and justification). All conditions were tested with eyes open. Considering that motor-evoked potentials (MEPs) using TMS (11) and EVS are difficult to obtain at rest (43), a slight contraction of back muscles allowed to obtain consistent motor responses. Thus, during neurophysiological testing, participants had to contract LES at an amplitude of 15 ± 5% of maximal voluntary contraction (MVC) (see *Electromyography* for the details of MVC measurement).

Measurements using all neurophysiological techniques were realized before, during, and after the pain induction or heat application. The order of the techniques was randomized for all periods of measurement. After the first period of measurements (prepain/heat), experimental pain was induced for the “pain” group and heat was applied for the “control” group. Participants of the “pain” group were asked to rate their pain level on a numeric pain rating scale (NPRS) every 2 min (0 = no pain; 10 = worst pain imaginable) from the capsaicin application until pain disappearance. When the pain intensity reached a level of 4 out of 10 for the “pain” group or after a 12-min heat application for the “control” group, during-pain/heat measurements were realized. The 12-min heat application corresponded to the mean delay observed in pilot participants to obtain a score of 4/10 on NPRS. Unlike the pre- and postpain/heat periods, the order of measurements was only randomized between TMS and EVS during-pain/heat period, and the SR was always tested at the end. This was done since the hot pack had to be removed to test the SR. Thus, testing SR at the end of the during-pain/heat period ensured that TMS and EVS were always tested at continuous pain and skin temperature level.

The third period of measurements (postpain/heat) started when the pain level returned to 0 for the “pain” group or when the skin temperature returned to its baseline level for the “control” group. Each measurement period lasted ~30 min.

**Experimental pain model (pain group).**

The experimental pain model consisted of the application of a hot pack (average temperature of 61°C) before the application of capsaicin cream on the low back area (22). The preheating of the skin was done for 5 min by covering the low back area bilaterally and symmetrically with the hot pack (Fig. 1A). Afterward, the hot pack was removed, and a thin layer of 0.075% capsaicin cream was applied onto the preheated zone in an area delimited by four anatomical markers: left posterosuperior inferior spine (PSIS), L5 spinous process, right PSIS, and the S1 vertebra (illustrated in Fig. 2A). Five minutes after the application of the capsaicin cream, the hot pack was replaced on the low back spine. The objective of the skin heating was to potentiate the effect of capsaicin. Indeed, a previous study showed that the combination of capsaicin and skin heating increased pain intensity compared with capsaicin alone (22) probably via a synergistic activation by capsaicin and heat of TRPV1 receptors (23). For most participants, pain intensity remained at least 4 out of 10 during all the pain measurement periods.

After the pain measurement period, a glycerin-based cream (Glysomed) was applied to the area where the capsaicin cream was applied. This was done to accelerate pain reduction since it could take up to 45 min for the pain to disappear without using this cream (44). Glycerin “neutralizes” capsaicin effects through chemical processes (hygroscopicity and water solubility) rather than inducing an analgesic effect (45) limiting its impact on the results.

**Heat model (control group).**

Considering that heat was necessary for the pain group to achieve the target pain level, the use of a control group was
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<figure><img src="image_7.png" /><figcaption>**Figure 2.** Area of the capsaicin application (A) and the pain intensity induced by the experimental low back pain model (B). The area of capsaicin application was delimited at the top by the L5 spinous process, at the bottom by the S1 spinous process and by both posterosuperior inferior spines (PSIS). The pain level was rated on a numeric pain rating sale (NPRS) each 2 min after capsaicin application. Gray lines represent each participant, and the bold line represents the group median. L5, 5th lumbar vertebra; NPRS, numeric pain rating sale; PSIS, posterosuperior inferior spine; S, 1st sacrum vertebra.</figcaption></figure>

necessary to control for any systematic effects of heat and time on the outcome tested. A protocol similar to the pain group was used (Fig. 1B). The hot pack was applied for 12 min to match the duration of heat application in the pain group. The experimenter ensured that the heat did not produce pain by questioning participants during the application of the hot pack. None of the participants reported pain. Skin temperature was measured before the application of heat (baseline) and after the end of the during-heat period. From that moment, the temperature was assessed every 2 min until the heat came back to its baseline level (±2°C). All measurements were made using an infrared thermometer (LFR30B, LEPU Medical Technology, Beijing) at three different sites: left PSIS, L5 spinous process, and right PSIS. The average of the three sites was considered as the skin temperature.

