Neuroprosthetic baroreflex controls haemodynamics after spinal cord injury.

Spinal cord injury (SCI) induces haemodynamic instability that threatens survival1-3, impairs neurological recovery4,5, increases the risk of cardiovascular disease6,7, and reduces quality of life8,9. Haemodynamic instability in this context is due to the interruption of supraspinal efferent commands to sympathetic circuits located in the spinal cord10, which prevents the natural baroreflex from controlling these circuits to adjust peripheral vascular resistance. Epidural electrical stimulation (EES) of the spinal cord has been shown to compensate for interrupted supraspinal commands to motor circuits below the injury11, and restored walking after paralysis12. Here, we leveraged these concepts to develop EES protocols that restored haemodynamic stability after SCI. We established a preclinical model that enabled us to dissect the topology and dynamics of the sympathetic circuits, and to understand how EES can engage these circuits. We incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic haemodynamic regulator that operates in a closed loop. This 'neuroprosthetic baroreflex' controlled haemodynamics for extended periods of time in rodents, non-human primates and humans, after both acute and chronic SCI. We will now conduct clinical trials to turn the neuroprosthetic baroreflex into a commonly available therapy for people with SCI.

Common carotid artery responses to the cold-pressor test are impaired in individuals with cervical spinal cord injury.

Cervical spinal cord injury (SCI) leads to autonomic cardiovascular dysfunction that underlies the three- to fourfold elevated risk of cardiovascular disease in this population. Reduced common carotid artery (CCA) dilatory responsiveness during the cold-pressor test (CPT) is associated with greater cardiovascular disease risk and progression. The cardiovascular and CCA responses to the CPT may provide insight into cardiovascular autonomic dysfunction and cardiovascular disease risk in individuals with cervical SCI. Here, we used CPT to perturb the autonomic nervous system in 14 individuals with cervical SCI and 12 uninjured controls, while measuring cardiovascular responses and CCA diameter. The CCA diameter responses were 55% impaired in those with SCI compared with uninjured controls (P = 0.019). The CCA flow, velocity, and shear response to CPT were reduced in SCI by 100% (P < 0.001), 113% (P = 0.001), and 125% (P = 0.002), respectively. The association between mean arterial pressure and CCA dilation observed in uninjured individuals (r = 0.54, P = 0.004) was absent in the SCI group (r = 0.22, P = 0.217). Steady-state systolic blood pressure (P = 0.020), heart rate (P = 0.003), and cardiac contractility (P < 0.001) were reduced in those with cervical SCI, whereas total peripheral resistance was increased compared with uninjured controls (P = 0.042). Relative cerebral blood velocity responses to CPT were increased in the SCI group and reduced in controls (middle cerebral artery, P = 0.010; posterior cerebral artery, P = 0.026). The CCA and cardiovascular responsiveness to CPT are impaired in those with cervical SCI.NEW & NOTEWORTHY This is the first study demonstrating that CCA responses during CPT are suppressed in SCI. Specifically, CCA diameter, flow, velocity, and shear rate were reduced. The relationship between changes in MAP and CCA dilatation in response to CPT was absent in individuals with SCI, despite similar cardiovascular activation between SCI and uninjured controls. These findings support the notion of elevated cardiovascular disease risk in SCI and that the cardiovascular responses to environmental stimuli are impaired.

Acute heat stress reduces biomarkers of endothelial activation but not macro- or microvascular dysfunction in cervical spinal cord injury.

