Autonomic Nerve Fibers Research Articles

Autonomic Nerve Fibers Aberrantly Reinnervate Denervated Facial Muscles and Alter Muscle Fiber Population.

The surgical redirection of efferent neural input to a denervated muscle via a nerve transfer can reestablish neuromuscular control after nerve injuries. The role of autonomic nerve fibers during the process of muscular reinnervation remains largely unknown. Here, we investigated the neurobiological mechanisms behind the spontaneous functional recovery of denervated facial muscles in male rodents. Recovered facial muscles demonstrated an abundance of cholinergic axonal endings establishing functional neuromuscular junctions. The parasympathetic source of the neuronal input was confirmed to be in the pterygopalatine ganglion. Furthermore, the autonomically reinnervated facial muscles underwent a muscle fiber change to a purely intermediate muscle fiber population myosin heavy chain type IIa. Finally, electrophysiological tests revealed that the postganglionic parasympathetic fibers travel to the facial muscles via the sensory infraorbital nerve. Our findings demonstrated expanded neuromuscular plasticity of denervated striated muscles enabling functional recovery via alien autonomic fibers. These findings may further explain the underlying mechanisms of sensory protection implemented to prevent atrophy of a denervated muscle.SIGNIFICANCE STATEMENT Nerve injuries represent significant morbidity and disability for patients. Rewiring motor nerve fibers to other target muscles has shown to be a successful approach in the restoration of motor function. This demonstrates the remarkable capacity of the CNS to adapt to the needs of the neuromuscular system. Yet, the capability of skeletal muscles being reinnervated by nonmotor axons remains largely unknown. Here, we show that under deprivation of original efferent input, the neuromuscular system can undergo functional and morphologic remodeling via autonomic nerve fibers. This may explain neurobiological mechanisms of the sensory protection phenomenon, which is because of parasympathetic reinnervation.

Stereological and electrophysiological evaluation of autonomic involvement in amyotrophic lateral sclerosis

ObjectivePrevious studies have identified autonomic dysfunction in amyotrophic lateral sclerosis (ALS) using mostly neurophysiological techniques. In this study, stereological evaluation of autonomic fibers and sweat glands has been performed to identify structural evidence of autonomic denervation in patients with ALS. MethodsIn this study, 29 ALS patients were compared to 29 controls using COMPASS-31 questionnaire, sympathetic skin response (SSR), and heart rate variability (HRV) at rest. From the same cohorts, 20 ALS patients and 15 controls were further evaluated using staining of autonomic nerve fibers and sweat glands in skin biopsies. SSR and resting HRV were repeated in the ALS patient cohort one year later. ResultsCOMPASS-31 total score, gastrointestinal- and urinary-sub scores were higher in ALS patients than controls (P = 0.004, P = 0.005, and P = 0.049, respectively). In the ALS patient cohort, SSR amplitudes in hands and feet were lower than in controls (P<0.0001 and P = 0.0009, respectively), but there was no difference in resting HRV (P>0.05). While there was no change in nerve fibers innervating sweat glands, their density was lower in ALS patients than controls, and semi-quantitative analysis also showed structural damage (P = 0.02 and P = 0.001, respectively). SSR and resting HRV of ALS patients remained stable during the one-year follow-up period (P>0.05). DiscussionSupporting abnormal neurophysiological tests, stereological analysis revealed direct evidence of autonomic denervation in ALS patients. However, the degenerative process in autonomic nerve fibers is relatively slow, compared to the rate of motor neuron degeneration in this condition.

In vivo peripheral nerve activation using sinusoidal low-frequency alternating currents.

