FIGURE 4 | (A–F) Delta scores of hemodynamic variables, i.e., the difference (1) between the value measured before bed rest (at BDC−7) and the corresponding value measured after bed rest (at R+10, see text) for the supine (Sup) and the sitting (Sit) position: adjusted means ± SE. For each panel: control group (CTRL) red bars on the left-hand side, and training group (TRAIN) blue bars on the right-hand side. Asterisks above whiskers indicate delta scores significantly different from zero. Horizontal lines with asterisks indicate significant differences between supine and sitting delta scores within the same group. Pound signs indicate significant differences between groups at the same position.

# DISCUSSION

Our study investigated the alterations induced by 60 days of HDT in hemodynamics and autonomic modulations of heart rate. To the best of our knowledge, this study involved the highest number of participants to investigate these specific effects during long-term HDT bed rest so far. Our main findings show that: (1) HR progressively increased some days after the start of the HDT; (2) changes in SV and HR vagal modulations appeared almost synchronously; and (3) alterations in these variables and SBP were detectable several days after the end of bed rest, indicating persistent cardiovascular deconditioning. Furthermore, this high-intensity/shortduration exercise alleviated the cardiovascular deconditioning, counteracting the autonomic alterations and improving recovery. Although the adopted exercise protocol mainly involved the lower part of the body, it likely influenced central mechanisms of cardiac modulation and appears to be a promising countermeasure for long-term spaceflight missions. Different exercise-based countermeasures have been tested so far to reduce cardiovascular deconditioning. A previous study showed that low-magnitude whole body vibration with

resistive exercise prevented the increase of the autonomic index of cardiac sympathovagal balance after an HDT period lasting 60 days (as was the case in our study) without, however, improving orthostatic tolerance (Coupé et al., 2011). Other studies were different from the present in their design and duration. Nonetheless, these studies highlight the crucial role of exercise as a countermeasure against cardiovascular deconditioning. The intermittent exposure to hypergravity coupled with ergometric exercise limited the decrease in parasympathetic activity after 14 days of HDT (Iwasaki et al., 2005). Daily rowing ergometry and biweekly strength exercise training after 5 weeks of HDT prevented orthostatic intolerance only when combined with volume loading (Hastings et al., 2012). Finally, supine cycling could counteract orthostatic intolerance after 18-day bed rest only in combination with plasma volume restoration (Shibata et al., 2010). However, the vast range of different study designs and countermeasures complicate a direct comparison with the sledge jump training protocol.

# Time Course of Hemodynamic Variables and Autonomic Indices During HDT

We described the time course of long-term HDT adaptations by comparing values during HDT with baseline measures in the supine position (0 degrees). Compared to sitting, the recumbent position is characterized by a fluid shift to the upper body, which increases stroke volume and stimulates baroreceptors and volume receptors, inducing cardiac vagal activation. By choosing this reference we could describe the isolated effect of the prolonged −6 degrees bed rest and this makes our results comparable with the cardiovascular changes observed during mid- and long-term spaceflight (Baevsky et al., 2007; Di Rienzo et al., 2008; Demontis et al., 2017). In the CTRL group, HR significantly increased from baseline starting from the 28th day of HDT and remained higher than baseline on the 56th day, in the recovery phase, and 10 days after the end of bed rest (R+10 supine; **Figure 2A**). A similar pattern was observed in another 60-day HDT study (Liu et al., 2015). Interestingly, this pattern was missing in the TRAIN group, where HR remained stable during and after HDT. The HR increase is a crucial feature of cardiovascular deconditioning, and the lack of this feature in the TRAIN group is a clear marker of the efficacy of the proposed training protocol as a cardiovascular countermeasure. A question arises about the type of training we adopted as short duration HIIT is not usually considered to act as a vagal enhancer. However, some data confirm that also this type of training may induce a parasympathetic adaptation of HR when performed in the supine position (Kiviniemi et al., 2014). An alternative hypothesis for the unchanged HR in TRAIN group after 28 days of bed rest might be constant increments in left atrial volume that could have induced a bradycardic response by stretching the sinus node. However, this unlikely occurred in our study because we found a significant reduction in SV in both groups (**Figure 2A**). SV depends on contractility, on arterial blood pressure, and on atrial pressure. Since contractility did not change (as sympathetic indices of HRV remained stable in the TRAIN group) and arterial blood pressure did not change from HTD28 onwards, we may hypothesize that atrial pressure, although not directly measured, was chronically reduced (perhaps via reduced blood volume and hence preload) in both groups of subjects. A previous echocardiographic study during bed rest confirmed that the left ventricular end-diastolic volume (a surrogate of cardiac preload) progressively decreases throughout 60 days of bed rest (Westby et al., 2016). Hence, it appears that the main reason for the unchanged HR in the trained subjects could be a training-induced enhancement of vagal tone. SV progressively decreased in both groups during HDT, reaching a minimum at the end of bed rest (i.e., about 90% of the baseline value). The SV reduction is in line with the literature on HDT, which reports a decrease in plasma and blood volume by 10 to 30% within the first 24 to 72 h of confinement (Convertino, 2007). A decrease in SV suggests a dehydration condition, which was probably due to different reasons. One factor was the increased renal sodium excretion and thus reduced water retention (Convertino, 2007). Another factor could be related to tissue compression in lying position that dehydrated areas of weight bearing because of greater interstitial flow into the microcirculation (Hargens and Vico, 2016). The reduced daily physical activity might also have been a cause of dehydration (Convertino, 2007).

The training not only failed in counteracting the decrease in SV, but it might have even accelerated it. On the 28th day of bed rest, SV was 92% of the baseline value in both groups, but on the 2nd day it was equal to 100% in CTRL participants and decreased to 91% in TRAIN participants. Moreover, on the 2nd day of bed rest SBP decreased significantly only in the TRAIN group, and DBP changes tended to be lower in the TRAIN when compared to the CTRL group (**Figures 2E** and **2F**). This contrast suggests that exercise training might quickly influence the hemodynamic balance, inducing post-exercise hypotension likely due to an early blood volume reduction. We speculate that training might accelerate the loss of plasma

Horizontal lines with asterisks indicate significant differences between supine and sitting delta scores within the same group. Pound signs indicate significant differences between groups at the same position. RRI, R-R intervals; (A) HF, High-Frequency power; (B) LF/HF, Low-Frequency to High-Frequency powers ratio; (C) LF, Low-Frequency power; (D) DFA1, short-term fractal index by detrended fluctuations analysis. \*\*\*p < 0.001, \*p < 0.05, #p < 0.05.

volume, as demonstrated by recent works showing that lower limb exercise (cycling) produced a different adaptation of the autonomic sympathetic tone in supine vs. upright position (Ried-Larsen et al., 2017). Supine position activated the stretch receptors of heart, veins, and pulmonary circulation, increasing central blood volume, and blunting the metaboreflex activation. Such a response reduced heart contractility, limiting SV, and reducing blood pressure via a non-renal mechanism. At the same time, this reaction could be responsible for a reduction in plasma renin activity and therefore for an early increase in water loss (Ried-Larsen et al., 2017). Thus, a potential additive effect on the cardiovascular system of acute blood volume changes and sympathetic response to exercise might occur in the first days of training and HDT. We can suggest that, in order to prevent such additive effect, the exercisebased countermeasures should start at full load a few days after exposure to microgravity or its analog. The only other time point at which we observed a significant difference in blood pressure between groups was 10 days after the end of HDT (R+10), when CTRL participants showed a decrease in supine SBP compared to baseline of 17 mmHg (see **Table 2**), a marked phenomenon of hypotension absent in the TRAIN group. As will be discussed later, this suggested that prolonged bed rest had long-term effects on blood pressure control mechanisms, potentially leading to orthostatic hypotension at the restoration of normal gravity conditions. The implemented training protocol showed positive effects on these cardiovascular modifications. With respect to the cardiac autonomic modulations of HR, previous studies documented a decrease in HRV total power and vagal indices in early and chronic HDT (Fortrat et al., 1998; Sigaudo et al., 1998; Pavy-Le Traon et al., 2007), as well as contrasting findings on the sympathetic cardiovascular control (Hughson et al., 1994; Sigaudo et al., 1998; Fortrat et al., 2001; Ferretti et al., 2009). In our study, the HF power decreased significantly in the CTRL group on the 28th and 56th day of bed rest (**Figure 3**). The breathing rate was stable before, during, and after HDT, always falling within the HF band (**Table 2**). In our experimental set-up, the HF power thus correctly represented the respiratory component of the parasympathetic modulations of HR. Therefore, our data indicated that HDT induced a substantial reduction in vagal modulations of HR in the respiratory band. The LF/HF powers ratio is an index of cardiac sympathovagal balance: in the CTRL group, it tended to increase on the 28th and 56th day (+9 and +13% after log transformation, **Figure 3F**). Additionally, DFA1 quantifies changes in the sympathovagal balance, but unlike the LF/HF powers ratio, it considers fractal components of the HR dynamics not related to the amplitude of the oscillations. Concurrently with the HF power reductions (**Figure 3A**), DFA1 also tended to increase in the CTRL group on the 28th and 56th day of bed rest and remained higher than baseline even 10 days (i.e., R+10) after the end of bed rest (**Figure 3D**). The LF power reflects both the vagal and sympathetic cardiac modulations; in CTRL participants it decreased in a similar fashion as the HF power, suggesting the predominance of the vagal withdrawal compared to possible sympathetic activation (**Figure 3B**). The VLF power reflects the cardiac modulations of different humoral and thermoregulatory mechanisms superimposed on the autonomic cardiac control; the time course of the VLF power during bed rest was remarkably similar in the two groups, suggesting that the effects of training on the changes in HR variability during bed rest mainly regards the fast-vagal modulations of HR (**Figure 3C**). Unlike DFA1 or the LF/HF powers ratio, the power of DBP oscillations in the LF band is a measure of sympathetic vascular control not influenced by parasympathetic modulations. This index did not show any significant effect of bed rest (**Figure 3E**). Therefore, the analysis of changes occurring during bed rest in the cardiovascular autonomic indices suggested a reduction of vagal heart rate modulations and an increase in the sympathovagal balance without evidence of an altered sympathetic tone in the CTRL group. This effect was detectable up to 10 days after the end of bed rest. The trends were different in the TRAIN group without apparent alterations during the HDT period with regard to any autonomic index. Therefore, our results suggested that during HDT the reactive jumps training reduced the cardiac autonomic deconditioning.

# Hemodynamic and Autonomic Response to the Postural Test

The postural test allowed for the evaluation of the effects of the 60-day HDT on the cardiovascular system as it operates around different working points. In the supine position, the upper part of the body contains a larger volume of fluids than in sitting position. The fluid shift from sitting to supine posture is expected to increase the volume of the large vessels and the filling of the heart chambers, stimulating volume receptors which induce an autonomic response. The descriptive statistics of hemodynamic variables and autonomic indices in **Table 2** showed higher SV and vagal index, and lower HR, sympatho/vagal balance indices, and TPR in supine compared to a sitting position. Our results indicate that in the recovery phase 10 days after bed rest, the cardiovascular deconditioning affects some variables more in one position than in the other. For instance, this is the case with HR (**Figure 4A**) because the HR delta score of the CTRL group significantly differed from zero in only the supine position. Such a finding points out that after HDT without countermeasures, the cardiovascular deconditioning affects HR more in supine than in sitting position. HR delta scores of TRAIN participants were indeed closer to zero in both positions and lower than those of the CTRL group in the supine position (**Figure 4A**). This finding confirms the efficacy of the administered training protocol as a countermeasure for cardiovascular deconditioning. In contrast to HR, SV showed the same significant reduction in the recovery phase, between −5 and −7 mL, independent of the posture in both groups, suggesting that the training protocol did not affect the loss of body fluids caused by HDT. Interestingly, the postural test was able to detect a significant reduction in TPR in the CTRL group (**Figure 4D**), but in the supine position only. The difference between the two postures was also highly significant in the CTRL group. It is possible that the fall in supine TPR induced by the 60-day HDT was responsible for the significant reduction in supine SBP observed at R+10 only in the CTRL group (**Figure 2E**)—a hypotensive effect also evidenced by the negative delta score of supine SBP (**Figure 4E**). The significant differences between supine and sitting delta scores of TPR, SBP, and DBP in CTRL participants further highlighted that longterm effects of head-down-tilt bed rest depended on posture. In this regard, the crucial point is that the sledge jump training protocol showed positive effects. No significant delta scores were observed in the TRAIN group for TPR and BP in the supine position, indicating the ability of the administered training protocol to accelerate recovery after HDT bed rest. Interestingly, in the TRAIN group the significantly positive delta score of TPR in sitting position (**Figure 4D**) indicates that exercise training might even have improved the capability to increase the total peripheral resistance in sitting position. An improved endothelial function induced by training (Ashor et al., 2015) could mediate such an effect. The autonomic indices (**Figure 5**) also shows the effects of HDT related to the posture. When sitting in the recovery phase, the CTRL group had lower sympathovagal activation and vagal withdrawal (**Table 2**). This is demonstrated statistically by significant negative delta scores of the LF/HF powers ratio and DFA1 and by a significant positive delta score of the HF power in sitting position (**Figure 5**). This phenomenon, suggests an impaired autonomic response to a postural shift after prolonged bed rest, a possible marker of orthostatic intolerance. By contrast, the TRAIN group had unchanged (i.e., null) delta scores for the indices of sympathovagal balance in both supine and sitting positions, whereas the index of vagal modulations of HR (HF power, **Figure 5A**) increased after bed rest in a similar manner for both postures. These findings therefore suggest that the proposed training protocol allowed for a faster recovery of the physiological autonomic responses to posture changes.