Cardiovascular diseases (CVD) are highly prevalent in spinal cord injury (SCI), and peripheral vascular dysfunction might be a contributing factor. Recent evidence demonstrates that exposure to heat stress can improve vascular function and reduce the risk of CVD in uninjured populations. We therefore aimed to examine the extent of vascular dysfunction in SCI and the acute effects of passive heating. Fifteen participants with cervical SCI and 15 uninjured control (CON) participants underwent ultrasound assessments of vascular function and venous blood sampling for biomarkers of endothelial activation (i.e., CD62e+) and apoptosis (i.e., CD31+/42b-) before and after a 60-min exposure to lower limb hot water immersion (40°C). In SCI, macrovascular endothelial function was reduced in the brachial artery [SCI: 4.8 (3.2)% vs. CON: 7.6 (3.4)%, P = 0.04] but not the femoral artery [SCI: 3.7 (2.6)% vs. CON: 4.0 (2.1)%, P = 0.70]. Microvascular function, via reactive hyperemia, was ~40% lower in SCI versus CON in both the femoral and brachial arteries ( P < 0.01). Circulating concentrations of CD62e+ were elevated in SCI versus CON [SCI: 152 (106) microparticles/µl vs. CON: 58 (24) microparticles/µl, P < 0.05]. In response to heating, macrovascular and microvascular function remained unchanged, whereas increases (+83%) and decreases (-93%) in antegrade and retrograde shear rates, respectively, were associated with heat-induced reductions of CD62e+ concentrations in SCI to levels similar to CON ( P = 0.05). These data highlight the potential of acute heating to provide a safe and practical strategy to improve vascular function in SCI. The chronic effects of controlled heating warrant long-term testing. NEW & NOTEWORTHY Individuals with cervical level spinal cord injury exhibit selectively lower flow-mediated dilation in the brachial but not femoral artery, whereas peak reactive hyperemia was lower in both arteries compared with uninjured controls. After 60 min of lower limb hot water immersion, femoral artery blood flow and shear patterns were acutely improved in both groups. Elevated biomarkers of endothelial activation in the spinal cord injury group decreased with heating, but these biomarkers remained unchanged in controls.

Cerebrovascular function is preserved during mild hyperthermia in cervical spinal cord injury.

STUDY DESIGN: Experimental study. OBJECTIVES: Compromised cerebrovascular function likely contributes to elevated neurological risk in spinal cord injury (SCI). Passive heating offers many cardiovascular and neurological health benefits; therefore, we aimed to determine the effects of an acute bout of heating on cerebrovascular function in chronic SCI. METHODS: Persons with cervical SCI (n = 15) and uninjured controls (CON; n = 15) completed 60 min of lower limb hot water immersion (40 °C). Assessments of middle cerebral (MCA) and posterior cerebral artery (PCA) velocities, pulsatilities, and neurovascular coupling (NVC) were performed using transcranial Doppler ultrasound. Duplex ultrasonography was used to index cerebral blood flow via the internal carotid artery (ICA), and carotid-femoral pulse-wave velocity (PWV) was measured using tonometry. The NVC response was quantified as the peak hyperemic value during 30-s cycles of visual stimulation. RESULTS: Mean arterial pressure changed differentially with heating [mean (standard deviation); SCI: +6(14) mmHg, CON: -8(12) mmHg; P = 0.01]. There were no differences in any intracranial artery measures (all P > 0.05), except for small (~10%) increases in MCA conductance in CON after heating vs. SCI (interaction P = 0.006). Resting ICA flow was greater in SCI vs. CON (P = 0.03) but did not change with heating in either group (interaction P = 0.34). There were also no between-group differences in the NVC response (ΔPCA conductance) pre- [SCI: 29(19)% vs. CON: 30(9)%] or post-heating [SCI 30(9)% vs. 25(9)%; interaction P = 0.22]. CONCLUSIONS: Mild acute heating does not impair or improve cerebrovascular function in SCI or CON. Thus, further study of the effects of chronic heating interventions are warranted.

Wavelet decomposition analysis is a clinically relevant strategy to evaluate cerebrovascular buffering of blood pressure after spinal cord injury.