The sinusoidal low-frequency alternating current (LFAC) waveform was explored recently as a novel means to evoke nerve conduction block. In the present work, we explored whether increasing the amplitude of the LFAC waveform results in nerve fiber activation in autonomic nerves. In-silico methods and preliminary work in somatic nerves indicated a potential frequency dependency on the threshold of activation. The Hering-Breuer (HB) reflex was used as a biomarker to detect cervical vagus nerve activation. Experiments were conducted in isoflurane-anesthetized swine (n=5). Two stimulating bipolar cuff electrodes and a tripolar recording cuff electrode were implanted on the left vagus nerve. To ensure the electrical stimulation affects only the afferent pathways, the nerve was crushed caudal to the electrodes to eliminate cardiac effects. (1) Standard pulse stimulation (Vstim) using a monophasic train of pulses was applied through the caudal electrode to elicit HB reflex and to identify the activated nerve fiber type. (2) Continuous sinusoidal LFAC waveform with a frequency ranging from 5 through 20 Hz was applied to the rostral electrode without Vstim to explore the activation thresholds at each LFAC frequency. In both cases, the activation of nerve fibers was detected by a HB reflex-induced reduction in the breathing rate. LFAC was found to be capable of eliciting an HB response. The LFAC activation thresholds were found to be frequency-dependent. The HB threshold was 1.02 ± 0.3 mAp at 5Hz, 0.66 ± 0.3 mAp at 10Hz, and 0.44 ± 0.2 mAp at 20 Hz. In comparison, it was 0.7 ± 0.47 mA for a 100 μs pulse. The LFAC amplitude was within the linear limits of the electrode interface. Damage to the cuff electrodes or the nerve tissues was not observed. Analysis of Vstim-based compound nerve action potentials (CNAP) indicated that the decrease in breathing rate was found to be correlated with the activation of slower components of the CNAP suggesting that LFAC reached and elicited responses from these slower fibers associated with afferents projecting to the HB response. These results suggest the feasibility of the LFAC waveform at 5, 10, and 20 Hz to activate autonomic nerve fibers and potentially provide a new modality to the neurorehabilitation field.

A study of heart rate variability in diabetic mellitus patients

Background. Heart rate variability (HRV) is reduced in diabetes mellitus (DM) patients, suggesting dysfunction of cardiac autonomic regulation and an increased risk for cardiac events. Cardiac autonomic neuropathy (CAN), which results from damage to autonomic nerve fibers that innervate the heart and blood vessels, is a serious complication of DM. During progression of CAN, the parasympathetic nerve fibers innervating the heart are affected before the sympathetic nerve fibers leading to a reduced heart rate variability. The purpose of this study was to examine type 2 diabetes patients with heart rate variability in order to diagnose autonomic dysfunction and to relate the findings to other complications of diabetes mellitus. Materials and methods. 41 type 2 M patients and 45 age- and sex-matched controls were included. In the time domain we measured the mean R–R interval (NN), the standard deviation of the R–R interval index (SDNN), the standard deviation of the 5-min R–R interval mean (SDANN), the root mean square of successive R–R interval differences (RMSSD) and the percentage of beats with a consecutive R–R interval difference&gt;50 ms (pNN50). In the frequency domain we measured high-frequency power (HF), low-frequency power (LF) and the LF/HF ratio. Results. There was no statistically significant difference between DM patients and controls for age and sex distribution. All time- and frequency-domain parameters except mean R–R interval and the LF/HF ratio were significantly lower in diabetes patients than in controls. When chronic complications of DM were examined, diabetic retinopathy and nephropathy were usually present together. For example, among six patients with nephropathy five also had retinopathy. There were 13 diabetes patients with complications (diabetic nephropathy and/or retinopathy) and nine patients with no diabetic complications. Although the chronological ages of the diabetes patients with and without complications were similar (53±9 and 49±12 years, respectively; P&gt;0.05), the duration of DM in patients with complications was significantly greater than that of those without complications (14±9 versus 5±7 years; P=0.002). Diabetes patients had lower HRV values for time-domain and frequency-domain parameters than controls. Conclusions. Majority of heart rate variability parameters were lower in diabetes patients with chronic complications than in those without complications.

HFAC Dose Repetition and Accumulation Leads to Progressively Longer Block Carryover Effect in Rat Sciatic Nerve.

This paper describes high-frequency nerve block experiments carried out on rat sciatic nerves to measure the speed of recovery of A fibres from block carryover. Block carryover is the process by which nerve excitability remains suppressed temporarily after High Frequency Alternative (HFAC) block is turned off following its application. In this series of experiments 5 rat sciatic nerves were extracted and prepared for ex-vivo stimulation and recording in a specially designed perfusion chamber. For each nerve repeated HFAC block and concurrent stimulation trials were carried out to observe block carryover after signal shutoff. The nerve was allowed to recover fully between each trial. Time to recovery from block was measured by monitoring for when relative nerve activity returned to within 90% of baseline levels measured at the start of each trial. HFAC block carryover duration was found to be dependent on accumulated dose by statistical test for two different HFAC durations. The carryover property of HFAC block on A fibres could enable selective stimulation of autonomic nerve fibres such as C fibres for the duration of carryover. Block carryover is particularly relevant to potential chronic clinical applications of block as it reduces power requirements for stimulation to provide the blocking effect. This work characterizes this process toward the creation of a model describing its behavior.

Tau protein quantification in skin biopsies differentiates tauopathies from alpha-synucleinopathies.