## Electromyography

Pairs of surface electrodes (Ag/AgCl disks, 10 mm in diameter, Ambu, Denmark) were placed on the right LES (2–3 cm lateral to the L3–L4 spinous process). The left M1 was stimulated for each participant, considering that previous studies did not find any effect of handedness on TMS outcomes of the back muscles (46–50). A ground electrode was placed over the right iliac crest (9160 F, 3 M, Saint Paul). SENIAM recommendations were followed for skin preparation and electrode placement (51). Electromyography (EMG) data were amplified 1,000 times, bandpass filtered between 10 Hz and 500 Hz using a D360 EMG amplifier (Digitimer Ltd, Hertfordshire, UK), and sampled at 2 kHz using a Power1401 Data Acquisition System with Spike2 software (Cambridge Electronic Design, Cambridge, UK).

The MVC was calculated at the beginning of the session, just after the EMG installation. To measure MVC, participants performed three 3-s maximal resisted trunk extensions or maximal anterior pelvic tilt in sitting, according to the task that produced the largest level of LES EMG activity. This method was used as pilot experiments showed that some participants were not able to contract LES using one task or the other. Experimenters provided encouragements to maximize MVC. The maximal value out of the three trials was considered as MVC [root mean square (rms) EMG

amplitude calculated using a 100-ms time window]. As recommended by the Consensus for Experimental Design in Electromyography (CEDE) project, amplitude normalization was realized using an MVC task that matched the patient's position used during the experiment (52). Although we did not measure muscle length and joint angle, testing MVC in the same position as the experimental task (i.e., in sitting) ensured it was more comparable than MVC testing performed in any other positions. MVC in sitting has been used for normalization in most TMS studies of back muscles (47, 53–56).

Following MVC (but before any neurophysiological measurements), we tested if participants were able to activate their LES at 15% MVC. In some participants, the LES EMG activity exceeded the 15% MVC level even though LES were relaxed (i.e., while flexing the low back spine in sitting) or when they were asked to sit upright. These conditions were often caused by the small absolute EMG amplitude produced by the MVC task. Considering it would have been very difficult to elicit MEPs and VMEPs with small or no LES activation (11, 43), we decided to adjust the relative level of LES contraction for these participants. In these cases, the level of contraction requested was increased by steps of 5% until participants could maintain an upright sitting position with a slight lumbar lordosis. Once the adjustment was done, the EMG was kept constant at each measurement period (see details in RESULTS). To ensure that participants maintained a constant level of LES contraction during the experimental tasks, visual feedback was displayed on a computer screen positioned in front of (TMS and SR) or beside them (EVS). To activate LES to 15 ± 5% MVC, participants were asked to perform an anterior pelvic tilt or to slightly lean forward (Fig. 1C) because it was shown to activate the LES (57, 58). These motor strategies are frequently used in TMS (11, 53, 54, 56) and EVS (59) studies targeting back muscles to activate LES. The visual feedback consisted of a line positioned at 15% MVC and a smoothed LES rms EMG signal (time window = 0.5 s). Participants had to reach and maintain their LES EMG activity on this line as precisely as possible. Two additional dotted lines positioned at 10% and 20% MVC were displayed on the monitor as the margin of error to delimit the 15 ± 5% MVC. The experimenter asked participants to adjust their
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level of contraction when LES activation was outside this window. Also, it ensured that the motor responses obtained using the different neurophysiological techniques had similar motoneuron excitability during testing (60). Breaks were taken between series of stimulation to avoid the apparition of fatigue during the experiment.

## Transcranial Magnetic Stimulation

Monophasic transcranial magnetic stimulation (TMS) was applied over the left M1 using a Magstim Bistim² with a double cone coil (126 mm diameter per wing; Magstim Company Limited, Whitland, UK) coupled to a Brainsight frameless stereotaxic neuronavigation system (Brainsight, Rogue Research, Canada). The coil was oriented to induce a posteroanterior current. The first step was to determine the hotspot and the active motor threshold (AMT). The hotspot consisted of the site on the scalp where TMS elicited the largest LES MEP amplitudes at a given intensity. The AMT was defined as the TMS intensity eliciting visible MEPs in 3 out of 6 stimuli at a physiological latency (~14–18 ms) (48, 61). The AMT was confirmed at each period of measurement to control for any variation and ensure that paired-pulse paradigms and the recruitment curve were tested at the same intensities relative to the AMT throughout the experiment.

