The heart is controlled by dynamic interactions within the cardiac autonomic nervous system (ANS). This interaction occurs between intrathoracic extracardiac and intrinsic cardiac ganglia as well as between peripheral autonomic ganglia, spinal cord, medulla oblongata, and higher centers. Imbalances in this interdependent neural network at any level in the hierarchy can play an important role in the genesis and maintenance of cardiac diseases. Cardiac neuromodulation therapies targeted to various ganglia in this neural hierarchy to restore such balance can improve cardiac function. In this chapter, different neuromodulation therapies for cardiac diseases with their detailed neuromodulation mechanism will be discussed.

In our original white paper published in the The Journal of Physiology in 2016, we set out our knowledge of the structural and functional organization of cardiac autonomic control, how it remodels during disease, and approaches to exploit such knowledge for autonomic regulation therapy. The aim of this update is to build on this original blueprint, highlighting the significant progress which has been made in the field since and major challenges and opportunities that exist with regard to translation. Imbalances in autonomic responses, while beneficial in the short term, ultimately contribute to the evolution of cardiac pathology. As our understanding emerges of where and how to target in terms of actuators (including the heart and intracardiac nervous system (ICNS), stellate ganglia, dorsal root ganglia (DRG), vagus nerve, brainstem, and even higher centres), there is also a need to develop sensor technology to respond to appropriate biomarkers (electrophysiological, mechanical, and molecular) such that closed-loop autonomic regulation therapies can evolve. The goal is to work with endogenous control systems, rather than in opposition to them, to improve outcomes.

Objective: This study evaluated the effects of cessation of both conventional low-frequency (50 Hz) and high-frequency (10 kHz) spinal cord stimulation (SCS) on the cardiospinal neural network activity in pigs with myocardial infarction (MI). The objective is to provide an insight into the memory effect of SCS. Materials and Methods: In nine Yorkshire pigs, chronic MI was created by delivering microspheres to the left circumflex fl ex coronary artery. Five weeks after MI, anesthetized pigs underwent sternotomy to expose the heart for performing acute ischemia intervention, and laminectomy to expose the T1-T4 - T4 spinal regions for extracellular in vivo neural recording and SCS. Cardiac ischemic-sensitive neurons were identified fi ed by selective responsiveness to left anterior descending (LAD) coronary artery occlusion. SCS episodes were delivered in a random order between low- (50 Hz) and high- (10 kHz) frequency, for 1 minute, at 90% of the motor threshold current. Neural fi ring and synchrony of ischemic-sensitive spinal neurons were evaluated before vs after SCS. Results: Using a 64-channel microelectrode array, 2711 spinal neurons were recorded extracellularly. LAD ischemia excited 228 neurons that were labeled as ischemic-responsive neurons. The cessation of 50-Hz SCS caused a higher activation than did inhibition of ischemic-responsive neurons (41 activated vs 19 inhibited), whereas the cessation of 10-kHz SCS caused an opposite response with higher inhibition (11 activated vs 28 inhibited, p < 0.01 vs 50 Hz). Termination of low-frequency SCS caused an increase in ischemic-responsive neuronal fi ring rate compared with high-frequency SCS (50 Hz: 0.39 Hz +/- 0.16 Hz, 10 kHz: - 0.11 Hz +/- 0.057 Hz, p < 0.01). In addition, SCS delivered at 50 Hz increased the number of synchronized pairs of neurons by 205 pairs, whereas high-frequency SCS decreased the number of synchronized pairs by 345 pairs (p < 0.01). Conclusions: High-frequency (10 kHz) stimulation provides persistent suppression of the ischemia-sensitive neurons after termination of SCS. In contrast, the spinal neural network reverted to excitatory state after termination of low-frequency (50 Hz) stimulation.

