Photoplethysmography for Quantitative Assessment of Sympathetic Nerve Activity (SNA) During Cold Stress

The differences in the degree of sympathetic nerve activity (SNA) over cutaneous blood vessels, although known to be more prominent in the periphery than the core vasculature, has not been thoroughly investigated quantitatively. Hence, two studies were carried out to investigate the differences in SNA between the periphery and the core during the cold pressor test (CPT) (right-hand immersion in ice water) and cold exposure (whole body exposed to cold air) using photoplethysmography (PPG). Two methods utilizing PPG, namely differential multi-site PTT measurements and low-frequency spectral analysis were explored for quantitative determination of SNA. Each study involved 12 healthy volunteers, and PPG signals were acquired from the right index finger (RIF), left index finger (LIF) (periphery) and the ear canal (core). During CPT, Pulse Transit Time (PTT) was measured to the respective locations and the mean percentage change in PTT during ice immersion at each location was used as an indicator for the extent of SNA. During cold exposure, the low-frequency spectral analysis was performed on the acquired raw PPGs to extract the power of the sympathetic [low-frequency (LF): 0.04–0.15 Hz] and parasympathetic components [high-frequency (HF): 0.15–0.4 Hz]. The ratio of LF/HF components was then used to quantify the differences in the influence of SNA on the peripheral and core circulation. PTT measured from the EC, and the LIF has dropped by 5 and 7%, respectively during ice immersion. The RIF PTT, on the other hand, has dropped significantly (P < 0.05) by 12%. During the cold exposure, the LF/HF power ratio at the finger has increased to 86.4 during the cold exposure from 19.2 at the baseline (statistically significant P = 0.002). While the ear canal LF/HF ratio has decreased to 1.38 during the cold exposure from 1.62 at baseline (P = 0.781). From these observations, it is evident that differential PTT measurements or low-frequency analysis can be used to quantify SNA. The results also demonstrate the effectiveness of the central auto-regulation during both short and long-term stress stimulus as compared to the periphery

Functional Imaging of Autonomic Regulation: Methods and Key Findings.

Central nervous system processing of autonomic function involves a network of regions throughout the brain which can be visualized and measured with neuroimaging techniques, notably functional magnetic resonance imaging (fMRI). The development of fMRI procedures has both confirmed and extended earlier findings from animal models, and human stroke and lesion studies. Assessments with fMRI can elucidate interactions between different central sites in regulating normal autonomic patterning, and demonstrate how disturbed systems can interact to produce aberrant regulation during autonomic challenges. Understanding autonomic dysfunction in various illnesses reveals mechanisms that potentially lead to interventions in the impairments. The objectives here are to: (1) describe the fMRI neuroimaging methodology for assessment of autonomic neural control, (2) outline the widespread, lateralized distribution of function in autonomic sites in the normal brain which includes structures from the neocortex through the medulla and cerebellum, (3) illustrate the importance of the time course of neural changes when coordinating responses, and how those patterns are impacted in conditions of sleep-disordered breathing, and (4) highlight opportunities for future research studies with emerging methodologies. Methodological considerations specific to autonomic testing include timing of challenges relative to the underlying fMRI signal, spatial resolution sufficient to identify autonomic brainstem nuclei, blood pressure, and blood oxygenation influences on the fMRI signal, and the sustained timing, often measured in minutes of challenge periods and recovery. Key findings include the lateralized nature of autonomic organization, which is reminiscent of asymmetric motor, sensory, and language pathways. Testing brain function during autonomic challenges demonstrate closely-integrated timing of responses in connected brain areas during autonomic challenges, and the involvement with brain regions mediating postural and motoric actions, including respiration, and cardiac output. The study of pathological processes associated with autonomic disruption shows susceptibilities of different brain structures to altered timing of neural function, notably in sleep disordered breathing, such as obstructive sleep apnea and congenital central hypoventilation syndrome. The cerebellum, in particular, serves coordination roles for vestibular stimuli and blood pressure changes, and shows both injury and substantially altered timing of responses to pressor challenges in sleep-disordered breathing conditions. The insights into central autonomic processing provided by neuroimaging have assisted understanding of such regulation, and may lead to new treatment options for conditions with disrupted autonomic function

