Abstract

Article Figures and data Abstract eLife digest Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract Human standing balance relies on self-motion estimates that are used by the nervous system to detect unexpected movements and enable corrective responses and adaptations in control. These estimates must accommodate for inherent delays in sensory and motor pathways. Here, we used a robotic system to simulate human standing about the ankles in the anteroposterior direction and impose sensorimotor delays into the control of balance. Imposed delays destabilized standing, but through training, participants adapted and re-learned to balance with the delays. Before training, imposed delays attenuated vestibular contributions to balance and triggered perceptions of unexpected standing motion, suggesting increased uncertainty in the internal self-motion estimates. After training, vestibular contributions partially returned to baseline levels and larger delays were needed to evoke perceptions of unexpected standing motion. Through learning, the nervous system accommodates balance sensorimotor delays by causally linking whole-body sensory feedback (initially interpreted as imposed motion) to self-generated balance motor commands. eLife digest When standing, neurons in the brain send signals to skeletal muscles so we can adjust our movements to stay upright based on the requirements from the surrounding environment. The long nerves needed to connect our brain, muscles and sensors lead to considerable time delays (up to 160 milliseconds) between sensing the environment and the generation of balance-correcting motor signals. Such delays must be accounted for by the brain so it can adjust how it regulates balance and compensates for unexpected movements. Aging and neurological disorders can lead to lengthened neural delays, which may result in poorer balance. Computer modeling suggests that we cannot maintain upright balance if delays are longer than 300-340 milliseconds. Directly assessing the destabilizing effects of increased delays in human volunteers can reveal how capable the brain is at adapting to this neurological change. Using a custom-designed robotic balance simulator, Rasman et al. tested whether healthy volunteers could learn to balance with delays longer than the predicted 300-340 millisecond limit. In a series of experiments, 46 healthy participants stood on the balance simulator which recreates the physical sensations and neural signals for balancing upright based on a computer-driven virtual reality. This unique device enabled Rasman et al. to artificially impose delays by increasing the time between the generation of motor signals and resulting whole-body motion. The experiments showed that lengthening the delay between motor signals and whole-body motion destabilized upright standing, decreased sensory contributions to balance and led to perceptions of unexpected movements. Over five days of training on the robotic balance simulator, participants regained their ability to balance, which was accompanied by recovered sensory contributions and perceptions of expected standing, despite the imposed delays. When a subset of participants was tested three months later, they were still able to compensate for the increased delay. The experiments show that the human brain can learn to overcome delays up to 560 milliseconds in the control of balance. This discovery may have important implications for people who develop balance problems because of older age or neurologic diseases like multiple sclerosis. It is possible that robot-assisted training therapies, like the one in this study, could help people overcome their balance impairments. Introduction The nervous system learns and maintains motor skills by forming probabilistic estimates of self-motion. The resulting inferred relationships between sensory and motor signals form a representation of the world and self that allows the brain to identify unexpected behavior and adapt motor control (Friston, 2010; Krakauer and Mazzoni, 2011; Wolpert et al., 2011). Due to neural conduction delays, these estimates of self-motion rely on the expected timing between motor commands and resulting sensory feedback. As such, errors associated with self-generated movement increase with larger feedback delays (Gifford and Lyman, 1967; Miall et al., 1985; Smith et al., 1960). Through repeated exposure to an imposed delay, the brain can learn to expect the delayed feedback associated with self-motion, leading to improvements in movement control with delays up to 430 ms (Cunningham et al., 2001; Miall and Jackson, 2006). When balancing upright, sensory feedback associated with lower-limb motor commands is delayed by up to ~100–160 ms (Forbes et al., 2018; Kuo, 2005; van der Kooij et al., 1999). As a consequence of these relatively long delays, computational feedback models of upright standing predict that balance controllers cannot adjust their sensorimotor gains and stabilize balance in the anteroposterior (AP) direction with imposed delays larger than ~300–340 ms (Milton and Insperger, 2019; van der Kooij and Peterka, 2011). These predictions contrast the reported upper-limb sensorimotor adaptation to imposed delays (Cunningham et al., 2001; Miall and Jackson, 2006). The present study aims to directly quantify the destabilizing effects of imposed delays between ankle torque and