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Aims/Introduction Clinical studies show that either heart rate variability (HRV) or electrochemical skin conductance (ESC) alone can serve as a simple and objective method for screening cardiovascular autonomic neuropathy (CAN). We tested the hypothesis that combining these two quantitative approaches can not only reinforce accuracy in CAN screening but also provide a better estimate of CAN severity in patients with type 2 diabetes (T2DM) who had already had CAN in outpatient clinics. Materials and Methods Each patient received a complete battery of cardiovascular autonomic reflex tests (CARTs), with ESC measured by SUDOSCAN, time domain of HRV measured by standard deviation of all normal RR intervals (SDNN) and frequency domain of HRV (low frequency [LF], high frequency [HF], and LF/HF ratio), and peripheral blood studies for vascular risk factors. Severity of CAN was measured by CAN score. Results The 90 T2DM patients included 50 males and 40 females. Those with more severe CAN had lower values in feet ESC (P = 0.023) and SDNN (P

Introduction The clinical characteristics and outcomes of small fiber neuropathy (SFN) in Chinese patients with type 2 diabetes mellitus (T2DM) have not been thoroughly described. In this study, we investigated the metabolic and neurological indexes and the prognosis of patients with T2DM based on skin biopsy. Methods A total of 34 healthy Chinese volunteers were recruited for skin biopsy to establish the reference range of intra-epidermal nerve fiber density (IENFD), and 89 patients with T2DM attending the Nanjing Drum Tower Hospital were evaluated at baseline. Of these 89 patients, 17 with pure SFN and nine with mixed diabetic polyneuropathy (DPN) were reassessed at the end of the follow-up. Results Glycated hemoglobin and postprandial blood glucose levels were lower (P = 0.005 and P = 0.041, respectively) and postprandial C-peptide and insulin levels were higher (P = 0.001 and P = 0.019, respectively) in the pure SFN group than in the mixed DPN group. A partial correlation study showed that there was a negative correlation between IENFD of the distal leg and cardiovascular autonomic reflex test (CART) scores (r = − 0.513, P = 0.001) after adjusting for age and duration of diabetes. Only vitamin B12 level (P = 0.028) and motor nerve conduction velocity (MCV) of the common peroneal nerve (P = 0.045) were increased in the patients with pure SFN at the final visit while MCVs of the common peroneal nerve (P = 0.025) and tibial nerve (P = 0.047) were decreased in the mixed DPN group at the final visit. Conclusion Better islet function and cardiovascular autonomic function were observed in patients with pure SFN compared with mixed DPN. The metabolic and neurological indexes remained relatively stable in the patients with pure SFN during the follow-up. Supplementary Information The online version contains supplementary material available at 10.1007/s13300-021-01111-0.

Introduction: Deeply embedded within the inner ear, the sensory organs of the vestibular system are exquisitely sensitive to the orientation and movement of the head. This information constrains aspects of autonomic reflex control as well as higher-level processes involved in cognition and affect. The anatomical pathways that underline these functional interactions project to many cortical and sub-cortical brain areas, and the question arises as to whether they can be therapeutically harnessed. Areas covered: The body of work reviewed here indicates that the controlled application of galvanic or thermal current to the vestibular end-organs can modulate activity throughout the ascending vestibular network and, under appropriate conditions, reduce motor and non-motor symptoms associated with Parkinson’s disease, a disease of growing prevalence and continued unmet clinical need. Expert opinion: The appeal of vestibular stimulation in Parkinson’s disease is underpinned by its noninvasive nature, favorable safety profile, and capacity for home-based administration. Clinical adoption now rests on the demonstration of cost-effectiveness and on the commercial availability of suitable devices, many of which are only permitted for research use or lack functionality. Dose optimization and mechanisms-of-action studies are also needed, along with a broader awareness amongst physicians of its therapeutic potential.

Cardiovascular autonomic neuropathy (CAN) is a debilitating condition that mainly occurs in long-standing type 2 diabetes patients but can manifest earlier, even before diabetes is diagnosed. CAN is a microvascular complication that results from lesions of the sympathetic and parasympathetic nerve fibers, which innervate the heart and blood vessels and promote alterations in cardiovascular autonomic control. The entire mechanism is still not elucidated, but several aspects of the pathophysiology of CAN have already been described, such as the production of advanced glycation end products, reactive oxygen species, nuclear factor kappa B, and pro-inflammatory cytokines. This microvascular complication is an important risk factor for silent myocardial ischemia, chronic kidney disease, myocardial dysfunction, major cardiovascular events, cardiac arrhythmias, and sudden death. It has also been suggested that, compared to other traditional cardiovascular risk factors, CAN progression may have a greater impact on cardiovascular disease development. However, CAN might be subclinical for several years, and a late diagnosis increases the mortality risk. The duration of the transition period from the subclinical to clinical stage remains unknown, but the progression of CAN is associated with a poor prognosis. Several tests can be used for CAN diagnosis, such as heart rate variability (HRV), cardiovascular autonomic reflex tests, and myocardial scintigraphy. Currently, it has already been described that CAN could be detected even during the subclinical stage through a reduction in HRV, which is a non-invasive test with a lower operating cost. Therefore, considering that diabetes mellitus is a global epidemic and that diabetic neuropathy is the most common chronic complication of diabetes, the early identification and treatment of CAN could be a key point to mitigate the morbidity and mortality associated with this long-lasting condition.

Solitary chemosensory cells and chemosensory cell clusters are distributed in the pharynx and larynx. In the present study, the morphology and reflexogenic function of solitary chemosensory cells and chemosensory cell clusters in the nasal cavity and pharynx were examined using immunofluorescence for GNAT3 and electrophysiology. In the nasal cavity, GNAT3-immunoreactive solitary chemosensory cells were widely distributed in the nasal mucosa, particularly in the cranial region near the nostrils. Solitary chemosensory cells were also observed in the nasopharynx. Solitary chemosensory cells in the nasopharyngeal cavity were barrel like or slender in shape with long lateral processes within the epithelial layer to attach surrounding ciliated epithelial cells. Chemosensory cell clusters containing GNAT3-immunoreactive cells were also detected in the pharynx. GNAT3-immunoreactive cells gathered with SNAP25-immunoreactive cells in chemosensory clusters. GNAT3-immunoreactive chemosensory cells were in close contact with a few SP- or CGRP-immunoreactive nerve endings. In the pharynx, GNAT3-immunoreactive chemosensory cells were also attached to P2X3-immunoreactive nerve endings. Physiologically, the perfusion of 10 mM quinine hydrochloride (QHCl) solution induced ventilatory depression. The QHCl-induced reflex was diminished by bilateral section of the glossopharyngeal nerve, suggesting autonomic reflex were evoked by chemosensory cells in pharynx but not in nasal mucosa. The present results indicate that complex shape of nasopharyngeal solitary chemosensory cells may contribute to intercellular communication, and pharyngeal chemosensory cells may play a role in respiratory depression.