IntroductionMyocardial ischemia disrupts the cardio-spinal neural network that controls the cardiac sympathetic preganglionic neurons, leading to sympathoexcitation and ventricular tachyarrhythmias (VTs). Spinal cord stimulation (SCS) is capable of suppressing the sympathoexcitation caused by myocardial ischemia. However, how SCS modulates the spinal neural network is not fully known. MethodsIn this pre-clinical study, we investigated the impact of SCS on the spinal neural network in mitigating myocardial ischemia-induced sympathoexcitation and arrhythmogenicity. Ten Yorkshire pigs with left circumflex coronary artery (LCX) occlusion-induced chronic myocardial infarction (MI) were anesthetized and underwent laminectomy and a sternotomy at 4-5 weeks post-MI. The activation recovery interval (ARI) and dispersion of repolarization (DOR) were analyzed to evaluate the extent of sympathoexcitation and arrhythmogenicity during the left anterior descending coronary artery (LAD) ischemia. Extracellular in vivo and in situ spinal dorsal horn (DH) and intermediolateral column (IML) neural recordings were performed using a multichannel microelectrode array inserted at the T2-T3 segment of the spinal cord. SCS was performed for 30 min at 1 kHz, 0.03 ms, 90% motor threshold. LAD ischemia was induced pre- and 1 min post-SCS to investigate how SCS modulates spinal neural network processing of myocardial ischemia. DH and IML neural interactions, including neuronal synchrony as well as cardiac sympathoexcitation and arrhythmogenicity markers were evaluated during myocardial ischemia pre- vs. post-SCS. ResultsARI shortening in the ischemic region and global DOR augmentation due to LAD ischemia was mitigated by SCS. Neural firing response of ischemia-sensitive neurons during LAD ischemia and reperfusion was blunted by SCS. Further, SCS showed a similar effect in suppressing the firing response of IML and DH neurons during LAD ischemia. SCS exhibited a similar suppressive impact on the mechanical, nociceptive and multimodal ischemia sensitive neurons. The LAD ischemia and reperfusion-induced augmentation in neuronal synchrony between DH-DH and DH-IML pairs of neurons were mitigated by the SCS. DiscussionThese results suggest that SCS is decreasing the sympathoexcitation and arrhythmogenicity by suppressing the interactions between the spinal DH and IML neurons and activity of IML preganglionic sympathetic neurons.

Myocardial infarction (MI) causes neural remodeling in the cardio-spinal network leading to sudden cardiac death. Spinal cord stimulation (SCS), as a novel therapy for cardiac disease, reduces such cardiac sympathoexcitation. In this study, we evaluated the consequence of the cessation of conventional low frequency vs. high-frequency SCS on the cardio-spinal neural network.

Electroacupuncture (EA) is widely used as an effective method to treat stress-related disorders. However, its mechanisms remain largely unknown. The aim of this study was to investigate the effects and mechanisms of EA on gastric slow wave (GSW) dysrhythmia and c-Fos expression in the nucleus of the solitary tract (NTS) induced by stress in a rodent model of functional dyspepsia (FD). Rats in the neonatal stage were treated using intragastric iodoacetamide. Eight weeks later, the rats were implanted with electrodes in the stomach for the measurement of GSW and electrodes into accupoints ST36 for EA. Autonomic functions were assessed by spectral analysis of heart rate variability. Rats were placed for 30 min in a cylindrical plastic tube for acute restraint stress. The involvement of a central afferent pathway was assessed by measuring c-Fos-immunoreactive cells in the NTS. 1) EA normalized restraint stress-induced impairment of GSW in FD rats. 2) EA significantly increased vagal activity ( P = 0.002) and improved sympathovagal balance ( P = 0.004) under stress in FD rats. 3) In FD rats under restraint stress, plasma norepinephrine concentration was increased substantially ( P < 0.01), which was suppressed with EA. 4) The EA group showed increased c-Fos-positive cell counts in the NTS compared with the sham EA group ( P < 0.05) in FD rats. Acute restraint stress induces gastric dysrhythmia in a rodent model of FD. EA at ST36 improves GSW under stress in FD rats mediated via the central and autonomic pathways, involving the NTS and vagal efferent pathway.

This chapter discusses potential neural mechanisms that underlie the referral of anginal pain to somatic structures by using the spinothalamic system as the model. It addresses possible neurophysiological mechanisms that might explain why severe myocardial ischemia could occur without the experience of pain. Mechanosensitive and chemosensitive receptors located in heart transmit information via afferent fibers to the spinal cord. A common feature of cardiac pain sensation is its perceived location in somatic structures overlying or nearby the heart. Vagal afferent fibers do not appear to be involved with the eventual perception of cardiac pain, but evidence has accumulated to suggest that vagal afferent fibers have the capacity to modulate the cardiovascular and pain systems. Electrical and chemical stimulation of vagal afferent fibers can suppress responses to visceral stimuli in conscious animals. The neural mechanisms and pathways involved in the suppression of pinothalamic tract cell activity are unknown, but anatomical, electrophysiological and behavioral results suggests potential pathways for producing this suppression.