# CONCLUSION

Considering that a supine position on Earth mimics acute cardiovascular effects of weightlessness, which induces a robust vagal activation immediately after the fluid shift to the upper body, we described the time course of long-term changes by comparing HDT to supine baseline recordings. Our data revealed different dynamics of cardiovascular adaptations. The acute autonomic changes induced by the supine position persisted throughout short-term HDT exposure and were strongly attenuated during mid-term and long-term HDT exposure, whereas SV adaptations showed an enduring trend. The administered training protocol appeared to mitigate some of the autonomic cardiovascular adaptations occurring during mid- or long-term HDT exposure and to accelerate their recovery after bed rest. The hypotensive phenomenon observed in the TRAIN group only during short-term HDT exposure, however, suggests that administering this exercise with initially light but progressively heavier loads during the first days of bed rest is an effective countermeasure.

# AUTHOR CONTRIBUTIONS

MM, PC and AS wrote the manuscript and processed the data. AS designed and directed the project. KB helped supervise the project and performed data collections with support from AW and SM. PC and MM preprocessed data for statistical analyses. AS performed statistical analyses and prepared the figures and tables. PC, MM, GM, and AS drafted the manuscript. H-CG, LR, MS, and OO provided critical feedback and contributed to the interpretation of the results. All authors discussed the results and contributed to the final manuscript.

# REFERENCES

# FUNDING

This investigation was supported by ESA (European Space Agency) and by the German Aerospace Center (Deutsches Zentrum für Luft- und Raumfahrt; DLR) through grant 50WB1525.

# ACKNOWLEDGMENTS

We thank Edwin Mulder, Alexandra Noppe, Melanie von der Wiesche, Wolgang Sies, and the entire DLR team for their operational, technical and logistic support. We also thank the European Space Agency (ESA) for providing the opportunity to participate in this study. We thank Dorothée Grevers for editing and proofreading the manuscript. In addition, we acknowledge support from the German Research Foundation (DFG) and the Open Access Publication Fund of Charité - Universitätsmedizin Berlin.

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Wickham, H. (2016), ggplot2: Elegant Graphics for Data Analysis (Use R!), 2nd Edn. New York, NY: Springer Verlag.

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2018 Maggioni, Castiglioni, Merati, Brauns, Gunga, Mendt, Opatz, Rundfeldt, Steinach, Werner and Stahn. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Critical Role of Somatosensation in Postural Control Following Spaceflight: Vestibularly Deficient Astronauts Are Not Able to Maintain Upright Stance During Compromised Somatosensation

#### Edited by:

Recep A. Ozdemir<sup>1</sup>†

William H. Paloski<sup>4</sup>

, Rahul Goel<sup>2</sup>†

\*

Jack J. W. A. van Loon, VU University Amsterdam, Netherlands

#### Reviewed by:

Joyce McClendon Evans, University of Kentucky, United States Irene Di Giulio, King's College School, United Kingdom Giovanni Bertolini, University of Zurich, Switzerland

#### \*Correspondence:

William H. Paloski<EMAIL_ADDRESS>†These authors have contributed equally to this work

#### Specialty section:

This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology

Received: 19 June 2018 Accepted: 08 November 2018 Published: 27 November 2018

#### Citation:

Ozdemir RA, Goel R, Reschke MF, Wood SJ and Paloski WH (2018) Critical Role of Somatosensation in Postural Control Following Spaceflight: Vestibularly Deficient Astronauts Are Not Able to Maintain Upright Stance During Compromised Somatosensation. Front. Physiol. 9:1680. doi: 10.3389/fphys.2018.01680 <sup>1</sup> Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States, <sup>2</sup> Department of Health and Human Performance, University of Houston, Houston, TX, United States, <sup>3</sup> Neurosciences Laboratory, Johnson Space Center, National Aeronautics and Space Administration, Houston, TX, United States, <sup>4</sup> Human Research Program, Johnson Space Center, National Aeronautics and Space Administration, Houston, TX, United States

, Millard F. Reschke<sup>3</sup>

, Scott J. Wood<sup>3</sup> and

The free-fall of orbital spaceflight effectively removes the gravitational vector used as a primary spatial orientation reference on Earth. Sustained absence of this reference drives adaptive changes in the internal perception-action models of the central nervous system (CNS), most notably in the processing of the vestibular otolith inputs. Upon landing, the return of the gravitational signal triggers a re-adaptation that restores terrestrial performance; however, during this period, the individual suffers from a functional vestibular deficiency. Here we provide evidence of a transient increase of the weighting of somatosensory inputs in postural control while the CNS resolves these vestibular deficiencies. Postural control performance was measured before and after spaceflight in 11 Shuttle astronauts and 11 matched controls and nine elderly who did not experience spaceflight. A quiet-stance paradigm was used that eliminated vision, modulated the lower extremity somatosensory cues by subtly modulating the orientation of the support surface beneath feet of subjects in all groups. Additionally, in astronauts and matched controls, we challenged the vestibular system with dynamic head tilts. Postural stability on the landing day (R+0) was substantially decreased for trials with absent visual and altered somatosensory cues, especially those also requiring dynamic head tilts ( ± 5 ◦ @ 0.33 Hz) during which 20/22 trials ended prematurely with a fall. In contrast, none of the astronauts fell during eyes-closed, dynamic head tilt trials with unaltered somatosensory cues, and only 3/22 trials resulted in falls with eyes-closed and altered somatosensory cues, but static upright head orientation. Furthermore, postural control performance of astronauts was either statistically not different or worse than that of healthy elderly subjects during the most challenging vestibular conditions on R+0. Overall, our results demonstrate a transient reweighting of sensory cues associated with microgravity-induced vestibular deficiencies, with a significant increase in reliance

on somatosensory cues, which can provide an effective reference even without vision and with dynamic vestibular challenges. The translation of these results to aging population suggests that elderly individuals with visual and vestibular deficits may benefit from therapeutic interventions enhancing sensorimotor-integration to improve balance and reduce the risk of falling.

Keywords: sensory reweighting, postural control, spaceflight, somatosensory inputs, elderly

# INTRODUCTION

All neurophysiological systems including sensorimotor networks controlling reflexive and coordinated voluntary motor behaviors have evolved to function in Earth's gravity (Anken and Rahmann, 2002; Clement and Reschke, 2008). In the context of human upright stance and locomotion, gravitational sensory inputs from vestibular otolith organs serve as the primary sensory modality to establish a vertical spatial reference (Shumway-Cook and Woollacott, 2007; Macpherson and Horak, 2013; Pfeiffer et al., 2014) critical for controlling upright stance and terrestrial navigation. Adaptation of this essential spatial reference in response to sustained microgravity during spaceflight drives adaptive changes in the central nervous system (CNS) and leads to modification of internal models governing the input-integration-output characteristics of relevant sensorimotor repertoire (Clement and Reschke, 2008). The neural reorganizations that happen during spaceflight help to mitigate space motion sickness and optimize motor performance in the microgravity environment. However, these neural reorganizations are maladapted to gravitational constraints and, thus, significantly disrupt coordinated motor behaviors immediately upon returning to Earth (Paloski et al., 1992).

Upright stance control depends on the continuous integration of vestibular, visual, and somatosensory afference, and any ambiguous or disrupted inputs from one of these sensory modalities may cause destabilization of standing balance (Jacobs and Horak, 2007). Previous studies have consistently reported an increase in body sway and impaired upright stance control in astronauts following prolonged exposure to microgravity (Paloski et al., 1992, 1993; Wood et al., 2015). Misinterpretation of otolith signals (the otolith tilttranslation reinterpretation –OTTR-hypothesis), for example, has been proposed as possible mechanism of microgravityinduced maladaptive vestibular reorganization that degrade postural control and spatial orientation in astronauts while they are re-adapting to the return of gravitational inputs during early post-flight period (Young et al., 1984; Parker et al., 1985). One compensatory strategy the CNS is capable of employing during this maladapted early post-flight period can be the dynamic update of relevant internal models through sensory reweighting (Peterka, 2002). Sensory reweighting is an adaptive filtering process that regulates the relative contribution of each sensory modality to the internal model by down-weighting ambiguous afferences (e.g., vestibular) while up-weighting reliable sensory modalities to maximize overall gain and reduce signal-tonoise ratio (Polastri et al., 2012). For example, if the surface conditions are firm and stable, somatosensory inputs from the feet mechanoreceptors and ankle proprioceptors are more reliable than when standing on a soft and compliant surface.

Numerous previous studies have reported functional contribution (i.e., maintaining upright stance) of somatosensory inputs to postural control in healthy young adults with normal (Vuillerme et al., 2008) or disrupted vestibular function (Dietz et al., 1992; Mittelstaedt, 1992; Clapp and Wing, 1999; Kavounoudias et al., 2001; Bringoux et al., 2003; Modig et al., 2012), as well as in the elderly (Pasma et al., 2015) and clinical populations (Bronstein, 1999; Vaugoyeau et al., 2008). Research has shown increased reliance on somatosensory information under alcohol intoxication in healthy young adults (Modig et al., 2012), higher somatosensory weights in older adults with visual impairments (Pasma et al., 2015) and patients with unilateral vestibular loss (Peterka et al., 2011), and compensatory effects of using electro-tactile biofeedback during altered vestibular inputs in healthy young adults (Vuillerme et al., 2008). These studies have greatly improved our knowledge of the relative use of somatosensory information for maintaining postural control in various sensory contexts. However, the functional role of somatosensory inputs, signaling orientation of the body relative to surface-vertical, for stabilizing postural control during the early post-flight recovery period in vestibularly deficient astronauts is not well understood (Lowrey et al., 2014; Strzalkowski et al., 2015). Additionally, microgravity-induced musculoskeletal deconditioning and the transient vestibular deficiency can provide a unique model to better understand underlying mechanisms of impaired postural control in the elderly individuals with increased fall risks, and develop preventive rehabilitation protocols utilizing principles of sensory reweighing.

Thus, the primary goal of this study was to investigate the role of somatosensory inputs on postural control performance during disturbed/impaired vestibular conditions in vestibularly deficient astronaut subjects immediately after spaceflight. We administered dynamic head tilts during postural control tasks to further distort the accuracy of vestibular inputs following exposure to microgravity. Previous studies have shown that

**Abbreviations:** AP, anterior-posterior; CDP, computerized dynamic posturography; CNS, central nervous system; COM, center of mass; COP, center of pressure; EQ, equilibrium score; FAM, familiarization; HD, head dynamic; HE, head erect; iTTB, integrated time to boundary; JSC, Johnson Space Center; KSC, Kennedy Space Center; L-x, x days before launch of spaceflight; OTTR, otolith tilt-translation reinterpretation; PAR-Q, physical activity readiness questionnaire; R+x, x days after return from spaceflight; SOT, sensory organization tests; TTB, time to boundary.

standard sensory organization tests (SOTs) may not be sensitive enough to detect subtle upright stance control dysfunctions in patients with vestibular disorders (Paloski et al., 2006; Mishra et al., 2009; Honaker et al., 2016), who may compensate upright stance control performance by task vigilance during SOTs. Therefore, modified SOTs with dynamic head movements have been suggested for better fall risk diagnosis during functional postural control performance assessments, both in elderly (Pang et al., 2011) and clinical populations (Mishra et al., 2009). Furthermore, when vision is absent, introducing an additional experimental challenge to the vestibular system by dynamic head movements would also allow us to better understand the compensatory role of sensory reweighting as a function of the availability of reliable somatosensory inputs. Therefore, we hypothesized that: availability of reliable somatosensory cues, in the absence of vision, will mitigate destabilizing effects of both impaired (due to microgravity) and distorted (due to head tilts) vestibular function during upright stance control. As a secondary purpose, we compared postural control performance from pre-flight and return day sessions' of astronauts with healthy elderly individuals to better understand aging-related sensorimotor aspects of increased body sway.