The capacity of the cerebrovasculature to buffer changes in blood pressure (BP) is crucial to prevent stroke, the incidence of which is three- to fourfold elevated after spinal cord injury (SCI). Disruption of descending sympathetic pathways within the spinal cord due to cervical SCI may result in impaired cerebrovascular buffering. Only linear analyses of cerebrovascular buffering of BP, such as transfer function, have been used in SCI research. This approach does not account for inherent nonlinearity and nonstationarity components of cerebrovascular regulation, often depends on perturbations of BP to increase the statistical power, and does not account for the influence of arterial CO2 tension. Here, we used a nonlinear and nonstationary analysis approach termed wavelet decomposition analysis (WDA), which recently identified novel sympathetic influences on cerebrovascular buffering of BP occurring in the ultra-low-frequency range (ULF; 0.02-0.03Hz). WDA does not require BP perturbations and can account for influences of CO2 tension. Supine resting beat-by-beat BP (Finometer), middle cerebral artery blood velocity (transcranial Doppler), and end-tidal CO2 tension were recorded in cervical SCI ( n = 14) and uninjured ( n = 16) individuals. WDA revealed that cerebral blood flow more closely follows changes in BP in the ULF range ( P = 0.0021, Cohen's d = 0.89), which may be interpreted as an impairment in cerebrovascular buffering of BP. This persisted after accounting for CO2. Transfer function metrics were not different in the ULF range, but phase was reduced at 0.07-0.2 Hz ( P = 0.03, Cohen's d = 0.31). Sympathetically mediated cerebrovascular buffering of BP is impaired after SCI, and WDA is a powerful strategy for evaluating cerebrovascular buffering in clinical populations.

The auditory midbrain mediates tactile vibration sensing.

Vibrations are ubiquitous in nature, shaping behavior across the animal kingdom. For mammals, mechanical vibrations acting on the body are detected by mechanoreceptors of the skin and deep tissues and processed by the somatosensory system, while sound waves traveling through air are captured by the cochlea and encoded in the auditory system. Here, we report that mechanical vibrations detected by the body's Pacinian corpuscle neurons, which are unique in their ability to entrain to high frequency (40-1000 Hz) environmental vibrations, are prominently encoded by neurons in the lateral cortex of the inferior colliculus (LCIC) of the midbrain. Remarkably, most LCIC neurons receive convergent Pacinian and auditory input and respond more strongly to coincident tactile-auditory stimulation than to either modality alone. Moreover, the LCIC is required for behavioral responses to high frequency mechanical vibrations. Thus, environmental vibrations captured by Pacinian corpuscles are encoded in the auditory midbrain to mediate behavior.

Passive leg cycling increases activity of the cardiorespiratory system in people with tetraplegia.

Individuals with cervical spinal cord injury (SCI) are at an increased risk for cardiovascular disease. Exercise is well-established for preventing cardiovascular disease; however, there are limited straightforward and safe exercise approaches for increasing the activity of the cardiorespiratory system after cervical SCI. The objective of this study was to investigate the cardiorespiratory response to passive leg cycling in people with cervical SCI. Beat-by-beat blood pressure, heart rate, and cerebral blood flow were measured before and throughout 10 minutes of cycling in 11 people with SCI. Femoral artery flow-mediated dilation was also assessed before and immediately after passive cycling. Safety was monitored throughout all study visits. Passive cycling elevated systolic blood pressure (5 ± 2 mm Hg), mean arterial pressure (5 ± 3 mm Hg), stroke volume (2.4 ± 0.8 mL), heart rate (2 ± 1 beats/min) and cardiac output (0.3 ± 0.07 L/min; all p < 0.05). Minute ventilation (0.67 ± 0.23 L/min), tidal volume (70 ± 30 mL) and end-tidal PO2 (2.6 ± 1.23 mm Hg) also increased (all p < 0.05). Endothelial function was improved immediately after exercise (1.62 ± 0.13%, p < 0.01). Passive cycling resulted in an incidence of autonomic dysreflexia. Therefore, passive leg cycling increased the activity of the cardiorespiratory system and improved endothelial function, indicating it may be a beneficial exercise intervention for the cardiovascular and respiratory systems in people with cervical SCI. Novelty: Passive leg cycling increases the activity of the cardiorespiratory system and improves markers of cardiovascular health in cervical SCI. Passive leg cycling exercise is an effective, low-cost, practical, alternative exercise modality for people with cervical SCI.

Network analysis identifies consensus physiological measures of neurovascular coupling in humans.

