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Autonomic Dysfunction in Neurological Disorders: Novel Mechanisms and Targets

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: 31 July 2025 | Viewed by 5242

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Special Issue Editors

Dr. De-Pei Li

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Guest Editor

Department of Medicine, Center for Precision Medicine, University of Missouri, Columbia, MO 65203, USA
Interests: autonomic nervous system; synaptic plasticity in neurological disorders; Ion channel

Prof. Dr. Zixi Cheng

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Guest Editor

UCF College of Medicine, Orlando, FL, USA
Interests: cardiovascular autonomic nerve innervation; digestive system autonomic innervation; gut-brain interaction

Special Issue Information

Dear Colleagues,

The dysfunction of the autonomic nervous system is associated with many neurological diseases as a consequence or causality of primary diseases. Studies have been carried out to determine the mechanisms of dysautonomia in neurological disorders such as Alzheimer’s disease, Parkinson’s disease, depression, and neurogenic hypertension. In addition, dysautonomia also importantly contributes to metabolic diseases, such as diabetes, obesity, and metabolic syndrome, because it may lead to insulin resistance, altered lipid metabolism, and hypertension in metabolic syndrome. In a certain sensorium, autonomic dysfunction is associated with multiple diseases (e.g., diabetes mellitus and depression), suggesting that autonomic dysfunction is possibly a common mechanism that governs their pathological process. However, the role of autonomic dysfunction in creating or maintaining the pathology of neurological diseases is not still completely understood. Recovering altered autonomic function provides a potential therapy that can be used to treat certain neurological diseases. This Special Issue invites investigators to contribute original research articles and review articles that will help us understand the novel mechanisms of autonomic dysfunction in neurological diseases. Potential topics include, but are not limited to, the following: autonomic dysfunction in neurological disorders (such as Alzheimer's disease, Parkinson's disease, and depression); dysautonomia in insulin resistance in metabolic diseases; and dysautonomia in response to external environmental changes (such as stress, traumatic brain injury, or hormonal imbalances).

Dr. De-Pei Li
Prof. Dr. Zixi Cheng
Guest Editors

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Keywords

sympathetic nervous system
parasympathetic nervous system
novel mechanisms
novel molecular
genetic predisposition

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Published Papers (4 papers)

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Research

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20 pages, 2507 KiB

Open AccessArticle

Cellular and Molecular Mechanisms Underlying Altered Excitability of Cardiac Efferent Neurons in Cirrhotic Rats

by Choong-Ku Lee, Huu Son Nguyen, Seong Jun Kang and Seong-Woo Jeong

Biomedicines 2024, 12(8), 1722; https://doi.org/10.3390/biomedicines12081722 - 1 Aug 2024

Viewed by 1049

Abstract

Patients with cirrhosis often exhibit cardiac autonomic dysfunction (CAD), characterized by enhanced cardiac sympathetic activity and diminished cardiac vagal tone, leading to increased morbidity and mortality. This study delineates the cellular and molecular mechanisms associated with altered neuronal activities causing cirrhosis-induced CAD. Biliary and nonbiliary cirrhotic rats were produced by common bile duct ligation (CBDL) and intraperitoneal injections of thioacetamide (TAA), respectively. Three weeks after CBDL or TAA injection, the assessment of heart rate variability revealed autonomic imbalance in cirrhotic rats. We observed increased excitability in stellate ganglion (SG) neurons and decreased excitability in intracardiac ganglion (ICG) neurons in cirrhotic rats compared to sham-operated controls. Additionally, threshold, rheobase, and action potential duration exhibited opposite alterations in SG and ICG neurons, along with changes in afterhyperpolarization duration. A- and M-type K⁺ channels were significantly downregulated in SG neurons, while M-type K⁺ channels were upregulated, with downregulation of the N- and L-type Ca²⁺ channels in the ICG neurons of cirrhotic rats, both in transcript expression and functional activity. Collectively, these findings suggest that cirrhosis induces an imbalance between cardiac sympathetic and parasympathetic neuronal activities via the differential regulation of K⁺ and Ca²⁺ channels. Thus, cirrhosis-induced CAD may be associated with impaired autonomic efferent functions within the homeostatic reflex arc that regulates cardiac functions. Full article