Effects of acute sympathetic activation on eye temperature using infrared thermography

Using physiological markers to measure sympathetic activation can be used to infer pain and stress in humans. To date, the only methods in humans that reproducibly do this are invasive and poses an undesired risk to participants. Previous work on cattle (Bos taurus) has used infrared thermography to measure the temperature of the lacrimal caruncle region and provides a promise of a novel method for measuring stress and pain non-invasively. The current study attempted to determine if this method could be transferred for use in humans. Sixteen participants were recruited for the study and underwent temporary painful stimuli using validated methods (that have previously been shown to induce sympathetic activity known as the cold pressor test and the muscle chemoreflex). During the trials, measurements included temperature of the lacrimal caruncle, heart rate, mean arterial blood pressure and pulse transit time. Following each trial, blood was drawn to measure concentrations of norepinephrine and epinephrine in the plasma. An enzyme-linked immunosorbent assay was then performed to attempt to quantify the catecholamine concentrations, however, the standards of the concentrations were not reliably determined so these results were excluded from the study. A two-way repeated measures analysis of variance was performed with the factors of condition and time. A condition x time interaction was observed in heart rate (df= 8, F= 8.020, p<0.01), mean arterial pressure (df= 6 F= 12.6, p<0.01), and pulse transit time (df= 8, F= 2.269, p= 0.03), but not temperature of the lacrimal caruncle. The results of this study suggest that infrared thermography is not a reliable tool to measure sympathetic activation in humans. This study also suggests that changes in blood flow at the lacrimal caruncle region in response to sympathetic activation may be more complicated than previously proposed

Optimizing the neural response to electrical stimulation and exploring new applications of neurostimulation

Electrical stimulation has been successful in treating patients who suffer from neurologic and neuropsychiatric disorders that are resistant to standard treatments. For deep brain stimulation (DBS), its official approved use has been limited to mainly motor disorders, such as Parkinson\u27s disease and essential tremor. Alcohol use disorder, and addictive disorders in general, is a prevalent condition that is difficult to treat long-term. To determine whether DBS can reduce alcohol drinking in animals, voluntary alcohol consumption of alcohol-preferring rats before, during, and after stimulation of the nucleus accumbens shell were compared. Intake levels in the low stimulus intensity group (n=3, 100&mgr;A current) decreased by as much as 43% during stimulation, but the effect did not persist. In the high stimulus intensity group (n=4, 200&mgr;A current), alcohol intake decreased as much as 59%, and the effect was sustained. These results demonstrate the potent, reversible effects of DBS.^ Left vagus nerve stimulation (VNS) is approved for treating epilepsy and depression. However, the standard method of determining stimulus parameters is imprecise, and the patient responses are highly variable. I developed a method of designing custom stimulus waveforms and assessing the nerve response to optimize stimulation selectivity and efficiency. VNS experiments were performed in rats aiming to increase the selectivity of slow nerve fibers while assessing activation efficiency. When producing 50% of maximal activation of slow fibers, customized stimuli were able to activate as low as 12.8% of fast fibers, while the lowest for standard rectangular waveforms was 35.0% (n=4-6 animals). However, the stimulus with the highest selectivity requires 19.6nC of charge per stimulus phase, while the rectangular stimulus required only 13.2nC.^ Right VNS is currently under clinical investigation for preventing sudden unexpected death in epilepsy and for treating heart failure. Activation of the right vagal parasympathetic fibers led to waveform-independent reductions in heart rate, ejection ratio, and stroke volume. Customized stimulus design with response feedback produces reproducible and predictable patterns of nerve activation and physiological effects, which will lead to more consistent patient responses