Background Modulating brainstem activity, via electrical vagus nerve stimulation (VNS), influences cognitive functions, including memory. However, controlling for changes in stimulus efficacy during chronic studies, and response variability between subjects, is problematic. Objective/Hypothesis: We hypothesized that recruitment of an autonomic reflex, the Hering-Breuer reflex, would provide robust confirmation of VNS efficacy. We compared this to measurement of electrode resistance over time. We also examined whether VNS modulates contextual memory extinction. Methods Electrodes for VNS and diaphragm electromyography recording were implanted into anesthetized Sprague Dawley rats. When conscious, we measured the electrode resistance as well as the minimum VNS current required to evoke the Hering-Breuer reflex, before, and after, an inhibitory avoidance assay - a two chamber, dark/light model, where the dark compartment was paired with an aversive foot shock. The extinction of this contextual memory was assessed in sham and VNS treated rats, with VNS administered for 30 s at 1.5 times the Hering-Breuer reflex threshold during extinction memory formation. Results Assessment of VNS-evoked Hering-Breuer reflex successfully identified defective electrodes. VNS accelerated extinction memory and decreased multiple physiological metrics of fear expression. We observed an inverse relationship between memory extinction and respiratory rate during the behavioural assay. Additionally, no current - response relationship between VNS and extinction memory formation was established. Conclusion These data demonstrate that reliable, experimental VNS studies can be produced by verifying reflex initiation as a consequence of stimulation. Further, studies could be standardised by indexing stimulator efficacy to initiation of autonomic reflexes.

Objective Orthostatic intolerance (OI) is a common manifestation of autonomic dysfunction. It is characterized by light-headedness and palpitations in the upright position, with relief when supine. It can affect the quality of life. Other symptoms that may accompany OI include headache, fatigue, nausea, palpitations and abdominal pain. The prevalence and characteristics of autonomic symptoms in childhood hypersomnia disorders of childhood has not been examined, and hence were studied. Methods The medical records of children and adolescents with hypersomnia disorders were reviewed. Subjects had been diagnosed with narcolepsy types 1 or 2 (NT1 or NT2), idiopathic hypersomnia (IH) or the KLS, or hypersomnia related to medical conditions, were under 18 years of age at sleep diagnosis, and had been evaluated at our sleep center between 2000 and 2018. Those with comorbidities such as obstructive sleep apnea and major depression were excluded. The medical records were reviewed for symptoms at initial presentation suggestive of autonomic dysfunction, such as orthostatic intolerance, headache, fatigue, nausea, palpitations and abdominal pain. If these symptoms had been recorded, the chart was examined further to determine if an autonomic reflex screen (ARS) battery had been conducted. The ARS battery examines both sympathetic and parasympathetic function. It is composed of a tilt table test, heart rate and blood pressure responses to the Valsalva maneuver and deep breathing, a quantitative sudomotor axon reflex test and beat-to-beat blood pressure measurements during the Valsalva maneuver. Results of the ARS battery were interpreted by an autonomic neurology specialist (WS), who was not otherwise involved in the care of the patients. Medications taken at the time of autonomic testing were recorded. Results There were 89 patients with hypersomnia disorders. Forty six patients had NT1, 17 had NT2, 18 had IH, 1 with KLS, and 7 had hypersomnia associated with medical disorders. Thirty three of 89 subjects (37%) had the symptom of OI at initial presentation, hence had undergone autonomic reflex screen testing. The median age at diagnosis of hypersomnia in the 33 subjects with the OI symptom was 14.5 years (interquartile range 12–16) and similar (14.5 years, interquartile range 11.5–16) in the 56 subjects without OI. In the group with OI, 25/33 had not received medications for treating hypersomnia at the time of autonomic testing. OI was not related to the degree of sleepiness– the mean sleep latency in the subjects with OI was 5.3 ± 2.9 min while in those without OI it was 4.5 ± 3.8 min. The symptom of OI was not more likely to occur in any specific type of hypersomnia. OI however tended to occur predominantly in females – the female: male ratio in the OI subgroup was 2:1 (n = 33) while in the subgroup without OI, it was 1: 2.1 (n = 56; p = 0.0015). Additional symptoms recorded in the OI subgroup included lightheadedness in 25/33, palpitations in 6/33, nausea and vomiting in 4/33, fatigue in 25/33, headache in 15/33 and constipation in 3/33. The symptoms of OI were reproduced during the tilt table test in 17/33 subjects; 5 of these patients had a rise in heart rate consistent with postural orthostatic tachycardia syndrome (POTS). Conclusion In this retrospective sample, one third of children with hypersomnia disorders exhibited the symptom of OI at initial presentation, with female predominance. A smaller subgroup met criteria for POTS. Screening for autonomic symptoms in children with hypersomnia is important because the former seems to be a treatable co-morbidity that impacts the sense of well-being.

Background: Cardiovascular autonomic neuropathy (CAN) is a common complication of type 2 Diabetes mellitus (T2D), and prevalence varies according to the methodology used. CAN should be diagnosed in the subclinical stage when an intensive treatment of T2D could avoid the progression to irreversible phases. Objective: Determine the prevalence of early involvement (EI) of CAN in T2D individuals comparing two methodologies. Methods: This was a cross-sectional study that included 183 T2D individuals who were monitored in a Tertiary centre. The diagnosis of CAN was based on the results of four cardiovascular autonomic reflex tests (CARTs: expiration-inspiration index, Valsalva maneuver, orthostatic test, and changes in blood pressure after standing) and of seven heart rate variability (7HRV) indices (CARTs plus the spectral analysis). The findings were validated in an independent cohort comprised of 562 T2D individuals followed in a Primary care setting. Results: With the use of 7HRV, 30.6% and 77.8% of individuals in the Tertiary and in the Primary centers, respectively, were classified as without CAN; 25.1% and 15.3% as EI and 44.3% and 6.9% as definitive CAN, respectively. The use of CARTs decreased the proportion of individuals without CAN in both centers (7.1% and 47%) and increased the frequency of EI (30.6% and 36.6%) and definitive CAN (62.3% and 16.4%), respectively. The concordance between both evaluated methodologies was weak. Conclusion: Higher proportions of T2D individuals were diagnosed with EI and with definitive CAN with the use of CARTs.