(This article belongs to the Special Issue Autonomic Dysfunction in Neurological Disorders: Novel Mechanisms and Targets)

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Figure 1

Figure 1
Design of the experiments. Rats were allocated into three groups: sham-control (n = 20), CBDL (n = 20), and TAA (n = 20). Body weight and hemodynamic parameters were measured in the control and cirrhotic rats three weeks post-sham-operation or post-CBDL, and six weeks post-saline or TAA injections. Subsequent to hemodynamic assessment, liver histology and blood analysis were conducted. HRV was evaluated in six rats per group via ECG recordings to confirm the development of CAD. Following ECG recording, liver tissues were visually inspected, and SG and ICG were harvested for the dissociation of individual neurons for electrophysiological measurements and single-cell RT-PCR. This protocol was also followed for rats in each group not utilized for hemodynamics and HRV assessments. Full article ">Figure 2
Power spectral analysis of HRV in normal and cirrhotic rats. Representative traces show the power spectral densities (PSDs) of various frequency components calculated from the R-R interval variability using the fast Fourier transform algorithm in sham (A), CBDL (B), and TAA rats (C). (D) Summary of the LF/HF power ratio in normal and cirrhotic rats. Total power densities were calculated within the frequency range of 0 to 3 Hz. LF and HF powers were defined as the area under the curve in the frequency ranges of 0.04–1.0 Hz and 1.0–3.0 Hz for rats, respectively. Data are presented as the mean ± SEM. The number of experiments is indicated in parentheses. ** p < 0.01 compared with normal rats. Full article ">Figure 3
Cirrhosis-induced alterations in the excitability of SG and ICG neurons. Representative traces of AP discharges in response to depolarizing current steps to 1, 2, and 3 times-threshold (1×, 2×, and 3× Th) for 1 s in (A) SG, (C) ICG neurons from the sham, CBDL, and TAA rats. Each neuron was depolarized from a resting membrane potential between −51 and −56 mV. All recordings were performed under the gramicidin-perforated configuration of the whole-cell current-clamp technique. (B,D) Summary of the number of spikes per second measured respectively in SG and ICG neurons in the sham, CBDL, and TAA rats. Data are presented as the mean ± SEM. The number of neurons tested is indicated in parentheses. * p < 0.05, ** p < 0.01, *** p < 0.001 compared with the sham-operated rats. Full article ">Figure 4
Downregulation of A-type K+ currents in the SG neurons of cirrhotic rats. (A) Representative traces of the total, delayed rectifier (KDR), and A-type (KA) K+ currents recorded in the SG neurons of the sham-operated, CBDL, and TAA rats. Total outward K+ (KVTotal) and KDR currents were elicited by 1-s depolarizing pulses ranging from −50 mV to +20 mV, starting from holding potentials of −100 mV and −60 mV, respectively. KA current traces were derived by subtracting the KDR current from the KVTotal currents. (B) Summary of the KDR and KA current densities measured at −20 mV in the SG neurons of the sham, CBDL, and TAA rats. (C) Summary of the relative expression of the transcripts encoding Kv4.1, Kv4.2, and Kv4.3 in the SG neurons of the sham, CBDL, and TAA rats. Data are presented as the mean ± SEM. The number of neurons tested is indicated in parentheses. ** p < 0.01, *** p < 0.001 compared with the sham rats. Full article ">Figure 5
Differential regulation of KM channels in cardiac efferent neurons of cirrhotic rats. (A) Representative KM current traces are recorded in the SG and ICG neurons of the sham-operated, CBDL, and TAA rats. KM currents were deactivated by a 500 ms test pulse to −60 mV from a holding potential of −30 mV (inset shows the pulse protocol). (B) Summary of the KM current densities in the SG and ICG neurons of the sham, CBDL, and TAA rats. (C) Summary of the relative expression of transcripts encoding KCNQ2 and KCNQ3 in the SG and ICG neurons of the sham, CBDL, and TAA rats. Data are presented as the mean ± SEM. The number of neurons tested is indicated in parentheses. ** p < 0.01, *** p < 0.001 compared with the sham rats. Full article ">Figure 6
Regulation of AP firing by the inhibition of VDCCs in normal SG and ICG neurons and downregulation of the transcripts encoding N- and L-type Ca2+ channel isoforms in the SG and ICG neurons of cirrhotic rats. (A) Effects of various VDCCs blockers on AP firing in SG and ICG neurons of normal rats. CdCl2 (0.1 mM), a non-specific VDCC blocker, ω-conotoxin GVIA (1 µM), an N-type Ca2+ channel blocker, and nimodipine (10 µM), an L-type Ca2+ channel blocker were bath applied. Each neuron was depolarized from a resting membrane potential (SG neuron: −52 mV and ICG neuron: −54 mV). All recordings were performed under the gramicidin-perforated configuration of the whole-cell current-clamp technique. (B,C) Relative expression of the transcripts encoding N-type (α1B) and L-type (α1C and α1D) VDCCs, normalized to the β-actin transcript. Data are presented as the mean ± SEM. The number of neurons tested is indicated in parentheses. * p < 0.05, ** p < 0.01 compared with the sham rats. Full article ">Figure 7
Downregulation of L− and N−type Ca2+ channels in the ICG neurons of cirrhotic rats. (A) Representative traces of Ca2+ currents evoked by depolarizing voltage steps ranging from −60 mV to +50 mV from a holding potential of −80 mV (inset shows the pulse protocol). (B) Current–voltage relationships of Ca2+ channel currents. (C) Summary of the peak Ca2+ channel currents measured at +10 mV. (D) Summary of the relative contributions (% of total currents) of nifedipine-sensitive L-type and ω-conotoxin GVIA-sensitive N-type currents to the total Ca2+ currents in the ICG neurons of the sham, CBDL, and TAA rats. Data are presented as the mean ± SEM. The number of neurons tested is indicated in parentheses. * p < 0.05, ** p < 0.01, *** p < 0.001 compared with the sham rats. Full article ">