Assessment and Mechanisms of Autonomic Function in Health and Disease

The autonomic nervous system is a master regulator of homeostasis, and the conviction that autonomic outflow is important on a patient-by-patient, minute-to-minute basis in both health and disease is the motivation for this thesis. The dissertation explores three aims that advance our understanding of the autonomic nervous system by elucidating the molecular mechanisms of autonomic regulation, validating widely used techniques for autonomic assessment, and developing and applying a new method to assess sympathetic vascular control. The first aim of the dissertation was to investigate the role of the Rho kinase pathway as a mediator of the autonomic effects of central angiotensin-II. This study was performed in conscious, chronically instrumented rabbits that received intracerebroventricular infusions of angiotensin-II, angiotensin-II with the specific Rho kinase inhibitor Fasudil, Fasudil alone, or a vehicle control over two weeks. Baseline hemodynamics were assessed daily, and cardiac and global vasomotor sympathetic tone was assessed by the hemodynamic response to autonomic blockers. Angiotensin-II raised blood pressure and cardiac and global vasomotor sympathetic outflow in a Rho-kinase dependent manner. In a separate cohort, renal sympathetic nerve activity was directly recorded and sympathetic baroreflex sensitivity was assessed, providing clear evidence that angiotensin-II increases renal sympathetic nerve activity and impairs baroreflex control thereof via a Rho kinase-dependent mechanism. In summary, the pressor, sympatho-excitatory, and baroreflex dysfunction caused by central angiotensin-II depend on Rho kinase activation. The second aim was to investigate the relationship between measures of pulse rate variability obtained by a chronically implanted arterial pressure telemeter with measures of heart rate variability derived by the standard electrocardiogram and the ability of pulse rate variability to reflect the autonomic contributions of heart rate variability. This study was conducted in conscious rabbits chronically instrumented with epicardial leads and arterial pressure telemeters. The autonomic contribution to pulse rate variability was assessed by pharmacological blockade, and the intrinsic variability of pulse rate was assessed by ventricular pacing. This study showed that pulse rate variability is a generally acceptable surrogate for heart rate variability for time- and frequency-domain measures, but the additional contribution of respiration to and the differing nonlinear properties of pulse rate variability should be considered by investigators. The third aim was to critically test the idea that the renal sympathetic nerves do not participate in the physiological control of renal blood flow. This study was conducted in conscious rabbits that underwent unilateral renal denervation and chronic instrumentation with arterial pressure telemeters and bilateral renal blood flow probes. Using time-varying transfer function analysis, this study showed active, rhythmic vasoconstriction of the renal vasculature with baroreflex properties in normally innervated kidneys, consistent with sympathetic vasomotion, which was absent in denervated kidneys. This refutes the long-held idea that sympathetic control of the renal vasculature is not physiological and has important applications to the burgeoning field of therapeutic renal denervation for cardiovascular disease

Validity of telemetric-derived measures of heart rate variability: a systematic review

Heart rate variability (HRV) is a widely accepted indirect measure of autonomic function with widespread application across many settings. Although traditionally measured from the 'gold standard' criterion electrocardiography (ECG), the development of wireless telemetric heart rate monitors (HRMs) extends the scope of the HRV measurement. However, the validity of telemetric-derived data against the criterion ECG data is unclear. Thus, the purpose of this study was twofold: (a) to systematically review the validity of telemetric HRM devices to detect inter-beat intervals and aberrant beats; and (b) to determine the accuracy of HRV parameters computed from HRM-derived inter-beat interval time series data against criterion ECG-derived data in healthy adults aged 19 to 62 yrs. A systematic review of research evidence was conducted. Four electronic databases were accessed to obtain relevant articles (PubMed, EMBASE, MEDLINE and SPORTDiscus. Articles published in English between 1996 and 2016 were eligible for inclusion. Outcome measures included temporal and power spectral indices (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (1996). The review confirmed that modern HRMs (Polar® V800™ and Polar® RS800CX™) accurately detected inter-beat interval time-series data. The HRV parameters computed from the HRM-derived time series data were interchangeable with the ECG-derived data. The accuracy of the automatic in-built manufacturer error detection and the HRV algorithms were not established. Notwithstanding acknowledged limitations (a single reviewer, language bias, and the restricted selection of HRV parameters), we conclude that the modern Polar® HRMs offer a valid useful alternative to the ECG for the acquisition of inter-beat interval time series data, and the HRV parameters computed from Polar® HRM-derived inter-beat interval time series data accurately reflect ECG-derived HRV metrics, when inter-beat interval data are processed and analyzed using identical protocols, validated algorithms and software, particularly under controlled and stable conditions

Methods and considerations for the analysis and standardization of assessing muscle sympathetic nerve activity in humans.

