The effects of acute normobaric hypoxia on standing balance while dual-tasking with and without visual input.

PURPOSE: To investigate the influence of acute normobaric hypoxia on standing balance under single and dual-task conditions, both with and without visual input. METHODS: 20 participants (7 female, 20-31 years old) stood on a force plate for 16, 90-s trials across four balance conditions: single-task (quiet stance) or dual-task (auditory Stroop test), with eyes open or closed. Trials were divided into four oxygen conditions where the fraction of inspired oxygen (FIO2) was manipulated (normoxia: 0.21 and normobaric hypoxia: 0.16, 0.145 and 0.13 FIO2) to simulate altitudes of 1100, 3,400, 4300, and 5200 m. Participants breathed each FIO2 for ~ 3 min before testing, which lasted an additional 7-8 min per oxygen condition. Cardiorespiratory measures included heart rate, peripheral blood oxygen saturation, and pressure of end tidal (PET) CO2 and O2. Center of pressure measures included total path length, 95% ellipse area, and anteroposterior and mediolateral velocity. Auditory Stroop test performance was measured as response accuracy and latency. RESULTS: Significant decreases in oxygen saturation and PETO2, and increased heart rate were observed between normoxia and normobaric hypoxia (P < 0.0001). Total path length was higher at 0.13 compared to 0.21 FIO2 for the eyes closed no Stoop test condition (P = 0.0197). No other significant differences were observed. CONCLUSION: These findings suggest that acute normobaric hypoxia has a minimal impact on standing balance and does not influence auditory Stroop test or dual-task performance. Further investigation with longer exposure is required to understand the impact and time course of normobaric hypoxia on standing balance.

Cerebellar Brain Inhibition Is Associated With the Severity of Cervical Dystonia.

PURPOSE: Cerebellar connectivity is thought to be abnormal in cervical dystonia (CD) and other dystonia subtypes, based on evidence from imaging studies and animal work. The authors investigated whether transcranial magnetic stimulation-induced cerebellar brain inhibition (CBI), a measure of cerebellar efficiency at inhibiting motor outflow, is abnormal in patients with CD and/or is associated with clinical features of CD. Because of methodological heterogeneity in CBI reporting, the authors deployed additional controls to reduce potential sources of variability in this study. METHODS: Cerebellar brain inhibition was applied in 20 CD patients and 14 healthy control subjects. Cerebellar brain inhibition consisted of a cerebellar conditioning stimulus delivered at four different interstimulus intervals (ISIs) before a test stimulus delivered to hand muscle representation in the motor cortex. The average ratio of conditioned to unconditioned motor evoked potential was computed for each ISI. Cervical dystonia clinical severity was measured using the Toronto Western Spasmodic Torticollis Rating Scale. Control experiments involved neuronavigated transcranial magnetic stimulation, neck postural control in patients, and careful screening for noncerebellar pathway inhibition via cervicomedullary evoked potentials. RESULTS: There was no difference between CBI measured in healthy control subjects and CD patients at any of the four ISIs; however, CBI efficiency was significantly correlated with worsening CD clinical severity at the 5 ms ISI. CONCLUSIONS: Cerebellar brain inhibition is a variable measure in both healthy control subjects and CD patients; much of this variability may be attributed to experimental methodology. Yet, CD severity is significantly associated with reduced CBI at the 5 ms ISI, suggestive of cerebello-thalamo-cortical tract dysfunction in this disorder.

Cerebrovascular and blood pressure responses during voluntary apneas are larger than rebreathing.

