Bed rest impairs the vestibular control of balance.

Prolonged bed rest impairs standing balance but the underlying mechanisms are uncertain. Previous research suggests strength loss is not the cause, leaving impaired sensorimotor control as an alternative. Here we examine vestibular control of posture in 18 male volunteers before and after 60 days of bed rest. Stochastic vestibular stimulation (SVS) was used to evoke sway responses before, 1 and 6 days after bed rest under different head yaw orientations. The directional accuracy and precision of these responses were calculated from ground reaction force vectors. Bed rest caused up to 63% increases in spontaneous standing sway and 31% reductions in leg strength, changes which were uncorrelated. The increase in sway was exacerbated when the eyes were closed. Mean directions of SVS-evoked sway responses were unaffected, being directed towards the anodal ear and rotating in line with head orientation in the same way before and after bed rest. However, individual trial analysis revealed 25%-30% increases in directional variability, which were significantly correlated with the increase in spontaneous sway (r = 0.48-0.71; P ≤ 0.044) and were still elevated on day 6 post-bed rest. This reveals that individual sway responses may be inappropriately oriented, a finding masked by the averaging process. Our results confirm that impaired balance following prolonged bedrest is not related to loss of strength. Rather, they demonstrate that the sensorimotor transformation process which converts vestibular feedback into appropriately directed balance responses is impaired. KEY POINTS: Prolonged inactivity impairs balance but previous research suggests this is not caused by loss of strength. Here we investigated vestibular control of balance before and after 60 days of bed rest using electrical vestibular stimulation (EVS) to evoke sway responses. Spontaneous sway significantly increased and muscle strength reduced following bed rest, but, in keeping with previous research, these two effects were not correlated. While the overall accuracy of EVS-evoked sway responses was unaffected, their directional variability significantly increased following bed rest, and this was correlated with the increases in spontaneous sway. We have shown that the ability to transform head-centred vestibular feedback into an appropriately directed body sway response is negatively affected by prolonged inactivity; this may contribute to the impaired balance commonly observed following bed rest.

Intrinsic ankle stiffness is associated with paradoxical calf muscle movement but not postural sway or age.

Due to Achilles tendon compliance, passive ankle stiffness is insufficient to stabilise the body when standing. This results in 'paradoxical' muscle movement, whereby calf muscles tend to shorten during forward body sway. Natural variation in stiffness may affect this movement. This may have consequences for postural control, with compliant ankles placing greater reliance upon active neural control rather than stretch reflexes. Previous research also suggests ageing reduces ankle stiffness, possibly contributing to reduced postural stability. Here we determine the relationship between ankle stiffness and calf muscle movement during standing, and whether this is associated with postural stability or age. Passive ankle stiffness was measured during quiet stance in 40 healthy volunteers ranging from 18 to 88 years of age. Medial gastrocnemius muscle length was also recorded using ultrasound. We found a significant inverse relationship between ankle stiffness and paradoxical muscle movement, that is, more compliant ankles were associated with greater muscle shortening during forward sway (r ≥ 0.33). This was seen during both quiet stance as well as voluntary sway. However, we found no significant effects of age upon stiffness, paradoxical motion or postural sway. Furthermore, neither paradoxical muscle motion nor ankle stiffness was associated with postural sway. These results show that natural variation in ankle stiffness alters the extent of paradoxical calf muscle movement during stance. However, the absence of a clear relationship to postural sway suggests that neural control mechanisms are more than capable of compensating for a lack of inherent joint stiffness.

Is activation of the vestibular system by electromagnetic induction a possibility in an MRI context?

In recent years, an increasing number of studies have discussed the mechanisms of vestibular activation in strong magnetic field settings such as occur in a magnetic resonance imaging scanner environment. Amid the different hypotheses, the Lorentz force explanation currently stands out as the most plausible mechanism, as evidenced by activation of the vestibulo-ocular reflex. Other hypotheses have largely been discarded. Nonetheless, both human data and computational modeling suggest that electromagnetic induction could be a valid mechanism which may coexist alongside the Lorentz force. To further investigate the induction hypothesis, we provide, herein, a first of its kind dosimetric analysis to estimate the induced electric fields at the vestibular system and compare them with what galvanic vestibular stimulation would generate. We found that electric fields strengths from induction match galvanic vestibular stimulation strengths generating vestibular responses. This review examines the evidence in support of electromagnetic induction of vestibular responses, and whether movement-induced time-varying magnetic fields should be further considered and investigated.