whole-body motion during standing balance, and to determine the underlying mechanisms responsible for any subsequent adaptation and learning. Imposed delays inserted within the balance control task are expected to increase postural oscillations and, past a critical delay, lead to falls (Bingham et al., 2011; Milton and Insperger, 2019; van der Kooij and Peterka, 2011). The sensorimotor mechanisms underlying these predicted effects, however, are unknown. Of particular interest is the vestibular control of balance due to its task-dependent modulations (Fitzpatrick and McCloskey, 1994; Forbes et al., 2016; Luu et al., 2012; Mian and Day, 2014), which rely on predictable associations between self-generated motor and resulting sensory signals. For example, participants exposed to novel vestibular feedback of balance motion initially exhibit increased postural oscillations but decreased muscle responses to a vestibular error signal (Héroux et al., 2015). With practice, participants improve their balance and vestibular-evoked muscle responses return to baseline amplitudes, suggesting that the brain updated its vestibular estimates of self-motion. Based on these observations, we hypothesized that increasing balance delays would initially increase whole-body motion and attenuate vestibular-evoked responses but these effects would diminish following a learning period. Another critical feature of probabilistic associations between motor and sensory cues is our ability to perceptually distinguish between self-generated or externally imposed motions. Imposed sensorimotor delays during self-generated movements evoke a sensation interpreted to arise from external causes rather than oneself (Blakemore et al., 1999; Farrer et al., 2008; Wen, 2019). Repeated exposures to delayed self-generated touch can re-align the perceived timing of the contact with the imposed delay (Kilteni et al., 2019; Stetson et al., 2006). Therefore, we further hypothesized that balance behavior under imposed delays would be inferred as externally imposed motion but this likelihood would decrease through repeated exposure to the delay. To test these hypotheses, we performed three experiments where participants balanced in a robotic simulator (Figure 1) in the AP direction with imposed delays ranging from 20 to 500 ms. These delays were in addition to the physiological delays (~100–160 ms) inherent to standing balance. In Experiment 1, we characterized standing behavior across this range of delays. Generally, whole-body sway variability increased with larger imposed delays and participants repeatedly fell into virtual limits of the balance simulation (i.e., 6° anterior and 3° posterior) for added delays larger than ~200–300 ms. In Experiment 2, participants trained to balance upright with a 400 ms added delay (testing beyond the critical delay previously proposed) for 100 min over five consecutive days. We probed the vestibular-evoked muscle responses and the perception of body motion before, after and 3 months following training to assess how the brain adapted to and processed the delayed sensory feedback. Initially, participants exhibited increased postural oscillations while the vestibular contributions to balance decreased and their perception of unexpected balance motion increased. After training, participants' balance behavior improved, their vestibular-evoked responses increased, and larger imposed delays were needed to elicit perceptions of unexpected balance motion. To further evaluate the effect of imposed delays on the vestibular control and perception of balance, we exposed participants to transient delays (Experiment 3). Within a few seconds of transitioning to a 200 ms delay, whole-body sway variability increased, vestibular responses attenuated (~70–90% decline) and participants perceived unexpected balancing motion. Collectively, our findings demonstrate how novel sensorimotor delays disrupt standing balance and suggest that the nervous system can learn to maintain standing balance with imposed delays by associating delayed whole-body motion with self-generated balancing motor commands. Figure 1 Download asset Open asset Experimental setup and block diagram of robotic simulation. (A) The participant stood on a force plate mounted to an ankle-tilt platform and was securely strapped to a rigid backboard. The ankle-tilt platform and backboard were independently controlled by rotary motors. In all experiments, the ankle-tilt platform was held at horizontal (earth-fixed reference) while the backboard rotated the participant in the anteroposterior plane. Motion of the backboard was controlled by ankle torques exerted on the force plate based on the mechanics of an inverted pendulum. The backboard rotated about an axis that passed through the participant's ankles (dashed line). Participants wore 3D goggles and viewed a virtual scene of a courtyard. (B) Participants balanced the robotic simulator as it operated with a 20–500 ms delay. Torque signals (T) from the force plate were buffered in the robotic simulation computer model such that angular rotation of the whole body (θ) about the ankle joint could be delayed. (C) Experimental design. Experiment 1 involved testing standing balance when naïve participants (n = 13) were first exposed to delays. Experiment 2 involved learning to balance with delays and was performed in two groups: vestibular testing