Measuring and Quantifying Sympathetic Control of the Cutaneous Microvasculature
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Climate change is the biggest global health threat of the 21st century and will continue to result in more intense, more frequent, and longer lasting extreme heat events, all of which have dire implications for nearly every aspect of human life. Older adults are particularly vulnerable to heat exposure, and excessive heat-related mortality in aged adults can be partly attributed to the cardiovascular consequences of age-related impairments in thermoregulatory reflex function. In a series of studies, Dr. Jody Greaney’s laboratory has used microneurography to directly record skin sympathetic nervous system activity in conscious aged humans during environmental provocations as a means to examine the efferent arc of the thermoregulatory reflex axis. This presentation will provide a brief overview of the development of the technique of microneurography, with a focus on the unique issues related to its analysis, quantification and interpretation. It will also discuss how this approach, coupled with laser Doppler flowmetry-derived estimates of skin blood flow, has helped to advance our understanding of age-related alterations in thermoregulatory reflex function. Key Topics Include: - Understand the utility of microneurography as a means to measure and quantify skin sympathetic nervous system activity during thermal perturbations in humans - Understand the considerations related to the analysis, quantification, and interpretation of microneurographic recordings of skin sympathetic nervous system activity - Understand the application of these methodological approaches for assessing sympathetic control of microvascular function during whole-body environmental stressors
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Measuring and Quantifying Sympathetic Control of the Cutaneous Microvasculature
- 1. Jody Greaney, PhD Assistant Professor Neurovascular Physiology Laboratory University of Texas at Arlington Measuring and Quantifying Sympathetic Control of the Cutaneous Microvasculature
- 2. Dr. Jody Greaney provides an overview of microneurography to measure skin sympathetic nervous system activity, with a focus on data analysis, interpretation and its application coupled with laser Doppler flowmetry. Measuring and Quantifying Sympathetic Control of the Cutaneous Microvasculature
- 3. InsideScientific is an online educational environment designed for life science researchers. Our goal is to aid in the sharing and distribution of scientific information regarding innovative technologies, protocols, research tools and laboratory services To access webinar content, Q&A reports, FAQ documents, and information on lab workshops, subscribe to our mail list
- 4. Measuring and Quantifying Sympathetic Control of the Cutaneous Microvasculature Jody Greaney, PhD February 24, 2021 InsideScientific / ADInstruments Webinar disclosures: none
- 5. Learning Objectives • Understand the utility of microneurography as a means to measure and quantify skin sympathetic nervous system activity (SSNA) during thermal perturbations in humans. • Understand the considerations related to the analysis, quantification, and interpretation of microneurographic recordings of SSNA. • Understand the application of these methodological approaches for assessing sympathetic control of microvascular function during whole-body environmental stressors in humans.
- 6. Clinical Impact / Significance Global Climate Report – Annual 2020; NOAA National Centers for Environmental Information
- 7. Clinical Impact / Significance Kaiser et al, Am J Public Health, 2007; Kenney et al, Med Sci Sports Exerc, 2014