Abnormal accumulation of microtubule-associated protein tau (τ) is a characteristic feature of atypical parkinsonisms with tauopathies, such as progressive supranuclear palsy and corticobasal degeneration. However, pathological τ has also been observed in α-synucleinopathies like Parkinson's disease and multiple system atrophy. Based on the involvement of the peripheral nervous system in several neurodegenerative diseases, we characterized and compared τ expression in skin biopsies of patients clinically diagnosed with Parkinson's disease, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration and in healthy control subjects. In all groups, τ protein was detected along both somatosensory and autonomic nerve fibres in the epidermis and dermis by immunofluorescence. We found by western blot the presence of mainly two different bands at 55 and 70 kDa, co-migrating with 0N4R/1N3R and 2N4R isoforms, respectively. At the RNA level, the main transcript variants were 2N and 4R, and both were more expressed in progressive supranuclear palsy/corticobasal degeneration by real-time PCR. Enzyme-linked immunosorbent assay demonstrated significantly higher levels of total τ protein in skin lysates of progressive supranuclear palsy/corticobasal degeneration compared to the other groups. Multivariate regression analysis and receiver operating characteristics curve analysis of τ amount at both sites showed a clinical association with tauopathies diagnosis and high diagnostic value for progressive supranuclear palsy/corticobasal degeneration versus Parkinson's disease (sensitivity 90%, specificity 69%) and progressive supranuclear palsy/corticobasal degeneration versus multiple system atrophy (sensitivity 90%, specificity 86%). τ protein increase correlated with cognitive impairment in progressive supranuclear palsy/corticobasal degeneration. This study is a comprehensive characterization of τ in the human cutaneous peripheral nervous system in physiological and pathological conditions. The differential expression of τ, both at transcript and protein levels, suggests that skin biopsy, an easily accessible and minimally invasive exam, can help in discriminating among different neurodegenerative diseases.

Abnormal photoplethysmography waveforms are associated with chemotherapy induced neuropathy.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-dependent adverse event of many chemotherapy agents that affects autonomic, motor, and sensory nerve fibers. The purpose of this study is to describe abnormal photoplethysmography waveforms (PPGs) in the setting of CIPN in cancer patients screened for peripheral arterial disease (PAD), which to our knowledge has not been previously described. Patients and methods: 147 patients who underwent vascular physiologic testing in evaluation for PAD with an ankle brachial index (ABI) or toe brachial index (TBI), segmental pressures, pulse volume recordings, and toe PPGs, in a tertiary cancer center's vascular lab between January 1, 2019 and January 31, 2021 were included in the study. Results: Odds ratio analysis demonstrates 3 times increased odds of abnormal PPGs in patients with PAD (OR 3.2256 95% CI 1.523-6.832, p=0.002), 7 times increased odds of abnormal PPGs in patients with CIPN (OR 7.802 95% CI 3.606-16.880, p<0.001), 9 times increased odds of abnormal PPGs in patients with both CIPN and PAD (9.895 95% CI 2.643-37.043, p=0.001), and 7 times increased odds of abnormal PPGs in patients with chemotherapy agent known to cause CIPN (7.821 95% CI 3.619-16.902, p<0.001). Logistic regression demonstrated that PAD (coefficient 1.171 std. error 0.383 wald 9.354 p=0.002), CIPN (coefficient 2.054 std. error 0.394 wald 27.227 p<0.001), and chemo agent known to cause CIPN (coefficient 2.057 std. error 0.393 wald 27.370 p<0.001) were all predictors of abnormal PPGs. Conclusions: CIPN had greater odds for abnormal PPGs than PAD. Additional larger studies are needed to assess if PPG analysis could be utilized to assess for early diagnosis of CIPN.