At each measurement period, three paradigms were tested: MEP at 120% 140%, and 160% AMT, short-interval intracortical inhibition (SICI), and short-interval intracortical facilitation (SICF) in a randomized order. For the different TMS intensities, 120%, 140%, and 160% AMT were tested in a randomized order with six single stimuli per intensity, randomly spaced from 5 to 8 s between each stimulus. Paired-pulse TMS paradigms were used to test SICI and SICF. For SICI, a subthreshold stimulus of 80% AMT (conditioning stimulus) was followed by a suprathreshold stimulus at 120% AMT (test stimulus) at 3-ms interstimulus interval (47). For SICF, a suprathreshold TMS at 120% AMT was followed by a TMS stimulus at 100% AMT at 1.5-ms interstimulus interval (47, 62). SICF paradigm was chosen rather than a more conventional ICF (conditioning stimulus: 80%-90% AMT; ISI: 10–15 ms; test stimulus: 120% AMT) because studies from our group observed significant facilitation of the MEP test using the SICF paradigm whereas no facilitation was observed using ICF (16, 63). Ten single TMS (120% AMT-MEP test) and 10 paired-pulse TMS (SICI and SICF) were applied on M1 to measure the unconditioned and conditioned MEP amplitude, respectively.

## Electrical Vestibular Stimulation

A pair of surface electrodes (Axelgaard Manufacturing Co. Ltd., Fallbrook, CA) was positioned over both mastoid processes and connected to a constant current stimulator (Digitimer DS5, UK) synchronized with the data acquisition system. Bipolar binaural EVS was applied with the anode placed onto the right mastoid process and the cathode on the left mastoid process. An anesthetic cream (Maxilene 5, Ferndale Laboratories, Inc., Ferndale, MI) was applied over the mastoid to reduce discomfort during EVS. EVS was applied at 3, 4, and 5 mA using a 20-ms square wave stimulus duration while participants maintained a

right cervical rotation with eyes open. The head was turned to the right to the maximal comfortable position (33). A tape measure was used to measure the range of motion of the cervical rotation (distance between the acromion and the chin) at each EVS measurement period to ensure that the rotation was the same throughout the experiment. Twenty stimulations were realized per intensity tested. These parameters were selected based on the literature and results from a published project performed by our group (59).

## Stretch Reflex (Muscle Tap)

A homemade electromagnetic hammer device was designed and built to elicit SR. The hammer was powered by a 24-V solenoid and controlled via a homemade script on CED Spike2 software and a CED Power1401-3A (Cambridge Electronic Design Ltd.). A spring ensures the impinger to return and keeps the duration of the impact as short as possible which is important to trigger a reflex (64). A force sensor (FlexiForce A201, Tekscan) located at the end of the impinger indicated the moment of contact and allowed identifying the latency of the SR. Twenty muscle taps were applied ~1–2 cm medial and cranial to the PSIS, at the maximal force of the hammer. Although other studies taped between the electrodes on the muscle belly (3, 65, 66), we were unable to produce an SR without EMG artifact using this technique in pilot studies. Taping at the vicinity of the PSIS produced consistent SR without EMG artifact.

## Data Analysis

To determine the impact of experimental LBP on the different networks controlling the back muscles, several dependent variables were measured. For TMS, the outcomes were:

i) the excitability of M1 neural elements (AMT),

ii) the excitability of the corticospinal projections to LES muscles (MEP amplitude),

iii) the level of excitability of inhibitory (SICI) and excitatory (SICF) M1 networks; for EVS:

iv) inhibitory (SL amplitude) and excitatory (ML amplitude) response to vestibular inputs (VMEP);

v) the motoneuronal (R1 amplitude) and transcortical (R2 amplitude) excitability of the SR.

All motor responses were analyzed using homemade MATLAB (v. R2019a) scripts (The MathWorks Inc., Natick, MA). First, the EMG signals were rectified and then averaged for each series of stimulation. The onset and offset of the motor responses were identified visually when the rectified EMG activity exceeded or was back to the prestimulus EMG level, respectively. Visual identification of EMG responses of back muscles is frequently used (34, 59, 67, 68) and considered valid (69). The rms EMG amplitude of the motor response (window between onset and offset) was calculated. To control for any changes in the prestimulus EMG, the prestimulus rms EMG amplitude (50 ms before the stimulation) was calculated and subtracted from the motor response, which was finally normalized by each participant's MVC (67). In addition, prestimulus EMG amplitude was calculated for each measurement period (all trials averaged) and expressed as MVC ratio. SICI and
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SICF were calculated by dividing the MEP amplitude of the paired-pulse TMS (conditioned) by the MEP amplitude of the TMS at 120% AMT (MEP test), then multiplied by 100. SICI and SICF are therefore expressed in percentage of the MEP test.