- 8. Clinical Impact / Significance Rowell LB et al, J Appl Physiol, 1969; Minson et al, J Appl Physiol, 1998; Kenney et al, Med Sci Sports Exerc, 2014
- 9. Thermoregulatory Sympathetic Reflex Axis Greaney and Kenney, J Neurophysiol, 2017
- 10. Methodological Approach to Measuring SNA: (peroneal) microneurography
- 11. Methodological Approach to Measuring SNA: (peroneal) microneurography
- 12. Methodological Approach to Measuring SNA: (peroneal) microneurography
- 13. Methodological Approach to Measuring SSNA: distinguishing muscle SNA • Bursts are short-lasting, pulse synchronous • Bursts occur during spontaneous reductions in blood pressure • Responsiveness to breath- holds, Valsalva maneuver • Lack of response to arousal stimuli • Afferent discharge during percussion over tendons/muscle belly or stretch of muscle Greaney and Kenney, J Neurophysiol, 2017; Charkoudian and Wallin, Compr Physiol, 2014
- 14. Methodological Approach to Measuring SSNA: distinguishing skin SNA • Bursts have variable shapes and longer durations • Bursts display less cardiac rhythmicity • Responsiveness to arousal stimuli, deep inspiratory breaths, and changes in skin temperature • Lack of response to breath- holds or Valsalva maneuver • Afferent discharge during touching/stroking of skin in area of innervation Greaney and Kenney, J Neurophysiol, 2017; Charkoudian and Wallin, Compr Physiol, 2014
- 15. Methodological Approach to Measuring SNA: distinguishing skin SNA from muscle SNA skin SNA muscle SNA bursts: variable shapes, longer durations, less rhythmicity bursts: consistent shape, short- lasting, pulse synchronous Greaney and Kenney, J Neurophysiol, 2017; Charkoudian and Wallin, Compr Physiol, 2014
- 16. Methodological Approach to Measuring SSNA: use of whole-body thermal perturbations
- 17. • Tcore: esophageal probe • Tsk: thermocouples • Sympathetic Outflow (SSNA): microneurography • Thermoeffector Output (CVC): laser Doppler flowmetry • Heart Rate: ECG • Blood Pressure: finometer; automated brachial Methodological Approach to Measuring SSNA: use of whole-body thermal perturbations
- 18. Methodological Approach to Measuring SSNA: use of whole-body thermal perturbations
- 19. Methodological Approach to Measuring SSNA: use of whole-body thermal perturbations
- 20. Methodological Approach to Measuring SSNA: use of whole-body thermal perturbations
- 21. • Impulse activity: vasoconstrictor, sudomotor, & piloerector (vasodilator?) • Anatomical structure: fiber composition • Burst pattern: no apparent rhythmicity, irregular shape & duration Greaney and Kenney, J Neurophysiol, 2017; Charkoudian and Wallin, Compr Physiol, 2014 Analytical Approach to Quantify SSNA: challenges, complexities, and limitations
- 22. Greaney and Kenney, J Neurophysiol, 2017; Barry et al, J Physiol, 2020, Young CN et al, J Physiol, 2009; Charkoudian and Wallin, Compr Physiol, 2014; Low et al, J Appl Physiol, 2011 Analytical Approach to Quantify SSNA: analysis of total integrated SSNA 1. Quantify total integrated SSNA (i.e., sum of total area of all bursts during given time epoch of interest) 2. Normalize to baseline 3. Assess responsiveness to stimulus relative to baseline • mean total SSNA • largest spontaneous burst • mean voltage of quiescent period
- 23. Analytical Approach to Quantify SSNA: ‘mathematical’ analysis of total integrated SSNA • Interval histogram analysis • Power spectral analysis • Wavelet analysis • Autoregressive parametric algorithms Bernjak et al, J Physiol, 2012; Bini et al, J Physiol, 1980; Cui et al, Am J Physiol Heart Circ Physiol, 2006; Delius et al, Acta Physiol Scand; Fatouleh and Macefield, Exp Physiol, 2013