Both voluntary rebreathing (RB) of expired air and voluntary apneas (VA) elicit changes in arterial carbon dioxide and oxygen (CO2 and O2) chemostimuli. These chemostimuli elicit synergistic increases in cerebral blood flow (CBF) and sympathetic nervous system activation, with the latter increasing systemic blood pressure. The extent that simultaneous and inverse changes in arterial CO2 and O2 and associated increases in blood pressure affect the CBF responses during RB versus VAs are unclear. We instrumented 21 healthy participants with a finometer (beat-by-beat mean arterial blood pressure; MAP), transcranial Doppler ultrasound (middle and posterior cerebral artery velocity; MCAv, PCAv) and a mouthpiece with sample line attached to a dual gas analyzer to assess pressure of end-tidal (PET)CO2 and PETO2. Participants performed two protocols: RB and a maximal end-inspiratory VA. A second-by-second stimulus index (SI) was calculated as PETCO2/PETO2 during RB. For VA, where PETCO2 and PETO2 could not be measured throughout, SI values were calculated using interpolated end-tidal gas values before and at the end of the apneas. MAP reactivity (MAPR) was calculated as the slope of the MAP/SI, and cerebrovascular reactivity (CVR) was calculated as the slope of MCAv or PCAv/SI. We found that compared to RB, VA elicited ~ fourfold increases in MAPR slope (P < 0.001), translating to larger anterior and posterior CVR (P ≤ 0.01). However, cerebrovascular conductance (MCAv or PCAv/MAP) was unchanged between interventions (P ≥ 0.2). MAP responses during VAs are larger than those during RB across similar chemostimuli, and differential CVR may be driven by increases in perfusion pressure.

Acute hyperglycemia does not affect central respiratory chemoreflex responsiveness to CO2 in healthy humans.

The central respiratory chemoreceptor complex (CCRC) is comprised of brainstem neurons and surrounding interoceptors, which collectively increase ventilation in response to elevated brainstem tissue CO2/[H+] (i.e., central chemoreflex; CCR). The extent that the CCRC detects/responds to other metabolically related chemostimuli is unknown. We aimed to test the effects of acute oral glucose ingestion on CCR reactivity in heathy human participants (n = 38). We instrumented participants with a pneumotachometer (minute ventilation) and a gas sample line connected to a dual gas analyzer (pressure of end-tidal CO2). Following a baseline (BL) period and capillary blood [glucose] (BG) sample, fasted (F) participants underwent a modified hyperoxic rebreathing test to assess CCR reactivity. Participants then consumed a 75 g standard glucose beverage (glucose loaded; GL). Following 30-min, they underwent a second BL, BG sample and hyperoxic rebreathing test. BG and metabolic rate were higher in GL, confirming the metabolic stimulus. However, the ventilatory recruitment threshold and the CCR responses were unchanged between F and GL states.

Case studies in neuroscience: deep brain stimulation changes upper limb cortical motor maps in dystonia.

Deep brain stimulation of the globus pallidus pars interna (GPi-DBS) is an effective treatment for primary dystonia; however, its therapeutic mechanism is poorly understood. Because improvement is gradual, GPi-DBS treatment likely involves short- and long-term mechanisms. Abnormal plasticity resulting in somatotopic reorganization is involved in the development of dystonia and has been proposed as a possible mechanism for this gradual improvement, yet it has not been directly investigated. We hypothesized that GPi-DBS will lead to progressive changes in the cortical representations (motor maps) of upper limb muscles. Neuronavigated robotic transcranial magnetic stimulation was used to map the cortical representation of five upper limb muscles in six healthy controls and a 45-yr-old female cervical dystonia patient before (Pre) and at four time points (Post5 to Post314), 5 to 314 days after GPi-DBS. Motor map area and volume decreased in all muscles following GPi-DBS, while changes in overlap and center of gravity distance between muscles were variable. Despite these motor map changes, only dystonic tremor improved after a year of DBS; neck position worsened slightly. These preliminary findings suggest that GPi-DBS may reduce the cortical representation and excitability of upper limb muscles in dystonia and that these changes can occur without clinical improvement.NEW & NOTEWORTHY Neuronavigated robotic transcranial magnetic stimulation was used to investigate changes in upper limb muscle representation in a cervical dystonia patient before and at four time points up to 314 days after globus pallidus pars interna deep brain stimulation (GPi-DBS). GPi-DBS altered excitability and motor cortical representation of upper limb muscles; however, these changes were not associated with clinical improvement.

Both 50 and 30 Hz continuous theta burst transcranial magnetic stimulation depresses the cerebellum.