# MATERIALS AND METHODS

# Subjects

Postural control performance during disturbed vestibular function and compromised somatosensory inputs was systematically monitored in 11 astronauts (7 males, 4 females; age range 38–49 years) before and after short-duration (11–13 days) Shuttle flights, and 11 matched controls who followed the same timeline as astronauts but did not fly into space. Postural control performance of astronauts before and immediately after returning from spaceflight was also compared with nine healthy elderly subjects (3 males, 6 females; age range 73–86 years) to infer sensory mechanisms underlying postural control impairments in the elderly population. Each astronaut subject was a first-time flier. Each control subject was matched with an astronaut subject in terms of age (±4 years), sex, height (±5 cm), weight (±5 kg), and postural control performance [same quartile of Composite Equilibrium Score (EQ)]. Time spacing between pre- and post- "flight" sessions for controls was the same as that of matched astronauts. Postural control performance was assessed using computerized dynamic posturography (CDP). All subjects were participating in the CDP testing for the first time; hence any learning effects should have been similar for all groups. All astronauts passed NASA spaceflight physical examination prior to their missions, and control subjects had passed an Air Force Class III physical examination within 12 months of beginning the study. None of the astronaut or control subjects reported any history of balance or vestibular abnormalities. Elderly subjects were selected among those with no known neurological, cardiovascular, vestibular or musculoskeletal disorders, and no history of falls for at least 6 months before the start of the study. Overall health status of elderly subjects was screened by using the Physical Activity Readiness Questionnaire PAR-Q (Canadian Society for Exercise Physiology, 2002). Experimental protocols and voluntary participation procedures were explained to all subjects before they gave their written consent. All subjects were consented before inclusion. The selection criteria and experimental procedures for astronaut and control subjects were approved by the NASA Johnson Space Center (JSC) Committee for Protection of Human Subjects. The study protocol for elderly subjects was approved by the Institutional Review Board of the University of Houston.

To establish pre-flight postural stability baseline data, each astronaut subject participated in four pre-flight testing sessions at JSC, occurring 141 (± 35), 133 (± 35), 50 (± 7), and 14 (± 1) days before launch (mean ± standard error of mean (SEM)), designated as familiarization (FAM), L-60, L-30, and L-10 sessions, respectively (**Figure 1**). The first pre-flight session, which occurred at least two days before the second pre-flight session, was considered FAM training for the postural tests using the standard SOTs, and data from this session were excluded from the analyses. The other three pre-flight sessions were considered to be independent estimates of a putatively stable individual. While nominally scheduled for 60, 30, and 10 days before the flight, launch schedules often shifted after one or more sessions had been completed. Since we did not have any reason to believe that the usual performance of astronauts would have been affected by launch delays, we accepted the actual timing while still classifying them based on expected timing. The first post-flight session (R+0) was performed at the Kennedy Space Center (KSC), Florida within 2–5 h after return from spaceflight using an experimental setup identical to that at JSC. All subsequent post-flight sessions were performed at JSC at 2 (R+2), 3 (R+3) and 7 or 8 (R+7/8) days after return from spaceflight. The second (L-60) and third (L-30) pre-flight sessions, and the third (R+3) post-flight session included the experimental postural tasks before and after exposure to shortradius centrifugation. However, only pre-centrifugation data are presented here. Astronaut and control subjects were instructed to avoid exposure to other unusual motion environments, strenuous physical activities or other experiments that might disrupt their recovery of balance function. Elderly subjects participated in a single session which included both familiarization and testing trials.

# Experimental Procedures and Data Collection

Postural control performance was evaluated using a modified CDP system (Neurocom Balance Manager, Natus Medical Incorporated, Pleasanton, CA, United States). The CDP system enabled SOT procedures, documented elsewhere (Paloski et al., 1992). During the FAM session, three trials of each of the six SOT conditions were carried out to familiarize astronaut and control subjects with the CDP system and to assess their baseline postural control performance which was also one of the metrics used to match astronaut and control subjects. During each experimental session (L-60, L-30, L-10, R+0, R+2, R+3, R+7/8), twelve 20 s trials were conducted with eyes closed using a combination of modulation of the sway of the support surface

session. All trials were conducted with eyes closed.

and head tilt conditions. The support surface was either fixed (SOT-2) or sway-referenced in the sagittal plane (SOT-5) in direct proportion to the estimated instantaneous center-of-mass (COM) sway angle (i.e., a gain of 1 was used). Subjects were instructed to either maintain the position of their head static and upright (head erect, HE) or perform continuous ± 20◦ dynamic (head dynamic, HD) pitch tilt oscillations at 0.33 Hz paced by an audible tone transmitted through lightweight headphones. Two trials were conducted for each of the HE and HD head conditions during both SOT-2 and SOT-5 support-surface conditions. Schematic representations of the experimental setup and postural task conditions used for astronaut and control subjects are shown in **Figure 1**. The trial order was counterbalanced across astronaut and control subjects and held constant across sessions. Throughout each trial, the astronaut or control subject was instructed to maintain a stable upright posture with arms folded across the chest. White noise supplied through headphones masked external auditory orientation cues. Infrared markers placed on the headset frame were used to quantify head position using an OptoTrak System (Model 3020, Northern Digital Inc., ON, Canada). Before beginning each dynamic head tilt trial, the test operator used real-time head position display information to guide the subject in achieving the desired head tilts, providing corrective instruction. Amplitude and phase of head pitch position during dynamic head tilts were obtained from both sinusoidal curve fits and detection of the maximum and minimum position in each cycle. Phase shift was made relative to the sinusoidally varying audio tone. Every dynamic head tilt trial began only after the operator has ascertained that the head tilts are approximately ± 20◦ . Once the dynamic head tilt trial began, the audible tone continued, but no feedback was provided for the remainder of the trial.

For specific details of the experimental procedures used with elderly subjects, please see Ozdemir et al. (2018). In brief, elderly subjects performed postural tasks with no head tilts under three different sensory conditions: (1) stable surface with eyes-open (SOT-1), (2) stable surface with eyes-closed (SOT-2), and (3) sway-referenced surface with eyes-closed (SOT-5). Two 90 s long trials were performed with 30 s testing duration for each of the three conditions continuously, without having a break among sensory conditions within each trial. Only the first 20 s of the data from the SOT-2 and SOT-5 conditions of the first trial were

FIGURE 2 | Representative time to boundary (TTB) time series for an astronaut and an elderly subject. Effects of spaceflight on postural control performance can be observed from head erect (HE) trials obtained from a representative astronaut subject before spaceflight (L-10) and immediately after landing (R+0) for both SOT-2 (A) and SOT-5 (B) conditions. Similarities in postural control performance between spaceflight and aging can be observed from head dynamic (HD) trials obtained on return day (R+0) in a representative astronaut subject and head erect (HE) trials obtained in a representative elderly subject for both SOT-2 (C) and SOT-5 (D) conditions. Black lines with shaded regions depict the TTB trace in anterior-posterior direction over each trial truncated at 10 s. Shaded areas indicate the iTTB (absolute) for each trial. The iTTB (%) is computed by dividing the iTTB (absolute) by the total area shown in the plot. The shaded region in (D) for an astronaut subject also show the time instance when TTB value hit zero, indicating a fall.

analyzed and presented here to compare with the performance of the astronaut subjects in their first session (L-60) and on return day (R+0).

# Data Reduction and Analyses

For the experimental sessions, the subject's center of pressure (COP) was computed directly from force transducers in the support platform sampled at 100 Hz. The extremes of the feet defined the base of support. The COM was estimated based on a 2nd order low-pass Butterworth filter (0.85 Hz cutoff) applied to the COP (Ozdemir et al., 2013). Time-to-boundary (TTB) was calculated by dividing the instantaneous anterior-posterior (AP) COM distance to the boundary of the base of support by the instantaneous COM velocity (Forth et al., 2007). The TTB at each instance suggest the time it would take to reach the boundary of the base of support if you were to continue to move in the same direction and at the same speed. A higher value of TTB implies more stability. This measure has the advantage of combining both the spatial and temporal aspects of sway by also evaluating the influence of velocity (Haddad et al., 2006), and is sensitive to changes in stability limits with aging and support surface compliance (Haibach et al., 2007). The primary postural control performance measure was the integrated area of TTB (iTTB) below an arbitrary 10 s threshold that represents an estimate of relative stability over the entire trial (**Figure 2**). The iTTB is expressed as a fraction of the total area beneath the threshold (i.e., 10 s × trial duration) and is not affected by "falls" (subject raising a foot or arm to maintain balance), which are discrete events

that cannot be considered part of the continuous EQ distribution. A lower value of iTTB represent higher stability.

The primary goal of this study was to investigate the role of somatosensory inputs on postural control performance in vestibularly deficient astronaut subjects immediately after spaceflight. SOT-5 trials for which the peak support surface tilt was less than 1◦ were discarded both in astronaut and in control subjects, as we do not expect any distortion of somatosensory cues in those trials. We chose to use 1◦ to discard trials as Peterka (2002) observed reweighting only when support surface perturbations were greater or equal to 2◦ . Such trials were identified by plotting peak support surface sway as a function of peak AP COM sway for SOT-5 trials across all head conditions for data from astronaut and control subjects. All data analyses were performed using customized MATLAB (MathWorks, Natick, MA, United States) scripts and functions.

Owing to sensory reweighting, we hypothesized that the availability of reliable somatosensory inputs, a stable platform in SOT-2, would reduce the destabilizing effects of HD tilts on postural control performance. To test this hypothesis, we calculated a series of sensory ratios using control and astronaut data from the R+0 day session. First of all, to follow similar interpretation of sensory ratios as used by ratios obtained using EQ (Neurocom, 2009), we subtracted iTTB (%) from 100 for these analyses, such that higher (100 – iTTB) % represents good balance. Somatosensory index (SI) was then calculated as a ratio of (100 – iTTB) % of HD by HE conditions and represents the subject's ability to use input from the somatosensory system to maintain balance. Somatosensory reweighing index (SRwI) was calculated as a ratio of SI of SOT-2 by SOT-5. The SRwI measure helped us to test our primary hypothesis as it represents how well the availability of somatosensory inputs can compensate for destabilizing effects of HD. Vestibular index (VI) was calculated as a ratio of (100 – iTTB) % of SOT-5 by SOT-2 conditions and represents the subject's ability to use input from the vestibular system to maintain balance. We also calculated somatosensory change index (SCI) as a ratio of SI of astronaut by control representing how much SI changed due to spaceflight, and vestibular change index (VCI) as a ratio of VI of astronaut by control representing how much VI changed due to spaceflight. SCI was calculated only for SOT-2 and not SOT-5 as during SOT-2, subjects are supposed to rely more on somatosensory inputs. Similarly, VCI was calculated only for HD and not HE as HD has been shown to be a more sensitive test to assess vestibular changes (Jain et al., 2010).

# Statistical Analyses

Preliminary analyses revealed that there was no statistical difference between iTTB values of first and second trial and thus data from only the first trial of each postural testing condition (SOT-2 and SOT-5; HE and HD as applicable) were used in statistical analyses for all groups (Control, Astronaut, Elderly). For all the "within-subject" comparisons (learning effect in control and astronaut subjects, and effects of spaceflight in astronauts), we used pairwise comparisons. If the underlying data were normally distributed [assessed using Shapiro–Wilk test (p > 0.05)], paired t-tests were carried out, else Wilcoxon Signed-rank tests were carried out. Independent sample t-tests (if data were normally distributed), or Mann–Whitney U-tests were performed for all the "betweensubject" comparisons (control vs. astronaut pre-flight, control vs. astronaut return day, elderly vs. astronaut pre-flight, elderly vs. astronaut return day). Statistical significance was accepted at p < 0.05 (SPSS version 21, SPSS Inc., Chicago, IL, United States).

# RESULTS

**Figure 2** illustrates the time series data during different postural control performance conditions from a representative astronaut subject and an elderly subject.

# Learning Effects in Control Subjects

For the SOT-2 HE condition (**Figure 3**. blue triangles), there was a significant improvement (i.e., lower iTTB) at R+0 in comparison to L-60 (Z = 2.134, p = 0.033). However, no change was observed from R+0 to R+7/8 sessions (p > 0.05), indicating that postural control was fine-tuned from L-60 to R+0 sessions and was stabilized after R+0. For the SOT-2 HD condition, postural control performance was stable across sessions. During SOT-5, significant learning effect was observed between L-60 and L-10 in the HE condition [t(8) = 3.161, p = 0.013], and then the performance remained stable for the following sessions. For the HD condition during SOT-5, there was a decreasing trend. However it was not significant (p > 0.05), and thus we can conclude that the postural control performance was stable across sessions.

# Postural Control Performance Before and After Spaceflight

Results of the independent sample t-tests showed no significant (p > 0.05) difference in postural control performance between control and astronaut subjects during any of the pre-flight sessions (L-60, L-30, and L-10) for either head condition (HE, HD) or support surface condition (SOT-2, SOT-5). Nor were any learning effects observed for astronaut subjects during pre-flight sessions for either head condition or support surface condition (p > 0.05).