- 24. Experimental Approach: assessing thermoregulatory control of SSNA in aging baseline whole-body cooling Tsk = 34.0°C (thermoneutrality) Tsk = 30.5°C (thermoneutral ity) baseline whole-body heating Tes = ~36.6°C (thermoneutrality) ∆Tes = +1.0°C (thermoneutral ity) 0.0 0.2 0.4 0.6 0.8 1.0 100 300 500 700 D Tes (°C) Total SSNA (% baseline ) * * * * * * * * young older † † † † † † † † † † † † † † † 100 200 300 Tsk (°C) Total SSNA (% baseline ) * * * * * * young older 34.0 33.0 32.0 31.0 † † † † † † † Adapted from Stanhewicz et al J Appl Physiol, 2016, Greaney et al J Physiol, 2015 *p<0.05 vs. young; †p<0.05. vs. “baseline”
- 25. Experimental Approach: assessing sympathetic control of the cutaneous microvasculature Greaney and Kenney, J Neurophysiol 118:2181-93, 2017
- 26. Efferent Sympathetic Outflow: SSNA Experimental Approach: assessing sympathetic control of the cutaneous microvasculature Thermoeffector Responsiveness: reflex vasodilation (CVC) (sweating)
- 27. 0.0 0.2 0.4 0.6 0.8 1.0 100 300 500 700 D Tes (°C) Total SSNA (% baseline ) * * * * * * * * young older † † † † † † † † † † † † † † † 0.0 0.2 0.4 0.6 0.8 1.0 0 10 20 30 40 50 60 D Tes (°C) Cutaneous Vascular Conductance (% max ) * * * * * * * * * * † Adapted from Stanhewicz et al J Appl Physiol, 2016 *p<0.05 vs. young; †p<0.05. vs. “baseline” Experimental Approach: assessing sympathetic control of the cutaneous microvasculature baseline whole-body heating Tes = ~36.6°C (thermoneutrality) ∆Tes = +1.0°C (thermoneutral ity)
- 28. Adapted from Stanhewicz et al J Appl Physiol, 2016 young older 0 500 1000 0 20 40 60 80 D Total SSNA (%baseline) D Cutaneous Vascular Conductance (% max ) 0 500 1000 0 20 40 60 80 D Total SSNA (%baseline) D Cutaneous Vascular Conductance (% max ) Experimental Approach: assessing sympathetic control of the cutaneous microvasculature
- 29. Adapted from Stanhewicz et al J Appl Physiol, 2016 0 200 400 600 0 20 40 60 D Total SSNA (%baseline) D Cutaneous Vascular Conductance (% max ) young older * interpretation: reflex cutaneous vasodilatory sensitivity to whole-body heating- induced increases in SSNA is blunted in older adults *p<0.05 vs. young Experimental Approach: assessing sympathetic control of the cutaneous microvasculature
- 30. Adapted from Stanhewicz et al J Appl Physiol, 2016, Stanhewicz et al Am J Physiol Reg Integr Comp Physiol, 2017, Greaney et al J Physiol, 2019 *p<0.05 vs. young/normal; †p<0.05 vs. “treatment” normal high statin 0.00 0.05 0.10 0.15 0.20 slope (%CVC max / SSNA % baseline ) * † 0 200 400 600 0 20 40 60 D Total SSNA (%baseline) D Cutaneous Vascular Conductance (% max ) young older older+folate * † Experimental Approach: assessing sympathetic control of the cutaneous microvasculature
- 31. Experimental Approach: assessing neural control of body temperature Barry et al J Physiol, 2020 *p<0.05 vs. pre
- 32. Experimental Approach: assessing sympathetic control of thermoregulatory reflex arcs Greaney and Kenney, J Neurophysiol 118:2181-93, 2017
- 33. Learning Objectives • Understand the utility of microneurography as a means to measure and quantify skin sympathetic nervous system activity (SSNA) during thermal perturbations in humans. • Understand the considerations related to the analysis, quantification, and interpretation of microneurographic recordings of SSNA. • Understand the application of these methodological approaches for assessing sympathetic control of microvascular function during whole-body environmental stressors in humans.
- 34. Acknowledgments Funding: ACSM Research Endowment NIH F32 HL120471 NIH R01 AG07004 Collaborators: W. Larry Kenney, PhD Anna Stanhewicz, PhD Lacy Alexander, PhD
- 35. • To learn more and watch the webinar, go to: www.insidescientific.com/webinar/measuring… • Want to learn more? Visit: www.adinstruments.com Thanks for participating!
