Sympathetic Nervous System Dysfunction Research Articles

Comparisons of Evoked Skin Vasomotor and Sudomotor Responses to Single Pulse Median Nerve Stimulation

The sensorimotor dysfunction caused by cervical and thoracic spinal cord injury (SCI) is concomitant with sympathetic nervous system dysfunction, evidenced by the high prevalence of orthostatic hypotension and autonomic dysreflexia. Although the International Standards for Neurological Classification of SCI evaluate sensorimotor function both above and below the injury level, there are limited quantitative measures for gauging sympathetic outflow and the extent of dysautonomia resulting from neurological damage. Despite studies on the effects of SCI on electrodermal activity (EDA) and blood pressure (BP), there is a lack of detailed feature comparisons involving EDA, skin vasomotor activity, and BP. Therefore, we investigated the relationship between EDA, skin vasomotor, and BP responses to sympathetic activation via median nerve stimulation in persons with and without SCI. Adults with and without SCI (cohort demographics presented in poster) participated in this study. Lead II electrocardiogram (ECG), pneumogram (P), photoplethysmogram (PPG), and EDA were recorded from either the trunk (ECG, P) or both limbs (PPG, EDA). Beat-by-beat BP was recorded from the middle finger of the left hand (VitalStream, CareTaker Medical). Evoked responses in the above signals were measured surrounding a cathodal electrical pulse (30 mA, 200 μs) delivered to the distal right median nerve 1-2 cm proximal and medial to the radial styloid process either during systole or diastole of the cardiac cycle. There were notable differences between baseline signals before and after the experimental session, along with a consistent reduction of limb temperature (> 2° Celsius). Increases in EDA (greater than two standard deviations from baseline) were found across non-SCI participants following stimulation both during systole and diastole, along with skin vasoconstriction following the onset of EDA modulation (> 50% of trials). Individual differences were noted in evoked responses to stimulation at systole vs. diastole. Furthermore, attenuated responses were observed in individuals with SCI. Stimulation caused no evoked signal response habituation across trials within participants. Additionally, evoked BP changes were not consistent across all individuals with respect to stimulation. Our results show a fixed relationship between evoked skin vasomotor and sudomotor responses to single pulse stimuli across participants and had consistent waveform features. Potential individual effects of stimulation delivered at systole vs. diastole warrant an in-depth analysis of reflex gating of sudomotor and skin vasomotor responses. This would present insight into the population with SCI, where dysfunction could greatly exaggerate reflex gating. 1R01NS131493-01. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Lipid profile, inflammatory biomarkers, endothelial dysfunction, and heart rate variability in adolescents with type 1 diabetes. A case-control study among UAE population

BackgroundType 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the chronic inflammation and cause of endothelial dysfunction (ED). Heart rate variability (HRV) is a marker of sympathetic and parasympathetic autonomic nervous system dysfunction. We investigated the association of lipid profile, inflammatory biomarkers, endothelial dysfunction, and heart rate variability in adolescents with T1DM among UAE population. MethodIn this case-control study we recruited 126 adolescents (13–22 years) from Abu Dhabi, UAE (United Arab Emirates). Demographic, anthropometric, blood and urine samples were collected after an overnight fasting. HRV measurements were determined per Task Force recommendations. Independent t-test or Mann-Whitney U test and Pearson's Chi-squared test were used to compare groups. Adjusted conditional logistic regression model was used to identify the determinants independently associated with T1DM. ResultsThe mean ages in control (n = 47) and patient (n = 79) groups were 17.5 ± 4.6 and 18.6 ± 4.8 years, respectively. A family history of diabetes and waist and hip circumferences significantly differed between the groups (p = 0.030 and 0.010). The patients with T1DM exhibited significantly higher levels of atherogenic markers than control. Endothelial dysfunction biomarkers such as levels of sICAM-1 (p < 0.001), adiponectin (p < 0.001) and 25-hydroxyvitamin D (p < 0.001) were significantly different in the control group compared with those in the T1DM group. There was a significant difference in SDNN intervals, NN50, pNN50, and SD1/SD2 among the two groups. In adjusted analysis, total cholesterol (adjusted Odds Ratio (aOR): 2.78, 95 % CI:1.37–5.64; p = 0.005), LDL (2.66, 95%CI:1.19–5.92; p = 0.017), and triglycerides (5.51, 95%CI:1.57–19.41; p = 0.008) were significantly associated with developing T1DM. The HRV indicators were significantly associated with decrease odds of T1DM after controlling for SBP, BMI, and family history of DM. ConclusionIn this study, adolescents with T1DM showed a significant association with lipid profile, ED, and HRV compared with controls. Thus, an early attention to diabetes control is required to reduce the risk of cardiac autonomic neuropathy leading to various cardiovascular diseases.