The cerebellum is implicated in the pathophysiology of numerous movement disorders, which makes it an attractive target for noninvasive neurostimulation. Continuous theta burst stimulation (cTBS) can induce long lasting plastic changes in human brain; however, the efficacy of different simulation protocols has not been investigated at the cerebellum. Here, we compare a traditional 50-Hz and a modified 30-Hz cTBS protocols at modulating cerebellar activity in healthy subjects. Seventeen healthy adults participated in two testing sessions where they received either 50-Hz (cTBS50) or 30-Hz (cTBS30) cerebellar cTBS. Cerebellar brain inhibition (CBI), a measure of cerebello-thalamocortical pathway strength, and motor evoked potentials (MEP) were measured in the dominant first dorsal interosseous muscle before and after (up to ~ 40 min) cerebellar cTBS. Both cTBS protocols induced cerebellar depression, indicated by significant reductions in CBI (P < 0.001). No differences were found between protocols (cTBS50 and cTBS30) at any time point (P = 0.983). MEP amplitudes were not significantly different following either cTBS protocol (P = 0.130). The findings show cerebellar excitability to be equally depressed by 50-Hz and 30-Hz cTBS in heathy adults and support future work to explore the efficacy of different cerebellar cTBS protocols in movement disorder patients where cerebellar depression could provide therapeutic benefits.

Cutaneous afferent innervation of the human foot sole: what can we learn from single-unit recordings?

Cutaneous afferents convey exteroceptive information about the interaction of the body with the environment and proprioceptive information about body position and orientation. Four classes of low-threshold mechanoreceptor afferents innervate the foot sole and transmit feedback that facilitates the conscious and reflexive control of standing balance. Experimental manipulation of cutaneous feedback has been shown to alter the control of gait and standing balance. This has led to a growing interest in the design of intervention strategies that enhance cutaneous feedback and improve postural control. The advent of single-unit microneurography has allowed the firing and receptive field characteristics of foot sole cutaneous afferents to be investigated. In this review, we consolidate the available cutaneous afferent microneurographic recordings from the foot sole and provide an analysis of the firing threshold, and receptive field distribution and density of these cutaneous afferents. This work enhances the understanding of the foot sole as a sensory structure and provides a foundation for the continued development of sensory augmentation insoles and other tactile enhancement interventions.

Cutaneous sensitivity in unilateral trans-tibial amputees.

AIM: To examine tactile sensitivity in the leg and foot sole of below-knee amputees (diabetic n = 3, traumatic n = 1), and healthy control subjects (n = 4), and examine the association between sensation and balance. METHOD: Vibration perception threshold (VPT; 3, 40, 250Hz) and monofilaments (MF) were used to examine vibration and light touch sensitivity on the intact limb, residual limb, and homologous locations on controls. A functional reach test was performed to assess functional balance. RESULTS: Tactile sensitivity was lower for diabetic amputee subjects compared to age matched controls for both VPT and MF; which was expected due to presence of diabetic peripheral neuropathy. In contrast, the traumatic amputee participant showed increased sensitivity for VPT at 40Hz and 250Hz vibration in both the intact and residual limbs compared to controls. Amputees with lower tactile sensitivity had shorter reach distances compared to those with higher sensitivity. CONCLUSION: Changes in tactile sensitivity in the residual limb of trans-tibial amputees may have implications for the interaction between the amputee and the prosthetic device. The decreased skin sensitivity observed in the residual limb of subjects with diabetes is of concern as changes in skin sensitivity may be important in 1) identification/prevention of excessive pressure and 2) for functional stability. Interestingly, we saw increased residual limb skin sensitivity in the individual with the traumatic amputation. Although not measured directly in the present study, this increase in tactile sensitivity may be related to cortical reorganisation, which is known to occur following amputation, and would support similar findings observed in upper limb amputees.

The firing characteristics of foot sole cutaneous mechanoreceptor afferents in response to vibration stimuli.