Idiosyncratic Characteristics of Postural Sway in Normal and Perturbed Standing.

OBJECTIVE: Are people with a characteristically large physiological sway rendered particularly unstable when standing on a moving surface? Is postural sway in standing individuals idiosyncratic? In this study, we examine postural sway in individuals standing normally, and when subtle continuous sinusoidal disturbances are applied to their support platform. We calculate consistency between conditions to verify if sway can be considered characteristic of each individual. We also correlate two different aspects of participants' responses to disturbance; their sway velocity and their regulation of body orientation. METHODS: Nineteen healthy adults (age 29.2 ± 3.2 years) stood freely on footplates coaxially aligned with their ankles and attached to a motorized platform. They had their eyes closed, and hips and knees locked with a light wooden board attached to their body. Participants either stood quietly on a fixed platform or on a slowly tilting platform (0.1 Hz sinusoid; 0.2 and 0.4 deg). Postural sway size was separated into two entities: (1) the spontaneous sway velocity component (natural random relatively rapid postural adjustments, RMS body angular velocity) and (2) the evoked tilt gain component (much slower 0.1 Hz synchronous tilt induced by the movement of the platform, measured as peak-to-peak (p-p) gain, ratio of body angle to applied footplate rotation). RESULTS: There was no correlation between the velocity of an individual's sway and their evoked tilt gain (r = 0.34, p = 0.15 and r = 0.30, p = 0.22). However, when considered separately, each of the two measurements showed fair to good absolute agreement within conditions. Spontaneous sway velocity consistently increased as participants were subjected to increasing disturbance. Participants who swayed more (or less) did so across all conditions [ICC(3,k) = 0.95]. Evoked tilt gain also showed consistency between conditions [ICC(3,k) = 0.79], but decreased from least to most disturbed conditions. CONCLUSION: The two measurements remain consistent between conditions. Consistency between conditions of two very distinct unrelated measurements reflects the idiosyncratic nature of postural sway. However, sway velocity and tilt gain are not related, which supports the idea that the short-term regulation of stability and the longer-term regulation of orientation are controlled by different processes.

Individual differences in intrinsic ankle stiffness and their relationship to body sway and ankle torque.

When standing, intrinsic ankle stiffness is smaller when measured using large perturbations, when sway size is large, and when background torque is low. However, there is a large variation in individual intrinsic ankle stiffness. Here we determine if individual variation has consequences for postural control. We examined the relationship between ankle stiffness, ankle torque and body sway across different individuals. Ankle stiffness was estimated in 19 standing participants by measuring torque responses to small, brief perturbations. Perturbation sizes of 0.2 & 0.9 degrees (both lasting 140 ms) measured short- and long-range stiffness respectively, while participants either stood quietly on a fixed platform or were imperceptibly tilted to reduce stability (0.1 Hz sinusoid; 0.2 & 0.4 deg). The spontaneous body sway component (natural random relatively rapid postural adjustments) and background ankle torque were averaged from sections immediately before perturbations. The results show that, first, intrinsic ankle stiffness is positively associated with ankle torque, and that this relationship is stronger for long-range stiffness. Second, intrinsic ankle stiffness is negatively associated with body sway, but, in contrast to the relationship with torque, this relationship is stronger for short-range stiffness. We conclude that high short-range intrinsic ankle stiffness is associated with reduced spontaneous sway, although the causal relationship between these two parameters is unknown. These results suggest that, in normal quiet standing where sway is very small, the most important determinant of intrinsic ankle stiffness may be stillness. In less stable conditions, intrinsic ankle stiffness may be more dependent on ankle torque.

Combined EZH2 and Bcl-2 inhibitors as precision therapy for genetically defined DLBCL subtypes.

