Closed-Loop Transcutaneous Auricular Vagal Nerve Stimulation: Current Situation and Future Possibilities

Closed-loop (CL) transcutaneous auricular vagal nerve stimulation (taVNS) was officially proposed in 2020. This work firstly reviewed two existing CL-taVNS forms: motor-activated auricular vagus nerve stimulation (MAAVNS) and respiratory-gated auricular vagal afferent nerve stimulation (RAVANS), and then proposed three future CL-taVNS systems: electroencephalography (EEG)-gated CL-taVNS, electrocardiography (ECG)-gated CL-taVNS, and subcutaneous humoral signals (SHS)-gated CL-taVNS. We also highlighted the mechanisms, targets, technical issues, and patterns of CL-taVNS. By reviewing, proposing, and highlighting, this work might draw a preliminary blueprint for the development of CL-taVNS.

Electroconvulsive therapy, electric field, neuroplasticity, and clinical outcomes

Electroconvulsive therapy (ECT) remains the gold-standard treatment for patients with depressive episodes, but the underlying mechanisms for antidepressant response and procedure-induced cognitive side effects have yet to be elucidated. Such mechanisms may be complex and involve certain ECT parameters and brain regions. Regarding parameters, the electrode placement (right unilateral or bitemporal) determines the geometric shape of the electric field (E-field), and amplitude determines the E-field magnitude in select brain regions (e.g., hippocampus). Here, we aim to determine the relationships between hippocampal E-field strength, hippocampal neuroplasticity, and antidepressant and cognitive outcomes. We used hippocampal E-fields and volumes generated from a randomized clinical trial that compared right unilateral electrode placement with different pulse amplitudes (600, 700, and 800 mA). Hippocampal E-field strength was variable but increased with each amplitude arm. We demonstrated a linear relationship between right hippocampal E-field and right hippocampal neuroplasticity. Right hippocampal neuroplasticity mediated right hippocampal E-field and antidepressant outcomes. In contrast, right hippocampal E-field was directly related to cognitive outcomes as measured by phonemic fluency. We used receiver operating characteristic curves to determine that the maximal right hippocampal E-field associated with cognitive safety was 112.5 V/m. Right hippocampal E-field strength was related to the whole-brain ratio of E-field strength per unit of stimulation current, but this whole-brain ratio was unrelated to antidepressant or cognitive outcomes. We discuss the implications of optimal hippocampal E-field dosing to maximize antidepressant outcomes and cognitive safety with individualized amplitudes.

Investigation of an embedded closed-loop stimulation current control principle based on the use of nonlinear ceramic capacitors

Over the years, a constant progress in the development of implantable medical devices (IMD’s) can be observed. On one hand, the advanced implantable electronics enable the implementation of numerous smart functionalities, on the other hand, the variety of electronic components including sensors and a bulky battery severely restrict their degree of miniaturization and reliability. To overcome this limitation, our approach is to realize smart functionalities in leadless and battery-free IMD’s emerging from frugal innovation by exploiting the intrinsic nonlinear properties of the components to be used anyway. The aim of this work is to deepen the understanding of the dynamic behavior of circuit topologies of nonlinear ferroelectric ceramic capacitors and to investigate their potential use for an embedded closed-loop control of the stimulation current. We characterized a selection of 40 commercial ceramic capacitors by measurement and simulation. The degree of nonlinearity resulting from a circuit topology consisting of one, two series and two parallel connected nonlinear capacitors was modeled and evaluated in Mathcad. We present a model with parameterized nonlinear capacitors to simulate the dynamic behavior of an inductively coupled implantable system. The stabilization and amplitude of the stimulation current is controlled by two features. These features are in turn controlled by the circuit topology and the degree of nonlinearity of the capacitors. We found that a high degree of nonlinearity allows the stimulation current to be stabilized within a reasonable range, but it makes the system more prone to instability. However, our model needs to include the dynamic behavior of ferroelectric materials used as dielectric in ceramic capacitors to extend the current investigations and to deepen the understanding of the physics behind the nonlinear properties of ferroelectric capacitors.

Influence of different transcranial magnetic stimulation current directions on the corticomotor control of lumbar erector spinae muscles during a static task