## Statistical Analysis

Nonparametric tests were used because of the presence of extreme values and our relatively small sample size. Demographic and anthropometric characteristics of the two groups were compared using Mann-Whitney U test for age, height, weight, physical activity, and body mass index. Also, the time elapsed between the end of the second period of measurement (during pain/heat) and the third period of measurement (postpain/heat), and the percent of MVC used as a contraction during the experiment were compared between groups using the Mann-Whitney U test. A $\chi^2$ test was used to compare the distribution of sex and handedness between the two groups. These analyses were performed using SPSS (70).

To test our study objectives, nonparametric rank-based ANOVA (nparLD tests) were computed on predefined outcomes, using “nparLD” package (functions fl ld. fl and fl ld. f2) on R (R Core Team 71, 72). NparLD is the nonparametric equivalent of repeated-measures ANOVA and a robust method for factorial designs (between- and within-group main effects and interactions) with small and inequivalent samples, and extreme values. It is also robust to missing data and does not require normal distributions and homoscedasticity. NparLD tests were performed on the dependent variables:

i) AMT, SICI, SICF, R1, and R2 using factors time (pre-, during-, and postpain/heat) and group (pain vs. control);

ii) MEP amplitude and SL- and ML-VMEP, using factors time, group, and intensity (MEP: 120%, 140%, and 160% AMT | VMEP: 3, 4, and 5mA);

Also, to ensure that prestimulus EMG amplitude was similar across the measurement periods and between groups, nparLD tests were performed using factors time and group. Post hoc tests were also conducted on R software using nonparametric rank-based ANOVA (function rankFD) for between-group comparisons and nparLD (function fl ld. fl from nparLD package) for within-group comparisons (73). Except for SICI and SICF which were reported as %MEPtest and AMT as %MSO, data are expressed as MVC ratio using the median (a measure of central tendency) and the 95% confidence interval of the median (a measure of dispersion) unless otherwise stated. The $\alpha$ threshold was fixed at $P < 0.05$.

## RESULTS

The details of the demographic and anthropometric characteristics for both groups and their comparisons are presented in Table 1.

In one participant, it was not possible to test 160% AMT because the intensity of stimulation exceeded 100% of the maximum stimulator output (MSO). In two participants (pain group), the analysis of SR was not possible due to the presence of artifacts in EMG signals produced by the muscle tap at all measurement periods. For two other participants (pain group), the problem occurred only at the first period of measurement for the first participant and at the third period of measurement for the second participant. Thus, 12 pre- and postpain data and 13 during-pain data were available for SR for the pain group. In some participants, the LES EMG background was adjusted before the beginning of any measurement periods and was kept constant throughout the study. Overall, EMG background was adjusted for 7 participants [10%: n = 1 (pain); 20%: n = 2 (1 pain, 1 control); 25%: n = 3 (1 pain, 2 controls); 30%: n = 1 (pain)]. The percentage of MVC used in each group did not differ [median: 15% (0.15;0.15) for each group | mean: pain group: 17 ± 5%; control group: 17 ± 4%; $P = 0.838$]. No adverse effects related to TMS, EVS, or SR were reported. Additional analyses including only participants who were tested at 15% MVC (11 in pain; 12 in control) did not modify the results.

### Pain Intensity

The median NPRS score during the “during-pain” period was 5.0 (4.5; 5.0; Fig. 2B). Median peak pain was 6 (5.5; 7) and the median time for participants to rate 4 out of 10 on the NPRS was 14 (8; 18) min. For one participant, it was longer to obtain and maintain 4 out of 10 compared with the rest of the pain group (see Fig. 2B). The median time elapsed between the second and third periods of measurements for each group was similar [median: pain group: 8 (6; 15) min, Control group: 8 (5; 14) min].

### Description of Motor Responses Observed at Baseline

Figure 3 shows representative EMG traces evoked by the different neurophysiological techniques for one participant. MEP was present at a latency of 17 ± 2 ms (means ± SD) with TMS. SL-VMEP was present at a latency of 48 ± 11 ms and an ML response at 75 ± 11 ms. R1 was evoked at a mean latency of 10 ± 5 ms and an R2 at 50 ± 7 ms.