Uncovering sympathetic nervous system dysfunction in disorders of consciousness via heart rate variability during head-up tilt test.

Few standardized tools are available for evaluation of disorders of consciousness (DOC). The potential of heart rate variability (HRV) during head-up tilt (HUT) test was investigated as a complementary evaluation tool. Twenty-one DOC patients and 21 healthy participants were enrolled in this study comparing clinical characteristics and HRV time- and frequency-domain outcomes and temporal changes during HUT test. During the 1st-5th min of the HUT, DOC group showed a significant increase and decrease in log low frequency (LF) (p = 0.045) and log normalized high frequency (nHF) (p = 0.02), respectively, compared to the supine position and had lower log normalized LF (nLF) (p = 0.004) and log ratio of low-to-high frequency (LF/HF) (p = 0.001) compared to healthy controls. As the HUT continued from the 6th to the 20th min, DOC group exhibited a significant increase in log LF/HF (16th-20th min) (p < 0.05), along with a decrease in log nHF (6th-10th and 16th-20th min) (p < 0.05) and maintained lower log LF, log nLF, and log LF/HF than controls (p < 0.05). 1st-10th min after returning to the supine position, DOC group demonstrated a significant decrease in log nHF (p < 0.01) and increases in log LF/HF (p < 0.01) and had lower log LF (p < 0.01) and log nLF (p < 0.05) compared to controls. In contrast, the control group exhibited a significant decrease in log nHF (p < 0.05) and increase in log LF/HF (p < 0.05) throughout the entire HUT test. Notably, no significant differences were observed when comparing time-domain outcomes reflecting parasympathetic nervous system between the two groups. HRV during HUT test indicated a delayed and attenuated autonomic response, particularly in the sympathetic nervous system, in DOC patients compared with healthy individuals.

Sympathetic nervous system responses to acute psychosocial stress in male physicians with clinical burnout

BackgroundOccupational burnout has been associated with an increased risk of cardiovascular disease, with sympathetic nervous system (SNS) dysfunction as one explanation. This study examined the effects of burnout on responses of SNS activity measures to acute psychosocial stress in male physicians, a population at risk for burnout. MethodsStudy participants were 60 male physicians, 30 with clinical burnout, assessed with the Maslach Burnout Inventory, and 30 without burnout (controls). All participants underwent the 15-min Trier Social Stress Test. Heart rate, blood pressure, salivary alpha-amylase, and plasma levels of epinephrine (EPI) and norepinephrine were assessed pre-stress, immediately post-stress, and 15 min and 45 min post-stress. ResultsPhysicians with burnout and controls differed in EPI changes over time, controlling for age, job stress and anxiety symptoms (F (3,147) = 5.18, p = .002 for 'Time by Group' interaction; η2p = .096). Burnout was associated with a smaller increase in EPI from pre-stress to immediately post-stress (r(54) = −.40, p = .004). The emotional exhaustion dimension of burnout was a significant driver of this effect. The area under the curve with respect to increase in EPI was also smaller in the burnout group (F (1,49) = 6.06, p = .017, η2p = .110). Group differences were not significant for the other SNS activity measures. ConclusionsBurnout may be linked to dysfunction of the sympathoadrenal medullary (SAM) system, when exposed to acute psychosocial stress. In keeping with the allostatic load concept, an insufficient SAM stress response in burnout could potentially contribute to cardiovascular disease.

ID: 205052 Sympathetic Nerve Blocks for Treating CRPS Type 1 of the Knee After Failed Genicular Blocks

Complex Regional Pain Syndrome (CRPS) is a complicated chronic pain condition defined by continued pain disproportionate to any inciting event with symptoms including allodynia, edema, motor dysfunction, skin color and texture, and temperature changes. CRPS type 1 presents with no peripheral nerve lesion and is often secondary to a sympathetic nervous system dysfunction that contributes to these debilitating symptoms. Sympathetic nerve blocks have remained a mainstay modality in physicians’ treatment plans for CRPS, particularly with limited other therapeutic options available. We present a case report resulting in significant relief due to sympathetic nerve blocks.