Acromioclavicular Disk as a Potential Source of Pain in AC Joint Injuries

Background: Injuries of the acromioclavicular joint (ACJ) are common shoulder injuries that often lead to pain and dysfunction of the affected shoulder. Regardless of operative or nonoperative treatment, a relatively large number of patients remain symptomatic and experience pain. However, the specific source of persistent pain in the ACJ remains ambiguous. Purpose: To investigate the presence of sensory nerve fibers or pain-generating neurotransmitters within the intra-articular disk of the ACJ to determine its potential role as an independent pain generator in ACJ disorders. Study Design: Descriptive laboratory study. Methods: Twelve paired ACJs from 6 fresh human cadavers (mean age, 56 years; range, 41-82 years) were harvested and freed from surrounding soft tissues, leaving only the ACJ capsule intact. The specimens were placed in 4.5% formaldehyde fixative for a minimum of 48 hours. Coronal plane sections were obtained and demineralized in EDTA for a week, embedded in paraffin for 12 hours, and dehydrated overnight. With a rotation microtome, 2-μm sections were cut and stained with hematoxylin and eosin to investigate tissue architecture and confirm the presence of a fibrocartilaginous intra-articular disk. The sections were immunohistochemically stained with antisera against S100, neuropeptide Y (NPY), and substance P (SP) to detect for neural tissue. Additionally, a nerve fiber count per 10 high-power fields representing an area of 0.2 mm2 was conducted for S100 stains. All sections were examined for the presence of positive immunoreactivity to S100, NPY, and SP. Results: The presence of a fibrocartilaginous intra-articular disk could be observed in all 12 examined ACJs. In all specimens, an immunoreactivity to S100, NPY, and SP could be observed within the superior peripheral region of the intra-articular disk. High-power field nerve counts of the S100 stains revealed a mean ± SD of 7.9 ± 2.28 nerves per 10 high-power fields (range, 4-12). Conclusion: The documented immunoreactivity to S100, NPY, and SP indicates the presence of somatic and autonomic nerve fibers within the intra-articular disk of the ACJ. Clinical Relevance: Confirming the presence of nerve fibers within the intra-articular disk of the ACJ suggests that the disk itself could be an independent source of pain after injury and thus a possible explanation for recalcitrant pain after treatment.

The Effect of Cigarette Smoking on Penile Vasculature and Cardiodynamics among Young Saudi Population

Erectile and cardiovascular dysfunctions in cigarette smokers are important signs resulting probably due to pelvic autonomic neuropathy with damage to the parasympathetic nervi erigentes. Evidence related to neuropathic etiology comes from studies that show structural changes in autonomic nerve fibers supplying the corpora cavernosa. The objective of this study was to evaluate the effect of cigarette smoking on penile mid shaft circumference and length, penile pulse amplitude, both systolic and diastolic blood pressures, and heart rate in response to erotic stimulation in young Saudi men living in Western region of Saudi Arabia (Makkah). In this free-living population study data was collected from100 men each (mild, moderate and heavy cigarette smokers) ages between 20 and 35 years with a mean age of 26.42 ± 10.69 years along with 100 age matched healthy non smokers who served as controls. Heavy cigarette smoker group showed a significant decrease (p&lt;0.0005) in mid shaft penile circumference and length and penile pulse amplitude where as both systolic and diastolic blood pressures and heart rate exhibited a significant increase (P&lt;0.025, P&lt;0.0005 and P&lt;0.005 respectively. However this difference was found to be non significant in mild smoker group when compared with non smoker controls. We hypothesized that heavy cigarette smoking seems to be associated with sub-fertility in these males with significant alteration in the penile vasculature and cardiodynamics in a dose-dependent manner.

Abstract P358: Cardiac Innervation Remodeling And Impaired Brain Derived Neurotrophic Factor (bdnf) Levels In Physiological Aging Vivo Model

Aging is a multifactorial process associated with gradual loss of function and decay involving several neurohormonal systems, such as the autonomic nervous system (ANS). Progressive remodeling of ANS, induces a circulating catecholamines spillover and cardiac autonomic fibers depletion with raising both morbidities and mortality risk. Neurotrophic factors (NF) play a pivotal role in modulating neuronal function and are impaired in cardiovascular disorders. Whether and how physiological aging impacts these neurobiomarkers and cardiac innervation remains still unclear. Therefore, we investigated the impact of aging on neurotrophins (such as BDNF and NGF) production and secretion and its consequences, on cardiac nervous system homeostasis. In vivo, we used young (age: 3 months; n=10) and old (age: 24 months; n=11) male Fisher rats. In vitro, human neuroblastoma cells (SH-SY5Y) were stimulated with serum withdrawn from both experimental groups. Old rats showed a significant reduction in overall ANS fiber density, sympathetic (marked by dopamine β-hydroxylase, dβh) and cholinergic compartment (evidenced by vesicular acetylcholine transporter, VaChT) compared to the young group, assessed by immunohistochemical staining. In addition, we observed a marked downregulation of GAP-43 and BDNF protein levels in left ventricle total lysates via immunoblot analysis, in aged hearts as opposed to young ones. Conversely, no changes were observed in NGF protein expression. To further investigate the autocrine effect of aging on autonomic nerve fibers, we treated SH-SY5Y cells in vitro, with blood serum obtained by young or old rats. Both stimuli induced a remarkable increase in neuronal sprouting, as evidenced via crystal violet assay. Nevertheless, we found a bulky drop in the neuronal function of cells stimulated with old rat serum. Interestingly, this effect was accompanied by a sizeable blunt in GAP-43 and BDNF protein levels, compared to cells treated with young rat serum. Taken together, our data suggest that neuronal function impairment aging-induced associated with significant BDNF impoverishment, might favor maladaptive remodeling of cardiac ANS.