Impaired gastric accommodation (GA) has been frequently reported in various gastrointestinal diseases. No standard treatment strategy is available for treating impaired GA. We explored the possible effect of sacral nerve stimulation (SNS) on GA and discovered a spinal afferent and vagal efferent mechanism in rats. Sprague-Dawley rats (450-500 g) with a chronically implanted gastric cannula and ECG electrodes were studied in a series of sessions to study: 1) the effects of SNS with different parameters on gastric tone, compliance, and accommodation using a barostat device; two sets of parameters were tested as follows: parameter 1) 5 Hz, 500 µs, 10 s on 90 s off; 90% motor threshold and parameter 2) same as parameter 1 but 25 Hz; 2) the involvement of spinal afferent pathway via detecting c-fos immunoreactive (IR) cells in the nucleus of the solitary tract (NTS) of the brain; 3) the involvement of vagal efferent activity via the spectral analysis of heart rate variability derived from the ECG; and 4) the nitrergic mechanism, Nω-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase (NOS) inhibitor, was given before SNS at 5 Hz. Compared with sham-SNS: 1) SNS at 5 Hz inhibited gastric tone and increased gastric compliance and GA. No difference was noted between the stimulation frequencies of 5 and 25 Hz. 2) SNS increased the expression of c-fos in the NTS. 3) SNS increased cardiac vagal efferent activity and decreased the sympathovagal ratio. 4) l-NAME blocked the relaxation effect of SNS. In conclusion, SNS with certain parameters relaxes gastric fundus and improves gastric accommodation mediated via a spinal afferent and vagal efferent pathway.NEW & NOTEWORTHY Currently, there is no adequate medical therapy for impaired gastric accommodation, since medications that relax the fundus often impair antral peristalsis and thus further delay gastric emptying that is commonly seen in patients with functional dyspepsia or gastroparesis. The advantage of the potential sacral nerve stimulation therapy is that it improves gastric accommodation by enhancing vagal activity, and the enhanced vagal activity would lead to enhanced antral peristalsis rather than inhibiting it.

Acupuncture has been widely accepted for treatments of many diseases. This study was performed to determine effects and mechanisms of electroacupuncture (EA) by chronically implanted electrodes at acupoint ST36 on colonic inflammation induced by TNBS in rats.

Although sacral nerve stimulation (SNS) has been applied for treating constipation, its parameters were adopted from SNS for fecal incontinence, its effects are limited, and mechanisms are largely unknown. We investigated the effects and mechanism of SNS with appropriate parameters on constipation in rats treated with loperamide. First, using rectal compliance as an outcome measure, an experiment was performed to derive effective SNS parameters. Then, a 7-day SNS was performed in rats with constipation induced by loperamide. Autonomic functions were assessed by spectral analysis of heart rate variability (HRV) derived from an electrocardiogram. Serum levels of pancreatic polypeptide (PP), norepinephrine (NE), and acetylcholine (ACh) in colon were assessed. 1) Acute SNS at 5 Hz, 100 µs was found effective in enhancing rectal compliance and accelerating distal colon transit ( P < 0.05 vs. sham SNS). 2) The 7-day SNS normalized loperamide-induced constipation, assessed by the number, weight, and water content of fecal pellets, and accelerated the distal colon transit (29.4 ± 3.7 min with sham SNS vs. 16.4 ± 5.3 min with SNS but not gastric emptying or intestinal transit. 3) SNS significantly increased vagal activity ( P = 0.035) and decreased sympathetic activity ( P = 0.012), assessed by spectral analysis of HRV as well as by the serum PP. 4) SNS increased ACh in the colon tissue; atropine blocked the accelerative effect of SNS on distal colon transit. We concluded that SNS with appropriate parameters improves constipation induced by loperamide by accelerating distal colon motility, mediated via the autonomic-cholinergic function. NEW & NOTEWORTHY Although sacral nerve stimulation (SNS) has been applied for treating constipation, its parameters were adopted from SNS for fecal incontinence, effects are limited, and mechanisms are largely unknown. This paper shows that SNS with appropriate parameters improves constipation induced by loperamide by accelerating distal colon motility mediated via the autonomic-cholinergic function.

The purpose of this study was to define the mechanism by which cardiac neuraxial decentralization or spinal cord stimulation (SCS) reduces ischemia-induced ventricular fibrillation (VF). Direct measurements of norepinephrine (NE) levels in the left ventricular interstitial fluid (ISF) by microdialysis, in response to transient (15-minute) coronary artery occlusion (CAO), were performed in anesthetized canines. Responses were studied in animals with intact neuraxes and were compared with those in which the intrathoracic component of the cardiac neuraxes (stellate ganglia) or the intrinsic cardiac neuronal (ICN) system was surgically delinked from the central nervous system and those with intact neuraxes with preemptive SCS (T1-T3). With intact neuraxes, animals with exaggerated NE release due to CAO were at increased risk for VF. During CAO, there was a 152% increase in NE when the neuraxes were intact compared with 114% following stellate decentralization and 16% following ICN decentralization. During SCS, CAO NE levels increased by 59%. Risk for CAO-induced VF was 38% in controls, 8% following decentralization, and 11% following SCS. These data indicate that ischemia-related afferent neuronal transmission differentially engages central and intrathoracic sympathetic reflexes and amplifies sympathoexcitation. Differences in regional ventricular NE release are associated with increased risk for VF. Surgical decentralization or SCS reduced NE release and VF.