Intimate communication between neural and vascular structures is required to match neuronal metabolism to blood flow, a process termed neurovascular coupling. The number of laboratories assessing neurovascular coupling in humans is increasing due to clinical interest in disease states, and basic science interest in a non-anesthetized, non-craniotomized, unrestrained, in vivo model. However, there is a lack of knowledge regarding how best to characterize the neurovascular response. To address this knowledge gap, we have amassed a highly powered human neurovascular coupling dataset, and deployed a network-based approach to reveal the most powerful and consistent metrics for quantifying neurovascular coupling. Using dimensionality reduction, community-based clustering, and majority-voting of traditional metrics (e.g. peak response, time to peak) and non-traditional metrics (e.g. varying time windows, pulsatility), we have identified which of the existing metrics predominantly characterize the neurovascular coupling response, are stable within and across participants, and explain the vast majority of the variance within our dataset of over 300 trials. We then harnessed our empirical approach to generate powerful novel metrics of neurovascular coupling, termed iAmplitude, iRate, and iPulsatility, which increase sensitivity when capturing population differences. These metrics may be useful to optimally understand neurovascular coupling in health and disease.

Sleep-disordered breathing is associated with brain vascular reactivity in spinal cord injury.

OBJECTIVE: To determine the population-level odds of individuals with spinal cord injury (SCI) experiencing fatigue and sleep apnea, to elucidate relationships with level and severity of injury, and to examine associations with abnormal cerebrovascular responsiveness. METHODS: We used population-level data, meta-analyses, and primary physiologic assessments to provide a large-scale integrated assessment of sleep-related complications after SCI. Population-level and meta-analyses included more than 60,000 able-bodied individuals and more than 1,800 individuals with SCI. Physiologic assessments were completed on a homogenous sample of individuals with cervical SCI and matched controls. We examined the prevalence of (1) self-reported chronic fatigue, (2) clinically identified sleep apnea, and 3) cerebrovascular responsiveness to changing CO2. RESULTS: Logistic regression revealed a 7-fold elevated odds of chronic fatigue after SCI (odds ratio [OR] 7.9, 95% confidence interval [CI] 3.5-16.2), and that fatigue and trouble sleeping are correlated with the level and severity of injury. We further show that those with SCI experience elevated risk of clinically defined sleep-disordered breathing in more than 600 individuals with SCI (pooled OR 3.1, 95% CI 1.3-7.5). We confirmed that individuals with SCI experience a high rate of clinically defined sleep apnea using primary polysomnography assessments. We then provide evidence using syndromic analysis that sleep-disordered breathing is a factor strongly associated with impaired cerebrovascular responsiveness to CO2 in patients with SCI. CONCLUSIONS: Individuals with SCI have an increased prevalence of sleep-disordered breathing, which may partially underpin their increased risk of stroke. There is thus a need to integrate sleep-related breathing examinations into routine care for individuals with SCI.

Spinal Cord Disruption Is Associated with a Loss of Cushing-Like Blood Pressure Interactions.

The capacity of the cerebrovasculature to buffer changes in blood pressure (BP) likely plays an important role in the prevention of stroke, which is three- to fourfold more common after spinal cord injury (SCI). Although the directional relationship between BP and cerebral blood flow (CBF) has traditionally been thought to travel solely from BP to CBF, a Cushing-like mechanism functioning in the inverse direction, in which changes in CBF influence BP, has recently been revealed using Granger causality analysis. Although both CBF buffering of BP and the Cushing-like mechanism are influenced by the sympathetic nervous system, we do not understand the impact of disruption of descending sympathetic pathways within the spinal cord, caused by cervical SCI on these regulatory systems. We hypothesized that people with cervical SCI would have greater BP to CBF transmission, as well as a reduced Cushing-like mechanism. The directional relationships between mean arterial BP (MAP; Finometer® PRO) and middle cerebral artery blood velocity (MCAv; transcranial Doppler) were assessed at rest in 14 cervical SCI subjects and 16 uninjured individuals using Granger causality analysis, while also accounting for end-tidal CO2 tension. Those with SCI exhibited 66% increased forward MAP→MCAv information transmission as compared with the uninjured group (p = 0.0003), indicating reduced cerebrovascular buffering of BP, and did not have a predominant backward Cushing-like MCAv→MAP phenotype. These results indicate that both forward and backward communication between BP and CBF are influenced by SCI, which may be associated with impaired cerebrovascular BP buffering after SCI as well as widespread BP instability.

Is Technology for Orthostatic Hypotension Ready for Primetime?