Vagal afferent fibers contact neurons in the nucleus of the solitary tract (NTS) and release glutamate via three distinct release pathways: synchronous, asynchronous, and spontaneous. The presence of TRPV1 in vagal afferents is predictive of activity-dependent asynchronous glutamate release along with temperature-sensitive spontaneous vesicle fusion. However, pharmacological blockade or genetic deletion of TRPV1 does not eliminate the asynchronous profile and only attenuates the temperature-dependent spontaneous release at high temperatures (>40°C), indicating additional temperature-sensitive calcium conductance(s) contributing to these release pathways. The transient receptor potential cation channel melastatin subtype 3 (TRPM3) is a calcium-selective channel that functions as a thermosensor (30–37°C) in somatic primary afferent neurons. We predict that TRPM3 is expressed in vagal afferent neurons and contributes to asynchronous and spontaneous glutamate release pathways. We investigated these hypotheses via measurements on cultured nodose neurons and in brainstem slice preparations containing vagal afferent to NTS synaptic contacts. We found histological and genetic evidence that TRPM3 is highly expressed in vagal afferent neurons. The TRPM3-selective agonist, pregnenolone sulfate, rapidly and reversibly activated the majority (∼70%) of nodose neurons; most of which also contained TRPV1. We confirmed the role of TRPM3 with pharmacological blockade and genetic deletion. In the brain, TRPM3 signaling strongly controlled both basal and temperature-driven spontaneous glutamate release. Surprisingly, genetic deletion of TRPM3 did not alter synchronous or asynchronous glutamate release. These results provide convergent evidence that vagal afferents express functional TRPM3 that serves as an additional temperature-sensitive calcium conductance involved in controlling spontaneous glutamate release onto neurons in the NTS. NEW & NOTEWORTHY Vagal afferent signaling coordinates autonomic reflex function and informs associated behaviors. Thermosensitive transient receptor potential (TRP) channels detect temperature and nociceptive stimuli in somatosensory afferent neurons, however their role in vagal signaling remains less well understood. We report that the TRPM3 ion channel provides a major thermosensitive point of control over vagal signaling and synaptic transmission. We conclude that TRPM3 translates physiological changes in temperature to neurophysiological outputs and can serve as a cellular integrator in vagal afferent signaling.

Bilateral cardiac sympathetic denervation (BCSD) is an effective therapy for ventricular arrhythmias (VAs) in cardiomyopathies (CMPs). After BCSD, residual autonomic nervous system (ANS) function is unknown.The purpose of this study was to assess ANS responses in patients with CMP before and after BCSD as compared with demographically matched healthy controls.Patients with CMP undergoing BCSD and matched healthy controls were recruited. Noninvasive measures-finger cuff beat-to-beat blood pressure (BP), electrocardiography, palmar electrodermal activity (EDA), and finger pulse volume (FPV)-were obtained at rest and during autonomic stressors-posture change, handgrip, and mental stress. Maximal as well as specific responses to stressors were compared.Eighteen patients with CMP (mean age 54 ± 14 years; 16 men, 89%; left ventricular ejection fraction 36% ± 14%) with refractory VAs and 8 matched healthy controls were studied; 9 patients with CMP underwent testing before and after (median 28 days) BCSD, with comparable ongoing medication. Before BCSD, patients with CMP (n = 13) had lower resting systolic BP and FPV than did healthy controls (P.01). Maximal FPV and systolic BP reflex responses, expressed as percent change were similar, while diastolic BP, mean BP, and EDA responses were blunted. After BCSD, resting measurements were unchanged relative to presurgical baseline (n = 9). EDA responses to stressors were abolished, confirming BCSD, while maximal FPV and BP responses were preserved. Diastolic BP, mean BP, and FPV responses to orthostatic challenge pointed toward a better tolerance of active standing after BCSD as compared with before. Responses to other stressors remained unchanged.Patients with CMP and refractory VAs on optimal medical therapy have detectable but blunted adrenergic responses, which are not disrupted by BCSD.

Objective/Subjects To determine the autonomic effects of suboccipital release (SOR) during experimentally induced pain, 16 healthy subjects (eight women, eight men) experienced ischemic (forearm postexercise muscle ischemia [PEMI]) and cold (cold pressor test [CPT]) pain. Design Beat-to-beat heart rate (electrocardiogram), mean arterial blood pressure (finger photoplethysmography), baroreflex sensitivity (transfer function analysis), and pain perception were measured. SOR or a sham (modified yaw; 30 cycles/min) was performed in minute 2 of pain. Results PEMI increased blood pressure by 23 ± 2 and 20 ± 2 mmHg; no differences occurred between SOR or yaw. PEMI modestly elevated heart rate during ischemia, followed by significant reduction from baseline with SOR (–3 ± 2 bpm) and yaw (−4 ± 2 bpm); no differences were observed between treatments. CPT increased blood pressure (SOR = 11 ± 1, yaw = 9 ± 2 mmHg) and heart rate (SOR = 10 ± 2, yaw = 8 ± 3 bpm) before SOR and yaw. Neither treatment nor sham blunted blood pressure increases (SOR = 25 ± 2, yaw = 22 ± 2 mmHg) during CPT; both decreased heart rate (SOR = −3 ± 2, yaw = −2 ± 2 bpm) from baseline. PEMI and CPT caused increased pain without treatment modulation. Following pain and manual intervention, SOR increased baroreflex sensitivity in the 0.15–0.35 Hz range and decreased R-R interval power spectral density in the 0.03–0.5 Hz range compared with yaw. To probe potential mechanisms and interactions between manual treatment and a prototypic analgesic, oral aspirin (967 mg) was given 60 minutes before testing to reduce prostaglandin synthesis. Aspirin slightly attenuated pain but neither altered cardiovascular changes to PEMI nor interacted with SOR or yaw. Conclusions SOR has the capacity to modulate pain-induced autonomic control and regulation.

Introduction Assessment for cardiovascular autonomic neuropathy (CAN) remains difficult in everyday clinical practice. We sought to examine the diagnostic utility of various simple tools for diabetic peripheral neuropathy (DPN) in the detection of CAN in type 2 diabetes mellitus. Methods We examined 153 type 2 diabetes mellitus subjects by various DPN tools (vibration perception threshold, 10 g Semmes-Weinstein monofilament, Ipswich touch test, NC-stat®/DPNCheck, neuropathy disability score) for the detection of CAN. CAN was diagnosed by the standardised cardiovascular autonomic reflex function tests. Results For the diagnosis of CAN, assessment of small nerve fibre function (pinprick sensation, temperature perception) yielded a very high negative predictive value (97%), with high sensitivity (89%) and moderate specificity (73%). The vibration perception threshold was second in diagnostic utility (91% negative predictive value, 62% sensitivity and 75% specificity). Conclusions Based on their high negative predictive value, simple tools for DPN may prove useful to exclude CAN in type 2 diabetes mellitus. These encouraging results merit further evaluation to enable wider screening for CAN.

IntroductionDiabetes is increasing among Greenlandic Inuit; however, the prevalence of cardiovascular autonomic neuropathy (CAN) is yet unknown. The assessment of CAN requires an ability to differentiate between normal and abnormal. The aim was to establish normative reference data of cardiovascular autonomic function in Greenlandic Inuit.Research design and methodsIn this cross-sectional study, cardiovascular autonomic function was evaluated in participants without diabetes during the Greenlandic Population Study 2018 and in the town Qasigiannguit in 2020. Assessment included cardiovascular autonomic reflex tests (CARTs) and power spectral analysis of heart rate variability (HRV). Normative reference limits were estimated by applying piecewise linear quantile regression models at the fifth percentile. Models were adjusted for age and sex.ResultsBased on examinations of 472 participants (61.7% females), normative reference data was established for all outcomes. Mean age was 54 years (SD 13.1). Higher age was inversely associated with all outcomes of CARTs and HRV. A linear fall in cardiovascular autonomic function tended to level off beyond age of 60 or 70 years for supine-to-upright position ratio and low frequency power. However, the number of observations in subjects older than 60 or 70 years was limited, which may have caused a flattening of the curve around that age. No other associations were found.ConclusionsThe general level of the CARTs and HRV for all age groups is notably lower than in previous studies from other nationalities. We speculate that sociodemographic and cultural aspects of the Greenlandic Inuit population including body mass index, smoking, physical activity and alcohol consumption may have affected the cardiovascular autonomic function.

