Introductory Chapter: Electroceuticals of Autonomic Nervous System

1. Introduction

The electrical stimulation of human tissue for therapeutic purposes is not a recent concept. Scientists have long ago dallied with the idea of delivering electrical current with implanted devices on human tissue for the development of highly selective organ-specific treatment, instead of using systemic pharmacotherapy. Back on the 70’s Braunwald tested electrical stimulation of the carotid sinus nerve to treat cardiac disease [1]. Nowadays, cardiac pacemaker/defibrillator is widely applied as an electrical device used to deliver a current discharge on myocardial tissue in the attempt of setting the pace of cardiac activity or resetting cardiac electrical stability [2].

The nervous system is very appealing for the application of this notion. As an interconnected network of many billions of cells which communicate by sending electrical impulses, the nervous system regulates a vast landscape of organ function. Neuroscience has made a great deal of effort over the last century to understand how information is presented and processed by neuronal circuits in the brain and spinal cord. Neural interface technologies have been used for stimulation and recording. Electrical current applied to specific parts of the nervous system causes neurons to transmit signals to their targets, whereas in other cases electrical stimulation may disrupt the signal being conveyed by nearby neurons. Neurostimulation technology offers new opportunities. Ιn recent years stimulation of neural structures have been used for treatment of neurological disorders and injury. Paralyzed people have been able to move [3], lost hearing has been restored with cochlear implants [4] and Parkinson’s disease’s symptoms have been alleviated with deep brain stimulation.

Neurostimulation can be delivered selectively to specific parts of the nervous system by several means. Neural structures can be stimulated with electrical current passed through the skin or with non-implantable methods such as transcranial magnetic stimulation, focused ultrasound and high-frequency electrical fields. However, the mainstay of neurostimulation is implantation of electrodes within the body, a process which requires complex surgery on delicate neural tissues. The Central Nervous System (CNS) areas contain anatomically overlapping cell populations with diverse functions. Thus, lowering an electrode into a deep brain structure has the risk of producing non-selective effects and damaging surrounding areas. Autonomic Nervous System, which is used by the brain to influence other organs in the body, is different, though.

2. Specific applications

The Autonomic Nervous System (ANS) comprises neural cell bodies located in CNS and peripheral ganglia. The fibers of ANS neurons get mixed within cranial and spinal peripheral nerves creating afferent and efferent bundles that supply smooth muscle and glands. This way, complex peripheral neural networks that influence the function of internal organs are in intimate association with their target tissues [5]. These peripheral neural networks are located in the thorax and viscera influencing the function of internal organs. Functions controlled by these neural networks include tracheal and bronchial secretions, cardiac activity, arteriole diameter, pancreatic cell secretions, gastrointestinal motility and secretions, urinary bladder contraction, immune system function and mobilization of energy stores from liver and fat [6, 7, 8].

The aforementioned explain why ANS peripheral nerves and ganglia are principal targets for electrical neurostimulation therapy. They are typically located peripherally and so are easily accessed by surgery with lower risk of tissue damage. They lack the anatomical and physiological complexity of CNS regions, thus lowering the possibility of non-selective adverse effects. Finally, they are implicated in a large variety of body functions making it appealing to try to produce therapeutic effects by “fine tuning” their complex interactions.

The control of complex neural circuits with electroceutical therapy for treatment of diseases is based on the novel concept of the neural fulcrum. That is, when bioelectric interventions push the autonomic neural networks in one direction, the endogenous reflex control pushes back. The result is that, although there are minimal changes in basal function, the response of the entire network to stress is restrained. This way the hyperdynamic reflex responses, commonly associated with disease progression, are counteracted [9].

Stimulation of organs’ neural circuits requires sophisticated implantable electronic devices. These medical devices are called electroceuticals and they incorporate novel biocompatible materials, miniature electronics and computer software to modulate neuronal signaling. Over the past few years research focused on developing electronic devices for selective organ-specific treatment and fewer side-effects. The goal is to produce electroceuticals with grater selectivity and fewer complications [10]. In addition to functionality, device miniaturization, conformability, biocompatibility, and/or biodegradability are the main engineering targets [11].