Different directions of transcranial magnetic stimulation (TMS) can activate different neuronal circuits. While posteroanterior current (PA-TMS) depolarizes mainly interneurons in primary motor cortex (M1), an anteroposterior current (AP-TMS) has been suggested to activate different M1 circuits and perhaps axons from the premotor regions. Although M1 is also involved in the control of axial muscles, no study has explored if different current directions activate different M1 circuits that may have distinct functional role. The aim of the study was to compare the effect of different current directions (PA- and AP-TMS) on the corticomotor control and spatial cortical organisation of the lumbar erector spinae muscle (LES). Thirthy-four healthy participants were recruited for two independent experiments and LES motor-evoked potentials (MEP) were recorded. In experiment 1 (n=17), active motor threshold (AMT), MEP latencies, recruitment curve (90 to 160% AMT), excitatory and inhibitory intracortical mechanisms using paired-pulse TMS (80% followed by 120% AMT stimuli at 2-3-10 and 15ms inter-stimulus intervals) were tested using a double cone (n=12) and a figure-of-eight (n=5) coils. In experiment 2 (n=17), LES cortical representations were tested using PA- and AP-TMS. AMT was higher for AP- compared to PA-TMS (p=0.002). Longer latencies with AP-TMS were compared to PA-TMS (p=0.017). AP-TMS produced more inhibition compared to PA-TMS at 2ms and 3ms (p=0.010), but no difference was observed for longer intervals. No difference was found for recruitment curve and mapping. Those findings suggest that each PA- and AP-TMS may activate different cortical circuits controlling low back muscles as proposed for hand muscles.

Experimental Characterization of Ferroelectric Capacitor Circuits for the Realization of Simply Designed Electroceuticals

Currently, a large number of neurostimulators are commercially available for the treatment of drug-resistant diseases and as an alternative to pharmaceuticals. According to the current state of the art, such highly engineered electroceuticals require bulky battery units and necessitate the use of leads and extensions to connect the implantable electronic device to the stimulation electrodes. The battery life and the use of wired electrodes constrain the long-term use of such implantable systems. Furthermore, for therapeutic success and patient safety, it is of utmost importance to keep the stimulation current within a safe range. In this paper, we propose an implantable system design that consists of a low number of passive electronic components and does not require a battery. The stimulation parameters and power are transmitted inductively using an extracorporeal wearable transmitter at frequencies below 1 MHz. A simple circuit design approach is presented to achieve a closed-loop control of the stimulation current by exploiting the nonlinear properties of ferroelectric materials in ceramic capacitors. Twenty circuit topologies of series- and/or parallel-connected ceramic capacitors are investigated by measurement and are modeled in Mathcad. An approximately linear increase in the stimulation current, a stabilization of the stimulation current and an unstable state of the system were observed. In contrast to previous results, specific plateau ranges of the stimulation current can be set by the investigated circuit topologies. For further investigations, the consistency of the proposed model needs to be improved for higher induced voltage ranges.

Ultra-compact dual-band smart NEMS magnetoelectric antennas for simultaneous wireless energy harvesting and magnetic field sensing

Ultra-compact wireless implantable medical devices are in great demand for healthcare applications, in particular for neural recording and stimulation. Current implantable technologies based on miniaturized micro-coils suffer from low wireless power transfer efficiency (PTE) and are not always compliant with the specific absorption rate imposed by the Federal Communications Commission. Moreover, current implantable devices are reliant on differential recording of voltage or current across space and require direct contact between electrode and tissue. Here, we show an ultra-compact dual-band smart nanoelectromechanical systems magnetoelectric (ME) antenna with a size of 250 × 174 µm2 that can efficiently perform wireless energy harvesting and sense ultra-small magnetic fields. The proposed ME antenna has a wireless PTE 1–2 orders of magnitude higher than any other reported miniaturized micro-coil, allowing the wireless IMDs to be compliant with the SAR limit. Furthermore, the antenna’s magnetic field detectivity of 300–500 pT allows the IMDs to record neural magnetic fields.

Automatic Identification and Avoidance of Axon Bundle Activation for Epiretinal Prosthesis

ABSTRACTRetinal prostheses must be able to activate cells in a selective way in order to restore high-fidelity vision. However, inadvertent activation of far-away retinal ganglion cells (RGCs) through electrical stimulation of axon bundles can produce irregular and poorly controlled percepts, limiting artificial vision. Therefore, the problem of axon bundle activation can be defined as the axonal stimulation of RGCs with unknown soma and receptive field locations, typically outside the electrode array. Here, a new algorithm is presented that utilizes electrical recordings to determine the stimulation current amplitudes above which bundle activation occurs. The method exploits several spatiotemporal characteristics of electrically-evoked spikes to overcome the challenge of detecting small axonal spikes in extracellular recordings. The algorithm was validated using large-scale ex vivo stimulation and recording experiments in macaque retina, by comparing algorithmically and manually identified bundle activation thresholds. The algorithm could be used in a closed-loop manner by a future epiretinal prosthesis to reduce poorly controlled visual percepts associated with bundle activation. The method may also be applicable to other types of retinal implants and to cortical implants.ContributionsPT developed the algorithm and analyzed the data, with input from SMi and EJC. NB and NS helped with the analysis. SMa and LG performed dissections and collected the data. PT and VFH performed manual identification. PH, AS and AML developed and supported recording hardware and software. PT, EJC and SMi wrote the manuscript. NS and SMa edited it. EJC and SMi supervised the project.