Molecular alterations in the histone methyltransferase EZH2 and the antiapoptotic protein Bcl-2 frequently co-occur in diffuse large B-cell lymphoma (DLBCL). Because DLBCL tumors with these characteristics are likely dependent on both oncogenes, dual targeting of EZH2 and Bcl-2 is a rational therapeutic approach. We hypothesized that EZH2 and Bcl-2 inhibition would be synergistic in DLBCL. To test this, we evaluated the EZH2 inhibitor tazemetostat and the Bcl-2 inhibitor venetoclax in DLBCL cells, 3-dimensional lymphoma organoids, and patient-derived xenografts (PDXs). We found that tazemetostat and venetoclax are synergistic in DLBCL cells and 3-dimensional lymphoma organoids that harbor an EZH2 mutation and an IGH/BCL2 translocation but not in wild-type cells. Tazemetostat treatment results in upregulation of proapoptotic Bcl-2 family members and priming of mitochondria to BH3-mediated apoptosis, which may sensitize cells to venetoclax. The combination of tazemetostat and venetoclax was also synergistic in vivo. In DLBCL PDXs, short-course combination therapy resulted in complete remissions that were durable over time and associated with superior overall survival compared with either drug alone.

Effects of calf muscle conditioning upon ankle proprioception.

Ankle proprioception is crucial for balance and relies upon accurate input from calf muscle spindles. Spindle input, in turn, depends upon the physiological and mechanical properties of surrounding muscle tissue. Altering these properties could affect ankle proprioception, with potential consequences for balance. Here we determine the effects of prior muscle cooling, stretch and contraction upon performance of a contralateral ankle joint matching task. Participants stood passively leaning against a board oriented 22° rearward from vertical. Their right ankle was rotated to a randomised position between ± 6° plantar/dorsiflexion. The task was to align the left ankle to the same position, without vision. In the first experiment, immediately prior to each testing session, participants either produced a strong calf muscle contraction in a fully plantarflexed (tiptoe) posture or underwent 15° dorsiflexion stretch. Contraction had no effect on task performance, whereas stretch produced a significant bias in ankle placement of 0.89 ± 0.6°, indicating that participants perceived their foot to be more plantarflexed compared to a control condition. In the second experiment, the right lower leg was cooled in iced water (≤ 5°C) for 10 minutes. Cooling increased joint matching error by ~0.4°, through a combination of increased bias and variability. These results confirm that conditioning the triceps surae muscles can alter perception of ankle joint position. Since body movement during quiet stance is in the order of 1°, the magnitude of these changes are relevant for balance.

Epigenetic reprogramming sensitizes immunologically silent EBV+ lymphomas to virus-directed immunotherapy.

Despite advances in T-cell immunotherapy against Epstein-Barr virus (EBV)-infected lymphomas that express the full EBV latency III program, a critical barrier has been that most EBV+ lymphomas express the latency I program, in which the single Epstein-Barr nuclear antigen (EBNA1) is produced. EBNA1 is poorly immunogenic, enabling tumors to evade immune responses. Using a high-throughput screen, we identified decitabine as a potent inducer of immunogenic EBV antigens, including LMP1, EBNA2, and EBNA3C. Induction occurs at low doses and persists after removal of decitabine. Decitabine treatment of latency I EBV+ Burkitt lymphoma (BL) sensitized cells to lysis by EBV-specific cytotoxic T cells (EBV-CTLs). In latency I BL xenografts, decitabine followed by EBV-CTLs results in T-cell homing to tumors and inhibition of tumor growth. Collectively, these results identify key epigenetic factors required for latency restriction and highlight a novel therapeutic approach to sensitize EBV+ lymphomas to immunotherapy.

Comparing Ocular Responses to Caloric Irrigation and Electrical Vestibular Stimulation in Vestibular Schwannoma.

Electrical Vestibular Stimulation (EVS) is a non-invasive technique for activating the vestibular-ocular reflex, evoking mainly a torsional eye movement response. We have previously demonstrated that this response can be used to detect vestibular asymmetry in patients with vestibular schwannoma (VS). Here we perform a direct comparison of EVS with caloric irrigation in this patient group. We studied 30 patients with unilateral VS, alongside an equal number of aged-matched healthy control subjects. EVS current was delivered to the mastoid process in a monaural configuration using a sinusoidal stimulus (2 Hz; ± 2 mA; 10 s), with an electrode placed over the spinous C7 process. Evoked eye movements were recorded from the right eye in darkness using an infra-red sensitive camera while the subject sat relaxed with their head on a chinrest. Ocular torsion was subsequently tracked off-line using iris striations. Each subject separately underwent water caloric irrigation, in accordance with the British Society of Audiology guidelines. For the caloric test, eye movement was recorded in the yaw axis using electro-oculography. For both EVS and calorics, inter-aural response asymmetry was calculated to determine the extent of canal paresis. Both tests revealed impaired vestibular function in the ipsilesional ear of VS patients, with a mean asymmetry ratio of 15 ± 17% and 18 ± 16% for EVS and calorics, respectively. Overall, the caloric test results discriminated controls from patients slightly more effectively than EVS (Cohen's D effect size = 1.44 vs. 1.19). Importantly, there was a significant moderate correlation between the AR values produced by EVS and calorics (r = 0.53, p < 0.01), and no significant difference between mean AR estimates. When questioned, ≥85% of participants subjectively preferred the EVS experience, in terms of comfort. Moreover, it took ~15 min to complete, vs. ~1 h for caloric. These results confirm that the results of the EVS test broadly agree with those of caloric irrigation, in terms of detecting vestibular asymmetry. Furthermore, they suggest a higher degree of convenience and patient comfort.