Electroceutical targeting of the ANS highlights recent advances in the field of electrical neuromodulation and contributes to the treatment of numerous diseases. Targeting of cardiac disease is one clear example. The T₁–T₂ region of the paravertebral chain has been identified as a critical nexus point for sympathetic control of the heart [12]. Application of an electroceutical device to the T₁–T₂ region blocks the sympathetic outflow to the heart without compromising basal cardiac function. In this case electroceuticals aim to restrain the hyperdynamic sympathetic response/withdrawal of central parasympathetic tone which is implicated in the pathophysiology of heart failure [13] and arrhythmias [14]. Electrical stimulation of nerves innervating the carotid sinus activates local baroreceptors resulting in reduced sympathetic outflow and augmented parasympathetic tone providing effective treatment for patients with resistant hypertension [15]. Spinal cord stimulation is also used for pain management [16] and for promoting neural repair and regeneration after injury or for modulating neural plasticity mechanisms that may assist to recover lost functions [17].

Vagus nerve is an important therapeutic target of electroceuticals because it contains afferent and efferent pathways implicated in the communication between brain and abdominal organs. Gastrointestinal tract, pancreas and hepatic portal vein are innervated by vagal branches and their malfunction is linked to gastrointestinal, metabolic and inflammatory diseases. Abdominal vagus nerve stimulation is supported by clinical trials and has been approved for the treatment of gastrointestinal motility disturbances like gastroparesis [18] and for weight loss in moderately obese patients [19]. Cervical vagus nerve stimulation has been shown to reduce inflammatory cytokines and have anti-inflammatory actions [20] that extend for a long period of time after brief stimulation, providing promising results for clinical remission of Crohn’s disease [21] and rheumatoid arthritis [22]. Cervical vagus nerve stimulation devices are also used to control epileptic seizures [23] and treatment-resistant depression [24]. In this case the therapeutic mechanism is unclear, but large-scale changes in CNS activity are indicated by functional imaging studies [25]. However, the efficacy of vagus nerve stimulation in the treatment of epilepsy and depression is low (30%), because reduced stimulatory levels are obligatory in order to avoid adverse effects from non-selective stimulation of the cervical vagus trunk.

Bladder dysfunction affects a large population and control of bladder function is implicated in the field of electroceuticals of ANS. Sacral nerve stimulation is approved for treatment of urinary incontinence [26], while the efficacy of the method in neurogenic bladder dysfunction after spinal cord injury is under exploration [27].

Despite the application of electroceuticals of ANS in modern medicine and their participation in the treatment of several pathological conditions with important clinical effects, this technology has still a long way to go. The studies published include a large variety of organ systems, target nerves and diseases and the parameters of electrical stimulations used are diverse regarding amplitude, pulse duration, duty cycle and frequency. These parameters were often developed in animal studies and applied directly to human studies, and they were mostly empirically determined without in depth understanding of the underlying effects of stimulation.

3. Conclusions: perspectives

Electroceutical devices of ANS are unquestionably part of future medicine. An ongoing challenge is to refine electrode position and clarify stimulation patterns in order to achieve increased nerve region and physiological pathways selectivity. Another goal is to develop closed-loop circuits which use sensors designed to quantify neural activity from axons. This dynamic readout will be used by the device’s control center to adjust and “tune” the level of neuromodulation. Wireless power delivery to implanted electrodes using focused beam-forming energy to avoid complex or follow-up surgery for the removal of an implanted battery is also under research.

However, the most important parameter, remains the development of a deeper understanding of the underlying biological effects of electrical neurostimulation. Comprehension of precise molecular and physiological changes of ANS during electrical stimulation is the golden key for more effective future electroceutical devices.

Conflict of interests

The author has no conflict of interest.