9 pages, 221 KiB

Open AccessArticle

Impaired Modulation of the Autonomic Nervous System in Adult Patients with Major Depressive Disorder

by Elise Böttcher, Lisa Sofie Schreiber, David Wozniak, Erik Scheller, Frank M. Schmidt and Johann Otto Pelz

Biomedicines 2024, 12(6), 1268; https://doi.org/10.3390/biomedicines12061268 - 6 Jun 2024

Cited by 2 | Viewed by 1511

Abstract

Patients with major depressive disorder (MDD) have an increased risk for cardiac events. This is partly attributed to a disbalance of the autonomic nervous system (ANS) indicated by a reduced vagal tone and a (relative) sympathetic hyperactivity. However, in most studies, heart rate variability (HRV) was only examined while resting. So far, it remains unclear whether the dysbalance of the ANS in patients with MDD is restricted to resting or whether it is also evident during sympathetic and parasympathetic activation. The aim of this study was to compare the responses of the ANS to challenges that stimulated the sympathetic and, respectively, the parasympathetic nervous systems in patients with MDD. Forty-six patients with MDD (female 27 (58.7%), mean age 44 ± 17 years) and 46 healthy controls (female 26 (56.5%), mean age 44 ± 20 years) underwent measurement of time- and frequency-dependent domains of HRV at rest, while standing (sympathetic challenge), and during slow-paced breathing (SPB, vagal, i.e., parasympathetic challenge). Patients with MDD showed a higher heart rate, a reduced HRV, and a diminished vagal tone during resting, standing, and SPB compared to controls. Patients with MDD and controls responded similarly to sympathetic and vagal activation. However, the extent of modulation of the ANS was impaired in patients with MDD, who showed a reduced decrease in the vagal tone but also a reduced increase in sympathetic activity when switching from resting to standing. Assessing changes in the ANS during sympathetic and vagal activation via respective challenges might serve as a future biomarker and help to allocate patients with MDD to therapies like HRV biofeedback and psychotherapy that were recently found to modulate the vagal tone. Full article

(This article belongs to the Special Issue Autonomic Dysfunction in Neurological Disorders: Novel Mechanisms and Targets)