Ocular torsion responses to electrical vestibular stimulation in vestibular schwannoma.

OBJECTIVES: We determined if eye movements evoked by Electrical Vestibular Stimulation (EVS) can be used to detect vestibular dysfunction in patients with unilateral vestibular schwannoma (VS). METHODS: Ocular torsion responses to monaural sinusoidal EVS currents (±2 mA, 2 Hz) were measured in 25 patients with tumours ranging in size from Koos grade 1-3. For comparative purposes we also measured postural sway response to EVS, and additionally assessed vestibular function with the lateral Head Impulse Test (HIT). Patient responses were compared to age-matched healthy control subjects. RESULTS: Patients exhibited smaller ocular responses to ipsilesional versus contralesional EVS, and showed a larger asymmetry ratio (AR) than control subjects (19.4 vs. 3.3%, p < 0.05). EVS-evoked sway responses were also smaller in ipsilesional ear, but exhibited slightly more variability than the eye movement response, along with marginally lower discriminatory power (patients vs. controls: AR = 16.6 vs 2.6%, p < 0.05). The HIT test exhibited no significant difference between groups. CONCLUSIONS: These results demonstrate significant deficits in the ocular torsion response to EVS in VS patients. SIGNIFICANCE: The fast, convenient and non-invasive nature of the test are well suited to clinical use.

Sensory integration of a light touch reference in human standing balance.

In upright stance, light touch of a space-stationary touch reference reduces spontaneous sway. Moving the reference evokes sway responses which exhibit non-linear behavior that has been attributed to sensory reweighting. Reweighting refers to a change in the relative contribution of sensory cues signaling body sway in space and light touch cues signaling finger position with respect to the body. Here we test the hypothesis that the sensory fusion process involves a transformation of light touch signals into the same reference frame as other sensory inputs encoding body sway in space, or vice versa. Eight subjects lightly gripped a robotic manipulandum which moved in a circular arc around the ankle joint. A pseudo-randomized motion sequence with broad spectral characteristics was applied at three amplitudes. The stimulus was presented at two different heights and therefore different radial distances, which were matched in terms of angular motion. However, the higher stimulus evoked a significantly larger sway response, indicating that the response was not matched to stimulus angular motion. Instead, the body sway response was strongly related to the horizontal translation of the manipulandum. The results suggest that light touch is integrated as the horizontal distance between body COM and the finger. The data were well explained by a model with one feedback loop minimizing changes in horizontal COM-finger distance. The model further includes a second feedback loop estimating the horizontal finger motion and correcting the first loop when the touch reference is moving. The second loop includes the predicted transformation of sensory signals into the same reference frame and a non-linear threshold element that reproduces the non-linear sway responses, thus providing a mechanism that can explain reweighting.

Intrinsic ankle stiffness during standing increases with ankle torque and passive stretch of the Achilles tendon.

Individuals may stand with a range of ankle angles. Furthermore, shoes or floor surfaces may elevate or depress their heels. Here we ask how these situations impact ankle stiffness and balance. We performed two studies (each with 10 participants) in which the triceps surae, Achilles tendon and aponeurosis were stretched either passively, by rotating the support surface, or actively by leaning forward. Participants stood freely on footplates which could rotate around the ankle joint axis. Brief, small stiffness-measuring perturbations (<0.7 deg; 140 ms) were applied at intervals of 4-5 s. In study 1, participants stood at selected angles of forward lean. In study 2, normal standing was compared with passive dorsiflexion induced by 15 deg toes-up tilt of the support surface. Smaller perturbations produced higher stiffness estimates, but for all perturbation sizes stiffness increased with active torque or passive stretch. Sway was minimally affected by stretch or lean, suggesting that this did not underlie the alterations in stiffness. In quiet stance, maximum ankle stiffness is limited by the tendon. As tendon strain increases, it becomes stiffer, causing an increase in overall ankle stiffness, which would explain the effects of leaning. However, stiffness also increased considerably with passive stretch, despite a modest torque increase. We discuss possible explanations for this increase.