<table><caption>Table 1. Between-comparison for demographic and anthropometric characteristics</caption><thead><tr><th>Outcomes</th><th>Pain Group (n = 15)</th><th>Control Group (n = 15)</th><th>P Value</th></tr></thead><tbody><tr><td>Sex, n of female</td><td>7</td><td>8</td><td>0.715</td></tr><tr><td>Handedness, n of left-handed</td><td>2</td><td>1</td><td>0.543</td></tr><tr><td>Age, yr</td><td>24 (24; 27)</td><td>26 (24; 28)</td><td>0.587</td></tr><tr><td>Height, cm</td><td>173 (170; 182)</td><td>172 (164; 179)</td><td>0.361</td></tr><tr><td>Weight, kg</td><td>75 (61; 79)</td><td>66 (59; 71)</td><td>0.253</td></tr><tr><td>Physical activity, h/wk*</td><td>5 (2; 8)</td><td>4 (3; 7)</td><td>0.505</td></tr><tr><td>BMI, kg/m<sup>2</sup></td><td>23 (22; 24)</td><td>23 (22; 24)</td><td>0.983</td></tr></tbody></table>

Values are median (95% confidence interval). BMI, body mass index. *Participants were asked to determine how many hours of physical activity per week they usually perform.
<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /><figcaption>**Figure 3.** Averaged electromyography (EMG) traces for one participant at the first period of measurement evoked by TMS (A), muscle taps (B), and EVS (C). Note that EMG is averaged and rectified for EVS to facilitate the visualization of the responses. MEP, motor-evoked potential; ML, medium-latency response (EVS); R1, short-latency response (SR); R2, long-latency response (SR); SICF, short-interval intracortical facilitation; SICI, short-interval intracortical inhibition; SL, short-latency response (EVS); TMS, transcranial magnetic stimulation.</figcaption></figure>

## EMG Background

A main effect of time ($F = 1.603; P = 0.02$) was observed and explained by a larger prestimulus EMG amplitude at pre-pain/heat [0.111 (0.105; 0.122) ratio MVC] compared with during- [(0.107 (0.098; 0.114); $P = 0.004$)] and postpain/heat [0.110 (0.099; 0.121); $P = 0.03$] periods. No difference was present between during- and postpain/heat periods ($P = 0.70$). No main effect of Group ($F = 0.002; P = 0.96$) and group × time interaction ($F = 0.983; P = 0.36$) was observed.

## Effect of Pain on TMS Outcomes

Data for all dependent variables at each time point and for the two groups are provided as Supplemental Material S1 (https://doi.org/10.5683/SP3/QLIZ72).

### Active motor threshold.

For AMT, there was no main effect of group ($F = 1.356; P = 0.244$) or time ($F = 2.076; P = 0.138$), and no time × group interaction ($F = 1.183, P = 0.298$; Fig. 4A).

### MEP amplitudes.

A main effect of intensity ($F = 16.211; P < 0.001$) | 120% = 0.21 (0.19; 0.24); 140% = 0.30 (0.25;0.35); 160% = 0.33 (0.27; 0.37) was detected for MEP amplitude, but without main effect of time ($F = 2.443; P = 0.094$) and group ($F = 0.042; P = 0.840$). In addition, none of the interactions were significant (group × time: $P = 0.956$; group × intensity: $P = 0.754$; group × time × intensity: $P = 0.722$). Individuals and group data are presented in Fig. 4D.

### SICI and SICF.

For SICI and SICF, no main effect of group (SICI: $F = 0.076; P = 0.782$ | SICF: $F = 0.006; P = 0.940$), time (SICI: $F = 0.608; P = 0.542$ | SICF: $F = 0.251; P = 0.774$) or group × time were observed (SICI: $F = 0.488; P = 0.610$ | SICF: $F = 0.472; P = 0.620$) (Fig. 4, B and C).

## Effect of Pain on Muscle Tap Outcomes

### Short-latency SR (R1).

No main effect of time was found ($F = 0.335, P = 0.712$) but a main effect of group was present ($F = 5.309, P = 0.021$). A group × time interaction was observed for R1 amplitude ($F = 7.160; P < 0.001$; Fig. 5A).