The technique of microneurography and the assessment of muscle sympathetic nerve activity (MSNA) are used in laboratories throughout the world. The variables used to describe MSNA, and the criteria by which these variables are quantified from the integrated neurogram, vary among studies and laboratories and, therefore, can become confusing to those starting to learn the technique. Therefore, the purpose of this educational review is to discuss guidelines and standards for the assessment of sympathetic nervous activity through the collection and analysis of MSNA. This review will reiterate common practices in the collection of MSNA, but will also introduce considerations for the evaluation and physiological inference using MSNA

Heart rate responses to autonomic challenges in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is accompanied by structural alterations and dysfunction in central autonomic regulatory regions, which may impair dynamic and static cardiovascular regulation, and contribute to other syndrome pathologies. Characterizing cardiovascular responses to autonomic challenges may provide insights into central nervous system impairments, including contributions by sex, since structural alterations are enhanced in OSA females over males. The objective was to assess heart rate responses in OSA versus healthy control subjects to autonomic challenges, and, separately, characterize female and male patterns. We studied 94 subjects, including 37 newly-diagnosed, untreated OSA patients (6 female, age mean ± std: 52.1 ± 8.1 years; 31 male aged 54.3 ± 8.4 years), and 57 healthy control subjects (20 female, 50.5 ± 8.1 years; 37 male, 45.6 ± 9.2 years). We measured instantaneous heart rate with pulse oximetry during cold pressor, hand grip, and Valsalva maneuver challenges. All challenges elicited significant heart rate differences between OSA and control groups during and after challenges (repeated measures ANOVA, p&lt;0.05). In post-hoc analyses, OSA females showed greater impairments than OSA males, which included: for cold pressor, lower initial increase (OSA vs. control: 9.5 vs. 7.3 bpm in females, 7.6 vs. 3.7 bpm in males), OSA delay to initial peak (2.5 s females/0.9 s males), slower mid-challenge rate-of-increase (OSA vs. control: -0.11 vs. 0.09 bpm/s in females, 0.03 vs. 0.06 bpm/s in males); for hand grip, lower initial peak (OSA vs. control: 2.6 vs. 4.6 bpm in females, 5.3 vs. 6.0 bpm in males); for Valsalva maneuver, lower Valsalva ratio (OSA vs. control: 1.14 vs. 1.30 in females, 1.29 vs. 1.34 in males), and OSA delay during phase II (0.68 s females/1.31 s males). Heart rate responses showed lower amplitude, delayed onset, and slower rate changes in OSA patients over healthy controls, and impairments may be more pronounced in females. The dysfunctions may reflect central injury in the syndrome, and suggest autonomic deficiencies that may contribute to further tissue and functional pathologies

Somatosensory stimulation modulates heart rate variability changes induced by isometric handgrip exercise

Functional imaging reveals overlapping forebrain and basal ganglia regions associated with heart rate (HR) and heart rate variability (HRV) regulation. Somatosensory stimulation (STIM) and isometric handgrip (HG) were used to test the hypotheses that a) STIM would modulate HG-induced changes to HR and HRV, and b) HG+STIM would produce different cortical activation relative to HG alone (n=12). During STIM, high-frequency (HF)-HRV increased (p\u3c0.05), whereas HR did not change. During HG, HF-HRV decreased (p\u3c0.01) while HR increased (p\u3c0.001). HG+STIM reversed the HG-induced change in HF-HRV (p\u3c0.01). However, the HR response to HG remained unaffected. HG increased insular activation, while ventral medial prefrontal cortex (vMPFC) activity decreased. HG+STIM produced similar vMPFC deactivation. However, insular activation was no longer evident. These data indicate that somatosensory inputs through STIM can modulate HG-induced changes to HF-HRV. Different insular activations during HG versus HG+STIM suggest afferent signals to the insula may inhibit descending motor signals affecting HF-HRV