Single unit microneurography was used to record the firing characteristics of the four classes of foot sole cutaneous afferents [fast and slowly adapting type I and II (FAI, FAII, SAI, and SAII)] in response to sinusoidal vibratory stimuli. Frequency (3-250 Hz) and amplitude (0.001-2 mm) combinations were applied to afferent receptive fields through a 6-mm diameter probe. The impulses per cycle, defined as the number of action potentials evoked per vibration sine wave, were measured over 1 s of vibration at each frequency-amplitude combination tested. Afferent entrainment threshold (lowest amplitude at which an afferent could entrain 1:1 to the vibration frequency) and afferent firing threshold (minimum amplitude for which impulses per cycle was greater than zero) were then obtained for each frequency. Increases in vibration frequency are generally associated with decreases in expected impulses per cycle (P < 0.001), but each foot sole afferent class appears uniquely tuned to vibration stimuli. FAII afferents tended to have the lowest entrainment and firing thresholds (P < 0.001 for both); however, these afferents seem to be sensitive across frequency. In contrast to FAII afferents, SAI and SAII afferents tended to demonstrate optimal entrainment to frequencies below 20 Hz and FAI afferents faithfully encoded frequencies between 8 and 60 Hz. Contrary to the selective activation of distinct afferent classes in the hand, application of class-specific frequencies in the foot sole is confounded due to the high sensitivity of FAII afferents. These findings may aid in the development of sensorimotor control models or the design of balance enhancement interventions.NEW & NOTEWORTHY Our work provides a mechanistic look at the capacity of foot sole cutaneous afferents to respond to vibration of varying frequency and amplitude. We found that foot sole afferent classes are uniquely tuned to vibration stimuli; however, unlike in the hand, they cannot be independently activated by class-specific frequencies. Viewing the foot sole as a sensory structure, the present findings may aid in the refinement of sensorimotor control models and design of balance enhancement interventions.

Cutaneous Mechanoreceptor Feedback from the Hand and Foot Can Modulate Muscle Sympathetic Nerve Activity.

Stimulation of high threshold mechanical nociceptors on the skin can modulate efferent sympathetic outflow. Whether low threshold mechanoreceptors from glabrous skin are similarly capable of modulating autonomic outflow is unclear. Therefore, the purpose of this study was to examine the effects of cutaneous afferent feedback from the hand palm and foot sole on efferent muscle sympathetic nerve activity (MSNA). Fifteen healthy young participants (9 male; 25 ± 3 years [range: 22-29]) underwent microneurographic recording of multi-unit MSNA from the right fibular nerve during 2 min of baseline and 2 min of mechanical vibration (150 Hz, 220 µm peak-to-peak) applied to the left hand or foot. Each participant completed three trials of both hand and foot stimulation, each separated by 5 min. MSNA burst frequency decreased similarly during the 2 min of both hand (20.8 ± 8.9 vs. 19.3 ± 8.6 bursts/minute [Δ -8%], p = 0.035) and foot (21.0 ± 8.3 vs. 19.5 ± 8.3 bursts/minute [Δ -8%], p = 0.048) vibration but did not alter normalized mean burst amplitude or area (All p > 0.05). Larger reductions in burst frequency were observed during the first 10 s (onset) of both hand (20.8 ± 8.9 vs. 17.0 ± 10.4 [Δ -25%], p < 0.001) and foot (21.0 ± 8.3 vs. 18.3 ± 9.4 [Δ -16%], p = 0.035) vibration, in parallel with decreases in normalized mean burst amplitude (hand: 0.45 ± 0.06 vs. 0.36 ± 0.14% [Δ -19%], p = 0.03; foot: 0.47 ± 0.07 vs. 0.34 ± 0.19% [Δ -27%], p = 0.02) and normalized mean burst area (hand: 0.42 ± 0.05 vs. 0.32 ± 0.12% [Δ -25%], p = 0.003; foot: 0.47 ± 0.05 vs. 0.34 ± 0.16% [Δ -28%], p = 0.01). These results demonstrate that tactile feedback from the hands and feet can influence efferent sympathetic outflow to skeletal muscle.

Foot sole skin vibration perceptual thresholds are elevated in a standing posture compared to sitting.

Foot sole sensitivity is commonly assessed while individuals are seated or prone; however the primary role of foot sole cutaneous feedback is for the control of upright stance and gait. The aim of this study was to compare vibration perceptual thresholds across the foot sole between sitting and standing postures. Vibration perceptual thresholds were measured in sitting and standing postures in 18 healthy participants (8 male) using a custom vibration device. Two foot sole locations (heels and metatarsals) were tested at four vibration frequencies (3, 15, 40, and 250Hz) selected to target different cutaneous afferent populations. At each frequency, perceptual thresholds across the foot sole were significantly higher in the standing posture compared to the sitting posture; this is indicative of lower sensitivity while standing. In addition, threshold differences between the heels and metatarsals for lower frequency vibratory stimuli were more pronounced while standing, with higher thresholds observed at the heels. Our results demonstrate that standing significantly alters sensitivity across the foot sole. Therefore, conducting perceptual tests at the foot sole during stance could potentially provide more direct information about the ability of cutaneous afferents to signal tactile information in a state where this feedback can contribute to postural control.