This section presents pairwise comparisons to explain the significant group × time interaction. In the pain group, R1 amplitude was smaller in postpain [0.021 (0.006; 0.027)] compared with prepain [0.030 (0.018; 0.053) MVC ratio; $P = 0.012$]. No difference was present in R1 amplitude during pain [0.026 (0.001; 0.044)] compared with before ($P = 0.111$) and after pain ($P = 0.296$). For the control group, R1 amplitude was larger in postheat period [0.057 (0.036; 0.088)] compared with preheat [0.030 (0.020; 0.070); $P = 0.032$] and during-heat [0.033 (0.024; 0.059); $P = 0.004$]. No difference was present between preheat and during-heat periods ($P = 0.639$). For between-group comparisons, R1 amplitude was larger in the post-pain/heat period for the control group than pain group (postheat vs. postpain; $P < 0.0001$) but no difference was present at pre- ($P = 0.813$) and during ($P = 0.185$) pain/heat.
<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /></figure>

**Figure 4.** Individual and group (median and 95% CI) data for AMT (A), SICI (B), SICF (C), and MEP amplitude (D) at 120%, 140%, and 160% AMT before, during, and after pain/heat. Most participants were tested at 15% MVC (n = 23) and the remaining participants were tested between 10% and 30% MVC (10%: n = 1; 20%: n = 2; 25%: n = 3; 30%: n = 1). AMT, active motor threshold; MEP, motor-evoked potential; MSO, maximum stimulator output; MVC, maximal voluntary contraction; SICF, short-interval intracortical facilitation; SICI, short-interval intracortical inhibition; 95%CI, confidence interval at 95%.

**Long-latency SR (R2).**

No main effect of Group (F = 0.007, P = 0.934), time (F = 0.010, P = 0.985) or group × time interaction (F = 1.859, P = 0.161) was present for R2 amplitude (Fig. 5B).

**Long-latency SR (R2).**

No main effect of group (F = 0.044, P = 0.833), time (F = 0.723, P = 0.467), or group × time interaction (F = 1.903, P = 0.155) was present for R2 amplitude (Fig. 5B).

## Effect of Pain on EVS Outcomes

**Short-latency VMEP.**

A main effect of Intensity was observed [F = 6.539; P = 0.001 | 3 mA: -0.009 (-0.016; -0.006), 4 mA: -0.015 (-0.020; -0.012), 5 mA: -0.017 (-0.021; -0.014)]. No main effect of group (F = 0.037; P = 0.846), time (F = 0.778; P = 0.455), or interactions were found (group × time: P = 0.890; group × intensity: P = 0.113; group × time × intensity: P = 0.104) (Fig. 6A).

**Figure 5.** Individual (individual data point) and group (median and 95%CI) data for R1 (A and B, respectively) and R2 amplitude (C) before, during, and after pain/heat. Note that the group median and 95%CI is presented alone in B to facilitate the visualization of the group × time interaction. Most participants were tested at 15% MVC (n = 23) and the remaining participants were tested between 10% and 30% MVC (10%: n = 1; 20%: n = 2; 25%: n = 3; 30%: n = 1). MVC, maximal voluntary contraction; R1, short-latency response of the stretch reflex; R2, long-latency response of the stretch reflex; 95%CI, confidence interval at 95%. \*P < 0.05; \*\*P < 0.01; \*\*\*P < 0.001.

<figure><img src="image_14.png" /></figure>
<figure><img src="image_15.png" /></figure>

<figure><img src="image_16.png" /><figcaption>**Figure 6.** Individual and group (median and 95%CI) for short-latency (A) and medium-latency (B) VMEP amplitude (EVS outcomes) before, during, and after pain/heat. EVS intensity are presented in ascending order from left to right. Most participants were tested at 15% MVC (n = 23) and the remaining participants were tested between 10% and 30% MVC (10%: n = 1; 20%: n = 2; 25%: n = 3; 30%: n = 1). ML, medium latency; MVC, maximal voluntary contraction; SL, short latency; VMEP, vestibular motor-evoked potential; 95%CI, confidence interval at 95%.</figcaption></figure>

### Medium-latency VMEP.

A main effect of intensity was observed [$F$ = 11.935; $P$ < 0.001 | 3 mA: 0.026 (0.020; 0.032), 4 mA: 0.030 (0.024; 0.039), 5 mA: 0.034 (0.028; 0.044)]. No main effect of group ($F$ = 0.484; $P$ = 0.487), time ($F$ = 1.200; $P$ = 0.294) or interactions were found (group × time: $P$ = 0.951; group × intensity: $P$ = 0.340; group × time × intensity: $P$ = 0.700) (Fig. 6B).

## DISCUSSION

This study aimed to determine the effect of experimental LBP on the neural networks involved in the control of back muscles. Contrary to our hypotheses, experimental LBP did not alter the motor networks tested and involved in the control of back muscles (e.g., cortical, corticospinal, vestibular). However, the short-latency component (R1) of the SR representing motoneuronal excitability was reduced after pain disappearance but increased after heat application.