Spinal cord injury (SCI) often results in the devastating loss of motor, sensory, and autonomic function. After SCI, the interruption of descending sympathoexcitatory pathways disrupts supraspinal control of blood pressure (BP). A common clinical consequence of cardiovascular dysfunction after SCI is orthostatic hypotension (OH), a debilitating condition characterized by rapid profound decreases in BP when assuming an upright posture. OH can result in a diverse array of insidious and pernicious health consequences. Acute effects of OH include decreased cardiac filling, cerebral hypoperfusion, and associated presyncopal symptoms such as lightheadedness and dizziness. Over the long term, repetitive exposure to OH is associated with a drastically increased prevalence of heart attack and stroke, which are leading causes of death in those with SCI. Current recommendations for managing BP after SCI primarily include pharmacologic interventions with prolonged time to effect. Because most episodes of OH occur in less than 3 minutes, this delay in action often renders most pharmacologic interventions ineffective. New innovative technologies such as epidural and transcutaneous spinal cord stimulation are being explored to solve this problem. It might be possible to electrically stimulate sympathetic circuitry caudal to the injury and elicit rapid modulation of BP to manage OH. This review describes autonomic control of the cardiovascular system before injury, resulting cardiovascular consequences after SCI such as OH, and the clinical assessment tools for evaluating autonomic dysfunction after SCI. In addition, current approaches for clinically managing OH are outlined, and new promising interventions are described for managing this condition.

Minocycline Reduces the Severity of Autonomic Dysreflexia after Experimental Spinal Cord Injury.

Spinal cord injury (SCI) is a devastating neurological condition for which there is no effective treatment to restore neurological function. The development of new treatments for those with SCI may be hampered by the insensitivity of clinical tools to assess motor function in humans. Treatments aimed at preserving neuronal function through anti-inflammatory pathways (i.e., neuroprotection) have been a mainstay of pre-clinical SCI research for decades. Minocycline, a clinically available antibiotic agent with anti-inflammatory properties, has demonstrated promising neuroprotective effects in a variety of animal models and improved motor recovery in a Phase-2 human trial. Here, we leveraged our recently developed T3 severe contusion model in the rat to determine the ability of minocycline to preserve descending sympathoexcitatory axons and improve cardiovascular control after SCI. Forty-one male Wistar rats were randomized to either a treatment group (minocycline; n = 20) or a control group (vehicle; n = 21). All rats received a severe T3 contusion. Minocycline (or vehicle) was administered intraperitoneally at one hour post-injury (90 mg/kg), then every 12 h for two weeks (45 mg/kg). Neuroanatomical correlates (lesion area, descending sympathoexcitatory axons) were assessed, in addition to an assessment of cardiovascular control (hemodynamics, autonomic dysreflexia) and motor behavior. Here, we show that minocycline reduces lesion area, increases the number of descending sympathoexctitatory axons traversing the injury site, and ultimately reduces the severity of autonomic dysreflexia. Finally, we show that autonomic dysreflexia is a more sensitive marker of treatment stratification than motor function.

Alarming blood pressure changes during routine bladder emptying in a woman with cervical spinal cord injury.

INTRODUCTION: Many individuals with high-level spinal cord injury (SCI) experience secondary conditions such as autonomic dysreflexia (AD), which is a potentially life-threatening condition comprising transient episodes of hypertension up to 300 mmHg. AD may be accompanied by symptoms and signs such as headache, flushing, and sweating. Delay in AD recognition and management is associated with increased incidence of cardiovascular events and disease. As it is commonly triggered by bladder distension, AD continues to be a major concern for individuals living with SCI, both on a daily basis and in the long-term. CASE PRESENTATION: A 58-year-old woman with C3 AIS B SCI presented with low resting blood pressure (BP) at 100/64 mmHg. She reported frequent episodes of AD that were most commonly attributed to urinary bladder filling. During our testing session, her systolic BP rose to 130 mmHg, at which point her care aide stepped in to utilize the Credé maneuver, which was part of her daily routine for bladder emptying. Application of suprapubic pressure further elevated her systolic BP to 230 mmHg. Throughout the episode of AD, the participant experienced a pounding headache and erythema above the LOI. DISCUSSION: Clinical guidelines for bladder management after SCI recommend avoiding the Credé maneuver due to potential complications such as hernia or bruising. This current case report demonstrates the additional risk of inducing AD and dangerously high BP elevation.