Alcoholic polyneuropathy. Clinical forms and pathogenetically based approaches to therapy

The number of cases of alcoholism in Russia is gradually decreasing, but still significantly affects the overall health indicators of the population. One of its frequent complications is alcoholic polyneuropathy. The article deals with the pathogenetic mechanisms of the occurrence and development of the disease, its forms, classification, and clinical picture. The damage to the nervous system in patients with alcoholism depends on the frequency of alcohol consumption, the dose, the type of drinks that were consumed, malnutrition, genetic predisposition and individual characteristics that determine the level of alcohol dehydrogenase and aldehyde dehydrogenase. In the clinical picture, a toxic form of alcoholic polyneuropathy is currently distinguished, associated with the direct effect of toxic alcohol metabolites on somatic and autonomic nerve fibers, thiamine deficiency, resulting from a deficiency of B vitamins, and mixed forms. According to the rate of development of clinical manifestations, there are acute forms of alcoholic polyneuropathy (thiamine deficiency) and chronic forms (toxic). The article discusses the possibilities of diagnostics using modern instrumental and laboratory methods of research, primarily electroneuromyography. With the help of this method of investigation, in alcoholic polyneuropathy, signs of axonal damage are most often detected, and in the thiamine-deficient form, it is possible to determine signs of secondary demyelination. The authors emphasize the importance of differential diagnosis with other pathologies. The article highlights the current understanding of the main therapeutic strategies, treatment options for patients with alcoholic polyneuropathy. Therapy of patients suffering from alcoholic polyneuropathy includes refusal of alcohol abuse, normalization of nutrition, medication. For drug therapy, B vitamins and antioxidants are used. The drug with a recognized antioxidant effect is alpha-lipoic acid. A clinical case was analyzed on the basis of our own clinical observation of a mixed form of alcoholic polyneuropathy.

Left Ventricular Summit-Concept, Anatomical Structure and Clinical Significance.

The left ventricular summit (LVS) is a triangular area located at the most superior portion of the left epicardial ventricular region, surrounded by the two branches of the left coronary artery: the left anterior interventricular artery and the left circumflex artery. The triangle is bounded by the apex, septal and mitral margins and base. This review aims to provide a systematic and comprehensive anatomical description and proper terminology in the LVS region that may facilitate exchanging information among anatomists and electrophysiologists, increasing knowledge of this cardiac region. We postulate that the most dominant septal perforator (not the first septal perforator) should characterize the LVS definition. Abundant epicardial adipose tissue overlying the LVS myocardium may affect arrhythmogenic processes and electrophysiological procedures within the LVS region. The LVS is divided into two clinically significant regions: accessible and inaccessible areas. Rich arterial and venous coronary vasculature and a relatively dense network of cardiac autonomic nerve fibers are present within the LVS boundaries. Although the approach to the LVS may be challenging, it can be executed indirectly using the surrounding structures. Delivery of the proper radiofrequency energy to the arrhythmia source, avoiding coronary artery damage at the same time, may be a challenge. Therefore, coronary angiography or cardiac computed tomography imaging is strongly recommended before any procedure within the LVS region. Further research on LVS morphology and physiology should increase the safety and effectiveness of invasive electrophysiological procedures performed within this region of the human heart.

Aging is associated with cardiac autonomic nerve fiber depletion and reduced cardiac and circulating BDNF levels.

BackgroundAging is a multifactorial process associated with an impairment of autonomic nervous system (ANS) function. Progressive ANS remodeling includes upregulation of expression of circulating catecholamines and depletion of cardiac autonomic nerve fibers, and it is responsible, in part, for the increased susceptibility to cardiac diseases observed in elderly subjects. Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), are involved in synaptogenesis and neurite outgrowth processes, supporting neuronal cell differentiation and maturation. However, whether and how these factors and their downstream signaling are involved in cardiac aging remains unclear. Here, we tested whether, in the aged heart, the overall extent of autonomic fibers is reduced, owing to lower production of trophic factors such as BDNF and NGF.MethodsIn vivo, we used young (age: 3 months; n = 10) and old (age: 24 months; n = 11) male Fisher rats, whereas, we used human neuroblastoma (SH-SY5Y) cells in vitro. ResultsCompared to the young rats, old rats displayed a marked reduction in the overall ANS fiber density, affecting both sympathetic and cholinergic compartments, as indicated by dopamine β-hydroxylase (dβh) and vesicular acetylcholine transporter (VaChT) immunohistochemical staining. In addition, a marked downregulation of GAP-43 and BDNF protein was observed in the left ventricular lysates of old rats compared to those of young rats. Interestingly, we did not find any significant difference in cardiac NGF levels between the young and old groups. To further explore the impact of aging on ANS fibers, we treated SH-SY5Y cells in vitro with serum obtained from young and old rats. Sera from both groups induced a remarkable increase in neuronal sprouting, as evidenced by a crystal violet assay. However, this effect was blunted in cells cultured with old rat serum and was accompanied by a marked reduction in GAP-43 and BDNF protein levels. ConclusionsOur data indicate that physiological aging is associated with an impairment of ANS structure and function and that reduced BDNF levels are responsible, at least in part, for these phenomena.