and perceptual testing (see Experiment 2 methods). All participants who performed the learning experiments (vestibular testing group, n = 8; perceptual testing group, n = 8) completed an identical training protocol. The vestibular and perceptual tests were completed before, immediately after, and ~3 months following training. Training was completed over 5 days, in which the participant balanced the robotic simulator with a 400 ms delay (20 min per day). Experiment 3 tested a new group of participants (n = 7) and evaluated the time-dependent attenuation in vestibular-evoked responses together with changes in sway behavior and perception of unexpected balance motion. Trials in Experiment 3 were of similar design to perceptual testing in Experiment 2 (see panel E), except that the robot only transitioned between baseline (20 ms) and 200 ms delays. (D) Raw data of a sample participant from Experiment 2 vestibular testing. The participant was exposed to electrical vestibular stimulation while balancing the robotic simulator as it operated at fixed delays. Raw traces of the vestibular stimulus (green), soleus muscle EMG (blue), and whole-body position (black) are shown for a single trial at each delay condition. (E) During perceptual testing (Experiments 2 and 3), the participant balanced the robotic balance simulator and held a button switch. Delays were manipulated in the robotic balance simulation and the participant was required to press and hold the button when unexpected balance motion was detected. Raw data traces of whole-body position (black, upper trace), imposed simulation delay (black, lower trace), and the button switch (red) are shown during a perceptual trial from Experiment 2. Black arrows indicate examples of imposed delays that did not elicit a perceptual detection. Figure 1A was adapted from Shepherd, 2014. Results Experiment 1: imposed sensorimotor delays increase postural oscillations Thirteen healthy participants were instructed to stand quietly on a robotic balance simulator for 60 s trials (Materials and methods) while experiencing fixed imposed delays (20, 100, 200, 300, 400, 500 ms) between the torques generated at their feet and resulting whole-body motion. These delays were in addition to the ~100–160 ms sensorimotor feedback delays inherent to standing balance. Whole-body sway was recorded throughout these trials to quantify the effect of the additional delay on standing balance. The robot was programmed to rotate the whole body in the AP direction about the participant's ankles. Angular position limits of 6° anterior and 3° posterior from vertical were imposed into the simulation to represent the physical limits of sway during standing balance, whereby the robot constrained the angular rotation when these virtual limits were exceeded (see Materials and methods). While balancing on the robotic simulator at the 20 ms delay (baseline condition), all participants maintained standing balance with small postural oscillations around their preferred upright posture (sway velocity variance: 0.07 ± 0.07 [°/s]2 [mean ± standard deviation]). Whole-body oscillations increased with the imposed delays, leading to marked difficulties in maintaining a stable posture when a 400 ms delay was imposed. Representative data (Figure 2A) illustrate a participant exceeding the virtual balance limits (i.e., whole-body position traces exceeding dashed lines) 20 times within a 60 s period. This observation was confirmed in the group data. No participant exceeded these virtual balance limits at the 20 ms condition (only one participant reached the limit during the 100 ms condition) whereas every participant exceeded the virtual limits at least once within the 60 s balance period when delays were ≥200 ms. There was a main effect of delay on sway velocity variance (extracted over 2 s windows of continuous balance; Materials and methods), such that sway velocity variance was smallest for the 20 ms condition (0.07 ± 0.07 [°/s]2) and increased with the magnitude of the imposed delay and reached a maximum at 400 ms (21.08 ± 15.41 [°/s]2; p30 min) and this ability is partially retained 3 months later. Vestibular testing: sensorimotor delays decrease vestibular contributions to balance During vestibular testing, we probed the vestibular contribution to soleus muscle activity by exposing participants (n = 8) to a non-painful electrical vestibular stimulus (EVS) while they balanced on the robot at different delays (20–500 ms; Materials and methods) before, after, and 3 months following training. Vestibular-evoked muscle responses are known to attenuate when actual sensory feedback does not align with expected estimates from balancing motor commands (Héroux et al., 2015; Luu et al., 2012). Therefore, we hypothesized that increasing the delay between ankle torques and body motion would progressively diminish the vestibular response. We further hypothesized that learning to control balance with imposed delays would allow the brain to update its sensorimotor estimates of balance motion and consequently increase the vestibular-evoked muscle responses. Frequency domain measures (coherence and gain; see Materials and Methods) were evaluated qualitatively using the pooled participant estimates because with delays ≥ 200 ms, single-participant coherence only exceeded significance at sporadic frequencies and significant coherence is needed to