Notas del editor
- Annual Global Climate report from National Oceanic and Atmospheric Administration In 2020, each monthly temperature for the months of January through November ranked among the four warmest on record for their respective months. the year 2020 secured the rank of second warmest year in the 141-year record, with a global land and ocean surface temperature departure from average of +0.98°C (+1.76°F). This value is only 0.02°C (0.04°F) shy of tying the record high value of +1.00°C (+1.80°F) set in 2016 and only 0.03°C (0.05°F) above the now third warmest year on record set in 2019. The seven warmest years in the 1880–2020 record have all occurred since 2014, while the 10 warmest years have occurred since 2005. The year 2020 marks the 44th consecutive year (since 1977) with global land and ocean temperatures, at least nominally, above the 20th century average. The decadal global land and ocean surface average temperature anomaly for 2011–2020 was the warmest decade on record for the globe, with a surface global temperature of +0.82°C (+1.48°F) above the 20th century average. This surpassed the previous decadal record (2001–2010) value of +0.62°C (+1.12°F). Climate change is the biggest global health threat of the 21st century and will continue to result in more intense, more frequent, and longer lasting extreme heat events, all of which have dire implications for nearly every aspect of human life. https://www.ncdc.noaa.gov/sotc/global/202013
- The relation between heat waves and increased morbidity and mortality is well documented. Study by Kaiser et al reexamined all-cause and cause-specific mortality during the 1995 Chicago heat wave The highest temperature between June 22 and August 10, 1995, was 40° C (104° F) on July 13, 1995 (DOTTED LINE) Total mortality (GREEN) peaked 2 days later, on July 15, 1995, when a total of 439 deaths were recorded The main portion of excess mortality occurred during the week of July 14 through July 20, 1995, when average daily mortality increased to 241 deaths per day/1686/week Of those, 473 deaths, 93.7% were reported with an underlying cardiovascular cause (RED LINE) Older adults, even those without underlying disease, are particularly vulnerable to intense and/or prolonged heat exposure. Relative risk ration = 1.74 for adults >75yrs
- Excessive heat-related mortality in aged adults can be attributed, at least in part, to the cardiovascular consequences of age-related impairments in thermoregulatory reflex function. Classic studies by Rowell et al in 60s/70s. Cardiac output (Q˙c) in some subjects more than doubled from baseline to the limit of thermal tolerance. This dramatic increase in Q˙c was accomplished in the young subjects by an increase in heart rate (HR) and an increase in, or maintenance of, stroke volume (SV), despite a fall in central venous pressure (CVP). In addition, the high skin and core temperatures resulted in a redistribution of blood flow from the splanchnic and renal vascular beds. Using this model to study thermoregulatory control, Rowell (24) determined that total skin blood flow (SkBF) in young men could increase up to 7.6 l/min during maximal passive heat stress. Series of studies by Minson/Kenney characterized age-related alterations in thermoregulatory reflex function. Specifically,Q˙c was significantly lower in the older than in the young men, despite similar increases in skin and core temperatures. A lower SV, most likely due to an attenuated increase in inotropic function during the heat stress, was the primary factor for the lowerQ˙c observed in the older men. Furthermore, the older men redistributed less blood flow from the splanchnic and renal circulations. As a result of these combined attenuated cardiovascular responses, total blood flow directed to the skin was significantly lower in the older men. Given the rapidly aging global population , it is imperative to more fully understand the mechanistic regulation of the integrated neural-cardiovascular response to heat exposure, with the ultimate goal of identifying possible intervention strategies to alleviate the increase in risk incurred by older adults.
- In humans, the thermoregulatory system is governed by multiple interrelated independent neural reflex arcs (Romanovsky, 2018). During whole-body heat exposure, an increase in skin and core tissue temperatures activates peripheral thermoreceptors. The thermal input signal (I) is a weighted function of core (Tc) and mean skin (Tsk) temperatures (i.e., I = α1·Tc + α2·Tsk + b), where the ratio of α1:α2 is ~9:1 for whole body heating and 7:3 for whole body cooling. Signal input is also modified by local skin temperature and rate of change parameters (not shown), as well as nonthermoregulatory inputs. The resultant afferent neural signals are relayed to brainstem regions, primarily the preoptic anterior hypothalamus. The input signal I is compared with a “set point” (I0) in the preoptic area of the hypothalamus (POA), and the error signal (I − I0) determines the output efferent SSNA. Note that set point is conceptual only and not an actual temperature. central integration of this thermosensory input results in an increase in efferent skin sympathetic nervous system activity (SSNA). SSNA determines the onset and gain characteristics of the skin thermoregulatory effector organs, controlling vasoconstriction and piloerection in the cold and vasodilation and sweating in the heat. DRG, dorsal root ganglion; IML, intermediolateral nucleus; RMR, rostral medullary raphe.
