Next generation bioelectronic medicine: making the case for non-invasive closed-loop autonomic neuromodulation

Abstract

The field of bioelectronic medicine has advanced rapidly from rudimentary electrical therapies to cutting-edge closed-loop systems that integrate real-time physiological monitoring with adaptive neuromodulation. Early innovations, such as cardiac pacemakers and deep brain stimulation, paved the way for these sophisticated technologies. This review traces the historical and technological progression of bioelectronic medicine, culminating in the emerging potential of closed-loop devices for multiple disorders of the brain and body. We emphasize both invasive techniques, such as implantable devices for brain, spinal cord and autonomic regulation, while we introduce new prospects for non-invasive neuromodulation, including focused ultrasound and newly developed autonomic neurography enabling precise detection and titration of inflammatory immune responses. The case for closed-loop non-invasive autonomic neuromodulation (incorporating autonomic neurography and splenic focused ultrasound stimulation) is presented through its applications in conditions such as sepsis and chronic inflammation, illustrating its capacity to revolutionize personalized healthcare. Today, invasive or non-invasive closed-loop systems have yet to be developed that dynamically modulate autonomic nervous system function by responding to real-time physiological and molecular signals; it represents a transformative approach to therapeutic interventions and major opportunity by which the bioelectronic field may advance. Knowledge gaps remain and likely contribute to the lack of available closed loop autonomic neuromodulation systems, namely, (1) significant exogenous and endogenous noise that must be filtered out, (2) potential drift in the signal due to temporal change in disease severity and/or therapy induced neuroplasticity, and (3) confounding effects of exogenous therapies (e.g., concurrent medications that dysregulate autonomic nervous system functions). Leveraging continuous feedback and real-time adjustments may overcome many of these barriers, and these next generation systems have the potential to stand at the forefront of precision medicine, offering new avenues for individualized and adaptive treatment.

Keywords: Autonomic neurography; Bioelectronic medicine; Closed loop bioelectronic medicine; Focused ultrasound stimulation; Neurography; Neuromodulation; Vagus nerve.

Fig. 1

Closed Loop Neuromodulation/Cardiac Devices: input a signal that modulates the output of the neuromodulation target (Dark Orange Arrows = sensing, Light Green Arrows = Stimulation). By definition, closed loop neuromodulation requires a continuous sensing modality that then continuously modifies the stimulation parameter. Autonomic Neuromodulation may include invasive electrical neural stimulation, as well as non-invasive electrical (e.g., transcutaneous vagus nerve stimulation (tcVNS)] and directed energy devices that contribute to autonomic nervous system modulation effects, (e.g., with splenic focused ultrasound stimulation (sFUS)). Current devices on the market include conventional cardiac pacemakers (Diack et al. 1979) (A), and Closed Loop Evoked Compound Action Potential (ECAP) spinal cord stimulation (SCS) marketed for pain (Caylor et al. 2019) (B). Recent advances in brain recording have resulted in development of Close Loop Deep Brain Stimulation (DBS) and Closed Loop Transcranial Magnetic Stimulation (TMS) (C). Closed Loop DBS is now FDA approved for Parkinson’s Disease (PD) and epilepsy, while other disease states are currently being studied (e.g., PTSD or Depression (Widge 2023), Pain (Shirvalkar et al. 2018), and Alzheimer's Disease (Ríos et al. ; Hell et al. 2019)). Future Closed Loop Autonomic Neuromodulation (D) is under development in which inflammation is sensed with Autonomic Neurography (ANG) that can then drive autonomic neuromodulation delivered or to hone in on the dosage, aimed to amplify the body’s own vagus-driven anti-inflammatory reflex, thus throttling down inflammation by regulating macrophages that circulate through the spleen

Fig. 2

Current neuromodulation instantiates a one dose fits all approach. In the near future, personalized medicine employing sensing platforms may identify fingerprints of biomarkers. They will include inflammatory pathways, neuroimmune axis, and/or central sensitization (common in chronic pain syndromes) as bioindicators useful in titration of the therapeutic stimulation paradigm, such as with electrical stimulation or ultrasound stimulation of neural and non-neural cells. Titrated therapeutic stimulation may span dosage duration and/or frequency of dosage during a circadian cycle. Closed loop stimulation titrated in real time can provide an optimized density of therapeutic energy preventing neuroplasticity induced adaptation

Fig. 3

Current FDA approved closed loop devices include cardiac pacemakers, spinal cord stimulation (SCS) for pain, and closed-loop deep brain stimulation for epilepsy, Parkinson’s Disease (PD), and Essential Tremor (ET) and non-invasive closed-loop transcranial magnetic stimulation (TMS) for Depression (blue line: in development; light orange line: in trial; light green line: FDA approved). Clinical trials are currently underway testing efficacy of: closed loop SCS for stroke and motor paralysis, closed loop deep brain stimulation for depression and Alzheimer’s disease. Devices are in development to provide minimally and noninvasive closed loop autonomic neuromodulation. Invasive: vertical lined bar; minimally invasive: cross-hatched bar; and non-invasive: checkered bar. miVNS: minimally invasive VNS; tcVNS: transcutaneous cervical vagus nerve stimulation; taVNS: transauricular VNS; sFUS: focused ultrasound stimulation