obtain a reliable gain estimate. Our time-domain measure (cross-covariance; see Materials and methods), which estimates the net vestibular contribution to muscle activity at all stimulated frequencies, was extracted on a participant-by-participant basis and used for statistical analysis. Participants exhibited the largest vestibular-evoked muscle responses (coherence, gain,and cross-covariance) for the 20 and 100 ms delay conditions, where significant coherence was observed at frequencies between 0 and 25 Hz and cross-covariance responses were characterized by short (~60 ms) and medium (~100 ms) latency peaks exceeding the 95% confidence interval (see Figure 4A). Prior to learning, pooled coherence and gain decreased with imposed delays ≥ 200 ms, and coherence fell below the significance threshold at most frequencies for delays ≥ 300 ms. Similarly, cross-covariance amplitudes decreased with increasing delay (≥200 ms), with only five out of eight participants showing significant biphasic muscle responses (cross-covariance) for the 400 ms delay condition (and six out of eight participants at 500 ms).Across training conditions (pre, post, retention), increasing the delay reduced the cross-covariance peak-to-peak amplitudes (main effect of delay, p<0.001; Figure 4A and B, Table 1). Figure 4 Download asset Open asset Experiment 2 vestibular-evoked muscle responses. Data are from pre-learning (n = 8), post-learning (n = 8), and retention (n = 7) conditions. (A) Coherence, gain, and cross-covariance between vestibular stimuli and rectified soleus EMG activity were calculated from the data concatenated from all participants. Estimates are presented from all six delay conditions (see legend). Horizontal dashed lines represent 95% confidence limits for coherence and the 95% confidence intervals for cross-covariance. Note that gain estimates are only reliable at frequencies with significant coherence; therefore, at delays ≥ 300 ms, where coherence falls below significance at most frequency points, the corresponding gain in the pre-learning condition was plotted using light lines. EMG was scaled by baseline EMG from each testing session (see Materials and methods), resulting in units for gain and cross-covariance of %EMG/mA and %EMG mA, respectively. (B) Group cross-covariance amplitudes (peak-to-peak) plotted relative to imposed delay. Across pooled estimates and group data, vestibular responses attenuated with increasing imposed delays and their amplitudes partially recovered after training. (C) Average sway velocity variance during vestibular stimulation trials. Non-normally distributed group data (vestibular response amplitudes) are plotted as medians (horizontal lines in boxes), 25 and 75 percentiles (boxes) and extreme data points (error bars). Normally distributed data (sway velocity variance) are presented as means with s.e.m (error bars). Following training, pooled vestibular-evoked muscle responses (coherence, gain, cross-covariance) partially recovered in both the post-learning and retention phases. Every participant exhibited biphasic muscle responses that exceeded significance thresholds for every delay after training. A significant interaction between delay and learning was observed for the cross-covariance (p<0.001, Table 1), suggesting that the recovery of vestibular responses was dependent on the delay magnitude. Planned comparisons (Wilcoxon sign-rank test, Bonferroni corrected) revealed that cross-covariance response amplitudes were larger during post-learning relative to pre-learning for delays ≥ 200 ms (all p-values <0.05) and were larger during retention relative to pre-learning for 300 and 400 ms (p<0.05). Similar to Experiment 1, sway velocity variance generally increased with increasing delays (Figure 4C, Table 1, Table 2; p<0.001), while learning decreased sway velocity variance at almost all imposed delays (Figure 4C, Table 1; p<0.001), resulting in a significant delay × learning interaction (Figure 4C, Table 1; p<0.001). Planned comparisons (paired t-tests, Bonferroni corrected) revealed that sway velocity variance decreased during post-learning relative to pre-learning for delays between 20 and 400 ms (all p-values <0.05) and decreased during retention relative to pre-learning for delays between 100 and 400 ms (all p-values <0.05). Because training was only performed with the 400 ms delay, these training-related changes in vestibular responses (cross-covariance) and sway behavior across delays indicate that learning generalized to different sensorimotor delays. Table 2 Vestibular response magnitude and sway behavior from vestibular stimulation trials in Experiment 2 vestibular testing. Delay (ms)20100200300400500Pre-learning (n = 8)Cross-cov. (%EMG·mA)17.7/16.020.7/18.814.0/11.08.10/12.45.54/10.94.35/5.50Sway velocity variance [°/s]20.18 ± 0.170.93 ± 0.586.52 ± 4.4011.35 ± 5.1016.79 ± 8.5111.80 ± 6.53Post-learning (n = 8)Cross-cov. (%EMG·mA)20.4/23.220.4/26.721.5/19.619.1/20.515.7/16.014.1/21.4Sway velocity variance [°/s]20.05 ± 0.050.13 ± 0.090.54 ± 0.321.58 ± 0.744.20 ± 1.056.99 ± 2.61Retention (n = 7)Cross-cov. (%EMG·mA)18.8/20.015.3/17.619.3/20.116.4/12.511.8/9.1610.6/13.3Sway velocity variance [°/s]20.09 ± 0.110.20 ± 0.120.90 ± 0.482.91 ± 1.255.51 ± 0.986.48 ± 3.51 Perceptual testing: sensorimotor delays induce a perception of unexpected balance motion During perceptual testing, we assessed whether