Dataset Information

Closed-Loop Vagus Nerve Stimulation for the Treatment of Cardiovascular Diseases: State of the Art and Future Directions.

ABSTRACT: The autonomic nervous system exerts a fine beat-to-beat regulation of cardiovascular functions and is consequently involved in the onset and progression of many cardiovascular diseases (CVDs). Selective neuromodulation of the brain-heart axis with advanced neurotechnologies is an emerging approach to corroborate CVDs treatment when classical pharmacological agents show limited effectiveness. The vagus nerve is a major component of the cardiac neuroaxis, and vagus nerve stimulation (VNS) is a promising application to restore autonomic function under various pathological conditions. VNS has led to encouraging results in animal models of CVDs, but its translation to clinical practice has not been equally successful, calling for more investigation to optimize this technique. Herein we reviewed the state of the art of VNS for CVDs and discuss avenues for therapeutic optimization. Firstly, we provided a succinct description of cardiac vagal innervation anatomy and physiology and principles of VNS. Then, we examined the main clinical applications of VNS in CVDs and the related open challenges. Finally, we presented preclinical studies that aim at overcoming VNS limitations through optimization of anatomical targets, development of novel neural interface technologies, and design of efficient VNS closed-loop protocols.

SUBMITTER: Ottaviani MM

PROVIDER: S-EPMC9021417 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Closed-Loop Vagus Nerve Stimulation for the Treatment of Cardiovascular Diseases: State of the Art and Future Directions.

Ottaviani Matteo Maria MM Vallone Fabio F Micera Silvestro S Recchia Fabio A FA

Frontiers in cardiovascular medicine 20220407

The autonomic nervous system exerts a fine beat-to-beat regulation of cardiovascular functions and is consequently involved in the onset and progression of many cardiovascular diseases (CVDs). Selective neuromodulation of the brain-heart axis with advanced neurotechnologies is an emerging approach to corroborate CVDs treatment when classical pharmacological agents show limited effectiveness. The vagus nerve is a major component of the cardiac neuroaxis, and vagus nerve stimulation (VNS) is a pro ...[more]

PMID: 35463766

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Project description:Brain stimulation (BStim) encompasses multiple modalities (e.g., deep brain stimulation, responsive neurostimulation) that utilize electrodes implanted in deep brain structures to treat neurological disorders. Currently, BStim is primarily used to treat movement disorders such as Parkinson's, though indications are expanding to include neuropsychiatric disorders like depression and schizophrenia. Traditional BStim systems are "open-loop" and deliver constant electrical stimulation based on manually-determined parameters. Advancements in BStim have enabled development of "closed-loop" systems that analyze neural biomarkers (e.g., local field potentials in the sub-thalamic nucleus) and adjust electrical modulation in a dynamic, patient-specific, and energy efficient manner. These closed-loop systems enable real-time, context-specific stimulation adjustment to reduce symptom burden. Machine learning (ML) has emerged as a vital component in designing these closed-loop systems as ML models can predict / identify presence of disease symptoms based on neural activity and adaptively learn to modulate stimulation. We queried the US National Library of Medicine PubMed database to understand the role of ML in developing closed-loop BStim systems to treat epilepsy, movement disorders, and neuropsychiatric disorders. Both neural and non-neural network ML algorithms have successfully been leveraged to create closed-loop systems that perform comparably to open-loop systems. For disorders in which the underlying neural pathophysiology is relatively well understood (e.g., Parkinson's, essential tremor), most work has involved refining ML models that can classify neural signals as aberrant or normal. The same is seen for epilepsy, where most current research has focused on identifying optimal ML model design and integrating closed-loop systems into existing devices. For neuropsychiatric disorders, where the underlying pathologic neural circuitry is still being investigated, research is focused on identifying biomarkers (e.g., local field potentials from brain nuclei) that ML models can use to identify onset of symptoms and stratify severity of disease.

Project description:Stroke is a major disorder of the central nervous system that poses a serious threat to human life and quality of life. Many stroke victims are left with long-term neurological dysfunction, which adversely affects the well-being of the individual and the broader socioeconomic impact. Currently, post-stroke brain dysfunction is a major and difficult area of treatment. Vagus nerve stimulation is a Food and Drug Administration-approved exploratory treatment option for autism, refractory depression, epilepsy, and Alzheimer's disease. It is expected to be a novel therapeutic technique for the treatment of stroke owing to its association with multiple mechanisms such as altering neurotransmitters and the plasticity of central neurons. In animal models of acute ischemic stroke, vagus nerve stimulation has been shown to reduce infarct size, reduce post-stroke neurological damage, and improve learning and memory capacity in rats with stroke by reducing the inflammatory response, regulating blood-brain barrier permeability, and promoting angiogenesis and neurogenesis. At present, vagus nerve stimulation includes both invasive and non-invasive vagus nerve stimulation. Clinical studies have found that invasive vagus nerve stimulation combined with rehabilitation therapy is effective in improving upper limb motor and cognitive abilities in stroke patients. Further clinical studies have shown that non-invasive vagus nerve stimulation, including ear/cervical vagus nerve stimulation, can stimulate vagal projections to the central nervous system similarly to invasive vagus nerve stimulation and can have the same effect. In this paper, we first describe the multiple effects of vagus nerve stimulation in stroke, and then discuss in depth its neuroprotective mechanisms in ischemic stroke. We go on to outline the results of the current major clinical applications of invasive and non-invasive vagus nerve stimulation. Finally, we provide a more comprehensive evaluation of the advantages and disadvantages of different types of vagus nerve stimulation in the treatment of cerebral ischemia and provide an outlook on the developmental trends. We believe that vagus nerve stimulation, as an effective treatment for stroke, will be widely used in clinical practice to promote the recovery of stroke patients and reduce the incidence of disability.