Chronic Pain-Associated Cardiovascular Disease: The Role of Sympathetic Nerve Activity.

Chronic pain affects many people world-wide, and this number is continuously increasing. There is a clear link between chronic pain and the development of cardiovascular disease through activation of the sympathetic nervous system. The purpose of this review is to provide evidence from the literature that highlights the direct relationship between sympathetic nervous system dysfunction and chronic pain. We hypothesize that maladaptive changes within a common neural network regulating the sympathetic nervous system and pain perception contribute to sympathetic overactivation and cardiovascular disease in the setting of chronic pain. We review clinical evidence and highlight the basic neurocircuitry linking the sympathetic and nociceptive networks and the overlap between the neural networks controlling the two.

Long‐term neuroprosthetic hemotherapy treats autonomic dysreflexia after spinal cord injury

Disrupted descending supraspinal control results in a hyper‐excitable sympathetic nervous system connectome after spinal cord injury (SCI). A condition termed “autonomic dysreflexia” (AD) results, which is characterized by severe elevations in blood pressure that are life‐threatening. There are no effective therapies for AD. Long‐term epidural stimulation below the level of the SCI can promote functionally‐relevant plasticity of volitional motor circuits, and this paradigm may prevent the hyper‐excitable sympathetic connectome after SCI.Here we studied the potential rehabilitative effect of long‐term epidural stimulation, as well as the mechanisms that are responsible for the development of AD. For this experiment, we compared SCI rats that underwent 30 minutes of epidural stimulation 5x/week for 6 weeks to SCI rats receiving normal care. Long‐term epidural stimulation abrogated AD induced by colorectal distension (p&lt;0.0001; Figure 1). Viral tracing of ascending propriospinal neurons was also performed in these groups. Long‐term epidural stimulation normalized the sympathetic connectome as the axons and synapses were significantly reduced compared to SCI rats (p=0.0021; p=0.0127). We next performed chemogenetic silencing of excitatory and inhibitory interneurons, as well as sympathetic preganglionic neurons, in the lower thoracic spinal segments while experimentally inducing AD. Preliminary data indicate that AD is, at least in part, mediated by excitatory interneuronal connections to sympathetic preganglionic neurons.Long‐term epidural stimulation may be an effective hemotherapy for preventing AD after SCI. This project may provide direction for basic and clinical research to develop treatments for sympathetic nervous system dysfunction after SCI, and thereby improve health and patient quality of life over the long term.

Does quantification of [11C]meta-hydroxyephedrine and [13N]ammonia kinetics improve risk stratification in ischemic cardiomyopathy

BackgroundIn ischemic cardiomyopathy patients, cardiac sympathetic nervous system dysfunction is a predictor of sudden cardiac arrest (SCA). This study compared abnormal innervation and perfusion measured by [11C]meta-hydroxyephedrine (HED) vs [13N]ammonia (NH3), conventional uptake vs parametric tracer analysis, and their SCA risk discrimination. MethodsThis is a sub-study analysis of the prospective PAREPET trial, which followed ischemic cardiomyopathy patients with reduced left ventricular ejection fraction (LVEF ≤ 35%) for events of SCA. Using n = 174 paired dynamic HED and NH3 positron emission tomography (PET) scans, regional defect scores (%LV extent × severity) were calculated using HED and NH3 uptake, as well as HED distribution volume and NH3 myocardial blood flow by kinetic modeling. ResultsDuring 4.1 years follow-up, there were 27 SCA events. HED defects were larger than NH3, especially in the lowest tertile of perfusion abnormality (P < .001). Parametric defects were larger than their respective tracer uptake defects (P < .001). SCA risk discrimination was not significantly improved with parametric or uptake mismatch (AUC = 0.73 or 0.70) compared to HED uptake defect scores (AUC = 0.67). ConclusionQuantification of HED distribution volume and NH3 myocardial blood flow produced larger defects than their respective measures of tracer uptake, but did not lead to improved SCA risk stratification vs HED uptake alone.