Thresholds of cutaneous afferents related to perceptual threshold across the human foot sole.

Perceptual thresholds are known to vary across the foot sole, despite a reported even distribution in cutaneous afferents. Skin mechanical properties have been proposed to account for these differences; however, a direct relationship between foot sole afferent firing, perceptual threshold, and skin mechanical properties has not been previously investigated. Using the technique of microneurography, we recorded the monofilament firing thresholds of cutaneous afferents and associated perceptual thresholds across the foot sole. In addition, receptive field hardness measurements were taken to investigate the influence of skin hardness on these threshold measures. Afferents were identified as fast adapting [FAI (n = 48) or FAII (n = 13)] or slowly adapting [SAI (n = 21) or SAII (n = 20)], and were grouped based on receptive field location (heel, arch, metatarsals, toes). Overall, perceptual thresholds were found to most closely align with firing thresholds of FA afferents. In contrast, SAI and SAII afferent firing thresholds were found to be significantly higher than perceptual thresholds and are not thought to mediate monofilament perceptual threshold across the foot sole. Perceptual thresholds and FAI afferent firing thresholds were significantly lower in the arch compared with other regions, and skin hardness was found to positively correlate with both FAI and FAII afferent firing and perceptual thresholds. These data support a perceptual influence of skin hardness, which is likely the result of elevated FA afferent firing threshold at harder foot sole sites. The close coupling between FA afferent firing and perceptual threshold across foot sole indicates that small changes in FA afferent firing can influence perceptual thresholds.

Thresholds of skin sensitivity are partially influenced by mechanical properties of the skin on the foot sole.

Across the foot sole, there are vibration and monofilament sensory differences despite an alleged even distribution of cutaneous afferents. Mechanical property differences across foot sole sites have been proposed to account for these differences. Vibration (VPT; 3 Hz, 40 Hz, 250 Hz), and monofilament (MF) perception threshold measurements were compared with skin hardness, epidermal thickness, and stretch response across five foot sole locations in young healthy adults (n = 22). Perceptual thresholds were expected to correlate with all mechanical property measurements to help address sensitivity differences between sites. Following this hypothesis, the MedArch was consistently found to be the thinnest and softest site and demonstrated the greatest sensitivity. Conversely, the Heel was found to be the thickest and hardest site, and was relatively insensitive across perceptual tests. Site differences were not observed for epidermal stretch response measures. Despite an apparent trend of elevated sensory threshold at harder and thicker sites, significant correlations between sensitivity measures and skin mechanical properties were not observed. Skin hardness and epidermal thickness appeared to have a negligible influence on VPT and minor influence on MF within this young healthy population. When normalized (% greater or smaller than subject mean) to the subject mean for each variable, significant positive correlations were observed between MF and skin hardness (R(2) = 0.422, P < 0.0001) and epidermal thickness (R(2) = 0.433, P < 0.0001) providing evidence that skin mechanics can influence MF threshold. In young healthy adults, differences in sensitivity are present across the foot sole, but cannot solely be accounted for by differences in the mechanical properties of the skin.

Deficits in foot skin sensation are related to alterations in balance control in chronic low back patients experiencing clinical signs of lumbar nerve root impingement.

Chronic low back pain (LBP) patients with radiculopathy, or sciatica, experience pain, tingling or numbness radiating down their leg due to compression of the lumbar nerve root. The resulting reduction in somatosensory information from the foot sole may contribute to deficits in standing balance control. This work was designed to investigate the relationship between foot skin sensitivity and standing balance control in chronic LBP patients with associated radiculopathy. Patients (n=9) and matched healthy controls (n=9) were recruited to the study, and were tested for balance control in both quiet standing as well as during rapid arm raise perturbation trials on a force plate. Foot skin sensitivity was tested bilaterally for vibratory threshold (3, 40 and 250 Hz) and touch (monofilament) threshold. Results demonstrate that patients had reduced sensitivity to 250 Hz vibration in their affected compared to unaffected foot (at the great toe and heel), as well as compared to controls (at the great toe), but there were no differences with lower frequency vibratory testing or with monofilament testing. While there were no significant between-group differences in balance measures, moderate statistically significant correlations between 250 Hz sensitivity and quiet standing balance parameters were uncovered. Thus, patients demonstrate reduced high-frequency vibratory sensitivity at the foot sole, and correlations with quiet standing balance measures indicate a connection between these foot skin sensitivity deficits and alterations in balance control. Clinically, this identifies high frequency vibration testing as an important measure of skin sensitivity in patients with radiculopathy.