Evidence of a new hidden neural network into deep fasciae

It is recognized that different fasciae have different type of innervation, but actually nothing is known about the specific innervation of the two types of deep fascia, aponeurotic and epymisial fascia. In this work the aponeurotic thoracolumbar fascia and the epymisial gluteal fascia of seven adult C57-BL mice were analysed by Transmission Electron Microscopy and floating immunohistochemistry with the aim to study the organization of nerve fibers, the presence of nerve corpuscles and the amount of autonomic innervation. The antibodies used were Anti-S100, Anti-Tyrosine Hydroxylase and Anti-PGP, specific for the Schwann cells forming myelin, the sympathetic nerve fibers, and the peripheral nerve fibers, respectively. The results showed that the fascial tissue is pervaded by a rhomboid and dense network of nerves. The innervation was statistically significantly lower in the gluteal fascia (2.78 ± 0.6% of positive area, 140.3 ± 31.6/mm2 branching points, nerves with 3.2 ± 0.6 mm length and 4.9 ± 0.2 µm thickness) with respect to the thoracolumbar fascia (9.01 ± 0.98% of innervated area, 500.9 ± 43.1 branching points/mm2, length of 87.1 ± 1.0 mm, thickness of 5.8 ± 0.2 µm). Both fasciae revealed the same density of autonomic nerve fibers (0.08%). Lastly, corpuscles were not found in thoracolumbar fascia. Based on these results, it is suggested that the two fasciae have different roles in proprioception and pain perception: the free nerve endings inside thoracolumbar fascia may function as proprioceptors, regulating the tensions coming from associated muscles and having a role in nonspecific low back pain, whereas the epymisial fasciae works to coordinate the actions of the various motor units of the underlying muscle.

Neurodegenerative disorders affecting the autonomic nervous system: Pure autonomic failure and multiple system atrophy

AbstractPure autonomic failure (PAF) and multiple system atrophy (MSA) are representative neurodegerative diseases present with a severe autonomic dysfunction in the urinary, cardiovascular, and pupillary systems, as well as the gastrointestinal tract and skin/sweat glands. Clinically PAF is characterized by chronic progressive pure autonomic dysfunction occasionally associated with parkinsonism or cognitive dysfunction (Lewy body disease), whereas MSA is associated with cerebellar manifestation and/or parkinsonism. Pathology of both PAF and MSA is characterized by α‐synuclein deposition, but in PAF major involvement exists in the sympathetic ganglion and postganglionic autonomic nerve fibers, whereas MSA mainly affects the central autonomic system, such as the vagal nerve lateral nucleus, locus coeruleus, spinal cord medial lateral nucleus, and sacral Onuf's nucleus. Therefore, it is necessary to evaluate whether peripheral or central autonomic function is predominantly affected by the differential diagnosis of PAF and MSA. Autonomic dysfunction is also frequently present in patients with Parkinson's disease, but usually not so severe as in PAF or MSA. This review summarizes features of autonomic dysfunction in PAF and MSA.

Update on alpha-synuclein-based biomarker approaches in the skin, submandibular gland, gastrointestinal tract, and biofluids.

There is a need for objective diagnostic and prognostic biomarkers in Parkinson's disease (PD), partly given the expected increase in clinical trials aimed at demonstrating a disease-modifying effect in early disease. Alpha-synuclein (α-syn) plays a decisive role in the pathogenesis of PD. Here, we review recent publications exploring established and novel methodologies to detect α-syn species in tissues and biofluids. Using immunohistochemistry (IHC), recent studies have focused on the detection of phosphorylated α-syn (p-α-syn) in cutaneous nerve fibers, reporting varying sensitivity and high specificity for the diagnosis of PD. A predilection for p-α-syn depositions in cutaneous autonomic nerve fibers has emerged, possibly contrasting with other synucleinopathies.Novel studies utilizing the seeding propensity of pathological α-syn have generated encouraging results with regard to diagnostic performance in both tissues and biofluids including skin, submandibular gland, and cerebrospinal fluid. Detection of neuronal p-α-syn in skin punch biopsies remains a promising minimally invasive diagnostic tool in PD. Seeding assays have emerged as a new method with its diagnostic potential warranting replication in further studies from various tissues and biofluids. Longitudinal studies employing both IHC and seeding assays are needed to identify possible biomarkers of disease progression.