- Vaughn Macefiled / Jackie Limberg microneurography could be used as a tool to directly measure neural activity from unmyelinated nerve fibers, including efferent postganglionic sympathetic nerves. In microneurography, as applied to awake humans, a tungsten microelectrode, typically with a shaft diameter of 200 μm and a rounded tip of ~5 μm in diameter, is inserted percutaneously in unanesthetized skin and carefully positioned into an underlying peripheral nerve. A second subdermal microelectrode is inserted ~1 cm away from the active recording electrode to serve as a reference electrode. Primarily for practical reasons, the most commonly utilized peripheral nerves are the peroneal, popliteal, radial, median, and ulnar nerves. The electrodes are attached to a grounding unit and preamplifier, with further amplification and filtering occurring in the main amplifier. An analog or digital bandpass filter is applied, and the filtered neural signal is rectified, integrated, and displayed as a mean voltage neurogram. Recently, some investigators have adopted the use of ultrasound-guided microneurography to locate peripheral nerves and to guide the placement of microelectrodes into the nerve, allowing for greater accuracy (Curry and Charkoudian 2011; Gagnon et al. 2016). This adjunct procedure may be especially useful in populations in which locating nerves using conventional microneurography is more challenging (e.g., obese individuals). However, it is important to note that the ability to use ultrasound as an aid to find the peripheral nerve does not replace the need for basic training in the microneurographic technique itself. The Nerve Traffic Analyzer from Iowa Bioengineering (Solon, IA; formerly Iowa Biosystems) and the NeuroAmp EX from AD Instruments (New South Wales, Australia) are two widely used systems. Of these, only the NeuroAmp is currently commercially available.
- Multiunit sympathetic activity occurs as “bursts” of impulses separated by silent periods of varying duration. several distinct anatomical features make microneurographic recordings from the aforementioned peripheral nerves possible (Charkoudian and Wallin 2014; Delius et al. 1972a; Vallbo et al. 2004). 1: peripheral nerves contain several fascicles surrounded by a layer of connective tissue (perineurium), which largely prevents crosstalk between adjacent fascicles. 2: with some exceptions, notably the fascicle innervating the extensor halluces longus, all nerve fibers in a fascicle are directed to the same tissue (i.e., muscle or skin), although fascicles may be mixed in more proximal segments of a nerve. 3: sympathetic fibers lie in bundles (Tompkins et al. 2013), restricting the spread of the electrical current. These anatomical distinctions allow for single-unit recordings from one fiber or multiunit recordings from several fibers simultaneously. There are several excellent reviews available that discuss firing properties, methodological considerations, and analysis techniques related to single-unit postganglionic recordings in more detail (Macefield 2013; Macefield et al. 2002). The emphasis herein is on multiunit recordings of efferent SSNA.
- Depending on whether the active recording microelectrode is positioned into a muscle or skin nerve fascicle, the bursts have differing morphologies and temporal patterns and can be elicited by distinct stimuli (Table 1) (Delius et al. 1972a, 1972b). These differential characteristics allow the microneurographer to reliably identify recordings as either efferent MSNA or SSNA Multiunit bursts of MSNA are short lasting and display pulse synchronicity (Fig. 1A). Furthermore, rhythmic MSNA bursts occur during spontaneous reductions in blood pressure (Delius et al. 1972a). Increases in MSNA can be evoked by a breath hold or Valsalva maneuver, but not in response to startle stimuli (Delius et al. 1972a, 1972b; Hagbarth and Vallbo 1968; Vallbo et al. 1979). Verification that the recording is from a muscle fascicle can also be confirmed by stimulating muscle afferents. Nerve discharge during percussion over tendons or the muscle belly, stretch of the muscle by appropriate movements (for example, flexing the foot), and the lack of discharge with light touching of the skin on the foot or leg all verify muscle afferent innervation.