Introduction: Clinical high frequency spinal cord stimulation (hfSCS) (>=250Hz) applied at sub-perception amplitudes reduces neuropathic pain without paresthesias associated with direct dorsal column (DC) activation predicted by the Gate Control hypothesis. More recently, direct dorsal horn modulation has been implicated as a potential mechanism of action for therapeutic effects, but supporting evidence remains sparse. This study investigates whether hfSCS applied at amplitudes below DC threshold may directly modulate dorsal horn elements using computational modeling and immunohistochemical labeling for c-fos-a marker of neural activation.

Background/Aims Postoperative ileus increases healthcare costs and reduces the postoperative quality of life (QOL). The aim of this study is to investigate effects and mechanisms of electroacupuncture (EA) at ST36 and PC6 on gastrointestinal motility in rat model of postoperative ileus. Methods Laparotomy was performed in 24 rats (control [n = 8], sham-EA [n = 8], and EA [n = 8]) for the implantation of electrodes in the stomach and mid-jejunum for recording of gastric and small intestinal slow waves. Electrodes were placed in the chest skin for electrocardiogram (ECG). Intestinal manipulation (IM) was performed in Sham-EA and EA rats after surgical procedures. Small intestinal transit (SIT), gastric emptying (GE), postoperative pain, and plasma TNF-α were evaluated in all rats. Results (1) Compared with sham-EA, EA accelerated both SIT (P < 0.05) and GE (P < 0.05) and improved regularity of small intestinal slow waves. (2) Compared with the control rats (no IM), IM suppressed vagal activity and increased sympathovagal ratio assessed by the spectral analysis of heart rate variability from ECG, which were significantly prevented by EA. (3) EA significantly reduced pain score at 120 minutes (P < 0.05, vs 15 minutes) after the surgery, which was not seen with sham-EA. (4) Plasma TNF-α was increased by IM (P = 0.02) but suppressed by EA (P = 0.04) but not sham-EA. Conclusion The postoperative ileus induced by IM, EA at ST36 and PC6 exerts a prokinetic effect on SIT and GE, a regulatory effect on small intestinal slow waves and an analgesic effect on postoperative pain possibly mediated via the autonomic-cytokine mechanisms.

Flor, Herta; Foreman, Robert D.; Gebhart, Gerald F.; Jänig, Wilfrid; Schaible, Hans-Georg Author Information

BACKGROUND:Electroacupuncture (EA) has been shown to be effective in reducing symptoms in patients with functional dyspepsia (FD). However, its mechanisms remain largely unknown. The aim of this study was to investigate mechanisms of the prokinetic effects of EA in a rodent model of FD. METHODS:A FD model was established by neonatal treatment of iodoacetamide (IA). Eight weeks later, the rats were implanted with electrodes in the stomach for the measurement of gastric slow waves (GSW) and electrodes into acupoints ST36 for EA. Autonomic functions were assessed by the spectral analysis of heart rate variability. KEY RESULTS:(i) The IA-treated rats ("FD" rats) showed increased dysrhythmia in both fasting and fed states (P < .01) as well as during rectal distention (P < .02). EA reduced the percentage of dysrhythmia (P < .05 for both fasting and fed) and normalized RD-induced impairment in GSW in "FD" rats. Atropine blocked the effect of EA on GSW. (ii) "FD" rats showed delayed gastric emptying (P = .001 vs control) that was accelerated with EA (P = .01, vs sham-EA). (iii) "FD" rats showed increased plasma norepinephrine (P = .006, vs control) that was suppressed with EA (P = .003) and reduced vagal activity that was improved with EA. CONCLUSIONS AND INFERENCES:Gastric motility (GSW and GE) is impaired in rats treated with IA, possibly attributed to impaired autonomic functions. EA improves GSW and accelerates GE mediated via the autonomic and cholinergic mechanisms.

Postoperative ileus (POI) is a heavy burden for healthcare industries and reduces the postoperative quality of life. The aim of this study was to investigate the effects and mechanisms of the intraoperative vagus nerve stimulation (iVNS) on gastrointestinal motility in a rodent model of POI.