Regular fish consumption, a rich source of long-chain omega-3 (ω-3) docosahexaenoic acid (DHA), modifies cardiac electrophysiology. However, human studies investigating fish oil and cardiac electrophysiology have predominantly supplemented therapeutic (high) doses of fish oil (often ω-3 eicosapentaenoic acid (EPA) rich sources). This study examined whether non-therapeutic doses of DHA-rich fish oil modulate cardiac electrophysiology at rest and during cardiovascular reflex challenges to the same extent, if at all, in young healthy adults.Participants (N = 20) were supplemented (double-blinded) with (2x1g.dayThe baseline O3I (Control: 5.1 ± 1.0; FO: 5.4 ± 0.9;In young healthy adults, dietary achievable doses of ω-3 DHA-rich fish oil exerted a direct slowing effect on resting HR, without compromising the HR response to either dominant sympathetic or parasympathetic modulation.

Cardiac autonomic neuropathy (CAN) is a very common diabetes-related complication that has a major effect on CVD, mortality and morbidity in patients with DM. Careful and timely testing of CAN with easy standard bedside tests in patients with DM 1 and 2 is critically important for early diagnoses and prophylaxes of further CV complications. Aim of the study was to evaluate the CAN characteristics in DM 1 versus DM 2 patients and to identify the relationship between CAN and typical diabetic complications. Materials and methods. A descriptive and comparative cross-sectional study was developed with 75 patients with Diabetes Mellitus (DM 1 — 30 patients, DM 2 — 45 patients) who were hospitalized to the endocrinology department for treatment. All patients were investigated routinely – complains, anamnestic data, objective examination, lab and instrumental examination. For defining of CAN next five classical tests were done (cardiac autonomic reflex testing (CART)): Evaluating of the Resting tachycardia; Heart rate response to deep breathing; Valsalva maneuver; Systolic blood pressure response to standing; Diastolic blood pressure response to sustained handgrip. Results and discussions. Absence of CAN, according to proposed score, was defined in those patients without clinical features of CVD. 46.8% of all patients presented with early and definitive CAN, while the higher prevalence of definitive CAN was diagnosed in DM 2 patients. Severe CAN was confirmed more often in DM 2 patients also. Coexistence of CAN and peripheral neuropathy was higher in patients with DM 1 than in DM 2 patients. Among DM 1 patients with CAN only 11.8% persons had not sensory peripheral neuropathy, while 29.7% DM 2 patients with CAN, were free of sensory peripheral neuropathy. Positive correlations were found between the duration of the DM and manifestations of CAN in patients with DM II, the development of sensory polyneuropathy, retinopathy and CAN in patients with DM I, and this diabetic complication preceded the clinical manifestations of peripheral neuropathy. Thus, the proposed set of diagnostic measures should be obviously and easily used for the timely diagnosis of CAN in diabetic patients, especially in asymptomatic cases, and objectively assessing the effectiveness of the therapy.

Introduction. Diabetic neuropathy is the most wide-spread complication of diabetes mellitus and neuropathy is steadily progressing even with compensation of the underlying disease. The search of the new methods of treatment and diagnosis of neuropathy is required. Diabetic autonomic neuropathy lies in the base of early morbidity and mortality of diabetic patients.We estimated the potential of High-frequency Ultrasonic Dopplerography for diagnosis of autonomic neuropathy. Material and methods. 26 diabetic patients with sensorimotor neuropathy were examined. Microvascular blood flow of finger skin was assessed at rest as well as in functional tests: with cold impact and occlusion (cuff). Cardiac autonomic neuropathy was assessed using several cardiovascular autonomic reflex tests as a gold standard of diagnosis. Diagnostic values of microvascular blood flow test in detecting of cardiac autonomic neuropathy staging were evaluated in comparing with traditional modalities.Results. Cardiac autonomic neuropathy was found for all patients and definite/confirmed staging in 61.5 % cases. Initial parameters of microvascular blood flow velocity were significantly decreased in all patients in comparing with control (Vam= = (1.9±0.22); (1.7±0.51) and (6.7±0.51) sm/s in patients with early cardiac autonomic neuropathy, definite/confirmed staging and control subjects respectively, pConclusions. High-frequency Ultrasonic Dopplerography allowed to separate of cardiac autonomic neuropathy stages. This study is necessary to continue for revealing of all method possibilities.

Background Post-exercise recovery phase is associated with clustering of various cardiovascular events and, therefore, monitoring of cardiac autonomic control via heart rate variability (HRV) during this phase may allow identification of autonomic alterations that are not evident under resting conditions in type 2 diabetes mellitus (T2DM) patients. Purpose To investigate and compare the diagnostic performance of resting and post-exercise HRV for detecting cardiac autonomic neuropathy (CAN) in T2DM patients. Methods Forty-two T2DM patients were categorized as CAN-positive and CAN-negative based on standard cardiovascular autonomic reflex tests (CARTs). Short-term resting and post-exercise HRV after a graded exercise test were evaluated for each participant. Diagnostic performance of both resting and post-exercise HRV measures was computed using standard statistical procedures. Results Diagnostic testing yielded superior diagnostic performance of post-exercise HRV than resting HRV measures. Root mean square of successive differences (RMSSD) between adjacent R-R intervals (p = 0.01), percentage of consecutive N-N intervals that vary by >50 ms (pNN50) (p = 0.03) and total power (TP) (p = 0.01) were significantly better diagnostic indicators of CAN under post-exercise conditions than at rest. Predictive ability of these post-exercise HRV measures for CAN was maintained after adjusting various clinical confounders to cardiac autonomic function. Conclusion Post-exercise HRV measures such as TP, RMSSD and pNN50 were found to be more accurate diagnostic tests for detecting CAN than resting HRV. Hence, monitoring of the HRV measures proposed here during exercise testing protocols may provide important diagnostic information regarding CAN in T2DM.

Autonomic reflex responses are critical in restoring changes to circulatory factors reduced beyond the domain of homeostasis. Intermittent hypoxia triggers repeated activation of chemoreflexes, resulting in baroreflex dysfunction and widespread changes in cellular and neuronal activity regulated by sensory/motor pathways. Hypoglycaemia initiates a rapid neurally-mediated counter-regulatory response. This counter-regulatory response to hypoglycaemia increases plasma adrenaline levels, liver glycogenolysis, and thus blood glucose levels. Context-dependent activation of rostral ventral medullary neurons initiates baroreceptor unloading, peripheral chemoreflex firing and the counter-regulatory response to hypoglycaemia. In this review, we briefly focus on the functional integration between peripheral and medullary pathways comprising the sympathetic baroreflex, chemoreflexes, and the counter-regulatory response to hypoglycaemia.