Dysmetabolism and Sleep Fragmentation in Obstructive Sleep Apnea Patients Run Independently of High Caffeine Consumption.

Daytime hypersomnolence, the prime feature of obstructive sleep apnea (OSA), frequently leads to high coffee consumption. Nevertheless, some clinicians ask for patients’ caffeine avoidance. Caffeinated drinks are sometimes associated with more severe OSA. However, these effects are not consensual. Here we investigated the effect of caffeine consumption on sleep architecture and apnea/hypopnea index in OSA. Also, the impact of caffeine on variables related with dysmetabolism, dyslipidemia, and sympathetic nervous system (SNS) dysfunction were investigated. A total of 65 patients diagnosed with OSA and 32 without OSA were included after given written informed consent. Polysomnographic studies were performed. Blood was collected to quantify caffeine and its metabolites in plasma and biochemical parameters. 24 h urine samples were collected for catecholamines measurement. Statistical analyses were performed by SPSS: (1) non-parametric Mann-Whitney test to compare variables between controls and OSA; (2) multivariate logistic regression testing the effect of caffeine on sets of variables in the 2 groups; and (3) Spearmans’ correlation between caffeine levels and comorbidities in patients with OSA. As expected OSA development is associated with dyslipidemia, dysmetabolism, SNS dysfunction, and sleep fragmentation. There was also a significant increase in plasma caffeine levels in the OSA group. However, the higher consumption of caffeine by OSA patients do not alter any of these associations. These results showed that there is no apparent rationale for caffeine avoidance in chronic consumers with OSA.

Sympathetic neural responses to sleep disorders and insufficiencies.

Short sleep duration and poor sleep quality are associated with cardiovascular risk, and sympathetic nervous system (SNS) dysfunction appears to be a key contributor. The present review will characterize sympathetic function across several sleep disorders and insufficiencies in humans, including sleep deprivation, insomnia, narcolepsy, and obstructive sleep apnea (OSA). We will focus on direct assessments of sympathetic activation, e.g., plasma norepinephrine and muscle sympathetic nerve activity, but include heart rate variability (HRV) when direct assessments are lacking. The review also highlights sex as a key biological variable. Experimental models of total sleep deprivation and sleep restriction are converging to support several epidemiological studies reporting an association between short sleep duration and hypertension, especially in women. A systemic increase of SNS activity via plasma norepinephrine is present with insomnia and has also been confirmed with direct, regionally specific evidence from microneurographic studies. Narcolepsy is characterized by autonomic dysfunction via both HRV and microneurographic studies but with opposing conclusions regarding SNS activation. Robust sympathoexcitation is well documented in OSA and is related to baroreflex and chemoreflex dysfunction. Treatment of OSA with continuous positive airway pressure results in sympathoinhibition. In summary, sleep disorders and insufficiencies are often characterized by sympathoexcitation and/or sympathetic/baroreflex dysfunction, with several studies suggesting women may be at heightened risk.

Cardiac Sympathetic Positron Emission Tomography Imaging with Meta-[18F]Fluorobenzylguanidine is Sensitive to Uptake-1 in Rats.

Dysfunction of the cardiac sympathetic nervous system contributes to the development of cardiovascular diseases including ischemia, heart failure, and arrhythmias. Molecular imaging probes such as meta-[123I]iodobenzylguanidine have demonstrated the utility of assessing neuronal integrity by targeting norepinephrine transporter (NET, uptake-1). However, current radiotracers can report only on innervation due to suboptimal kinetics and lack sensitivity to NET in rodents, precluding mechanistic studies in these species. The objective of this work was to characterize myocardial sympathetic neuronal uptake mechanisms and kinetics of the positron emission tomography (PET) radiotracer meta-[18F]fluorobenzylguanidine ([18F]mFBG) in rats. Automated synthesis using spirocyclic iodonium(III) ylide radiofluorination produces [18F]mFBG in 24 ± 1% isolated radiochemical yield and 30-95 GBq/μmol molar activity. PET imaging in healthy rats delineated the left ventricle, with monoexponential washout kinetics (kmono = 0.027 ± 0.0026 min-1, Amono = 3.08 ± 0.33 SUV). Ex vivo biodistribution studies revealed tracer retention in the myocardium, while pharmacological treatment with selective NET inhibitor desipramine, nonselective neuronal and extraneuronal uptake-2 inhibitor phenoxybenzamine, and neuronal ablation with neurotoxin 6-hydroxydopamine reduced myocardial retention by 33, 76, and 36%, respectively. Clearance of [18F]mFBG from the myocardium was unaffected by treatment with uptake-1 and uptake-2 inhibitors following peak myocardial activity. These results suggest that myocardial distribution of [18F]mFBG in rats is dependent on both NET and extraneuronal transporters and that limited reuptake to the myocardium occurs. [18F]mFBG may therefore prove useful for imaging intraneuronal dysfunction in small animals.