Differential effects of vision upon the accuracy and precision of vestibular-evoked balance responses.

KEY POINTS: Effective balance control requires the transformation of vestibular signals from head- to foot-centred coordinates in order to move the body in an appropriate direction. This transformation process has previously been studied by analysing the directional accuracy of the averaged sway response to multiple electrical vestibular stimuli (EVS). Here we studied trial-by-trial variability of EVS responses to measure any changes in directional precision which may be masked by the averaging process. We found that vision increased directional variability without influencing the mean sway direction, demonstrating that response accuracy and precision are dissociable. These results emphasise the importance of single trial analysis in determining the efficacy of vestibular control of balance. ABSTRACT: Vestibular information must be transformed from head- to-foot-centred coordinates for balance control. This transformation process has previously been investigated using electrical vestibular stimulation (EVS), which evokes a sway response fixed in head coordinates. The craniocentric nature of the response has been demonstrated by analysing average responses to multiple stimuli. This approach misses any trial-by-trial variability which would reflect poor balance control. Here we performed single-trial analysis to measure this directional variability (precision), and compared this to mean performance (accuracy). We determined the effect of vision upon both parameters. Standing volunteers adopted various head orientations (0, ±30 and ±60 deg yaw) while EVS-evoked response direction was determined from ground reaction force vectors. As previously reported, mean force direction was orientated towards the anodal ear, and rotated in line with head yaw. Although vision caused a ∼50% reduction in response magnitude, it had no influence on the direction of the mean sway response, indicating that accuracy was unaffected. However, individual trial analysis revealed up to 30% increases in directional variability with the eyes open. This increase was inversely correlated with the size of the force response. The paradoxical observation that vision reduces the precision of the balance response may be explained by a multi-sensory integration process. As additional veridical sensory information becomes available, this lessens the relative contribution of vestibular input, causing a simultaneous reduction in both the magnitude and the precision of the response to EVS. Our novel approach demonstrates the importance of single-trial analysis in revealing the efficacy of vestibular reflexes.

Regulated Release of Cryptococcal Polysaccharide Drives Virulence and Suppresses Immune Cell Infiltration into the Central Nervous System.

Cryptococcus neoformans is a common environmental yeast and opportunistic pathogen responsible for 15% of AIDS-related deaths worldwide. Mortality primarily results from meningoencephalitis, which occurs when fungal cells disseminate to the brain from the initial pulmonary infection site. A key C. neoformans virulence trait is the polysaccharide capsule. Capsule shields C. neoformans from immune-mediated recognition and destruction. The main capsule component, glucuronoxylomannan (GXM), is found both attached to the cell surface and free in the extracellular space (as exo-GXM). Exo-GXM accumulates in patient serum and cerebrospinal fluid at microgram/milliliter concentrations, has well-documented immunosuppressive properties, and correlates with poor patient outcomes. However, it is poorly understood whether exo-GXM release is regulated or the result of shedding during normal capsule turnover. We demonstrate that exo-GXM release is regulated by environmental cues and inversely correlates with surface capsule levels. We identified genes specifically involved in exo-GXM release that do not alter surface capsule thickness. The first mutant, the liv7Δ strain, released less GXM than wild-type cells when capsule was not induced. The second mutant, the cnag_00658Δ strain, released more exo-GXM under capsule-inducing conditions. Exo-GXM release observed in vitro correlated with polystyrene adherence, virulence, and fungal burden during murine infection. Additionally, we found that exo-GXM reduced cell size and capsule thickness under capsule-inducing conditions, potentially influencing dissemination. Finally, we demonstrated that exo-GXM prevents immune cell infiltration into the brain during disseminated infection and highly inflammatory intracranial infection. Our data suggest that exo-GXM performs a distinct role from capsule GXM during infection, altering cell size and suppressing inflammation.

Ocular torsion responses to sinusoidal electrical vestibular stimulation.