- In contrast, multiunit bursts of SSNA have highly variable shapes and longer durations than MSNA bursts and display less cardiac cycle rhythmicity (Fig. 1B) (Delius et al. 1972b; Fatouleh and Macefield 2013). spontaneous volleys of bursts occurred independently of fluctuations in blood pressure. To further distinguish them from MSNA bursts, marked alterations in SSNA also occur in response to arousal stimuli, deep inspiratory breaths, and changes in skin temperature, but not during breath holds or Valsalva maneuvers (Delius et al. 1972a, 1972b). As with MSNA recordings, afferent SSNA discharges can be elicited and used to confirm a recording. In practice, this is commonly done by light touching or stroking of the skin on the dorsum of the foot or lateral aspect of the lower leg.
- Because neurons innervating muscle and skin traverse the same nerve, it is common to receive interference from one or the other while performing the technique. Recordings of such “mixed” sites are one of the many technical challenges associated with microneurography. Nonetheless, the differing characteristics of MSNA and SSNA recordings and their responsiveness to discrete stimuli not only illustrate that the sympathetic nervous system is highly differentiated but also enable investigations targeting skin-specific reflexes and control mechanisms.
- Variety of methods to passively heat individuals, focus on use of water-perfused suits it has become common to heat individuals by perfusing hot water (typically 45–50°C) through a tube-lined suit worn by the subject, or by covering the individual with a tube-lined blanket. With the aid of a pump, the heated water is circulated through the suit], which elevates and clamps skin temperature to 37 to 40°C and subsequently elevates internal temperature as high as 40°C, although most report increases within the 38 to 39°C range. This uncompensable technique has some of the previously discussed disadvantages of moderately high skin temperature in the areas under the suit. Importantly for purposes of understanding SSNA control of reflex dilation/constriction, these suits permit the evaluation of reflex induced cutaneous blood flow respsonses in areas not covered by the heating source. Other important advantages to this approach are the ability to access just about every region of the body (assuming the employed suit has openings, zippers, etc. to those regions), as well as the ability to rapidly modulate and clamp skin temperature at various temperatures. Being that the water within the suit imparts a thermal gradient but does not directly touch the skin, there are no hydrostatic pressures to induce central fluid displacement.
- Heating: to maximize the increase in Tcore, use an impermeable suit over water perfused suit to prevent evaporation of sweat Baseline SSNA Response to heating…increase in color intensity (freq) and height (burst size) SSNA burst appearance is morphologically different during cold vs. heat stress. At thermoneutrality and during whole body cooling, the predominant vasoconstrictor bursts are wider and have a longer duration (Fig. 4A; unpublished data) (Bini et al. 1980b; Greaney et al. 2015b). In contrast, in a hot environment when skin vasodilation and sweating are evoked, both SSNA burst duration and the interval between bursts are shorter than what is observed in normothermic conditions (Bini et al. 1980b; Gagnon et al. 2016). In our hands, during whole body passive heating (i.e., clamping high skin temperature and increasing core temperature by 1.0°C using a water-perfused suit), bursts of SSNA actually appear morphologically similar to recordings of MSNA (Fig. 4B; unpublished data). This observation is consistent with published original SSNA recordings from multiple laboratory groups that have used whole body heating paradigms (Bini et al. 1980b; Cui et al. 2004, 2013; Gagnon et al. 2016).