While diabetes is characterized by hyperglycemia, nutrient metabolic pathways like amino acid and tricarboxylic acid (TCA) cycle are also profoundly perturbed. As glycemic control alone does not prevent complications, we hypothesized that these metabolic disruptions are responsible for the development and progression of diabetic cardiovascular autonomic neuropathy (CAN). We performed standardized cardiovascular autonomic reflex tests and targeted fasting plasma metabolomic analysis of amino acids and TCA cycle intermediates in subjects with type 1 diabetes and healthy control subjects followed for 3 years. Forty-seven participants with type 1 diabetes (60% female and mean ± SD age 35 ± 13 years, diabetes duration 13 ± 7 years, and HbA1c 7.9 ± 1.2%) had lower fumarate levels and higher threonine, serine, proline, asparagine, aspartic acid, phenylalanine, tyrosine, and histidine levels compared with 10 age-matched healthy control subjects. Higher baseline fumarate levels and lower baseline amino acid levels—asparagine and glutamine—correlate with CAN (lower baseline SD of normal R-R interval [SDNN]). Baseline glutamine and ornithine levels also associated with the progression of CAN (lower SDNN at 3 years) and change in SDNN, respectively, after adjustment for baseline HbA1c, blood glucose, BMI, cholesterol, urine microalbumin-to- creatinine ratio, estimated glomerular filtration rate, and years of diabetes. Therefore, significant changes in the anaplerotic flux into the TCA cycle could be the critical defect underlying CAN progression.

The link between cardiac autonomic neuropathy and risk of cardiovascular disease is highlighted as an area in which research is needed. This study was undertaken to evaluate the association between measures of cardiac autonomic function and cardiac vascular function in type 1 diabetes using new and sensitive methods. This was a cross-sectional study in patients with type 1 diabetes, stratified by normoalbuminuria (n = 30) and macroalbuminuria (n = 30), and in healthy control subjects (n = 30). Cardiac autonomic function was evaluated using heart rate variability (HRV) indices, cardiovascular autonomic reflex tests (CARTs), and cardiac 123I-metaiodobenzylguanidine (MIBG) imaging. Cardiac vascular function was assessed as myocardial flow reserve (MFR) measured by cardiac 82Rb-positron emission tomography/computed tomography. The measures of cardiac autonomic function (except low frequency–to–high frequency ratio and the Valsalva test ratio) were positively correlated to MFR in unadjusted analysis. All the HRV indices lost significance after adjustment for age and heart rate. After further adjustment for relevant cardiovascular risk factors, the late heart-to-mediastinum ratio directly measuring the function of adrenergic receptors and sympathetic integrity (from the MIBG scintigraphy) and the 30-to-15 ratio (a CART), remained positively associated with MFR (P ≤ 0.04). Cardiac autonomic dysfunction, including loss of cardiac sympathetic integrity in type 1 diabetes, is associated with and may contribute to impaired myocardial blood flow regulation.

ObjectiveTo describe the natural history of afferent baroreflex failure (ABF) based on systematic review of clinical and laboratory data in patients with a diagnosis of ABF at Mayo Clinic Rochester.MethodsWe performed a retrospective chart review of all patients who underwent standardized autonomic reflex testing between 2000 and 2020 and had confirmation of the diagnosis of ABF by an autonomic disorders specialist. Patients were identified using a data repository of medical records. Variables included demographic, all-cause mortality, medications, ABF manifestations, comorbidities, and laboratory (autonomic testing, blood pressure monitoring, echocardiogram, brain imaging, plasma catecholamines, serum sodium level, and kidney function tests).ResultsA total of 104 patients with ABF were identified. Head and neck radiation was the most common etiology (86.5%), followed by neck surgery (5.8%) and other causes (7.7%). The most common findings were hypertension (87.5%), fluctuating blood pressure (78.8%), orthostatic hypotension (91.3%), syncope (58.6%), headache (22.1%), and tachycardia (20.2%). Patients commonly received antihypertensives (66.3%), pressor agents (41.3%), or a combination of both (19.2%). The median latency from completion of radiation to ABF was longer compared to the latency in the surgery group (p < 0.0001). Comorbidities, including complications from neck radiation, were frequently seen and all-cause mortality was 39.4% over a 20-year period.ConclusionsABF should be suspected in patients with prior head and neck cancer treated by radiation or surgery who present with labile hypertension and orthostatic hypotension. Management may require both antihypertensive and pressor medications. The morbidity and mortality in ABF are high.

Introduction Granulomatosis with polyangiitis (GPA) is a vasculitic process that can cause neurological dysfunction in addition to characteristic sinus and pulmonary manifestations. This case report highlights the spectrum of nervous system manifestations and includes rarely reported autonomic and pituitary involvement. Case report A 62-year-old woman presented with orthostatic intolerance, tachycardia, dry mouth, and temperature sensitivity; subsequent autonomic reflex study demonstrated widespread postganglionic sympathetic sudomotor, cardiovagal, and cardiovascular adrenergic impairment reflective of autonomic neuropathy and overall autonomic failure. Additional progressive symptoms included dysarthria, dysphagia, bilateral hearing loss, voice hoarseness, and right-sided facial numbness with multiple cranial neuropathies identified on neurological examination. The diagnosis of central diabetes insipidus was also confirmed. Pachymeningitis was present on brain magnetic resonance imaging. Pathologic review of the dural biopsy specimen revealed necrotizing granulomatous vasculitis consistent with GPA. She was treated with intravenous methylprednisolone and rituximab. Over the next 2 months, she had near-complete resolution of her symptoms with normalization on repeat autonomic testing. Conclusions This is a unique GPA case presenting with autonomic failure and pituitary dysfunction with conclusive objective findings of autonomic dysfunction. Autonomic dysfunction and other disease manifestations were responsive to immunosuppressive therapy.

Study Objectives To define the clinical implications of cutaneous phosphorylated α-synuclein (p-syn) and its association with subjective and objective measures of autonomic impairment and clinical features including antidepressant use in isolated rapid eye movement (REM) sleep behavior disorder (iRBD). Methods Twenty-five iRBD patients had quantified neurological and cognitive examinations, olfactory testing, questionnaires, autonomic function testing, and 3 punch skin biopsies (distal thigh, proximal thigh, neck). Skin biopsies were stained for the pan-axonal marker PGP 9.5 and co-stained with p-syn, and results were compared to 28 patients with Parkinson’s disease (PD) and 18 healthy controls. Equal numbers of iRBD patients on and off antidepressants were recruited. The composite autonomic severity scale (CASS) was calculated for all patients. Results P-syn was detected in 16/25 (64%) of iRBD patients, compared to 27/28 (96%) of PD and 0/18 controls. The presence of p-syn at any biopsy site was correlated with both sympathetic (CASS adrenergic r = 0.6, p < 0.05) and total autonomic impairment (CASS total r = 0.6, p < 0.05) on autonomic reflex testing in iRBD patients. These results were independent of the density of p-syn at each site. There was no correlation between p-syn and antidepressant use. Conclusions In patients with iRBD, the presence of cutaneous p-syn was detected in most patients and was associated with greater autonomic dysfunction on testing. Longitudinal follow-up will aid in defining the predictive role of both skin biopsy and autonomic testing in determining phenoconversion rates and future disease status.