Selective weighting of cutaneous receptor feedback and associated balance impairments following short duration space flight.

The present study investigated the perception of low frequency (3 Hz) vibration on the foot sole and its relationship to standing balance following short duration space flight in nine astronauts. Both 3 Hz vibration perception threshold (VPT) and standing balance measures increased on landing day compared to pre-flight. Contrary to our hypothesis, a positive linear relationship between these measures was not observed; however astronauts with the most sensitive skin (lowest 3 Hz VPT) were found to have the largest sway on landing day. While the change in foot sole sensitivity does not appear to directly relate to standing balance control, an exploratory strategy may be employed by astronauts whose threshold to pressure information is lower. Understanding sensory adaptations and balance control has implications to improve balance control strategies following space flight and in sensory impaired populations on earth.

Selective skin sensitivity changes and sensory reweighting following short-duration space flight.

Skin sensory input from the foot soles is coupled with vestibular input to facilitate body orientation in a gravitational environment. Anecdotal observations suggest that foot sole skin becomes hypersensitive following space flight. The veritable level of skin sensitivity and its impact on postural disequilibrium observed post space flight have not been documented. Skin sensitivity of astronauts (n = 11) was measured as vibration perception at the great toe, fifth metatarsal and heel. Frequencies targeted four classes of receptors: 3 and 25 Hz for slow-adapting (SA) receptors and 60 and 250 Hz for fast-adapting (FA) receptors. Data were collected pre- and post-space flight. We hypothesized that skin sensitivity would increase post-space flight and correlate to balance measures. Decreased skin sensitivity was found on landing day at 3 and 25 Hz on the great toe. Hypersensitivity was found for a subset of astronauts (n = 6) with significantly increased sensitivity to 250 Hz at the heel. This subset displayed a greater reduction in computerized dynamic posturography (CDP) equilibrium (EQ) scores (-54%) on landing vs. non-hypersensitive participants (-11%). Observed hyposensitivity of SA (pressure) receptors may indicate a strategy to reduce pressure input during periods of unloading. Hypersensitivity of FAs coupled with reduced EQ scores may reflect targeted sensory reweighting. Altered gravito-inertial environments reduce vestibular function in balance control which may trigger increased weighting of FAs (that signal foot contact, slips). Understanding modulations to skin sensitivity has translational implications for mitigating postural disequilibrium following space flight and for on-Earth preventative strategies for imbalance in older adults.

Cooling reduces the cutaneous afferent firing response to vibratory stimuli in glabrous skin of the human foot sole.

Skin on the foot sole plays an important role in postural control. Cooling the skin of the foot is often used to induce anesthesia to determine the role of skin in motor and balance control. The effect of cooling on the four classes of mechanoreceptor in the skin is largely unknown, and thus the aim of the present study was to characterize the effects of cooling on individual skin receptors in the foot sole. Such insight will better isolate individual receptor contributions to balance control. Using microneurography, we recorded 39 single nerve afferents innervating mechanoreceptors in the skin of the foot sole in humans. Afferents were identified as fast-adapting (FA) or slowly adapting (SA) type I or II (FA I n = 16, FA II n = 7, SA I n = 6, SA II n = 11). Receptor response to vibration was compared before and after cooling of the receptive field (2-20 min). Overall, firing response was abolished in 30% of all receptors, and this was equally distributed across receptor type (P = 0.69). Longer cooling times were more likely to reduce firing response below 50% of baseline; however, some afferent responses were abolished with shorter cooling times (2-5 min). Skin temperature was not a reliable indicator of the level of receptor activation and often became uncoupled from receptor response levels, suggesting caution in the use of this parameter as an indicator of anesthesia. When cooled, receptors preferentially coded lower frequencies in response to vibration. In response to a sustained indentation, SA receptors responded more like FA receptors, primarily coding "on-off" events.