Headache from clinically confirmed hemicrania continua arising from the sternocleidomastoid muscle: a case report

BackgroundA patient with a history of cluster headaches, now in remission, presented with confirmed hemicrania continua that resolved with a local anaesthetic injection into the Sternocleidomastoid (SCM) muscle. To the best of our knowledge, this is the first reported case of a trigeminal autonomic cephalalgia arising from a soft tissue source in the neck.Case presentationA 66-year-old man with a history of cluster headaches presented with a six-month history of a new constant right-sided headache. The new headaches were associated with tearing and redness of the right eye and responded to indomethacin, thus meeting the International Classification of Headache Disorders (ICHD-3) diagnostic criteria for hemicrania continua. The history and physical examination suggested a cervical source of the headache arising from the ipsilateral SCM muscle. Injection of the muscle with 1% lidocaine resulted in the elimination of the pain for 1 month without indomethacin.ConclusionsDue to the convergence of trigeminal, cervical and autonomic nerve fibres, various combinations of headache syndromes can result. This case report demonstrates how a meticulous examination is a crucial component of headache evaluation. Treatment directed to this muscle spared this patient further daily indomethacin and associated side effects.

Characterizing the Topography of the Vesical Portion of the Inferior Hypogastric Plexus and its Associated Endopelvic Fascial Planes: Informing Nerve‐sparing Ureteric Reimplantation Surgery

Extravesical ureteric reimplantation is an effective treatment for vesicoureteral reflux. Concerningly, when performed bilaterally, it is associated with a 10-15% incidence of postoperative urinary retention and is postulated to be caused by iatrogenic damage to the nearby pelvic autonomic nerves. Unfortunately, an effective nerve-sparing surgical approach is limited by a lack of comprehensive anatomical knowledge of these nerves (i.e., location, distribution, density). Thus, this study aims to investigate the anatomy of the autonomic nerves within the endopelvic fascial planes and in the vicinity of the ureterovesical junction (UVJ), in fresh and ethanol-phenol-fixed human cadavers. To address this, the present study utilized gross dissection to identify the course of the autonomic nerves within the endopelvic fascial planes to contextualize their anatomical position and aid in surgical identification (Objective 1). Subsequently, we sought to examine the position and density of pelvic autonomic nerve fibers in the soft tissue surrounding the UVJ using western blot and semi-quantitative densitometry analysis (Objective 2). Findings from nine specimens (n= 9 cadavers; 8 males, 1 female) revealed a common endopelvic fascial plane including the gonadal vessels, ureters, and hypogastric nerves (from lateral to medial, respectively), that overlays the abdominal aorta. The region posterior to this plane was found to be continuous with the pre-sacral space inferiorly. The fascial plane containing the vas deferens in male specimens was differentiable from this common plane and can be seen intersecting proximal to the UVJ. The characterization of pelvic autonomic nerve fiber density, specifically surrounding the UVJ using western blot analysis, is ongoing. This study provides the first identification of hypogastric nerves (medial), ureters (between) and gonadal vessels (lateral) situated in a common endopelvic fascial plane (n= 9), an inferior continuation of the renal fascia, specifically the internal layers of Gerota's & Zuckerkandle's. Knowledge of these endopelvic fascial planes, paired with ongoing densitometry analysis in Objective 2, will provide the necessary anatomical foundation for future research to further refine nerve-sparing surgical approaches of ureteric reimplantation. Acknowledgements: Kaitlin Marshall, Dale Fournier, Mariyan Jeyarajah, Stephen Renaud, Haley Linklater, Kevin Walker and the UWO anatomy lab donors.