Background People with type 2 diabetes mellitus (DM) are at increased risk of cardiovascular disease (CVD). Cardiovascular autonomic neuropathy (CAN) is an underdiagnosed risk factor for CVD, which is prevalent among people with 2DM and can lead to CVD and CVD-related mortality. Little is known about the risk factors associated with CAN in type 2DM. Thus, the study was aimed to assess CAN using five cardiovascular autonomic reflex tests (represented by Ewing’s score) and explore the factors associated with CAN in people with type 2DM. The studied factors include traditional and serological CVD risk factors obtained from a fasting blood sample and cardiorespiratory fitness (CRF) obtained via attainment of the highest peak of volumes of O2 (VO2Peak). Results Univariate analysis revealed a significant positive correlation between resting systolic blood pressure (SBP) and Ewing’s score (r=0.47, p=.02) and an inverse correlation between VO2Peak and Ewing’s score (r=−0.64, p=.001). Multivariate linear regression revealed that a significant model that included resting SBP and VO2Peak explained 93.8% of Ewing’s score variance. Conclusion CAN was associated with two CVD parameters, including resting SBP and CRF, which may indicate the importance of controlling these two factors to prevent or reduce CAN in people with type 2DM.

Objectives: To determine the prevalence of asymptomatic cardiac autonomic neuropathy and its association with risk factors among patients with Type-2 diabetes mellitus (T2DM) Methods: The present case-control study was conducted at Department of Medicine, Civil Hospital, Dow University of Health Sciences (DUHS), Karachi, Pakistan during the period September` 2016 to May` 2017. After taking informed consent, subjects from both genders, 72 healthy controls and 72 clinically diagnosed T2DM diabetic patients, age between 30-65 years were selected by non-probability sampling technique. After taking medical history and demographics, Cardiac Autonomic Neuropathy (CAN) was identified by using Ewing`s cardiac autonomic reflex tests (CARTs) and association of risk factors was also investigated. Results: Severe CAN was identified in 13.9% of T2DM patients while in none of the healthy controls. HR response to deep breathing test was most sensitive (sensitivity= 90%) among all tests. The most common symptoms were Numbness (75.9%) and constipation (69%), resting heart rate and diabetes duration was significantly associated with DCAN. Conclusions: CAN was highly prevalent in diabetic population that may lead to nephropathy and retinopathy in future. It is highly recommended to use sensitive and simple CARTs in clinics for early detection and early treatment of CAN. doi: https://doi.org/10.12669/pjms.37.4.3675 How to cite this:Naz T, Memon NN, Afzal K, Shakir A. Noninvasive exploration of Cardiac Autonomic Neuropathy by heart rate and blood pressure variability analysis in Type 2 Diabetic patients. Pak J Med Sci. 2021;37(4):1020-1024. doi: https://doi.org/10.12669/pjms.37.4.3675 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Aim An adverse side-effect of Liraglutide (LG), a Glucagon-Like Peptide 1 (GLP1)-analog commonly used in treatments for diabetes, is positive chronotropy. The goal of this study is to investigate on the mechanism of this drug-induced chronotropy and explore potential means to mitigate this side-effect so as to maximize the therapeutic benefits from LG. Main methods Experiments were conducted with: 1) Isolated rabbit hearts in a Langendorff set-up to assess for direct effects of drug actions and 2) Murine cardiomyocytes isolated from the sino-atrial node (SAN) to assess the effects of LG on spontaneous action potential (AP) firing and the hyperpolarization-activated current If. Key findings LG induced a dose-dependent increase in heart rate. Its effects on sinus node automaticity, which were not suppressed during β-blockade with Propranolol, were abolished by If blockade with Ivabradine. In isolated murine SAN myocytes, LG increased spontaneous AP firing frequency by an increase in diastolic depolarization slope without changing other electrophysiological parameters. Significance LG-induced positive chronotropy is partly due to a direct effect on the SAN and is independent of the adrenergic cascade and extrinsic autonomic reflex mechanisms. The direct LG-associated increase in heart rate should be mitigated with If blockers rather than β-blockade.

BACKGROUND: Ross syndrome is a rare disorder characterized by tonic pupils, hyporeflexia, and segmental anhidrosis. We sought to characterize the clinical presentation, associated autoimmune disorders, and autonomic profile in patients with Ross syndrome to further elucidate its pathophysiology. METHODS: We performed a retrospective chart review of all patients who underwent a thermoregulatory sweat test (TST) between 1998 and 2020 and had confirmation of the diagnosis of Ross syndrome by an autonomic disorders specialist. Standardized autonomic reflex testing was reviewed when available. RESULTS: Twenty-six patients with Ross syndrome were identified. The most common initial reported manifestation was an abnormal segmental sweating response in 16 patients (described as hyperhidrosis in 12 patients and anhidrosis in 4 patients) while a tonic pupil was the initial manifestation in 10 patients. Other commonly reported symptoms included fatigue, chronic cough, and increased urinary frequency. An associated autoimmune disorder was identified in one patient. Positive autoantibodies were found in a minority of patients often with unclear clinical significance. Distributions of anhidrosis encountered were segmental (n = 15), widespread (n = 7), and global (n = 4). Well-circumscribed small areas of preserved sweating within areas of anhidrosis were observed in the majority of patients (88.5%). Anhidrosis progressed slowly over time and sudomotor dysfunction was predominantly (post)ganglionic. Cardiovagal and adrenergic functions were preserved in most patients. CONCLUSIONS: The pattern of autonomic dysfunction in Ross syndrome is suggestive of a limited autonomic ganglioneuropathy. Sudomotor impairment is prominent and should be the focus of symptomatic management; however, clinicians should be aware of symptoms beyond the classic triad.

Dysfunction of the nervous system is well-known in diabetes and also among patients with prediabetes, obesity and hypertension. However, there is only a limited amount of data available on the changes in neuronal function in polycystic ovary syndrome (PCOs), despite the fact that this condition is also accompanied by metabolic and vascular abnormalities. The aim of our study was to assess the cardiovascular autonomic and peripheral sensory function in patients with PCOs. The study involved 27 women with PCOs, and 24 healthy women as control subjects. Autonomic neuropathy (AN) was assessed using the four standard cardiovascular reflex tests. Peripheral sensory function was determined using the Neurometer. Electric stimulation was applied transcutaneously and the current perception threshold (CPT) values were determined on the median and peroneal nerves. No significant differences were found between the PCOs patients and the control group regarding the cardiovascular autonomic reflex tests and the AN scores. The CPT values of PCOs patients in the median and peroneal nerves were lower at all frequencies in comparison to controls. Conclusions: The cardiovascular autonomic nerve function was normal in the patients with PCOs. The current perception thresholds were consequently lower in the PCOs patients both in the upper and lower extremities at all frequencies, which serves as an early sign of neuropathy. As a novel observation, our results suggest that early neuronal damage manifests in the form of sensory hyperaesthesia in patients with PCOs.