Autonomic failure in multiple sclerosis, complication or precursor?

Autonomic nervous system abnormalities are being increasingly recognized as an important aspect of multiple sclerosis (MS) on a clinical, neurophysiological and molecular level. Autonomic dysfunction in MS shows a distinctive pattern: the disease activity (manifested with relapses and MRI activity) is associated with sympathetic nervous system dysfunction, while the disease progression (manifested by increasing neurological disability) is associated with parasympathetic nervous system dysfunction, with highest percentages of involvement seen in advanced progressive MS. Furthermore, in MS, not only that autonomic symptoms are present, but may influence the disease course. A recent study has shown that presence of autonomic symptoms increase the risk of the second relapse after the diagnosis of clinically isolated syndrome by 2.7 folds. On the other hand, there is evidence suggesting that multiple sclerosis (MS) starts years before the first clinical presentation, and this period has become known as the MS prodrome. This period can span for more than a decade and the most well characterized symptom of it lies in the spectrum of autonomic nervous system abnormalities. Autonomic symptoms before the diagnosis increase the risk for the first clinical manifestation of MS, and if they are present at the diagnosis of MS, they increase the likelihood of the second relapse. All this data, emphasize the importance of studying ANS involvement in MS.

Melia azedarach Flowers and Their Volatile Components Improved Human Physiological and Psychological Functions

In the present study, we examined the modulatory effects of Melia azedarach Linn flowers on human physiological and psychological behaviors. Inhalation of fresh flowers for 20 min decreased salivary amylase activity. Electroencephalogram analysis exhibit that inhalation of fresh flowers reduced alpha brainwave, while gamma, delta, and theta-brainwaves were increased. Moreover, systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were decreased after inhalation of flowers. Furthermore, inhalation of flowers reduced sympathetic nervous system (SNS) activity and increased parasympathetic nervous system (PSNS) activity. In addition, we extracted volatiles from the flowers by the solid-phase micro-extraction (SPME) method and the chemical composition was determined by mass spectrometry. Fifteen compounds were identified, among them benzaldehyde (68.50 %) and phenylacetaldehyde (22.26 %) were the major compounds. Similarly, inhalation of 0.25 % benzaldehyde or phenylacetaldehyde reduced SBP, DBP, HR, and SNS activity, whereas PSNS was increased. Furthermore, the profile of mood states (POMS) scores support that inhalation of fresh flowers significantly reduced depression, confusion, and tension. Anger, fatigue, and vigor were also decreased. These results suggest that M. azedarach flowers or their major compounds can be novel modulators of SNS dysfunction as well as aromatherapy.

Association between nocturnal activity of the sympathetic nervous system and cognitive dysfunction in obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is associated with repetitive breathing obstructions during sleep. These episodes of hypoxia and associated arousals from sleep induce physiological stress and nocturnal over-activation of the sympathetic nervous system (SNS). One consequence of OSA is impairment in a range of cognitive domains. Previous research into cognitive impairment in OSA have focussed on intermittent hypoxia and disrupted sleep, but not nocturnal over-activation of the SNS. Therefore, we investigated whether nocturnal over-activity of the SNS was associated with cognitive impairments in OSA. The extent of nocturnal SNS activation was estimated from heart rate variability (HRV), pulse wave amplitude (PWA) and stress response biomarkers (cortisol and glucose levels). OSA severity was significantly associated with PWA indices and the HRV low frequency/ high frequency ratio (p < 0.05). Morning blood glucose levels were significantly associated with the duration of a blood oxygen saturation (SaO2) < 90% (p < 0.01). PWA and HRV were significantly associated with the time taken to perform a task involving visuospatial functioning (p < 0.05), but not with impairments in sustained attention, reaction time or autobiographical memory. These results suggest that the visuospatial dysfunction observed in people with OSA is associated with increased nocturnal activity of the SNS.

