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Closed-Loop Implantable Therapeutic Neuromodulation Systems Based on Neurochemical Monitoring

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Review

Closed-Loop Implantable Therapeutic Neuromodulation Systems Based on Neurochemical Monitoring

Khalid B Mirza et al. Front Neurosci.

Abstract

Closed-loop or intelligent neuromodulation allows adjustable, personalized neuromodulation which usually incorporates the recording of a biomarker, followed by implementation of an algorithm which decides the timing (when?) and strength (how much?) of stimulation. Closed-loop neuromodulation has been shown to have greater benefits compared to open-loop neuromodulation, particularly for therapeutic applications such as pharmacoresistant epilepsy, movement disorders and potentially for psychological disorders such as depression or drug addiction. However, an important aspect of the technique is selection of an appropriate, preferably neural biomarker. Neurochemical sensing can provide high resolution biomarker monitoring for various neurological disorders as well as offer deeper insight into neurological mechanisms. The chemicals of interest being measured, could be ions such as potassium (K+), sodium (Na+), calcium (Ca2+), chloride (Cl-), hydrogen (H+) or neurotransmitters such as dopamine, serotonin and glutamate. This review focusses on the different building blocks necessary for a neurochemical, closed-loop neuromodulation system including biomarkers, sensors and data processing algorithms. Furthermore, it also highlights the merits and drawbacks of using this biomarker modality.

Keywords: FSCV; chemometrics; closed loop neuromodulation; deep brain stimulation (DBS); neurochemical monitoring; vagus nerve stimulation (VNS).

Figures

Figure 1
Figure 1
(A) A typical neuron shows ionic and neurotransmitter transients induced due to neural activity. (B) The action potential propagation across the axon leads to ionic transients. The activation of the Na+/ATPase and Ca2+/ATPase leads to extracellular acidification and extracellular alkalinization, respectively. (C) Neurotransmitters are released into the synaptic cleft during propagation of neural response across neurons. (D) The two classes of neurochemicals i.e., neurotransmitters and ions can be detected using electrochemical methods such as voltammetry and potentiometry, respectively.
Figure 2
Figure 2
Different electrochemical methods (A) Amperometry: where a constant potential difference is applied between the working electrode (WE) and reference electrode (RE). The current between the WE and counter electrode (CE) is monitored as is an indication of the analyte concentration as the reaction progresses. (B) Cyclic Voltammetry: The potential difference between the WE, RE is changed periodically and the current between WE and CE is monitored. (C) Impedance Spectroscopy: Based on the modality, the impedance of an analyte is measured based on voltage applied between WE, RE and the current through CE. (D) Potentiometry: The potential difference between WE and RE is measured without applying any external potential difference.
Figure 3
Figure 3
A functional block diagram of a typical closed-loop neurochemical neuromodulation system is shown.
Figure 4
Figure 4
(Top) The potentiometric pH data recorded using IrOx electrodes, in vivo, in the subdiaphragmatic vagus nerve of male Wistar rats. The changes due to CCK are highlighted. (Middle) The recorded potentiometric waveform is pre-processed to remove drift using the technique described in Ahmed et al. (2018). (Bottom) The ΔpH is determined using the sensitivity of the IrOx pH electrodes, followed by simple linear regression to determine CCK-induced change in neural pH (Cork et al., 2018). This is a demonstration of responsive type of intelligent neuromodulation.
Figure 5
Figure 5
The training matrix can be constructed for as shown, for CCK induced pH changes in the vagus nerve (Mirza et al., 2017).
Figure 6
Figure 6
NAP profiles for different fiber types : A, B, and C based on Ward et al. (2015), the rheobase current (IRh in A) is depicted vs. the percentage fiber activation(λ).

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