Aims Sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduce blood pressure without compensatory heart rate elevation, possibly by modulating sympathetic/parasympathetic activity. This may contribute to their cardiovascular benefits in type 2 diabetes (T2D). We evaluated the effects of dapagliflozin (DAPA) on measures of cardiovascular autonomic neuropathy (CAN), cardiac function, and glucose variability (GV) in T2D. Methods Pilot, randomized, two-period crossover trial comparing 12-week DAPA versus 12-week glimepiride treatment on CAN measures (cardiovascular autonomic reflex tests and heart rate variability), B-type natriuretic peptide (BNP), and GV (Abbott's Libre Pro devices) using signed rank tests and mixed models from baseline to 12 weeks within and between each period. Results Forty-five T2D participants on metformin monotherapy (mean age 57 ± 8 years, duration 7 ± 6 years, HbA1c 7.8 ± 1.3%) were enrolled with 41 completing the trial. There were no differences in CAN indices or BNP with each drug compared to baseline and each other. Participants on DAPA demonstrated greater weight loss, reduced time in hypoglycemia, and improved GV compared to glimepiride. Conclusions Short term treatment with DAPA did not affect CAN measures or BNP in uncomplicated and relatively healthy T2D participants. Longer prospective studies in patients with advanced disease are needed to better understand relationships between SGLT-2 inhibitors and CAN. Clinical trial registration: NCT02973477

BackgroundWe are facing the outburst of coronavirus disease 2019 (COVID-19) defined as a serious, multisystem, disorder, including various neurological manifestations in its presentation. So far, autonomic dysfunction (AD) has not been reported in patients with COVID-19 infection.AimAssessment of AD in the early phase of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus).Patients and methodsWe analyzed 116 PCR positive COVID-19 patients. After the exclusion of 41 patients with associate diseases (CADG), partitioned to patients with diabetes mellitus, hypertension, and syncope, the remaining patients were included into a severe group (45 patients with confirmed interstitial pneumonia) and mild group (30 patients). Basic cardiovascular autonomic reflex tests (CART) were performed, followed by beat-to-beat heart rate variability (HRV) and systolic and diastolic blood pressure variability (BPV) analysis, along with baroreceptor sensitivity (BRS). Non-linear analysis of HRV was provided by Poincare Plot. Results were compared to 77 sex and age-matched controls.ResultsAD (sympathetic, parasympathetic, or both) in our study has been revealed in 51.5% of severe, 78.0% of mild COVID-19 patients, and the difference compared to healthy controls was significant (p = 0.018). Orthostatic hypotension has been established in 33.0% COVID-19 patients compared to 2.6% controls (p = 0.001). Most of the spectral parameters of HRV and BPV confirmed AD, most prominent in the severe COVID-19 group. BRS was significantly lower in all patients (severe, mild, CADG), indicating significant sudden cardiac death risk.ConclusionCardiovascular autonomic neuropathy should be taken into account in COVID-19 patients’ assessment. It can be an explanation for a variety of registered manifestations, enabling a comprehensive diagnostic approach and further treatment.

The mechanisms underlying premature ventricular contraction (PVC)-induced cardiomyopathy (PIC) remain unknown. Transient receptor potential vanilloid-1 (TRPV1) afferent fibers are implicated in the reflex processing of cardiac stress.The purpose of this study was to determine whether cardiac TRPV1 afferent signaling promote PIC.A PIC swine model (50% PVC burden) was created via an implanted pacemaker. We selectively depleted cardiac TRPV1 afferent fibers using percutaneous epicardial application of resiniferatoxin (RTX). Animals were randomized to PVC only (n = 11), PVC+RTX (n = 11), or control (n = 6). We examined early-stage (4 weeks after implantation; n = 5) and late-stage PIC (8 weeks after implantation; n = 6). At terminal experimentation, animals underwent echocardiography, serum sampling, and physiological and autonomic reflex testing.Depletion of cardiac TRPV1 afferents by RTX treatment was confirmed by absent sensory fibers and absent functional responses to TRPV1 activators. Left ventricular ejection fraction was worse in late-stage than early-stage PIC (P.01). At 4 weeks (early stage), left ventricular ejection fraction was higher in PVC+RTX vs PVC animals (51.7% ± 1.6% vs 45.0% ± 2.1%; P = .030), whereas no significant difference between PVC and PVC+RTX was observed at 8 weeks (late stage). Histologic studies demonstrated reduced fibrosis in PVC+RTX vs PVC alone at 4 weeks (2.27% ± 0.14% vs 3.01% ± 0.21%; P = .020), suggesting that RTX mitigated profibrotic pathways induced by persistent PVCs.TRPV1 afferent depletion alleviates left ventricular dysfunction in early- but not late-stage PIC. This temporal effect suggests that multiple pathways promote PIC, of which TRPV1 afferents are a part.

ObjectivesCardiovascular autonomic neuropathy (CAN) may affect the clinical course of SLE leading to reduced quality of life. CAN is assessed by heart rate variability (HRV) measures and cardiovascular autonomic reflex tests (CARTs). In patients with SLE, we aimed to determine the characteristics of CAN and if CAN associates with health-related quality of life (HRQoL).MethodsPatients with SLE and healthy controls (HCs) were CAN tested with 5 min HRV and three CARTs to determine parameters reflecting parasympathetic and mixed sympathetic–parasympathetic function. Subjects were classified as having no, early or definitive CAN by having none, one or more than one abnormal CART, respectively. HRQoL as determined by the Short Form 12 (SF-12) was assessed in SLE.ResultsOf 111 patients with SLE, 92 answered the SF-12 and 54 were matched with 54 HCs for characterisation of CAN. Definitive CAN was present in 24.1% (95% CI 15% to 37%) patients with SLE and 1.9% (95% CI 0.3% to 9.8%) HCs (OR 16.8, 95% CI 2.1 to 133.8, p=0.008). The corresponding prevalences of any CAN were 53.7% (95% CI 41% to 66%) and 22.6% (95% CI 13% to 35%). SLE patients with definitive CAN showed signs of mixed sympathetic–parasympathetic dysfunction, whereas patients without CAN primarily presented with impaired parasympathetic activity. Signs of parasympathetic as well as sympathetic–parasympathetic dysfunction were associated with low physical SF-12 component score (all: β>0.211, pConclusionsCAN was a frequent finding in SLE and associated to self-report on impaired physical HRQoL. Even patients without CAN showed signs of impaired parasympathetic function compared with controls.