Energy Expenditure Following Spinal Cord Injury: A Delicate Balance.

Following a spinal cord injury (SCI), neurogenic obesity results from changes in body composition, physical impairment, and endometabolic physiology and when dietary intake exceeds energy expenditure. Given the postinjury reductions in lean body mass, sympathetic nervous system dysfunction, and anabolic deficiencies, energy balance is no longer in balance, and thereby an obesogenic environment is created that instigates cardiometabolic dysfunction. Accurate determination of metabolic rate can prevent excess caloric intake while promoting positive body habitus and mitigating obesity-related comorbidities. Metabolic rate as determined by indirect calorimetry (IC) has not been adopted in routine clinical care for persons with SCI despite several studies indicating its importance. This article reviews current literature on measured and predicted metabolic rate and energy expenditure after SCI and stresses the importance of IC as standard of care for persons with SCI.

Abstract 15867: Flexibility Modifies the Age-related Arterial Stiffness in Women With Systemic Lupus Erythematosus

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune multisystemic disease associated with premature cardiovascular disease morbidity and mortality. Arterial stiffness is an age-dependent powerful cardiovascular risk predictor, which is elevated in SLE. The elasticity of the vascular wall and muscle flexibility are both partially determined by elastin-collagen composition, and whereas cardiorespiratory fitness seems to delay the age-related arterial stiffening in SLE, it might be speculated that flexibility (another component of physical fitness) could reduce the sympathetic nervous system dysfunction observed in patients with SLE and thus reduce arterial stiffness. However, whether higher flexibility is related to lower age-related arterial stiffness in SLE is unknown. Hypothesis: We assessed the hypothesis that flexibilitymay attenuate the negative effect of age on arterial stiffness in women with SLE. Methods: This cross-sectional study included 76 women with SLE (age 43.2, SD 13.8) with mild disease activity. Arterial stiffness was assessed with pulse wave velocity (PWV), flexibility by the back-scratch test, disease activity through SLEDAI, and cumulative organ damage with SDI, blood pressure by standardized methods and menopause status by questionnaire. Quantile regression tested the association of age, flexibility, and their interaction, with PWV (controlling for mean blood pressure, menopause, SLEDAI, SDI and corticosteroids exposure). Sample size was determined for a two-tailed test with a power of 0.8, significance p &lt; 0.05 and effect size &gt; 0.7 (n=34). Results: There was a back-scratchхage interaction effect on PWV ( p &lt;0.001). For women with -20 cm in the back-scratch test (i.e. short to touch her middle fingers behind the back), PWV was 0.107 m/s higher for 1-year increase in age, whereas for women with 15 cm, PVW was 0.064 m/s higher for 1-year increase in age. Conclusion: In conclusion, higher flexibility is associated with a lower increase in age-related arterial stiffness in SLE women. Further research is needed to determine whether improving flexibility through stretching exercises reduces the arterial stiffness associated with aging.

Sympathetic function and markers of inflammation in well-controlled HIV

PurposeHIV-associated autonomic neuropathy (HIV-AN) is common and may be associated with both sympathetic and parasympathetic dysfunction. Sympathetic nervous system (SNS) dysfunction occurs on a continuum of hyper-to hypo-adrenergic function, and may be a mediator between psychological stress and chronic inflammation. We sought to describe patterns of SNS dysfunction in people living with HIV, and to determine whether SNS dysfunction is associated with markers of systemic inflammation (focusing on IL-6 and TNF-α) and pain and anxiety. MethodsForty-seven people with well-controlled HIV and without confounding medical conditions or medications completed the Medical Outcomes Survey (MOS-HIV), quantification of a panel of 41 plasma cytokines/chemokines, and a standardized, non-invasive autonomic reflex screen (ARS). Adrenergic baroreflex sensitivity (BRSA) was calculated from the ARS as a measure of SNS function. ResultsPain (46%) and anxiety (52%) were commonly reported on the MOS-HIV. BRSA was reduced in 30% of participants and elevated in 9% with the latter occurring only in participants with normal to mild HIV-AN. BRSA was significantly associated with IL-6, but not with TNF-α, pain or anxiety. Exploratory analyses also revealed positive associations of BRSA with numerous other cytokines with no significant inverse associations. ConclusionHigher BRSA, indicative of a more hyperadrenergic state, can be part of the spectrum of early HIV-AN, and may be associated with elevations in multiple cytokines including IL-6. These associations do not appear to be driven by stressors such as pain or anxiety.