To understand the effects of spaceflight on postural control, a series of paired comparisons were carried out between postflight and pre-flight sessions' in astronaut subjects. Since no learning effect was observed in astronaut subjects pre-flight, data of L-60 was used to compare with the data of the post-flight sessions of astronauts. For SOT-2, postural control performance was significantly reduced, i.e., higher iTTB, in the R+0 session when compared to the pre-flight session [R+0 vs. L-60 – HE: t(10) = 3.020, p = 0.013; HD: t(9) = 3.763, p = 0.004] for both head conditions (**Figure 3**, red triangles). For the HE condition in SOT-2, postural control performance became similar to the pre-flight level at the R+2 (R+2 vs. L-60: p > 0.05) session and remained stable during the following two post-flight sessions (p > 0.05 for R+2 vs. R+3, and R+3 vs. R+7/8). For the

HD head condition in SOT-2, postural control performance returned to the pre-flight level only at the R+7/8 [R+2 vs. L-60: t(9) = 3.540, p = 0.006; R+3 vs. L-60: t(10) = 3.370, p = 0.007; R+7/8 vs. L-60: p > 0.05] session indicating a slower recovery in postural control performance during HD trials.

For SOT-5 trials, postural control performance significantly deteriorated in R+0 session when compared to the pre-flight session [R+0 vs. L-60 – HE: Z = 2.073, p = 0.038; HD: t(9) = 6.539, p < 0.001] for both head conditions (**Figure 3**, red circles). Pairwise comparisons showed that in the HE condition, postural control performance returned to the preflight level at the R+2 session (R+2 vs. L-60: p > 0.05) and remained stable during the following sessions (p > 0.05 for R+2 vs. R+3, and R+3 vs. R+7/8). In the HD head condition, however, postural control performance was still impaired at the R+2 session compared to the pre-flight sessions (R+2 vs. L-60: Z = 2.803, p = 0.005) and returned to the preflight level only at the R+3 session and remained stable after that (p > 0.05 for R+3 vs. L-60, and R+3 vs. R+7/8), indicating longer recovery time when vestibular system was challenged.

# The Role of Somatosensory Inputs

For both astronaut and control subjects, we used data from the R+0 session to examine whether the availability of reliable somatosensory information could compensate for dynamic head tilt related performance decrements in balance control especially when the vestibular system is in a maladapted state due to microgravity effects on vestibular functioning.

First of all, we compared SI between the SOT-2 and SOT-5 conditions in control subjects (**Figure 4B**) and found that the SI for SOT-2 was significantly higher than the SI for SOT-5 (Z = 2.756, p = 0.006). This confirms, as expected, the importance of a stable, veridical, Earth-fixed reference for somatosensory inputs in HD compared to HE. Next, we compared the effects of spaceflight on the SI for SOT-2 (**Figure 4C**) and found that the SI was significantly lower in astronauts on the return day than in controls [t(19) = 2.404, p = 0.027]. While this might suggest a reduction in reliance on somatosensory cues, it seems more

TABLE 1 | Number of falls across the head (HE and HD) and support-surface (SOT-2 and SOT-5) postural test conditions in 11 astronaut subjects during R+0, R+2, R+3, and R+7/8 sessions and in 11 control subjects during the R+0 session.

likely that there could be some inaccuracies in somatosensory processing associated with spaceflight or that the alterations in the vestibular system associated with spaceflight were too profound to be fully compensated for by the somatosensory system. Furthermore, we compared the effects of spaceflight on SRwI (**Figure 4D**) and found SRwI to be nearly an order of magnitude higher in astronaut subjects on the return day than in control subjects (Z = 2.746, p = 0.005). This suggests a much higher reliance on somatosensory cues after spaceflight, even when they are inaccurate, confirming our primary hypothesis.

We then compared VI in control subjects between the two head conditions (**Figure 4E**) and found that the VI of HE was significantly higher than that for HD (Z = 2.756, p = 0.006). This confirms that, as expected, reliance on vestibular input decreases with HD. As expected, VI during HD for astronaut subjects on the return day was significantly lower than that in controls (**Figure 4F**, Z = 3.380, p < 0.001), clearly demonstrating a decreased reliance on vestibular inputs early after spaceflight.

Finally, we assessed relative decrements in performance after spaceflight associated with the vestibular and somatosensory systems by comparing SCI and VCI on the return day (**Figure 4G**). We found that the VCI was significantly lower than the SCI (Z = 2.803, p = 0.005), suggesting that the relative decrement in reliance on vestibular inputs was far greater than that for somatosensory inputs, resulting in a relative increase in reliance on somatosensory inputs.

Another functional performance metric is the number of fall (loss-of-balance) incidences observed under each test condition (**Table 1**). None of the subjects lost balance on any trial of SOT-2. The only two fall incidences observed in control subjects occurred during SOT-5 trials with HD (**Table 1**; bottom row). Conversely, on return day, all 11 astronaut subjects fell on at least one of two HD trials during SOT-5, and three astronaut subjects fell on one of the two HE trials during SOT-5. By R+2, recovery was well underway, as the incidence of falls on SOT-5 trials with HD decreased to 5/22, and beyond that, recovery was essentially complete, with only one fall observed in each of the final two test sessions.

# Astronaut vs. Elderly Comparisons

To gain better insights regarding postural control impairments in the elderly subjects, we compared postural control performance of elderly subjects during SOT-2 and SOT-5 trials (only HE) with the astronaut subjects pre-flight (L-60) and immediately after return (R+0), in both head

conditions (**Figure 5**). Pre-flight comparisons showed that postural sway was significantly higher in elderly subjects when compared to the HE [SOT-2: t(18) = -3.437, p = 0.007, SOT-5: t(17) = -5.810, p < 0.001], and the HD [SOT-2: t(18) = -2.347, p = 0.031, SOT-5: t(18) = -2.279, p = 0.035] conditions in astronaut subjects. The R+0 performance comparisons for SOT-2 trials showed no significant difference in performance between the HD condition in astronaut subjects and the HE condition in elderly subjects (p > 0.05), while in the HE condition in astronauts, postural sway was still significantly lower than that of elderly subjects in the HE condition [t(18) = -2.370, p = 0.029]. For SOT-5 trials on R+0, however, astronaut performance in the HD condition was significantly worse [t(17) = 5.190, p < 0.001] than that of elderly subjects in the HE condition, and no significant differences were found in HE trials between astronauts and elderly subjects (p > 0.05). Overall comparisons show that astronauts on R+0 (i.e., with a maladapted vestibular system) perform better than elderly subjects only when somatosensory cues are reliable. Our results also show that astronauts on the return day perform comparable to the elderly when vestibular inputs are disrupted through HD or when somatosensory cues are compromised, and perform worse than the elderly when vestibular inputs are disrupted through HD in compromised somatosensory condition.

# DISCUSSION

The current study was designed to examine somatosensory contributions to upright stance control performance during distorted and maladapted vestibular functioning following shortterm spaceflight in astronauts. Consistent with previous studies (Paloski et al., 1992; Jain et al., 2010), astronauts' postural control performance was significantly degraded on the return day (R+0), in all postural control tasks and head conditions. Although somatosensory contributions to postural control may also have been degraded in astronauts, short-duration spaceflight primarily impaired vestibular functioning such that vestibularly deficient astronauts were able to maintain their upright stance when somatosensory cues were relatively reliable on a stable surface but inevitably fell when a sway-referenced surface further challenged the reliability of somatosensory cues in the absence of vision. Considering the incidence of falls during sway-referenced postural tasks, our analyses demonstrated the critical role of reliable somatosensory cues on functional upright postural control when the vestibular system is maladapted during the early post-flight period. Finally, comparable postural control performance between elderly and vestibularly deficient astronauts during challenging vestibular conditions on the return day supports current aging literature and suggests that therapeutic strategies enhancing sensorimotor integration can improve postural control performance in older adults.

# Spaceflight Disrupts Sensorimotor Control of Balance

Spaceflight causes distinct sensorimotor reorganizations due to the sustained absence of gravitational sensory inputs and lack of mechanical loading to the musculoskeletal system. Although adapted for a long-duration stay in space, these sensorimotor reorganizations are maladaptive to function in Earth's gravity and, thus, pose serious postural control and locomotor challenges for astronauts by significantly increasing their risk of falling while they are restoring terrestrial performance during the early post-flight period. One critical aspect of monitoring postflight sensorimotor re-adaptation is to employ valid testing paradigms to detect subtle changes in functional sensorimotor performance and determine the time course of sufficient recovery for astronauts such that they can safely return to their daily life activities. During the early history of human spaceflight, astronauts were allowed to return to their daily routines and duties two days after landing based on the results of standard clinical examinations (McCluskey et al., 2001; Clark, 2002). More recent reports (Jain et al., 2010; Wood et al., 2015)

different between panels.

employing both standard and modified SOTs, and quantifying standing postural control performance with EQ scores showed substantially higher fall rates and longer recovery period during dynamic head movements with unstable support than standard SOTs with head erect and fixed-support. Our results, using iTTB as a postural control performance metric, further extend these previous reports that fall incidences and significantly higher body sway can still be observed in some astronauts when compared to their pre-flight levels, during dynamic head movements, on the last follow-up (R+7/8) examination. For example, during standard SOTs (HE) pre-flight postural control performance was found to be restored on R+2 both for SOT-2 and SOT-5. However, SOT trials with HD clearly showed that the pre-flight performance level was not achieved until R+3 for SOT-5, and R+7/8 for SOT-2, suggesting that fall risks are still present for certain astronauts up to a week following return from spaceflight during compromised visual and somatosensory conditions (e.g., walking in dim light or in dark, and over a compliant surface like sand). Due to our small sample size, however, prolonged recovery for HD during SOT-2 should be interpreted with caution since a closer examination of the data show higher variability in post-flight sessions, although no outliers were detected.

# Somatosensory Functioning Is Less Affected by Spaceflight and Critical During Maladapted Vestibular Functioning in Astronauts

Our analyses on the sensory ratios showed that the destabilizing effects of dynamic head movements on upright stance control change, as a function of reliable somatosensory inputs with respect to the surface-vertical, considerably in healthy controls but critically in vestibularly deficient astronauts. Specifically, when control subjects performed dynamic head movements blindfolded on a fixed support surface (SOT-2), providing reliable somatosensory inputs regarding body orientation, SI index was very high (0.95 ± 0.05) indicating that the performance difference between HE and HD is negligible in SOT-2 (**Figure 4B** red bar). However, when the dynamic head movements were performed on a sway-referenced support surface (SOT-5), compromising the reliability of somatosensory inputs, SI index was significantly lower (0.76 ± 0.06), suggesting a notably destabilizing effect of HD on upright stance performance even in healthy controls for SOT-5 trials (**Figure 4B** blue bar). Additionally, we also recorded two fall incidences during SOT-5 HD condition, and no fall during SOT-5 HE condition (**Table 1**), suggesting that the availability of reliable somatosensory cues may compensate for disrupted vestibular inputs in healthy controls.

However, this somatosensory driven compensation may become critical in vestibularly deficient astronauts immediately after spaceflight. Although we observed decreased SI and VI indices (**Figures 4C,F**) in astronauts, suggesting both impaired somatosensory and vestibular functioning, the degree of impairment was substantially higher in vestibular functioning following spaceflight. By comparing the ratio of changes in SI and VI between astronauts and healthy controls (**Figure 4G**), we showed a relatively high SCI but substantially decreased VCI, meaning astronauts were almost as good as healthy controls to utilize reliable somatosensory but were unable to use vestibular cues for compensating the destabilizing effects of HD. This suggests that somatosensory inputs are still relatively reliable sensory feedback source for vestibularly deficient astronauts, and thus they rely more on the less affected sensory system (somatosensory cues) to monitor their standing balance in the absence of vision while the CNS resolve transient vestibular deficiencies immediately upon return. We further supported these findings by showing an increased reliance into somatosensory weights in vestibularly deficient astronauts immediately after spaceflight (**Figure 4D**). In fact, availability of relatively reliable somatosensory cues was crucial for astronauts such that 20 out of 22 trials (% 90.9) resulted in falls when the validity of somatosensory cues for referencing gravitational vertical is further challenged during SOT-5. On the other hand, no single fall was observed when somatosensory cues could be used to infer gravitational vertical during SOT-2 trials. Thus the primary finding of this study is the critically functional role of somatosensory inputs from foot sole cutaneous receptors and ankle joint proprioceptors for maintaining upright stance in vestibularly deficient astronauts following spaceflight. Considering all the analyses we performed along with fall incidences, the difference between falling and standing for an astronaut during maladapted vestibular functioning seems to heavily depend on the reliability of somatosensory cues monitoring body sway with respect to the gravitationalvertical.