Project description:ObjectiveFor epilepsy patients with drug-resistant, unresectable epilepsy, vagus nerve stimulation (VNS) is an option for seizure control. Approximately 40-70% of patients will achieve ≥50% seizure reduction with VNS. New closed loop VNS models detect ictal tachycardia and responsively stimulate the vagus nerve. The effectiveness of closed loop VNS compared to traditional VNS for pediatric epilepsy is unknown.MethodsAn 11-year retrospective electronic medical record review at Children's Hospital of Pittsburgh was performed. Patients with drug-resistant epilepsy who underwent VNS implantation were included. Patients were divided into groups based on VNS model: traditional versus closed loop. Those who transitioned from traditional to closed loop VNS were excluded. Given potential for selection bias, propensity scores matching was utilized to compare traditional to closed loop VNS patients. Patients with focal versus generalized epilepsy were also separately analyzed. The primary outcome was "VNS response", defined as at least 50% seizure frequency reduction from baseline.ResultsA total of 320 patients were included in this sample. The percentage of matched patients (total n = 220: n = 179 traditional VNS, n = 41 closed loop VNS) who responded to VNS after one year of therapy was 43% for traditional VNS and 39% for closed loop VNS (p = 0.64). After two years of therapy, a higher proportion of closed loop VNS patients than traditional VNS patients responded to VNS among all subgroups, though no differences were statistically significant (p>0.05). Notably, for those with generalized epilepsy, 73% of closed loop patients responded to VNS compared to only 46% of traditional patients (p = 0.10). After two years of VNS therapy, patients were taking approximately the same quantity of antiseizure medications as baseline (change of +0.074 +/- 0.90 ) with no difference between VNS models (p = 0.87).SignificanceAmong pediatric patients with drug-resistant epilepsy, closed loop VNS trends towards a higher rate of VNS response after two years of treatment, especially among generalized epilepsy patients. Neither model of VNS allows patients to reduce antiseizure medication quantity after two years.

Project description:BackgroundAutonomic nerve stimulation is used as a treatment for a growing number of diseases. We have previously demonstrated that application of efferent vagus nerve stimulation (eVNS) has promising glucose lowering effects in a rat model of type 2 diabetes. This paradigm combines high frequency pulsatile stimulation to block nerve activation in the afferent direction with low frequency stimulation to activate the efferent nerve section. In this study we explored the effects of the parameters for nerve blocking on the ability to inhibit nerve activation in the afferent direction. The overarching aim is to establish a blocking stimulation strategy that could be applied using commercially available implantable pulse generators used in the clinic.MethodsMale rats (n = 20) had the anterior abdominal vagus nerve implanted with a multi-electrode cuff. Evoked compound action potentials (ECAP) were recorded at the proximal end of the electrode cuff. The efficacy of high frequency stimulation to block the afferent ECAP was assessed by changes in the threshold and saturation level of the response. Blocking frequency and duty cycle of the blocking pulses were varied while maintaining a constant 4 mA current amplitude.ResultsDuring application of blocking at lower frequencies (≤ 4 kHz), the ECAP threshold increased (ANOVA, p < 0.001) and saturation level decreased (p < 0.001). Application of higher duty cycles (> 70%) led to an increase in evoked neural response threshold (p < 0.001) and a decrease in saturation level (p < 0.001). During the application of a constant pulse width and frequency (1 or 1.6 kHz, > 70% duty cycle), the charge delivered per pulse had a significant influence on the magnitude of the block (ANOVA, p = 0.003), and was focal (< 2 mm range).ConclusionsThis study has determined the range of frequencies, duty cycles and currents of high frequency stimulation that generate an efficacious, focal axonal block of a predominantly C-fiber tract. These findings could have potential application for the treatment of type 2 diabetes.

Dataset Information

Closed-Loop Vagus Nerve Stimulation for the Treatment of Cardiovascular Diseases: State of the Art and Future Directions.

Publications

Closed-Loop Vagus Nerve Stimulation for the Treatment of Cardiovascular Diseases: State of the Art and Future Directions.

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