The Impact of Omega‐3 Fatty Acids on Cardiac Autonomic Nerve Fiber Innervation in High Fat‐Fed Mice

Peripheral neuropathy and cardiac autonomic neuropathy (CAN) are common and serious complications of diabetes, characterized by loss of peripheral nerves that innervate the skin and loss of parasympathetic and sympathetic nerves that innervate the heart, respectively. CAN is associated with increased risk of myocardial infarction and mortality, yet often goes undetected in patients. Both prediabetic and diabetic patients develop peripheral neuropathy and CAN, suggesting that the level of hyperglycemia at which peripheral neuropathy and CAN develop precedes the onset of diabetes. Although evidence from human and rodent studies indicate that omega-3-fatty acids prevent and/or reverse the development of peripheral neuropathy, the effects of omega-3-fatty acids on CAN has not been investigated. PURPOSE Assess the effects of omega-3-fatty acids on cardiac autonomic nerve fiber innervation in high fat diet-induced prediabetic mice. We hypothesize that omega-3 fatty acids will attenuate a reduction in cardiac autonomic nerve fiber innervation in high fat-fed mice. METHODS Male C57BL/6 mice were randomized into four diet groups (n = 12-14/group) for 14 weeks: 10% low fat fish oil (LFFO), 54% high fat-fish oil (HFFO), 10% low fat-lard (LFL), or 54% high fat-lard (HFL). The von Frey behavioral test for hindpaw mechanical sensitivity was used to characterize peripheral neuropathy at baseline then biweekly for 14 weeks. At study completion, fasting glucose and insulin values were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR). Mice were anesthetized, transcardially perfused with 1% PBS, and heart tissue was harvested and frozen in O.C.T. Heart was sectioned in three planes (anterior coronal, posterior coronal, and sagittal) and mounted on slides. Fluorescence immunohistochemistry was performed on heart cryosections using anti-choline acetyl-transferase and anti-tyrosine hydroxylase followed by Alexa Fluor secondary antibodies to visualize parasympathetic and sympathetic nerve fibers. For each mouse, nerve fibers were quantified on three slides (1 from each plane) and at least 3 areas with the highest nerve fiber density for each slide were examined. Nerve fiber density was determined using Nikon Elements and was calculated as the total length of all counted nerve fibers divided by the total area examined (µm/mm2). RESULTS Body weight, fasting insulin and glucose, and HOMA-IR were higher in HFL compared to all other groups. Fasting glucose was also higher in LFL compared to LFFO. Hindpaw withdrawal threshold was lower in HFL compared to HFFO, indicative of hindpaw hypersensitivity in HFL. CONCLUSIONS Omega-3 fatty acids prevented excess body weight, insulin resistance, elevated glucose, and hindpaw hypersensitivity in mice fed a high fat diet. Based on this data, we expect a diet rich in omega-3 fatty acids will attenuate cardiac autonomic nerve fiber denervation. Taken together, these findings would suggest that omega-3 fatty acids might hold therapeutic potential in the prevention of metabolic derangements as well as peripheral and CAN in individuals who consume a high fat, high calorie diet.

Цукровий діабет і артеріальна гіпертензія

В огляді проведений аналіз літературних джерел, присвячених сучасному стану проблеми цукрового діабету (ЦД) і артеріальної гіпертензії (АГ). За даними Всесвітньої організації охорони здоров’я, АГ та ЦД 2-го типу після ожиріння є одними з провідних чинників серцево-судинного ризику, які найбільш поширені серед населення світу. За останні 30 років поширеність АГ зменшилась до однієї четвертої частини населення світу, але захворюваність на ЦД зросла з 4,7 до 8,5%, і прогноз на майбутнє свідчить про подальший драматичний приріст. Покращення обізнаності, лікування та контролю цих захворювань є основною метою глобальної системи охорони здоров’я. Поширеність АГ у хворих на ЦД 2-го типу до трьох разів вища, ніж у пацієнтів без ЦД, а поєднання АГ і ЦД суттєво збільшує ймовірність розвитку серцево-судинних захворювань. Несприятливий взаємозв’язок цих двох станів, прискорюючи процеси атеросклерозу, може спричинити негативні патофізіологічні зміни серцево-судинної системи. Крім того, відомо, що кардіоваскулярна автономна нейропатія, яка виникає в результаті пошкодження вегетативних нервових волокон, що іннервують серце та судини, є вагомим ускладненням ЦД 2-го типу, особливо за наявності системної АГ. Зокрема, аналізуються питання, пов’язані із спільними патофізіологічними механізмами, основними системними та метаболічними чинниками, що можуть сприяти коморбідності ЦД і АГ. Наведені класифікація, особливості діагностики АГ, особливості оцінки ураження органів, опосередкованого АГ. Аналізуються питання, пов’язані з основними підходами до лікування артеріальної гіпертензії при цукровому діабеті; використанням блокаторів ренін-ангіотензинової системи, блокаторів кальцієвих каналів, тіазидних і тіазидоподібних діуретиків, блокаторів бета-адренергічних рецепторів, альфа-адреноблокаторів, антагоністів мінералокортикоїдних рецепторів; особливостями комбінованої терапії та лікування резистентної артеріальної гіпертензії.