- Baseline Toral = 36.6
- Typically, multiunit microneurography recordings are quantified by burst frequency and/or burst size (e.g., burst strength). In contrast to the analysis of MSNA recordings, which is largely standardized (Hart et al. 2017; White et al. 2015), because SSNA bursts occur 1) with no apparent rhythmicity and 2) as bursts of irregular shape and duration, the analysis and quantification of multiunit SSNA present several unique challenges. Given the morphological variability that characterizes SSNA bursts—for example, single wide bursts with multiple peaks commonly occur (Fig. 1B)—quantification of SSNA burst number is difficult. In this regard, when simply counting SSNA burst frequency, one often cannot delineate distinct, nonoverlapping bursts or distinguish whether individual bursts are wide or narrow. Although comparisons of SSNA burst frequency between individuals and between subject groups appear in the literature (Grassi et al. 1998, 2014; Middlekauff et al. 1994; Park et al. 2008; Pozzi et al. 2001), caution should be used in interpreting such findings given the potential for multiple fiber types and the irregular nature of SSNA bursts. This is especially so if only SSNA burst frequency was reported
- To better understand the central mechanisms governing SSNA waveform variability and to glean insights as to whether changes in SSNA occur via an increase in burst amplitude, an increase in burst frequency, or both, investigators have also used histogram and spectral analyses. Power spectral analysis of integrated SSNA revealed both low- and high-frequency oscillatory components in the variability of bursts of SSNA (Cogliati et al. 2000), similar to those observed in MSNA variability; however, this is not a universal finding (Cui et al. 2006). Although power spectral distribution of the integrated signal, and other mathematical approaches such as wavelet analyses (Bernjak et al. 2012), may provide an alternative quantitative assessment of SSNA, these analytical tools have been used in relatively few investigations incorporating SSNA. Because varied mathematical methodologies can be employed (including the use of autoregressive parametric algorithms and the Welch method based on fast-Fourier transform algorithms), results from such analyses are difficult to compare across studies.
- Heating protocol SSNA increases substantially in young, almost immediately SSNA also increases in older, though not evident until higher Tcore; moreover, this response is blunted compared to young throughout heating protocol Cooling protocol - Thereafter, cool water (∼16°C) was perfused through the suit to gradually lower mean Tsk from 34°C to 30.5°C (∼30 min). This cooling stimulus elicits progressive gradual declines in mean Tsk but does not alter core temperature SSNA increases in young, magnitude less than heating Significantly blunted in older; in fact, does not increase above baseline at all
- central integration of this thermosensory input results in an increase in efferent skin sympathetic nervous system activity (SSNA). SSNA determines the onset and gain characteristics of the skin thermoregulatory effector organs, controlling vasoconstriction and piloerection in the cold and vasodilation and sweating in the heat. Alterations in SSNA responsiveness to passive heat stress have functional implications for impaired thermoregulation, especially so for some clinical populations. Increases in skin blood flow and sweating are substantially blunted in apparently healthy older adults during whole body heating (Holowatz and Kenney 2010; Kenney and Fowler 1988; Smith et al. 2013; Stanhewicz et al. 2015). Our laboratory recently completed a series of studies in which we examined the potential for age-related reductions in efferent SSNA responsiveness to contribute to impaired reflex cutaneous vasodilation
- To obtain an index of cutaneous blood flow, red blood cell flux was continuously measured directly on the dorsum of the foot and the lateral calf (each within the region of sympathetic innervation) with a laser Doppler flowmetry probe placed in a local heating unit (moorLab, Temperature Monitor, SHO2; Moor Instruments, Axminster, UK). To specifically isolate reflex mechanisms, the local heater was clamped at 33°C throughout baseline and whole-body heating.
- CVC and SSNA increased during heating in both subject groups; however, these responses were significantly attenuated in older adults
- Figure 2 presents individual regression lines for ΔSSNA and ΔCVC in young (Fig. 2A) and older (Fig. 2B) subjects throughout whole-body heating.
- There was a significant relation between the increase in SSNA and the increase in CVC during whole-body heating in both young (R2 = 0.87, P < 0.05) and older adults (R2 = 0.76, P < 0.05). However, the sensitivity of the reflex vasodilation response to increased SSNA was blunted in older adults, evidenced by a reduction in the mean slope of the linear regression (Fig. 2), in addition to a reduced operating range of responsiveness. In other words, sympathetic transduction to the cutaneous microvasculature during heat stress, estimated from the slope of the linear relation between increases in efferent SSNA and increases in microvascular cutaneous vascular conductance (CVC), is reduced in healthy older adults (Stanhewicz et al., 2016, 2017; Greaney et al., 2019), owing to reductions in both the sensitivity and the range of end-organ thermoeffector responsiveness. Thus healthy aging is characterized not only by a blunted increase in SSNA during heating but also by an impaired vasodilatory response to a given increase in SSNA. These results demonstrate that age-related alterations occur at multiple points along the efferent reflex axis and contribute, in part, to overall attenuations in reflex cutaneous vasodilation in healthy older adults exposed to environmental heat stress.