Background: Cardiovascular autonomic neuropathy (CAN) is an independent predictor of cardiovascular disease (CVD) in patients with diabetes as well as in patients with pre-diabetes and metabolic syndrome. Patients with schizophrenia have an increased rate of metabolic syndrome, pre-diabetes and diabetes as compared to the general population. Despite of this, occurrence CAN has not been investigated in patient with schizophrenia. Therefore, the aims of this study were (1) to evaluate the feasibility testing for CAN with a new clinical tool and (2) report the prevalence of early and manifest CAN in patients with schizophrenia. Methods and results: Patients with diagnosed schizophrenia and with a disease duration ≥10 years were matched 1:1 on age and gender at screening with psychiatric healthy controls. CAN was defined as ≥ two abnormal standard cardiovascular autonomic reflex tests (lying-to-standing, deep breathing, and Valsalva maneuver) using the VagusTM device. A total of 46 patients with schizophrenia were included and matched to psychiatric healthy controls. Manifest CAN were more frequently presented in patients with schizophrenia (39% vs. 6% for controls, p

The autonomic nervous system (ANS) is highly integrated with virtually all organs and systems of the human body. The ANS functions autonomously to regulate many internal processes including, but not limited to, heart rate (HR), breathing, blood pressure (BP), sweating, digestion, sexual functioning, respiration, urination, and defecation. Due to the systemic nature of the autonomic network, the impacts of autonomic dysfunction and failure can be extensive. Therefore, tests for reliably measuring autonomic health are of utmost importance. Several clinically standardized and validated tests of autonomic functioning are widely available, noninvasive, and easily performed in an awakened state, including the battery of tests that comprise the autonomic reflex screen and sympathetic skin responses. Additionally, a plethora of non-clinically validated tests exist, but still provide important and insightful information regarding healthy autonomic functioning. Some tests, which will be discussed herein, include direct measures of sympathetic function, via microneurography, tests of sympathetic nerve integrity and tests that evoke reproducible influences on cardiovascular responses. Finally, mammals, including humans, operate on a 24-hour circadian cycle. Many physiological systems demonstrate measurable shifts between a wakeful versus a sleep state, and the physiological processes under autonomic control are no exception. Therefore, techniques for objectively evaluating basic physiological phenomena, including, but not limited to, respiration, thermoregulation, neuroendocrine modulation, and cardiovascular functioning, provide key insight into autonomic neural function during sleep. Common techniques for measuring these variables will be reviewed here.

Gastroparesis and other gastrointestinal motility diseases can be associated with various autonomic neuropathies. The gastrointestinal tract has its own enteric nervous system, a branch of the autonomic nervous system (ANS), and exchanges modulatory signals with the extrinsic autonomic systems. Autonomic neuropathies impairing functions of the extrinsic autonomic pathways can contribute to gastroparesis. Neurological evaluation is needed in patients with gastroparesis to assess systemic or extra-intestinal autonomic involvements as well as to identify an underlying neurological etiology. Self-assessed autonomic questionnaires such as composite autonomic symptom score (COMPASS) are feasible tools for such purposes. Autonomic reflex tests can localize impaired branches of the ANS and to support a diagnosis of autonomic neuropathy. Because autonomic reflex tests clinically available at most autonomic laboratories are relevant to cardiovascular and sudomotor (sweating) autonomic systems, findings of tests do not always have a strong association with the presence and severity of gastroparesis or other localized autonomic/neurological conditions. Skin biopsy to estimate sensory small-fibers in the epidermal layers and autonomic fibers innervating sweat glands is a pathological diagnostic method for small-fiber neuropathy. Autonomic neuropathies associated with gastroparesis include diabetic autonomic neuropathy, Guillain-Barre syndrome, autoimmune autonomic ganglionopathy, paraneoplastic autonomic neuropathy, hereditary amyloid neuropathy. Other autonomic disorders with or without evidence of peripheral autonomic nerve involvements such as postural orthostatic tachycardia syndrome are discussed. Ehlers-Danlos Syndrome is a hereditary connective tissue disorder with multiple subtypes but it is worth mentioning due to its high association with postural orthostatic tachycardia syndrome.

Aims Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes and is associated with adipokines. The C1q tumor necrosis factor‐related protein 9 (CTRP9) is a newly discovered adipokine. This study aimed to evaluate the association of serum CTRP9 levels with the prevalence and severity of CAN in patients with type 2 diabetes mellitus. Materials and Methods We enrolled 262 patients (aged ≥18 years) with type 2 diabetes mellitus into this study. Standard cardiovascular autonomic reflex tests (CARTs) were used to assess CAN and patients were divided into three groups accordingly: a non‐CAN group, an early CAN group, and a definite CAN group. Serum CTRP9 levels were measured by enzyme‐linked immunosorbent assay, and the tertiles were calculated. Results Serum CTRP9 levels decreased significantly in the early CAN and definite CAN groups (P, We evaluated the association between CTRP9 levels and the prevalence and severity of cardiac autonomic neuropathy (CAN) in patients with type 2 diabetes mellitus. We found that serum levels of CTRP9 were reduced significantly in CAN patients with type 2 diabetes mellitus. Further, we found that decreased serum CTRP9 levels significantly correlated with an increased prevalence ratio of CAN. Moreover, after adjusting for other risk factors, decreased serum CTRP9 levels were associated with an increased prevalence ratio of definite CAN.

The neuroanatomical basis behind acupuncture practice is still poorly understood. Here we used intersectional genetic strategy to ablate NPY(+) noradrenergic neurons and/or adrenal chromaffin cells. Using endotoxin-induced systemic inflammation as a model, we found that electroacupuncture stimulation (ES) drives sympathetic pathways in somatotopy- and intensity-dependent manners. Low intensity ES at hindlimb regions drives the vagal-adrenal axis, producing anti-inflammatory effects that depend on NPY(+) adrenal chromaffin cells. High intensity ES at the abdomen activates NPY(+) splenic noradrenergic neurons via the spinal-sympathetic axis; these neurons engage incoherent feedforward regulatory loops via activation of distinct adrenergic receptors (ARs), and their ES-evoked activation produces either anti- or pro-inflammatory effects due to disease state-dependent changes in AR profiles. The revelation of somatotopic organization and intensity dependency in driving distinct autonomic pathways could form a road map for optimizing stimulation parameters to improve both efficacy and safety in using acupuncture as a therapeutic modality.

The "diving reflex" (DR) is a very powerful autonomic reflex that facilitates survival in hypoxic/anoxic conditions and could trigger multifaceted physiologic effects for the treatment of various diseases by modulating the cardiovascular, respiratory, and nervous systems. The DR can be induced by cold water or noxious gases applied to the anterior nasal mucosa and paranasal regions, which can stimulate trigeminal thermo- or chemo-receptors to send afferent signals to medullary nuclei which mediate the sympathetic and parasympathetic nervous systems. Although promising, these approaches have yet to be adopted in routine clinical practice due to the inability to precisely control exposure-response relationships, lack of reproducibility, and difficulty implementing in a clinical setting. In this study, we present the ability of electrical Trigeminal (Infraorbital) Nerve Stimulation (eTINS) to induce the DR in a dose-controllable manner. We found that eTINS not only triggered specific physiological changes compatible with the pattern of "classic" DR observed in animals/humans, but also controlled the induced-DR at varying levels. This study demonstrates, for the first time, that the intensity of the DR is controllable by dose and opens possibility to investigate its protective mechanism against various pathologies in well-controlled research settings.