Promising hypotheses have been proposed such that the perceptual mechanism of vestibular (mal)adaptation following prolonged exposure to microgravity is explained mainly by reinterpretation of otolith inputs (Wood et al., 2015). Since otolith graviceptors only respond to translations in space, but not tilts, prolonged exposure to microgravity results in neglecting afferent signals from head tilts during spaceflight, and thus any head tilt is perceived as translation immediately upon returning to the Earth (Young et al., 1984; Parker et al., 1985). With an impaired vestibular function on the return day, performing dynamic head pitch movements on a fixed support surface poses further challenge to the postural control system by causing a unique ambiguity across sensory channels such that while vestibular inputs would be transmitting translation signals, somatosensory inputs from foot soles and ankle proprioceptors would be transmitting COP displacements and rotational torques of body sway, respectively. Owing to its plasticity, the CNS can resolve such sensory conflicts through sensory reweighting. Various form of this dynamic and compensatory sensory readaptation process has been increasingly investigated over the last two decades in postural control research (Peterka, 2002; Jeka et al., 2008; Vuillerme et al., 2008; Peterka et al., 2011; Modig et al., 2012; Polastri et al., 2012; Asslander and Peterka, 2014). In his seminal study, for example, Peterka (2002) monitored body sway characteristics on a sway-referenced platform with a progressive increase in surface sway angle. His results showed that blindfolded healthy subjects initially rely on the vertical surface reference to control body orientation for up to two

degrees of surface sway angle but switches to a gravitational vertical reference by moving in the opposite direction to surface sway at larger sway amplitudes to maintain upright stance, indicating an accuracy based dynamic up-weighting and downweighting of vestibular and somatosensory cues, respectively.

Although majority of studies have focused on sensory reweighting mechanisms of vestibular and visual inputs, recent studies consistently reported importance of somatosensory reweighting by evidencing increased reliance to mechanoreceptor inputs from the foot sole, ankle proprioceptor, and/or tactile cues to compensate for the destabilizing effects of different forms of disrupted or impaired vestibular and visual functioning on upright stance control (Vuillerme et al., 2008; Modig et al., 2012; Lowrey et al., 2014; Strzalkowski et al., 2015). Our results further extend these findings that reliable somatosensory cues from a firm and stable surface are important in healthy adults to stabilize upright stance during disrupted vestibular function (i.e., HD condition), but crucial in vestibularly deficient astronauts to prevent them from falling during the early period of post-flight recovery.

Although our data suggest a transient increase of the weighting of somatosensory inputs to upright stance control, caution should be taken to understand falls during dynamic head tilts in vestibularly deficient astronauts. It is obvious that, in addition to the absence of reliable somatosensory cues, many other sensory and musculoskeletal factors might have also contributed to the inevitable falls observed in astronauts during dynamic head movements on sway-referenced surface conditions. For example, as previously reported in patients with the bilateral vestibular loss (Peterka, 2002), vestibularly deficient astronauts might have failed to employ functional sensory reweighting during sway-referenced support surface condition (SOT-5) which optimally requires down-weighting of somatosensory and up-weighting of vestibular inputs. It is likely that astronauts' increased reliance on somatosensory cues was maladapted during SOT-5 trials such that they were unable to switch from a surface reference to a gravity reference. Another important aspect to consider in falling astronauts is microgravityinduced musculoskeletal deconditioning: that can cause a decline in muscle stiffness and loss of force and power due to prolonged unloading; which may all contribute to falls (Wood et al., 2015). Considering all these mechanisms, however, we cannot rule out increased reliance on somatosensory cues when vestibular inputs are disrupted in astronauts during upright stance control task on the return day since we have observed the same strategy in control subjects with intact vestibular and musculoskeletal functioning. Our comparisons for the effects of dynamic head movements within the same sensory condition (**Figure 4**) strongly supports increased weighting of somatosensory inputs such that dynamic head movements do not further destabilize postural control performance on a fixed surface, but only on the sway-reference surface condition.

# Sensorimotor Impairments in the Elderly

In many ways, microgravity-induced physiological adaptations including overall deconditioning in musculoskeletal and cardiovascular systems, and a general decline in sensorimotor functions resemble the physiology of aging (Vernikos and Schneider, 2010). In this respect, spaceflight can be considered a unique model (Young, 1993) to probe underlying mechanisms of aging-related postural control impairments as older adults are long known to have increased body sway and thus highly prone to falls (Horak, 2006). Comparing postural control performance between elderly subjects and astronauts, our data suggest that the increased body sway in elderly subjects, in the absence of vision, can be attributed to vestibular deficiencies mainly, but also to somatosensory deficits. Post-flight comparisons indicate vestibular deficiencies in elderly subjects such that astronauts perform either comparable to or worse than elderly individuals on a sway referenced platform with HE and HD trials, respectively. No differences were also found between astronauts and elderly when astronauts perform HD trials on a stable support surface. Altogether post-flight comparisons suggest that astronauts perform a lot more comparable to elderly during the most challenging vestibular conditions (**Figure 5** right panels). However, when somatosensory cues are reliable during the fixed support surface condition, better postural control performance in astronauts either during pre-flight comparisons with HD trials or post-flight comparisons with HE trials suggest somatosensory deficits or compromised reweighting of somatosensory cues in elderly subjects. Alternatively, a general decrease in musculoskeletal function with age should also be considered as an important factor for increased postural sway in the elderly during challenging sensory conditions. Overall, our findings are in agreement with many previous reports arguing that the vestibular system degenerates the most with age (Horak et al., 1989; Sturnieks et al., 2008; Barin and Dodson, 2011; Faraldo-Garcia et al., 2012; Liston et al., 2014b), and sensory re-weighting is slower and/or compromised during challenging upright stance conditions in healthy elderly adults when compared to young adults (Pavlou et al., 2004; Jeka et al., 2010).

Many implications can be derived from this study. A firm, stable surface for standing and walking can compensate for challenges associated with reduced vision (darkness, smoke-filled cabin) and dynamic head movement requirements immediately after landing, which can be very critical for safe egress. The translation of these results to aging population suggests that elderly individuals with visual and vestibular deficits may benefit from therapeutic interventions (Liston et al., 2014a) enhancing sensorimotor integration to improve postural control and reduce the risk of falling.

# ETHICS STATEMENT

This study was carried out in accordance with the recommendations of "The Protection of Human Research Subjects, NASA Flight IRB" with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The study protocol for astronaut and control participants was approved by NASA Flight IRB, and for elderly participants was approved by the IRB of the University of Houston.

# AUTHOR CONTRIBUTIONS

fphys-09-01680 November 23, 2018 Time: 15:50 # 12

RO helped with data analyses, interpretation of results, and writing of the manuscript. RG also helped with data analyses, interpretation of results, and writing of the manuscript. MR and SW helped with the study design and data collection. WP designed the study, and helped with data collection, interpretation of results, and revision of the manuscript.

# REFERENCES

# ACKNOWLEDGMENTS

We wish to thank members of the Neurosciences Laboratory at NASA Johnson Space Center for data collection and analysis support, and the mission integration coordinators for implementation support. Finally, we thank all subjects for their willing participation and insightful feedback.

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2018 Ozdemir, Goel, Reschke, Wood and Paloski. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# The Role of Enhanced Cognition to Counteract Detrimental Effects of Prolonged Bed Rest: Current Evidence and Perspectives

#### Uros Marusic1,2 \*, Voyko Kavcic<sup>3</sup> , Rado Pisot<sup>1</sup> and Nandu Goswami2,4 \*

1 Institute for Kinesiology Research, Science and Research Centre Koper, Koper, Slovenia, <sup>2</sup> Department of Health Sciences, Alma Mater Europaea – European Center Maribor, Maribor, Slovenia, <sup>3</sup> Institute of Gerontology, Wayne State University, Detroit, MI, United States, <sup>4</sup> Head of Research Unit: "Gravitational Physiology, Aging and Medicine", Otto Loewi Research Center of Vascular Biology, Immunity and Inflammation, Medical University of Graz, Graz, Austria

#### Edited by:

Ovidiu Constantin Baltatu, Anhembi Morumbi University, Brazil

#### Reviewed by:

Alessandro Tonacci, Istituto di Fisiologia Clinica (IFC), Italy Omar Šerý, Masaryk University, Czechia

#### \*Correspondence:

Uros Marusic<EMAIL_ADDRESS>Nandu Goswami<EMAIL_ADDRESS>
#### Specialty section:

This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology

Received: 21 May 2018 Accepted: 11 December 2018 Published: 23 January 2019

#### Citation:

Marusic U, Kavcic V, Pisot R and Goswami N (2019) The Role of Enhanced Cognition to Counteract Detrimental Effects of Prolonged Bed Rest: Current Evidence and Perspectives. Front. Physiol. 9:1864. doi: 10.3389/fphys.2018.01864 Prolonged periods of physical inactivity or bed rest can lead to a significant decline of functional and cognitive functions. Different kinds of countermeasures (e.g., centrifugation, nutritional, and aerobic interventions) have been developed to attempt to mitigate negative effects related to bed rest confinement. The aim of this report is to provide an overview of the current evidence related to the effectiveness of computerized cognitive training (CCT) intervention during a period of complete physical inactivity in older adults. CCT, using a virtual maze navigation task, appears to be effective and has long-lasting benefits (up to 1.5 years after the study). Moreover, enhanced cognition (executive control) reduces decline in the ability to perform complex motor-cognitive dual-tasks after prolonged period of bed rest. It has been demonstrated that CCT administration in older adults also prevents bed rest stress-related physiological changes [these groups showed minimal changes in vascular function and an unchanged level of brain-derived neurotrophic factor (BDNF)] while control subjects showed decreased peripheral vascularization and increased plasma level of the neurotrophin BDNF during a 14-day bed rest. In addition, the effects of CCT are evident also from the brain electrocortical findings: CCT group revealed a decreased power in lower delta and theta bands while significant increases in the same EEG spectral bands power were found in control subjects. If we consider an increase of power in delta band as a marker of cortical aging, then the lack of shift of EEG power to lower band indicates a preventive role of CCT on the cortical level during physiological deconditioning induced by 2-week bed rest immobilization. However, replication on a larger sample is required to confirm the observed findings. Applications derived from these findings could be appropriate for implementation of hospital treatment for bed ridden patients as well as for fall prevention programs.

Keywords: non-pharmacological countermeasures, aging, cognitive training, geriatrics, falls prevention

# INTRODUCTION

fphys-09-01864 January 21, 2019 Time: 17:53 # 2

Hospitalization and prolonged bed rest represent major risk factors for older persons, often resulting in irreversible deterioration in functional status and a significant decline in the quality of life (Blain et al., 2016; Bousquet et al., 2017; Goswami, 2017; Goswami et al., 2017). The proportion of older persons (defined as ≥65 years) is increasing worldwide, and is projected to double by the year 2030 with an expansion in life span of another 10 years by the year 2050 (United Nations, 2013). In addition, the number of super-olds (≥80 years) is expected to triple, from 22 to 61 million from year 2008 to 2060, respectively (European Commission, 2009). It has been shown that the greater the age, the stronger the association of bed confinement with functional loss and failure to recover during hospitalization (Covinsky et al., 2003) or in the nursing home setting (Fortinsky et al., 1999). As a consequence of this trend in population aging, higher demands for public health and aging services together with concomitant increases in health care costs are foreseen (Blain et al., 2016; Bousquet et al., 2017; Goswami, 2017).

The bed rest model was first introduced in the 1960s to simulate acute adaptations to the microgravity environment involved in space flights (Adams et al., 2003; Goswami et al., 2015a). Indeed, bed rest confinement, especially during prolonged hospitalization, could be modeled on the so-called bed rest protocol where healthy participants spend a number of days in a horizontal or (more extreme) head-down tilt bed rest condition. The negative adaptations of the cardiovascular system were observed to be similar in spaceflight and bed rest confined persons (Goswami, 2017). The negative effects of bed rest confinement, however, occur ten times faster than those that arise due to the normal aging process (Vernikos and Schneider, 2009). Previous research has mainly focused on the effects of prolonged bed rest on cardiovascular and musculoskeletal physiology (Pavy-Le Traon et al., 2007; Pisot et al., 2016; Gao et al., 2018). With improved technological development and increasing availability of brain imaging techniques, changes and adaptations of the central nervous system can be more effectively studied and the application of these techniques has become of greater interest in bed rest research (Koppelmans et al., 2017; Van Ombergen et al., 2017a,b; Gandarillas and Goswami, 2018).  Both horizontal and headdown tilt bed rest protocols have been implemented. Important differences in the two protocols such as in the adaptation in tissue fluid redistribution and hydrostatic pressures, however, need to be taken into account (Hargens and Vico, 2016).