- Hopefully just convined you that healthy older men and women have blunted reflex cutaneous vasodilation, evidenced by decreased sensitivity of the cutaneous active vasodilator system, contributing to a blunted increase in skin blood flow for a given increase in mean body temperature. Mechanistically, this results from both a functional absence of cotransmitter signaling and attenuated nitric oxide (NO)-dependent vasodilation. Therefore, the NO pathway is an important molecular target for intervention strategies to increase reflex vasodilation in the aged cutaneous vasculature (23, 43a, 45). To this end, we recently demonstrated that high-dose folic acid supplementation increases thermoregulatory skin blood flow in healthy older adults through augmented NO-dependent mechanisms in the cutaneous vascular endothelium (44). In a follow up study, we examined sympathetic-cholinergic vascular sensitivity and neurovascular coupling during heat stress following 6-wk placebo (gray) and folic acid supplementation (5 mg) in 14 older adults folic acid had no effect on central sympathetic outflow as measured by SSNA responses to hyperthermia BUT increased the slope of the SSNA-to-CVC relation, suggesting an increased vasodilator sensitivity to efferent SSNA and augmenting reflex skin blood flow in healthy older adults Expanded this line of research to clinical populations. Cross section study, same protocol/research questions in normal cholesterolemia (LDL <130), high cholesterol (LDL>160), or current treatment with a statin and LDL <130)
- Mean body temperature onset thresholds (upper) and thermosensitivity (lower) of skin sympathetic nerve activity (SSNA, left), cutaneous vascular conductance (CVC, middle) and local sweat rate (LSR, right) during passive heating performed before (PRE) and after (POST) 7 consecutive days of heat exposure. The present study demonstrates that heat acclimation improves the neural control of body temperature in humans. This is demonstrated by a reduced mean body temperature onset threshold for the activation of skin sympathetic nerve activity that led to an earlier activation of heat loss thermoeffectors during passive heating following 7 consecutive days of heat exposure. By contrast, the thermosensitivity of skin sympathetic nerve activity and thermoeffector responses remained unchanged following heat acclimation.
- Microneurography, as with all experimental techniques, is not without its limitations. Experiments using microneurography are time-consuming and demanding for both the researcher and the participant. Prolonged periods searching for the nerve type of interest are not uncommon, during which the microneurographer has to make minute manual adjustments to the positioning of the electrode while paying constant attention to visual and auditory cues signaling a successful nerve recording. The microneurography technique does not allow for large movements by the research subject, and even subtle shifts in body position can impact the quality of the nerve recording, making long experiments physically taxing and limiting its utility during whole body perturbations (e.g., exercise). Despite the technical limitations of the technique itself and the challenges related to analyzing and interpreting multiunit SSNA recordings, research over the past three decades has substantially advanced our understanding of autonomic control of the cutaneous circulation. Direct recordings of SSNA in awake humans have arguably been most important in furthering our understanding of thermoregulatory function. Given that sympathetic activity directed to the skin largely determines and subserves thermoregulatory control of cutaneous vasomotor tone and sweating, this is perhaps not surprising. However, only recently have investigators applied this technique to further understand impaired reflex cutaneous vascular responsiveness to thermoregulatory challenges in aging and in various pathophysiological conditions, including hypertension (Grassi et al. 2003; Greaney et al. 2015b, 2017; Stanhewicz et al. 2016, 2017). This remains an area of active inquiry. Studies designed to further understand the integration of SSNA with respect to blood pressure regulation in health and in disease are also an important area of current and future research