### Lack of LBP Effect on Motor Networks during Pain

Under the current experimental conditions, experimental LBP did not impact motor networks involved in lumbar spine control during pain. Only two previous studies tested the effect of experimental LBP on motor networks controlling back muscles (3, 21). Tsao et al. (21) reported an increase in the excitability of corticospinal projections to LES at rest during experimental ligament LBP. However, similarly to our results, no effect was observed while trunk muscles were activated (21). Results from TMS studies of back muscles contrast with the consensus of an inhibitory effect of experimental pain on corticospinal excitability (26, 27, 30). This discrepancy may be due to methodological differences. First, the inhibitory effect of corticospinal excitability was confirmed with hand or face pain whereas more variability or a lack of evidence was present for

other body sites (27). Second, the inhibitory effect was only present when muscles were tested at rest (27). Throughout the study, constant within-participant EMG level during neurophysiological testing likely produced similar total synaptic inputs to the motoneuronal pool (74) before, during, and after pain. Thus, if an effect was present, it may have been compensated by voluntary drive. This may partly explain the differential effects of LBP on corticospinal projections to back muscles observed at rest and in activity, described previously (21).

The amplitude of the LES short-latency response of the SR (R1) was not changed during experimental LBP. R1 has been used as an indicator of motoneuronal excitability (3) representing a monosynaptic (or oligosynaptic) stretch reflex of back muscles (64, 75). Zedka et al. (3) in a study tested R1 of LES using three different LBP models and did not observe any effect of pain while maintaining a contraction. The effect of pain on R1 amplitude for other muscles is equivocal. Some observed an increase in the stretch reflex amplitude following injection of hypertonic saline in tibialis anterior (76) or an injection of capsaicin in the masseter (77) whereas others reported no modification of the biceps and triceps stretch reflexes amplitudes after the application of capsaicin on the elbow (78). Muscle tap also evokes the R2 response at medium-latency that would represent transcortical/supraspinal processing of afferent information (64–66, 79). Conversely to our results, Zedka et al. (3) observed an increase in R2 amplitude during electrical and mechanical cutaneous pain in the lower back area. Similarly, the effect of experimental pain on H-reflex amplitude is heterogeneous [i.e., increased, decreased, or unchanged depending on studies; for a review see Sanderson et al. (30)]. Again, pain location, muscle tested, pain type, and muscle state may explain, in part, the discrepancies observed between studies.
<figure><img src="image_17.png" /></figure>

Our experimental LBP model did not impact inhibitory (SICI) and excitatory (SICF) M1 networks. Apart from the current study, no study tested the effect of experimental LBP on motor networks involved in the control of back muscles. In TMS studies targeting upper limb muscles, SICI, mediated by GABA-A neurotransmitters (80), was immediately increased (i.e., more inhibition) after hand pain induction by cold (81) or an injection of hypertonic saline (82) but decreased following 4 days of experimental forearm muscle pain with injections of nerve growth factor and hypertonic saline (83). Thus, the time elapsed since pain apparition may differently influence intracortical networks suggesting different cortical mechanisms. However, the absence of effect on SICI and SICF in our study, does not support the modification of intracortical networks during experimental LBP. This is in line with recent TMS studies targeting back muscles that did not report any effect of peripheral electrical stimulation of the LES (31) and motor training (84) on SICI and SICF [in contrast to TMS of hand studies (85)] suggesting limited neuroplasticity in these specific cortical networks.

During experiment LBP, no change in the motor response elicited by EVS was observed. Our study is the first study, to our knowledge, evaluating the effect of experimental pain on motor responses to EVS. EVS evoked SL (usually inhibitory) and ML (usually excitatory) responses at a mean latency of 48 and 74 ms, respectively, similarly to EVS studies of back muscles (33, 34, 59, 86). Considering that some studies suggest a link between the vestibular system and pain processing (87–90), future studies need to test if other parameters of the experimental pain model (e.g., duration or intensity) may alter vestibular control of back muscles and other neural motor networks.