The aim of this review is to summarize the current scientific evidence regarding bed rest-related impacts on mainly cognitive outcomes of healthy adults, and to highlight the importance of non-physical countermeasures such as cognitive training. The primary application of such scientific knowledge is therefore to provide the basis for the development of possible countermeasures both for the negative consequences of bed rest confinement and space flight microgravity, in particular in regard to negative bed rest effects in older persons during hospitalization. Such countermeasures are potentially extendable to addressing important consequences of the aging process in general. Emphasis is placed in this review on cognitive countermeasures to prevent not only cognitive but also sensorimotor adaptations that occur during acute and chronic situations involving hospitalization, prolonged physical inactivity, and the general aging process.

# SEARCH STRATEGY AND STUDY SELECTION

Scientific literature in English language was acquired through searches conducted on PubMed/MEDLINE (NLM), Embase, and Web of Science databases until October 1, 2018. A search for manuscripts on "cognitive training" and "bed rest" (with specific deviations of keyword combinations, such as "hospitalization," "cognitive intervention," "brain training," "mental training," etc.) was conducted and yielded 807 results. Furthermore, reference sections of included manuscripts were inspected to identify additional manuscripts of interest. Our results showed that there were no other studies besides "Bed Rest Study – PANGeA, Valdoltra 2012 (Slovenia, EU)," which investigated effectiveness of cognitive interventions during bed rest. Therefore, the final search consisted of four manuscripts (Goswami et al., 2015b; Marusic et al., 2015, 2018a; Passaro et al., 2017) that represent the same bed rest campaign, while each manuscript reported results based on different outcome measures.

# IMPACT OF REDUCED PHYSICAL ACTIVITY AND BED REST ON FUNCTIONAL AND COGNITIVE OUTCOMES

The positive role of physical activity in maintaining effective mobility is well-established by research and promoted by the popular media (Hui and Rubenstein, 2006; Muller et al., 2016). Reduction of the appearance of illness and chronic disease, improvements in gait and balance, as well as reduction in the risk of falls are among the most important advantages of engagement in physical activity by elderly people (Kovacs et al., 2013). A recent review highlighted the fact that up to 82% of total brain gray matter volume can be modified by engaging in physical activity (Batouli and Saba, 2017). Also, several types of cognitive-motor interventions have been previously applied in an older adult population showing positive improvements in functional and cognitive performance (van Iersel et al., 2007; Fraser et al., 2017), which is recently supported by brain structural adaptations also in subjects with mild cognitive impairment (Maffei et al., 2017). However, seniors often have limited access and fewer opportunities to engage in physical exercise programs with a 50% dropout rate in such activities in the first 3–6 months (Allen and Morey, 2010). Regardless of the issues of limited access and/or lack of motivation for engaging in

physical exercises, older adults are often forced to limit or even completely eliminate physical activity due to injuries or surgeries, which results in a specific syndrome referred to as the "disuse syndrome" (Bortz, 1984). Among the main characteristics of this syndrome are premature aging, skeletomuscular fragility, obesity, cardiovascular vulnerability and depression (Bortz, 1984).

In general, frail seniors are often limited by a disability- or a disease-related burden preventing their physical activity, and for them engaging in real-world situations involving complex locomotion where higher cognitive-resource demands are required can be a challenge. Reduced levels of physical activity have also been shown to be associated with increased risk of cognitive impairment and various types of dementia (Laurin et al., 2001). Interestingly, the results of bed rest studies do not always point toward the same conclusions. Over the years, various stressors that could lead to cognitive impairment after periods of hospitalization have been proposed. The increased levels of stress created by hospitalization itself with accompanying alternations of stress-response hormones and neuro-chemicals, as well as delirium, medications and polypharmacy, and depression are important factors in this regard (for a detailed review, see Mathews et al., 2014).

The majority of bed rest trials in which cognitive performance was assessed were carried out in a head-down tilt position and yielded contradictory results. For example, impaired cognition was found in a study of Lipnicki et al. (2009). These authors reported alterations of cognitive processes associated with decision making after 50 days of head-down tilt bed rest. After a similar length (45 days) of head-down tilt bed rest, Liu et al. (2012) observed worsening of executive functions. On the other hand, a 16-day head-down bed rest study did not report any changes in executive functions (Ishizaki et al., 2009). Moreover, in other studies, neither 17 days, nor 60 or 90 days of head-down tilt bed rest affected general cognitive functioning (Shehab et al., 1998; Seaton et al., 2009).

There is a scarcity of literature available reflecting cognitive outcomes after horizontal bed rest. After 14-day horizontal bed rest with young adults, (Dolenc and Petri, 2013) observed a minor improvement in mental visualization and no change in other assessed cognitive functions. In the same study, older individuals showed significant impairments in delayed recall (Dolenc and Petri, 2013), which was, however, not the case for those subjects who had cognitively stimulating environment during bed rest (Marusic et al., 2018a).

As extensively summarized in the "bed rest and cognitive functioning review" by Lipnicki and Gunga (2009), results from experimental studies with healthy young and older individuals are also not conclusive and do not unequivocally point in the same direction. More specifically, only eight of 17 bed rest studies included in that review reported significant detrimental effects on cognitive performance. Six studies reported unchanged cognitive functioning after bed rest, whereas three studies surprisingly showed improvements in cognitive performance. In the latter case, task exposure and practice effects could mask the underlying detrimental effect of bed rest on cognitive functioning (Lipnicki and Gunga, 2009), suggesting that eliminating practice effects in neuropsychological tests is important for the better evaluation of bed rest on cognitive functioning.

The majority of bed rest trials assessing cognitive performance before and after bed rest fail to address the underlying adaptation of the brain and subsequent correlational analysis between behavioral and neural outcome measures. Differences also exist among bed rest designs which vary in terms of amount of days that the participants were bedridden, type of the bed rest protocol used (e.g., horizontal or head-down tilt), as well as the motivation behind the studies. Some of these studies aimed at replicating spaceflight conditions, lack of sensory-motor stimulation and immobilization, and/or post bed rest recovery (Lipnicki and Gunga, 2009; Marusic et al., 2014b). Thus, an open question remain how CCT could be used as a general approach for improving cognitive performance in bed rest confined older subjects.

# COGNITIVE TRAINING AS A POSSIBLE COUNTERMEASURE DURING PROLONGED BED REST

Cognitive training aimed at optimizing cognitive functioning and/or slowing brain aging has been extensively used, especially with healthy older adults. It generally involves guided practice on tasks representing different domains of cognition in order to increase or maintain particular cognitive functions such as memory or attention. Cognitive training programs are commonly run as a time-limited, daily sessions for a specified period of intervention (e.g., 1 hour per day for 5 days a week for a total of 20 sessions). The training tasks are often designed to present an increasing challenge to cognitive abilities and thereby induce learning. A variety of tasks and approaches have been used for cognitive training (for a detailed review, see Tardif and Simard, 2011), with most of the reviewed studies reporting significant improvements in cognitive functions associated directly to those trained (e.g., Ball et al., 2002; Willis et al., 2006; Klusmann et al., 2010; Bahar-Fuchs et al., 2017), while most studies demonstrated only a limited transfer to other cognitive functions and/or activities of daily living (Ball et al., 2002; Unverzagt et al., 2007).

In the past decades, several reviews have shown beneficial effects of cognitive interventions in healthy older adults (Papp et al., 2009; Martin et al., 2011; Tardif and Simard, 2011; Mowszowski et al., 2016; Mewborn et al., 2017; Webb et al., 2018). Each concluded that cognitive training can effectively improve various aspects of objective cognitive functioning, such as memory performance, executive functioning, processing speed, attention, fluid intelligence, and subjective cognitive performance. In a recent meta-analysis, authors Marusic et al. (2018b) reported the generalization of cognition-based interventions to a distal untrained domain, such as gait performance. The influence of cognition on mobility control in older adults has been shown previously (Heuninckx et al., 2005). This knowledge has opened

new perspectives for cognitive training interventions for older population in general or those older individuals who are reluctant or not able to follow a physical activity intervention.

Recently, there is an increased use of CCT, which allows structured practice on standardized, and cognitively challenging tasks. CCT has several advantages over traditional drill and practice methods, including visually appealing interfaces, efficient and scalable delivery, the ability to measure performance and response time changes in multiple methods, and the ability to constantly adapt training content and difficulty to individual performance. The advantage of performing CCT in a supine/horizontal position opens new perspectives for implementing such a protocol in hospital/rehabilitation institutions. For a summary of non-physical approaches, readers are referred to Marusic and Grosprêtre (2018). The next section summarizes the impact of CCT during prolonged bed rest as a novel tool for mitigating negative effects of hospitalized older patients in acute phase after injury/surgery and/or in the subsequent rehabilitation process.

# OUTCOMES OF THE CCT EFFECTS DURING BED REST

In this section we review the current evidence related to potential cognitive countermeasures in relation to extreme environments (e.g., experimental bed rest or hospitalization), which has not received much attention. A recent pilot study (Marusic et al., 2018a) showed the effectiveness of CCT intervention during bed rest in older adults. Sixteen healthy older male individuals (mean age of 60 years) were randomly assigned to an intervention and an active control group. Results revealed that CCT using virtual spatial navigation was effective and exerted long-lasting effects (up to 1.5 years after the study) as evaluated by improved performance on the virtual navigation task which was specifically targeted (Marusic et al., 2018a). In the same study, there were significant transfer effects of CCT, specifically on executive functions, attention, and processing speed (Marusic et al., 2018a). It was also observed that there was a detectable decline in the ability to perform complex motorcognitive dual-tasks in the control group of older adults, but that CCT reduced the negative impact of bed rest on these integrated tasks, indicating better outcomes for the cognitively active intervention group (Marusic et al., 2015). Consequently, participants who followed the CCT protocol started their 28-day rehabilitation period (immediately after 14-day bed rest) from a higher functional and cognitive level.

Additionally, these data also revealed that CCT-related effects were also observed on the peripheral vascular function, perfusion assessments (Goswami et al., 2015b) as well as in the level of plasma brain-derived neurotrophic factor (BDNF) (Passaro et al., 2017). Older adults who underwent CCT did not show bed rest stress-related physiological changes (e.g., minimal changes in vascular function and increased level of BDNF) which indicate a preventive role of CCT during physiological deconditioning induced by 2-week bed rest immobilization. The mechanism of augmented BDNF levels after bed rest was attributed to a protective overshooting of the brain to counteract the bed rest-related negative effects (Soavi et al., 2016).

In addition to the above-mentioned findings, the electroencephalographic (EEG) recordings were used to evaluate the effects of 14-days bed rest on the brain neuroelectric activity. EEG results obtained with baseline eye-closed recordings showed that older adults who underwent CCT showed decreased power in lower delta and theta bands while control subjects showed significantly increased power in the same EEG spectral bands (Marusic et al., 2014a,b; Marušic, ˇ 2015). A so-called global "slowing" of the baseline, intrinsic EEG [e.g., increases in power in the slower delta range (2– 4 Hz)], occurs with aging (Rossini et al., 2007). Vecchio et al. (2013) observed "slowing" of EEG in healthy older individuals progressing to mild cognitive impairment and probable Alzheimer's disease. We concluded that increased spectral power in baseline EEG in control subjects but not in intervention subjects supported the notion that the CCT prevented negative effects of 14 days bed rest on brain baseline neuroelectric activity (i.e., increased power in EEG lower spectral bands) indicative of brain aging. Moreover, when analyzing event-related potentials (early perceptual processing of a stimuli), additional neuronal recruitment for the same amount of processing was observed only in the control group while participants in CCT group did not show the same trend (Marušic, 2015 ˇ ). In the same study, greater working memory enhancements (reduced P200 latency component) were observed in the CCT group, as compared to the controls.

In addition to CCT, other non-physical/cognitionbased interventions, such as action observation and motor imagery might also be incorporated into experimental bed rest research.  The combination of both techniques induces even greater activity in motor areas of the brain as compared to either intervention alone (Taube et al., 2015). To date, no study has tested these nonphysical techniques during a bed rest, which might open new perspectives for mitigating bed rest-related adaptation of the central nervous system (Van Ombergen et al., 2017b; Marusic and Grosprêtre, 2018).

# CONCLUSION AND FUTURE DIRECTIONS

Overall, CCT interventions, developed from an underlying brain-based model (Marusic et al., 2018a), show that cognitive engagement during bed rest can trigger changes not only at

the behavioral level, but also at the peripheral physiological (peripheral perfusion and blood BDNF level) and neuroelectric level. Thus, CCT intervention might represent a new promising approach for mitigating possible bed rest-associated physiological, functional, and cognitive declines, especially when motor execution is constrained or limited (e.g., during acute hospitalization) and may particularly be of special value for addressing the impact of bed confinement in older persons. Finally, it may also represent a promising research avenue as well as an option for a practical implementation in hospital settings and fall prevention programs.

# REFERENCES

Bortz, W. M. II (1984). The disuse syndrome. West. J. Med. 141:691.

# AUTHOR CONTRIBUTIONS

UM drafted and wrote the article. VK performed to article drafting and final corrections. RP did final corrections. NG contributed to the article idea, drafting, and final corrections.