13 pages, 1659 KiB

Open AccessArticle

Cardiovascular Autonomic Dysfunction in Hospitalized Patients with a Bacterial Infection: A Longitudinal Observational Pilot Study in the UK

by Monica Arias-Colinas, Alfredo Gea, Joseph Kwan, Michael Vassallo, Stephen C. Allen and Ahmed Khattab

Biomedicines 2024, 12(6), 1219; https://doi.org/10.3390/biomedicines12061219 - 30 May 2024

Viewed by 1189

Abstract

Purpose: A temporal reduction in the cardiovascular autonomic responses predisposes patients to cardiovascular instability after a viral infection and therefore increases the risk of associated complications. These findings have not been replicated in a bacterial infection. This pilot study will explore the prevalence of cardiovascular autonomic dysfunction (CAD) in hospitalized patients with a bacterial infection. Methods: A longitudinal observational pilot study was conducted. Fifty participants were included: 13 and 37 participants in the infection group and healthy group, respectively. Recruitment and data collection were carried out during a two-year period. Participants were followed up for 6 weeks: all participants’ cardiovascular function was assessed at baseline (week 1) and reassessed subsequently at week 6 so that the progression of the autonomic function could be evaluated over that period of time. The collected data were thereafter analyzed using STATA/SE version 16.1 (StataCorp). The Fisher Exact test, McNemar exact test, Mann–Whitney test and Wilcoxon test were used for data analysis. Results: 32.4% of the participants in the healthy group were males (n = 12) and 67.6% were females (n = 25). Participants’ age ranged from 33 years old to 76 years old with the majority being 40–60 years of age (62.1%) (Mean age 52.4 SD = 11.4). Heart rate variability (HRV) in response to Valsalva Maneuver, metronome breathing, standing and sustained handgrip in the infection group was lower than in the healthy group throughout the weeks. Moreover, both the HRV in response to metronome breathing and standing up showed a statistically significant difference when the mean values were compared between both groups in week 1 (p = 0.03 and p = 0.013). The prevalence of CAD was significantly higher in the infection group compared to healthy volunteers, both at the beginning of the study (p = 0.018) and at the end of follow up (p = 0.057), when all patients had been discharged. Conclusions: CAD, as assessed by the HRV, is a common finding during the recovery period of a bacterial infection, even after 6 weeks post-hospital admission. This may increase the risk of complications and cardiovascular instability. It may therefore be of value to conduct a wider scale study to further evaluate this aspect so recommendations can be made for the cardiovascular autonomic assessment of patients while they are recovering from a bacterial infectious process. Full article

(This article belongs to the Special Issue Autonomic Dysfunction in Neurological Disorders: Novel Mechanisms and Targets)

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24 pages, 808 KiB

Open AccessReview

Chronic Stress and Headaches: The Role of the HPA Axis and Autonomic Nervous System

by Aleksandar Sic, Marko Bogicevic, Nebojsa Brezic, Clara Nemr and Nebojsa Nick Knezevic

Biomedicines 2025, 13(2), 463; https://doi.org/10.3390/biomedicines13020463 - 13 Feb 2025

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Abstract

Chronic stress significantly influences the pathogenesis of headache disorders, affecting millions worldwide. This review explores the intricate relationship between stress and headaches, focusing on the dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and autonomic nervous system (ANS). Persistent stress could lead to neuroinflammation, increased pain sensitivity, and vascular changes that could contribute to headache development and progression. The bidirectional nature of this relationship creates a vicious cycle, with recurrent headaches becoming a source of additional stress. Dysregulation of the HPA axis and ANS imbalance could amplify susceptibility to headaches, intensifying their frequency and severity. While pharmacological interventions remain common, non-pharmacological approaches targeting stress reduction, such as cognitive-behavioral therapy, biofeedback, and relaxation techniques, offer promising avenues for comprehensive headache management. By addressing the underlying stress-related mechanisms, these approaches provide a sustainable strategy to reduce headache frequency and improve patients’ quality of life. Full article

(This article belongs to the Special Issue Autonomic Dysfunction in Neurological Disorders: Novel Mechanisms and Targets)

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