Retrograde nerve growth factor signaling abnormalities in familial dysautonomia.

Familial dysautonomia (FD) is the most prevalent form of hereditary sensory and autonomic neuropathy (HSAN). In FD, a germline mutation in the Elp1 gene leads to Elp1 protein decrease that causes sympathetic neuron death and sympathetic nervous system dysfunction (dysautonomia). Elp1 is best known as a scaffolding protein within the nuclear hetero-hexameric transcriptional Elongator protein complex, but how it functions in sympathetic neuron survival is very poorly understood. Here, we identified a cytoplasmic function for Elp1 in sympathetic neurons that was essential for retrograde nerve growth factor (NGF) signaling and neuron target tissue innervation and survival. Elp1 was found to bind to internalized TrkA receptors in an NGF-dependent manner, where it was essential for maintaining TrkA receptor phosphorylation (activation) by regulating PTPN6 (Shp1) phosphatase activity within the signaling complex. In the absence of Elp1, Shp1 was hyperactivated, leading to premature TrkA receptor dephosphorylation, which resulted in retrograde signaling failure and neuron death. Inhibiting Shp1 phosphatase activity in the absence of Elp1 rescued NGF-dependent retrograde signaling, and in an animal model of FD it rescued abnormal sympathetic target tissue innervation. These results suggest that regulation of retrograde NGF signaling in sympathetic neurons by Elp1 may explain sympathetic neuron loss and physiologic dysautonomia in patients with FD.

Reliable quantification of myocardial sympathetic innervation and regional denervation using [11C]meta-hydroxyephedrine PET.

Cardiac sympathetic nervous system (SNS) dysfunction is associated with poor prognosis in chronic heart failure patients. This study characterized the reproducibility and repeatability of [11C]meta-hydroxyephedrine (HED) positron emission tomography (PET) quantification of cardiac SNS innervation, regional denervation, and myocardial blood flow (MBF). Dynamic HED PET-CT scans were performed 47 ± 22days apart in 20 patients with stable heart failure and reduced ejection fraction. Three observers, blinded to clinical data, used FlowQuant® to evaluate the test-retest repeatability and inter- and intra-observer reproducibility of HED tracer uptake and clearance rates to measure global (LV-mean) retention index (RI), volume of distribution (VT), and MBF. Values were also compared with and without regional partial-volume correction. Regional denervation was quantified as %LV defect size of values < 75% of the LV-maximum. Test-retest repeatability and observer reproducibility were evaluated using intra-class-correlation (ICC) and Bland-Altman coefficient of repeatability (NPC). Intra- and inter-observer correlations of both VT and RI were excellent (ICC = 0.93-0.99). Observer reproducibility (NPC = 3-13%) was lower than test-retest repeatability (NPC = 12-61%). Both regional (%LV defect size) and global (LV-mean) measures of sympathetic innervation were more repeatable using the simple RI model compared to VT (NPC = 12% vs. 19% and 30% vs. 54%). Using either model, quantification of regional denervation (defect size) was consistently more reliable than the global LV-mean values of RI or VT. Regional partial-volume correction degraded repeatability of both the global and regional VT measures by 2-12%. Test-retest repeatability of MBF estimation was relatively poor (NPC = 30-61%) compared with the RI. Quantitative measures of global and regional SNS innervation were most repeatable using the simple RI method of analysis compared with the more complex VT. Observer variability was significantly lower than the test-retest repeatability using a highly automated analysis program. These results support the use of the simple RI method for reliable analysis of HED PET images in clinical research studies for future evaluation of new therapies and for risk stratification in patients with heart failure.

Sympathetic Nervous System Dysfunction Correlates with Increased Blood Pressure Variability after Acute Stroke (P5.3-004)

Sympathetic Nervous System Dysfunction Correlates with Increased Blood Pressure Variability after Acute Stroke (P5.3-004)