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RESEARCH

Depression and Potential Novel Therapeutics

We are exploring the potential effects of a novel, non-invasive form of stimulation, called transcutaneous vagus nerve stimulation (tVNS). We have recently developed an optimized tVNS approach  that gates stimulation of the auricular branch of vagus nerve (ABVN) to the respiratory rhythm, and are studying the effects of this stimulation in the treatment of the comorbidity between major depression and cardiovascular disease.

The Background 

Figure 1. Vagus nerve distribution
Figure 1. Vagus nerve distribution
The vagus (Figure 1) is the longest nerve in the body, connecting the brain to visceral organs such as the heart and abdominal organs, allowing the vagus to regulate cardiac and gut functions. In addition, vagal information is transferred to brain areas involved in the regulation of emotional stress.Vagus Nerve Stimulation (VNS) is an already established brain stimulation technique consisting of implanting electrodes to electrically stimulate the vagus nerve in the neck and regulate its activity. This method has shown beneficial effects in the treatment of depression and epilepsy and promising findings for cardiovascular disease. Despite promising clinical applications, implanted VNS requires invasive surgery, and thus the costs and associated complications have limited its applicability. Interestingly, a branch of the vagus nerve extends to a specific, easily accessible location in the ear. Our group recently devised a novel, non-invasive VNS technique to stimulate this specific location (Figure 2), and use the person’s own respiratory and cardiac activity to enhance the efficacy of stimulation to activate brain areas regulating cardiac function and stress response (see Figure 3). Auricular information flows through jugular (superior) ganglion to the nucleus of the solitary tract (NTS) in the brainstem, from which tVNS can impact multiple clinically-relevant pathways (e.g,   hypothalamic-pituitary-adrenal axis. heart) (Figure 3).

Recent Work

In recent experiments , we have found important regulation of depressed mood, anxiety levels and blood pressure. Our group is now developing clinical studies aimed to evaluate the therapeutic potential of our intervention to regulate cardiovascular function, reduce the release of stress hormones, inflammatory factors, and depressed mood, and ultimately improve cardiovascular, metabolic and brain health. Our intention is also to advance the development of this technology to a wearable system that allows for easy administration of the stimulation while sensing physiological signals in the body to regulate the treatment accordingly. This system will be able to transmit data to a remote monitoring unit operated by healthcare personnel for the control of therapeutic goals. We believe that our technology has applications in patients with major depression and anxiety disorders with comorbid hypertension, coronary heart disease and heart failure among other cardiovascular disorders.

 Figure 2. Auricular Vagus nerve stimulation
Figure 2. Auricular Vagus nerve stimulation
Figure 3. Mechanisms for auricular non-invasive VNS
Figure 3. Mechanisms for auricular non-invasive VNS

The NTS receives inputs from ventral respiratory group (VRG) nuclei in the medulla: inhibitory during inhalation, and facilitatory during exhalation. The results of our recent study of RAVANS modulatory effects on brainstem acitivty and connectivity in at 3T, showed that RAVANS tVNS can augment NTS activity when stimuli are delivered during exhalation. Based on these findings, we believe NTS targeting can be optimized through exhalation-gated RAVANS.

Figure 4. Nucleus tractus solitarii activation with expiratory-gated tVNS.
Figure 4. Nucleus tractus solitarii activation with expiratory-gated tVNS.

Recent Work

Vagus Nerve Stimulation: Integration of Behavior and Cardiac Modulation

Principal Investigator: Jill Goldstein, PhD

We are looking at acute effects of tVNS on cerebral blood flow in MDD patients, the acute effects of tVNS on vagal tone and mood in MDD patients. In this study, we are also comparing the effects of exhalation-gated tVNS with inhalation-gated tVNS on cerebral blood flow, vagal tone and mood regulation in MDD patients.

Effects of Transcutaneous Vagal Nerve Stimulation on Hypertension

Principal Investigator: Riccardo Barbieri, PhD

We are evaluating the short term effects of respiratory-gated Transcutaneous Vagal Nerve Stimulation (tVNS) on cardiovagal activity in subjects with Hypertension. Additionally, we are testing the potential effects of respiratory-gated tVNS in regulating cardiac autonomic tone and blood pressure levels in hypertensive subjects.

Cardiorespiratory-gated tVNS for the Treatment of Hypertension and its Comorbidity with Major Depression

Principal Investigator: Jill Goldstein, PhD

In this study, we are testing the potential effects of respiratory-gated tVNS in regulating cardiac autonomic tone and blood pressure levels in hypertensive subjects as well as evaluating differences between HF-HRV (parasympathetic index), depressive symptomatology and presence of adverse events related to the administration of cardiorespiratory-gated tVNS.

Mapping the Linkage between Auricular Vagus Nerve Receptors and Cardiovagal Modulation

Principal Investigator: Vitaly Napadow, PhD, LicAc

Vagus nerve stimulation may be an important neuromodulatory approach to impact heart function, and cutaneous vagal receptors can be targeted as a non-invasive approach to vagus nerve stimulation. Our proposal will apply non-invasive ultrahigh field MRI in humans, and cervical vagus nerve activity recording in rats to map the neurophysiological pathway from the auricular branch of the vagus nerve to the heart.

A Translation Approach to Cardiorespiratory-Gated Stimulation of the of the Auricular Branch of the Vagus Nerve for the Treatment of Major Depression

Principal Investigator: Ronald Garcia, MD, PhD

The proposed work will evaluate the relationship between short term effects of this novel intervention in physiological markers in major depressed patients with reduction of depressive symptomatology after a two-week stimulation course.