## Reduction in Motoneuronal Excitability and Increase in Cortical Excitability after Pain Disappearance

A reduction in R1 amplitude was present after pain disappearance. Considering that MEP amplitude represents the sum of the excitability of both cortical and spinal networks, the absence of MEP and VMEP modification combined with the reduction in R1 amplitude suggest an increase in descending drive (brainstem or cortical) after pain disappearance. Considering that motoneuronal excitability was maintained constant (constant muscle contraction) throughout the experiment, some authors suggested that the additional modulation in motoneuronal excitability during contraction implies that inputs coming from groups III and IV afferents are distributed nonuniformly across the motoneuron pool (74). Indeed, considering that i) a low level of contraction first recruits lower threshold motoneurons (small motor units) based on the Henneman's size principle (91) and ii) the R1 represents the recruitment by the muscle tap of additional motoneurons that were not recruited by the voluntary contraction (including higher threshold motoneurons), the reduction in R1 amplitude suggests that these latter motoneurons may have been specifically inhibited after pain disappearance. Results from other studies revealed that nociceptive afferents might have a nonuniform influence on high- versus low-threshold motoneurons (30, 92–94). Another possibility could come from the reduction of the membrane potential of the tested motoneurons.

A reduction in soleus R1 amplitude after pain has also been reported after the injection of hypertonic saline in soleus and tibialis anterior muscles at rest (76). Although the role of this pain aftereffect is difficult to extrapolate, it has been observed for multiple motor variables such as MEP amplitude [for review see Rohel et al. (27)], SICI and ICF (82), and R2 (76) and could represent the implementation of long-term adaptive plasticity. However, none of these variables were modulated by pain in the current study, then, it remains difficult to explain the role of this change considering the lack of consistent results in the literature.

## Effect of Heat on Motoneuronal Sensitivity

Although the heat was used as a control condition mainly to control the peripheral effect of heat on EMG (95, 96), it increased motoneuronal excitability. Heat impacts muscle spindles and fusimotor excitability (97). For the reasons described previously, the increase in motoneuronal excitability (R1 amplitude) combined with the absence of effect on corticospinal and vestibulospinal excitability (MEP and VMEP amplitude) during constant muscle contraction suggests a reduction in descending drives and a nonuniform influence of heat on somatosensory afferents on the motoneuronal pool (74).

## Limitations

Our results need to be interpreted regarding some limitations. First, active contraction during neurophysiological testing made the interpretation of the results complex. We elected to test motor networks during active contractions because it is difficult (impossible in many adults) to obtain MEPs and VMEPs in back muscles at rest (11, 43). Second, a combination of heat with capsaicin introduced variability in the LBP model and likely makes the interpretation of mechanisms more difficult. Although the control group allows controlling for the peripheral effect of heat and the effect of time, it influenced motoneuronal excitability after pain disappearance. However, the presence of a control group is also a strength since very few studies testing the effect of experimental pain on neural motor control included a control group. Third, the adjustment of the level of background EMG for 7 participants may have influenced the results. Additional analyses, however, confirm that the results were similar when data from these 7 participants were excluded. Also, there was a significant reduction in EMG background during and after pain/heat (i.e., 0.4% and 0.1%, respectively) compared with the prepain/heat periods. It is unlikely that these slight changes in muscle activation had influenced the results. In addition, prestimulus EMG amplitude was subtracted from the evoked responses limiting the impact of these changes on the results. Fourth, the large number of variables tested may have increased type I errors. Fifth, although R1 amplitude was used as a measure of motoneuronal excitability, spindle sensitivity may also influence the amplitude of R1 (98).

## Conclusions

During experimental LBP, the various motor networks involved in the control of back muscles were not modified. After pain disappearance, the reduction of R1 amplitude and
<figure><img src="image_18.png" /></figure>

the absence of effect on MEP/VMEP amplitude suggest a decrease of spinal excitability compensated by an increase in descending drive. Further studies are needed to confirm the role of these pain aftereffects.

## SUPPLEMENTAL DATA

Supplemental Material S1 https://doi.org/10.5683/SP3/QLIZ72.

## ACKNOWLEDGMENTS

We acknowledge the help of Jean Leblond (senior statistician) for guidance on nParLD models for the statistics and of Sauro Salomoni for the development of the graphical user interface used for data analysis.

## GRANTS

The project was funded by REPAR (Quebec Rehabilitation Research Network – Fonds de recherche du Québec – Santé). G.L., C.M., and H.M.-A. are supported by a Research Scholar Awards from Fonds de recherche du Québec – Santé (H.M.-A.: 281961; C.M.: 251649) and by a discovery grant from the Natural Sciences and Engineering Research Council of Canada (H.M.-A.: RGPIN-2019-06529). A.R. is supported by a scholarship from Fonds de recherche du Québec – Santé (289953). M.D. is supported by a scholarship from Cirris. A.D. is supported by a scholarship from Fonds de recherche du Québec – Santé (305029).

## DISCLOSURES

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

## DISCLAIMER

The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

## AUTHOR CONTRIBUTIONS

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

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