# ACKNOWLEDGMENTS

The authors acknowledge the financial support from the Slovenian Research Agency (research core funding no. P5-0381).

studies (1986-2006). Eur. J. Appl. Physiol. 101, 143–194. doi: 10.1007/s00421- 007-0474-z

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2019 Marusic, Kavcic, Pisot and Goswami. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# The Promise of Stochastic Resonance in Falls Prevention

#### Olivier White1,2, Jan Babicˇ 3 , Carlos Trenado<sup>4</sup> , Leif Johannsen<sup>2</sup> and Nandu Goswami<sup>5</sup> \*

1 INSERM UMR1093-CAPS, Université Bourgogne Franche-Comté, UFR des Sciences du Sport, Dijon, France, <sup>2</sup> Acquired Brain Injury Rehabilitation, Faculty of Medicine and Health Sciences, School of Health Sciences, University of East Anglia, Norwich Research Park, Norwich, United Kingdom, <sup>3</sup> Laboratory for Neuromechanics and Biorobotics, Jožef Stefan Institute, Ljubljana, Slovenia, <sup>4</sup> Leibniz Research Centre for Working Environment and Human Factors TU Dortmund (ifADO), Institute of Clinical Neuroscience and Medical Psychology, University Hospital Düsseldorf, Düsseldorf, Germany, <sup>5</sup> Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria

Multisensory integration is essential for maintenance of motor and cognitive abilities, thereby ensuring normal function and personal autonomy. Balance control is challenged during senescence or in motor disorders, leading to potential falls. Increased uncertainty in sensory signals is caused by a number of factors including noise, defined as a random and persistent disturbance that reduces the clarity of information. Counter-intuitively, noise can be beneficial in some conditions. Stochastic resonance is a mechanism whereby a particular level of noise actually enhances the response of non-linear systems to weak sensory signals. Here we review the effects of stochastic resonance on sensory modalities and systems directly involved in balance control. We highlight its potential for improving sensorimotor performance as well as cognitive and autonomic functions. These promising results demonstrate that stochastic resonance represents a flexible and non-invasive technique that can be applied to different modalities simultaneously. Finally we point out its benefits for a variety of scenarios including in ambulant elderly, skilled movements, sports and to patients with sensorimotor or autonomic dysfunctions.

### Edited by:

Ovidiu Constantin Baltatu, Anhembi Morumbi University, Brazil

### Reviewed by:

Aiguo Song, Southeast University, China Alessandro Giuliani, Istituto Superiore di Sanità (ISS), Italy Lianchun Yu, Lanzhou University, China

> \*Correspondence: Nandu Goswami

<EMAIL_ADDRESS>
### Specialty section:

This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology

Received: 27 September 2018 Accepted: 11 December 2018 Published: 28 January 2019

### Citation:

White O, Babic J, Trenado C, ˇ Johannsen L and Goswami N (2019) The Promise of Stochastic Resonance in Falls Prevention. Front. Physiol. 9:1865. doi: 10.3389/fphys.2018.01865 Keywords: stochastic resonance, balance disorder, orthostatic intolerance, aging, falls

# THE CHALLENGE OF HEALTHY AGING

Life expectancy is increasing globally and functional contributions to society post-75 years are highly attainable. Over one third of adults over the age of 65 fall each year (Sattin et al., 1990). Two million patients present annually to emergency units, worldwide, complaining of dizziness upon standing up or after an accidental fall (Goswami, 2017; Goswami et al., 2017). Falls are ranked within top three causes in terms of years lived with disability in most regions of the world (WHO). Falls are not only associated with injury and morbidity, but also to reductions in physical, psychological, and social capacities (Myers et al., 1996; Blain et al., 2016; Bousquet et al., 2017). The direct cost of falling exceeds \$10 billion a year in the United States, with almost 9,500 deaths per year attributed to falling alone (Myers et al., 1996). The total costs of falls in the population of the United Kingdom has been estimated from more than two billion GBP to up to 4.4 billion GBP per year by the NHS (Public Health England with the National Falls Prevention Coordination Group Member Organisations, 2017) and is predicted to rise further. Critically, the consequences of a fall after 75 years old are much worse than between 65 and 75 years old and include fracture, frequent hospitalizations, increased morbidity and mortality. Preventing the occurrence of such events is therefore of paramount importance.

Epidemiological studies have shown that 30–70% of falls occur while walking on level ground. However, simple it appears, bipedal ambulation is demanding in many ways and gait relies on

**343**

complex sensorimotor integration. The act of balancing on our lower extremities is not learned until about 10–12 months of age. A healthy sensory system is necessary for successful postural control and locomotion. Indeed, the central nervous system must maintain accurate estimates of the position of the body in space and of the limbs in relation to each other (proprioception). Efficient postural reflexes must be triggered when external perturbations are detected. Furthermore, appropriate cardiovascular responses that keep blood pressure stable after the transition from lying/sitting to standing are required. The act of balancing needs to become automatic so that other tasks will not jeopardize it by interfering. During senescence, impairments in one or more of these systems, including cognitive functions, lead to increased risk of falls.  Intrinsic factors, or those related to the individual, include a decreased performance in the balance control system, with loss of mobility being a strong indicator for increased fall risk. In order to maintain stability, adequate levels of vision, vestibular function, musculoskeletal function, and proprioception are all required. Extrinsic factors, or those pertaining to environmental hazards, contribute significantly to fall incidents and include obstacles to trip over, poor lighting, slippery surfaces, or inappropriate furniture. Hence, an in-depth understanding of the multitude of neuromuscular, cognitive, sensory, sociological and environmental factors that contribute to balance control are necessary for early diagnosis and treatment of elderly who present significant risks of falls.

Since the process of balance control relies on many physiological factors and sensory signals, maintaining the quality of these signals at their optimal level is fundamental. Here, we review how a highly promising phenomenon called stochastic resonance could play an important role toward addressing balance control, and consequently, toward falls prevention.

# STOCHASTIC RESONANCE: WHEN NOISE BECOMES AN ALLIED TO THE BRAIN

To ensure optimal control of a system, adequate and accurate information inputs are required. For instance, navigating a computer mouse to a button on the screen entails the estimation of target position but also the hand/mouse position. These are available only through (biological) sensors that also embed uncertainties and are sometimes available as very weak delayed signals. Stochastic resonance can help enhancing detection and processing of a weak signal blurred by the many sources of uncertainties and perturbations.

# The Concept of Stochastic Resonance

In linear systems, optimal performance is obtained in the absence of noise. However, restricting models of natural systems to noise-free and linear systems is not realistic. First, noise is ubiquitous and can never be completely eliminated. Second, systems with thresholds characterize a large class of non-linear systems, e.g., from neurons to behaviors (such as the perception of sensory stimuli). This is where the concept of stochastic resonance becomes interesting: it describes any phenomenon where the presence of noise in a non-linear system improves the quality of an output signal compared to when there is no noise (McDonnell and Ward, 2011). Intuitively, noise is usually thought of as detrimental and associated with words such as nuisance or undesirable, and the concept of it being useful is apparently contradictory. The rationale behind stochastic resonance is concisely illustrated in the work of Gammaitoni et al. (1998). Let us consider a marble moving in a symmetric double well potential V(x) (**Figure 1A**). Without any external actuation force, the mass remains stuck in one of the wells. A potential barrier (1V) prevents the marble from swapping positions between wells. When a small periodic driving force is submitted to the system, it generates oscillations of the deepness of each well. Still, the potential barrier – although decreased compared to its resting state – is too high too allow transitions. An appropriate small dose of noise (stochastic) injected into the system will constructively (resonate) combine with the driving force and statistically allow periodic transitions between the wells. Hence, adding a small noise to a weak input signal can make the resultant signal surpass the threshold of a given neuron or neural circuit and hence provide useful information about the input weak signal for the central nervous system. On the other hand adding a too large unrelated noise signal will make the output of the threshold detection non-linear system useless in terms of providing information about the weak input signal. A trade-off must then be sought between these two extremes (**Figure 1B**). The graphical representation of such trade-off, namely a U-like curve represents the signature of the stochastic resonance phenomenon (**Figure 1C**).

By adopting this concept of stochastic resonance, it becomes possible to detect a weak signal using noise. In that case, the signal exceeds the detection threshold stochastically, generating an information that is transmitted to the output. This concept has been successfully demonstrated and applied to optimize logic operations in genetic regulatory networks blurred by various forms of noise (Wang and Song, 2016; Zhang and Song, 2018). The presence of a control noise in terms of a forcing signal enhanced the reliability of the logical function implemented in those networks. Furthermore, stochastic resonance is also effective to detect subthreshold signals at the single neuron level and can even be optimized in neuronal networks (Chen et al., 2008). Interestingly, this phenomenon does not only enhance the detection of subthreshold – but also superthreshold – signals in feedforward neuronal networks (Stocks, 2000; Yu et al., 2016). In biological systems, a threshold is reached when biological sensors (cutaneous mechanoreceptors in hands or feet, proprioceptors in muscles and joints, hair cells in the inner ear, etc) receive a signal. However, the amplitude of that signal must be large enough to elicit a response to the central nervous system that will eventually, once processed by the brain, trigger an action (e.g., a postural adjustment to prevent a fall). Unfortunately, these thresholds increase with age (Wells et al., 2003) hampering their detection. Stochastic resonance therefore makes the signal detectable again,

as if this technique actively adapted the sensitivity of the suboptimal sensor. In that way, the system can maintain the same responsiveness to hazardous situations. Therefore, shortening reaction latencies through decreased information processing time puts a system in better conditions to circumvent unwanted effects, such as falls (Toledo et al., 2017).

Stochastic resonance can be applied to a range of physiological systems.   Since stochastic resonance emerges in any thresholdactivated system, its effects may be relatively independent of any underlying pathology affecting perceptual uncertainty in sensory systems. All the above mentioned physiological systems are relevant for maintaining a stable body balance. While the effect of stochastic resonance may be small in absolute terms, utilizing it in situations where margins are important can lead to large benefits. The principle of system enhancement by stochastic resonance is well documented, and several small studies indicated improvements in more than one domain of balance control during exposure to sensory noise via different sensory modalities (multisensory stochastic resonance). However, this promising technique has thus far only been tested in a limited number of patients and healthy controls and for durations not exceeding 24 h. In the following sections, we review in detail these effects and identify emerging applications.

# The Vestibular System

The technique of applying stochastic vestibular stimulation instead of using a more traditional square-wave or sum of sinewave signals is relatively new. Several studies have focused on performance improvement with stochastic resonance applied on the vestibular system such as body responses in posture, balance, and gait (Fitzpatrick et al., 1996; Pavlik et al., 1999; Scinicariello et al., 2002). In addition, stochastic vestibular stimulation at imperceptible levels improves stability during balance tasks in normal, healthy subjects (Mulavara et al., 2011, 2012). Similarly, these stimulations also improve ocular stabilization reflexes in response to whole-body tilt and postural balance performance on

an unstable compliant surface in Parkinsonian patients (Pal et al., 2009; Samoudi et al., 2014).

The vestibular system is connected to spinal, cerebellar and cerebral motor control structures and can be selectively activated with external electrodes. A constant current stimulator developed to ensure imperceptibility of electrical stimulation of the vestibular system by subjects has been engineered (Mulavara et al., 2011). A series of evaluations on the efficacy of stochastic vestibular stimulation during standing and walking on unstable surfaces and on perception of tilt sensation in otolith-canal (intra-vestibular) conflict scenarios has also been done (Wuehr et al., 2016a,b). These researchers have evaluated the frequency characteristics of the electrical stimulus to optimize balance performance of subjects standing on a compliant surface with their eyes closed. Low imperceptible amplitude bipolar binaural electrical stimulation of the vestibular organs was applied using a constant-current stimulator through electrodes placed on the mastoid processes in the range of 30–330 µA root mean square (RMS) in 30 µA RMS steps. Using measures of head and trunk stability and a multivariate optimization criterion, and by employing a white noise-based stochastic stimulation signal, these researchers have shown that the stochastic vestibular stimulation in the range of 30–120 µA RMS improved balance performance in normal healthy subjects as well as in patients with Parkinson's disease. More recently, it was also shown that noisy galvanic vestibular stimulation can enhance roll vestibular motion perception (Keywan et al., 2018). Additionally, cross-planar improvements in balance performances in the range of 5–26% in normal healthy control subjects have been seen. These results indicate that stochastic vestibular resonance may be sufficient to provide a comprehensive countermeasure approach for improving postural stability.

# Haptics and Somatosensory Perception Are Relevant for Balance Control

For the control of body sway, human postural control system can flexibly utilize different sensory channels, such as nonplantar skin receptors. Uncertainty about the state of the body or a limb, such as its position in space can lead to erroneous motor planning and, consequently, injuries or falls. Should additional tactile and proprioceptive information become available, however, more accurate state estimates based on multisensory integration and prediction may decrease the likelihood of unsuccessful behaviors (Wolpert and Ghahramani, 2000; Todorov, 2004).