BACKGROUND: Eye movements evoked by electrical vestibular stimulation (EVS) offer potential for diagnosing vestibular dysfunction. However, ocular recording techniques are often too invasive or impractical for routine clinical use. Furthermore, the kinematic nature of the EVS signal is not fully understood in terms of movement sensations. NEW METHOD: We apply sinusoidal EVS stimuli varying from 0.05 to 20Hz, and record the eye in darkness using an infrared camera. Eye movement was measured offline using commercially available software to track iris striations. Response gain and phase were calculated separately for eye position, velocity and acceleration across all frequencies, to determine how the brain interprets the EVS signal. RESULTS: Ocular torsion responses were observed at the same frequency as the stimulus, for all frequencies, while lateral/vertical responses were minimal or absent. Response gain and phase resembled previously reported responses to natural rotation, but only when analysing eye velocity, not position or acceleration. COMPARISON WITH EXISTING METHOD(S): Our method offers a simple, affordable, reliable and non-invasive method for tracking the ocular response to EVS. It is more convenient than scleral coil recordings, or marking the sclera to aid video tracking. It also allows us to assess the torsional VOR at frequencies not possible with natural stimuli. CONCLUSIONS: Ocular torsion responses to EVS can be readily assessed using sinusoidal stimuli combined with an infrared camera. Gain and phase analysis suggests that the central nervous system interprets the stimulus as head roll velocity. Future work will assess the diagnostic potential for patients with vestibular disorders.

Co-ordination of the upper and lower limbs for vestibular control of balance.

KEY POINTS: When standing and holding an earth-fixed object, galvanic vestibular stimulation (GVS) can evoke upper limb responses to maintain balance. In the present study, we determined how these responses are affected by grip context (no contact, light grip and firm grip), as well as how they are co-ordinated with the lower limbs to maintain balance. When GVS was applied during firm grip, hand and ground reaction forces were generated. The directions of these force vectors were co-ordinated such that the overall body sway response was always aligned with the inter-aural axis (i.e. craniocentric). When GVS was applied during light grip (< 1 N), hand forces were secondary to body movement, suggesting that the arm performed a mostly passive role. These results demonstrate that a minimum level of grip is required before the upper limb becomes active in balance control and also that the upper and lower limbs co-ordinate for an appropriate whole-body sway response. ABSTRACT: Vestibular stimulation can evoke responses in the arm when it is used for balance. In the present study, we determined how these responses are affected by grip context, as well as how they are co-ordinated with the rest of the body. Galvanic vestibular stimulation (GVS) was used to evoke balance responses under three conditions of manual contact with an earth-fixed object: no contact, light grip (< 1 N) (LG) and firm grip (FG). As grip progressed along this continuum, we observed an increase in GVS-evoked hand force, with a simultaneous reduction in ground reaction force (GRF) through the feet. During LG, hand force was secondary to the GVS-evoked body sway response, indicating that the arm performed a mostly passive role. By contrast, during FG, the arm became actively involved in driving body sway, as revealed by an early force impulse in the opposite direction to that seen in LG. We then examined how the direction of this active hand vector was co-ordinated with the lower limbs. Consistent with previous findings on sway anisotropy, FG skewed the direction of the GVS-evoked GRF vector towards the axis of baseline postural instability. However, this was effectively cancelled by the hand force vector, such that the whole-body sway response remained aligned with the inter-aural axis, maintaining the craniocentric principle. These results show that a minimum level of grip is necessary before the upper limb plays an active role in vestibular-evoked balance responses. Furthermore, they demonstrate that upper and lower-limb forces are co-ordinated to produce an appropriate whole-body sway response.

Vestibular feedback maintains reaching accuracy during body movement.