Mechanically non-supportive fingertip contact (<1 N) with an earth-fixed reference reduces body sway in quiet standing with eyes closed and may be even more efficient than vision alone (Holden et al., 1994; Jeka and Lackner, 1994; Lackner et al., 1999). A review by Baldan et al. (2014) on the effect of light touch on postural sway in individuals with balance problems due to aging, brain lesions or other motor or sensory deficits concluded that light touch leads to very reliable body sway reductions irrespective of the underlying balance impairment. Most studies demonstrated the benefits of haptic feedback exclusively in a quiet standing posture but improvements have also been reported in more dynamic postural activities, such as balance compensation following a mechanical perturbation (Dickstein and Laufer, 2004; Johannsen et al., 2007, 2017; Forero and Misiaszek, 2013), overground and treadmill walking (Dickstein and Laufer, 2004; Fung and Perez, 2011; Forero and Misiaszek, 2013; Kodesh et al., 2015) and staircase negotiation (Reeves et al., 2008; Reid et al., 2011).

Reductions in body sway during upright standing observed with light fingertip contact to an external stationary reference can be further reduced by the application of vibratory noise to the touch contact (displacement <0.1 mm) (Magalhães and Kohn, 2011). A typical experimental setting that can be used to investigate these aspects is discussed in detail in Magalhães and Kohn (2011). Briefly the participant's posture is measured by means of a force plate. The area covered by the projection of the trajectory of the center of mass serves as performance index. Measurements can be performed in different sensory conditions involving the provision of visual feedback or not, and the availability of an external reference for fingertip light touch. Values obtained in experimental conditions are compared to a defined baseline performance. In the stochastic resonance condition, vibratory noise stimuli is applied to the fingertip. Power of low frequency components of body sway (<0.5 Hz) were particularly responsive to the vibratory noise stimulation (Magalhães and Kohn, 2011). This effect of vibratory noise stimulation on the frequency components of body sway, however, seems to depend on the relative vibratory amplitude. Kimura et al. demonstrated that vibratory stimulation with an amplitude of the 50% of each participant's vibrotactile threshold caused reduction in the power of high-frequency components (>1 Hz) of body sway in contrast to greater stimulation amplitudes (Kimura et al., 2012).

Aging is accompanied by a constant decline of the sense of touch: between the age of 20 to 80 years, acuity thresholds increase by approximately 1% per annum with the fingertips tending to be one of the most vulnerable body parts (Wells et al., 2003). This loss of sensory acuity impacts on various aspects of function in the elderly, including the manual handling of objects and control of postural stability. These impairments reduce quality of life and independence because elderly lose dexterity and might have falls with serious physical injury. However, older adults retain the ability to use fingertip contact for augmentation of body sway feedback despite reductions in their tactile sensitivity (Tremblay et al., 2004). In fact, the efficacy of tactile feedback for sway reduction seems to be even greater in older compared to younger adult participants perhaps due to more severe aging-related loss of somatosensory information in the distal parts of the lower extremities (Baccini et al., 2007). Differential effects noted between young and elderly indicate that elderly people gain more in motor control performance than do young people with the application of noise to the feet (Priplata et al., 2003). The benefits of tactile information for the control of body balance in quiet stance as well as dynamic activities is robust and has been demonstrated in a number of neurological disorders.

# Body Balance

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Increased postural instability and falls risk due to impaired somatosensation is associated with reduced plantar sensation in older adults, patients with diabetic neuropathy and stroke patients. In the past one and a half decades, however, the effect of stochastic resonance by noise enhanced stimulation on balance control has been demonstrated as a very robust phenomenon. For example, a meta-analysis by Woo et al. concluded that enhanced noise stimulation of the lower limbs results in moderate to high effects sizes on parameters of postural regulation and stability (Woo et al., 2017). Changes in postural performance with noise enhanced stimulation were evaluated with respect to diverse postural activities, such as standing and walking, the body location of the applied stimulation, such as the soles of the feet and more proximal regions of the lower extremities and the fingertips. In the majority, the stimulation modality was vibrotactile but electrical and auditory stimulation have also been used. Finally, target populations ranged from healthy young adults to patients with neurological impairments and reduced somatosensation. A systematic review by Bagherzadeh Cham et al. (2016) on the benefits of subthreshold vibratory noise stimulation of the soles of the feet in older adults and diabetic individuals concluded that vibratory stimulation improves balance and gait performance in these populations.

Mechanoreceptors in the soles of the feet, providing information about pressure distribution and shear forces, pose an important sensory modality for the control of posture during quiet standing as well as during walking. This is evidenced by systematic alterations of the center of pressure trajectories during quiet standing during suprathreshold vibrotactile stimulation of the plantar foot zones as well as plantar electrical stimulation in neurologically healthy individuals (Kavounoudias et al., 1998, 1999, 2001; Roll et al., 2002). These involuntary drifts away from the equilibrium state during suprathreshold vibrotactile stimulation may be a cause why suprathreshold vibrotactile noisy stimulation has a destabilizing effect on postural control in young and older adults (Simeonov et al., 2011).

In contrast to suprathreshold levels of vibratory stimulation, Priplata et al. demonstrated that subthreshold vibratory noise stimulation improves body sway stability in patients with peripheral and central somatosensory deficits such as following diabetic neuropathy and stroke (Priplata et al., 2006). This was also demonstrated for a more dynamic postural task such as Timed-Up-and-Go (Podsiadlo and Richardson, 1991), in which subthreshold (70–85% of the sensory threshold) plantar vibrotactile stimulation increased complexity of sway dynamics and mobility (Zhou et al., 2016). Not only performance in the Timed-Up-and-Go improves during plantar subthreshold vibrotactile stimulation but temporal gait variability is also reduced in older adults (Lipsitz et al., 2015). The individual falls risk seems not to play a role with respect to the benefit on gait variability (Galica et al., 2009). Stephen and coworkers showed, however, that the effect of noise-enhanced vibrotactile stimulation on gait variability in older adults is dependent on participants' initial variability levels (Stephen et al., 2012). Individuals with relatively low initial gait variability showed increases, while for those who expressed high gait variability initially, variability was strongly reduced. This shows that not every individual will gain an advantage of subthreshold vibrotactle noise stimulation. The frequency and the amplitude of plantar vibrotactile stimulation is relevant, as these affect longrange correlations in stride length and stride interval during walking in healthy young adults (Chien et al., 2017).

Kelty-Stephen and Dixon (2013) reanalyzed the original data by Priplata et al. (2002) and found that the effects of subthreshold noisy vibrotactile stimulation on body sway dynamics are modulated by the degree of autocorrelations present in body sway, which could explain differences in interindividual responsiveness. It is therefore crucial to adjust the stimulation parameters to an individual's specific requirements. For example, Wells et al. applied an adaptive psychophysical procedure to assess participants' vibrotactile thresholds of the foot soles in younger and older adults and demonstrated that subthreshold vibratory noise stimulation increased their plantar sensitivity (Well et al., 2005). Further, they suggested that their procedure allows a reliable a priori determination of participants' optimal stimulation noise level to augment plantar vibrotactile sensitivity.

Subthreshold vibrotactile noise stimulation augments postural performance under more difficult task conditions too. Noise-enhanced vibrotactile stimulation benefits gait variability in terms of stride width in a fatigued state, for example during inclined treadmill walking with 30% added body weight (Miranda et al., 2016). Dettmer et al. (2015) tested young and older adults in an intersensory conflict situation by sway-referencing the visual input, thereby removing any visual sway-related information. In this context, older adults have been shown to show dramatically increased postural instability due to overreliance on visual information for body sway control (Simoneau et al., 1999). Vibrotactile noisy stimulation was found to improve balance performance particularly in the older adults (Dettmer et al., 2015). This demonstrates the stimulation's potential to attenuate age-related visual overreliance and susceptibility to intersensory conflict. However, in a follow-up study which increased the challenge of balance control during standing by the addition of a secondary working memory task, Dettmer et al. (2016) did not find an enhanced effect of vibration despite moderate correlations between the vibrotactile plantar sensitivity and postural parameters.

A limitation of the capacity of subthreshold vibrotactile noise stimulation to reduce body sway seems to exist, however, when the postural context becomes too complex. Keshner et al. (2014) challenged control of body balance with two kinds of disruptive stimuli alone and in combination in healthy young adults: a continuous optokinetic visual field rotation around the pitch axis, which imposed intersensory motion conflict, and a mental calculation task imposing additional attentional demands. While plantar subthreshold noisy vibrotactile stimulation reduced body sway during either mental calculation or visual stimulation, the increased task complexity of the visual-conflict-dual-task combination diminished the influence of subthreshold vibrotactile stimulation on the dynamics of body sway. Also, it is important to consider,

that the sensitivity of the soles of the feet to vibrotactile stimulation can be affected by the general postural context (Mildren et al., 2016).

The alternative to subthreshold vibrotactile noisy stimulation of mechanoreceptors is electrical stimulation muscle proprioception. For example, subthreshold electrical noisy stimulation of the lower leg muscles (tibialis anterior, triceps surae) in seated and standing participants expressed a connection between reduced variability in isometric plantar flexion force and reduced body sway (Magalhães and Kohn, 2012, 2014). Cutaneous receptors respond to electrical noise stimulation as, when applied at the knee, it reduces sway during single-leg standing in older adults (Gravelle et al., 2002). Finally, in terms of balance control, auditory white noise stimulation reduces the variability in both the lower and higher frequency components of postural sway in young and older adults as well (Ross and Balasubramaniam, 2015; Ross et al., 2016).

# Hand Function and Tactile Sensitivity

As mentioned above, subthreshold vibrotactile noise stimulation to the fingertips augments balance performance. It also improves performance in manual fine motor control. For example, Sueda et al. (2013) demonstrated that subthreshold vibratory noise applied to the grip of a surgical device improves the tactile sensitivity mediated by the device. Similar effects were reported by Sawada et al. (2015). Furthermore, Beceren et al. (2013) demonstrated that adjusted subthreshold vibratory noise to the fingertips reduces the sensitivity threshold. Interestingly, normal vibration of the fingertip differed from the tangential vibration in their study. While normal vibration seemed to stimulate mainly fast-adapting Type I fibers, the tangential vibration also resulted in triggering slow-adapting Type II receptors (Beceren et al., 2013).

The augmenting effects of subthreshold vibratory noise stimulation may not be restricted to the actual body location of vibratory stimulation but can radiate to other locations as well. In stroke patients, for example, Enders and colleagues reported augmented fingertip sensitivity during stimulation at the wrist and dorsal skin surface of the paretic hand (Enders et al., 2013). Remarkably, fine motor dexterity of the paretic hand also seems to benefit from this remotely induced increased fingertip sensitivity (Seo et al., 2014). Suprathreshold vibration leads to reduced fingertip sensitivity, while the remote benefits of subthreshold stimulation seemingly do not depend on the exact location on the vibrated hand (Lakshminarayanan et al., 2015). The later finding led to the conclusion that any remote effects stem from central, possibly supraspinal origins. In a further study to follow-up the neurological basis of the remote effects of vibratory noise stimulation, Seo et al. reported increased somatosensory evoked potentials in the primary sensorimotor and premotor cortices during fingertip stimulation with simultaneous subthreshold wrist vibration of 60% of the vibrotactile threshold (Seo et al., 2015). Interestingly, it has also been suggested that improvement of sensorimotor performance during a visuomotor task via vibrotactile stimulation of the index finger is consistent with an increase in cortical motor spectral power and corticomuscular coherence (Trenado et al., 2014b).

Stochastic resonance can also influence motor learning. From the perspective of motor control, an error signal is exploited by the central nervous system to update its motor policy and reduce the discrepancy between observed and predicted errors (Diedrichsen et al., 2005). For instance, when playing darts, visual errors help us derive the best strategic change to eventually aim at the target. Improved signal quality can refine the internal state estimate and the accuracy of the error signal, therefore contributing to increased learning rates. As such, stochastic resonance can potentially facilitate movement learning processes that is based on integration of sensory inputs and sensorymotor coupling. Mendez-Balbuena et al. (2012) showed that an individually determined optimal level of mechanical noise significantly improves sensorimotor performance in a static force compensation task involving the index finger (Mendez-Balbuena et al., 2012). Effects of stochastic resonance were also studied in the context of sensorimotor performance during exercise induced muscle damage. Gleeson (2017) studied how application of mechanical vibrations to the biceps femoris muscle influences sensorimotor performance of target force replication (Gleeson, 2017). The study showed that subthreshold mechanical vibrations compensate the negative effects of muscle damage and suggested that more efficient means of delivering stochastic resonance (e.g., functional electrical stimulation) would be needed to improve the effectiveness to enhancing sensorimotor performance under adverse conditions of exercise stress.

# Visual Information