KEY POINTS: Reaching movements can be perturbed by vestibular input, but the function of this response is unclear. Here, we applied galvanic vestibular stimulation concurrently with real body movement while subjects maintained arm position either fixed in space or fixed with respect to their body. During the fixed-in-space conditions, galvanic vestibular stimulation caused large changes in arm trajectory consistent with a compensatory response to maintain upper-limb accuracy in the face of body movement. Galvanic vestibular stimulation responses were absent during the body-fixed task, demonstrating task dependency in vestibular control of the upper limb. The results suggest that the function of vestibular-evoked arm movements is to maintain the accuracy of the upper limb during unpredictable body movement, but only when reaching in an earth-fixed reference frame. ABSTRACT: When using our arms to interact with the world, unintended body motion can introduce movement error. A mechanism that could detect and compensate for such motion would be beneficial. Observations of arm movements evoked by vestibular stimulation provide some support for this mechanism. However, the physiological function underlying these artificially evoked movements is unclear from previous research. For such a mechanism to be functional, it should operate only when the arm is being controlled in an earth-fixed rather than a body-fixed reference frame. In the latter case, compensation would be unnecessary and even deleterious. To test this hypothesis, subjects were gently rotated in a chair while being asked to maintain their outstretched arm pointing towards either earth-fixed or body-fixed memorized targets. Galvanic vestibular stimulation was applied concurrently during rotation to isolate the influence of vestibular input, uncontaminated by inertial factors. During the earth-fixed task, galvanic vestibular stimulation produced large polarity-dependent corrections in arm position. These corrections mimicked those evoked when chair velocity was altered without any galvanic vestibular stimulation, indicating a compensatory arm response to a sensation of altered body motion. In stark contrast, corrections were completely absent during the body-fixed task, despite the same chair movement profile and arm posture. These effects persisted when we controlled for differences in limb kinematics between the two tasks. Our results demonstrate that vestibular control of the upper limb maintains reaching accuracy during unpredictable body motion. The observation that such responses occurred only when reaching within an earth-fixed reference frame confirms the functional nature of vestibular-evoked arm movement.

Physiological tremor reveals how thixotropy adapts skeletal muscle for posture and movement.

People and animals can move freely, but they must also be able to stay still. How do skeletal muscles economically produce both movement and posture? Humans are well known to have motor units with relatively homogeneous mechanical properties. Thixotropic muscle properties can provide a solution by providing a temporary stiffening of all skeletal muscles in postural conditions. This stiffening is alleviated almost instantly when muscles start to move. In this paper, we probe this behaviour. We monitor both the neural input to a muscle, measured here as extensor muscle electromyography (EMG), and its output, measured as tremor (finger acceleration). Both signals were analysed continuously as the subject made smooth transitions between posture and movement. The results showed that there were marked changes in tremor which systematically increased in size and decreased in frequency as the subject moved faster. By contrast, the EMG changed little and reflected muscle force requirement rather than movement speed. The altered tremor reflects naturally occurring thixotropic changes in muscle behaviour. Our results suggest that physiological tremor provides useful and hitherto unrecognized insights into skeletal muscle's role in posture and movement.

Sway-dependent changes in standing ankle stiffness caused by muscle thixotropy.

KEY POINTS: The passive stiffness of the calf muscles contributes to standing balance, although the properties of muscle tissue are highly labile. We investigated the effect of sway history upon intrinsic ankle stiffness and demonstrated reductions in stiffness of up to 43% during conditions of increased baseline sway. This sway dependence was most apparent when using low amplitude stiffness-measuring perturbations, and the short-range stiffness component was smaller during periods of high sway. These characteristics are consistent with the thixotropic properties of the calf muscles causing the observed changes in ankle stiffness. Periods of increased sway impair the passive stabilization of standing, demanding more active neural control of balance. Quiet standing is achieved through a combination of active and passive mechanisms, consisting of neural control and intrinsic mechanical stiffness of the ankle joint, respectively. The mechanical stiffness is partly determined by the calf muscles. However, the viscoelastic properties of muscle are highly labile, exhibiting a strong dependence on movement history. By measuring the effect of sway history upon ankle stiffness, the present study determines whether this lability has consequences for the passive stabilization of human standing. Ten subjects stood quietly on a rotating platform whose axis was collinear with the ankle joint. Ankle sway was increased by slowly tilting this platform in a random fashion, or decreased by fixing the body to a board. Ankle stiffness was measured by using the same platform to simultaneously apply small, brief perturbations (<0.6 deg; 140 ms) at the same time as the resulting torque response was recorded. The results show that increasing sway reduces ankle stiffness by up to 43% compared to the body-fixed condition. Normal quiet stance was associated with intermediate values. The effect was most apparent when using smaller perturbation amplitudes to measure stiffness (0.1 vs. 0.6 deg). Furthermore, torque responses exhibited a biphasic pattern, consisting of an initial steep rise followed by a shallower increase. This transition occurred earlier during increased levels of ankle sway. These results are consistent with a movement-dependent change in passive ankle stiffness caused by thixotropic properties of the calf muscle. The consequence is to place increased reliance upon active neural control during times when increased sway renders ankle stiffness low.