An investigation into closed-loop treatment of neurological disorders based on sensing mitochondrial dysfunction

Abstract

Dynamic feedback based closed-loop medical devices offer a number of advantages for treatment of heterogeneous neurological conditions. Closed-loop devices integrate a level of neurobiological feedback, which allows for real-time adjustments to be made with the overarching aim of improving treatment efficacy and minimizing risks for adverse events. One target which has not been extensively explored as a potential feedback component in closed-loop therapies is mitochondrial function. Several neurodegenerative and psychiatric disorders including Parkinson’s disease, Major Depressive disorder and Bipolar disorder have been linked to perturbations in the mitochondrial respiratory chain. This paper investigates the potential to monitor this mitochondrial function as a method of feedback for closed-loop neuromodulation treatments. A generic model of the closed-loop treatment is developed to describe the high-level functions of any system designed to control neural function based on mitochondrial response to stimulation, simplifying comparison and future meta-analysis. This model has four key functional components including: a sensor, signal manipulator, controller and effector. Each of these components are described and several potential technologies for each are investigated. While some of these candidate technologies are quite mature, there are still technological gaps remaining. The field of closed-loop medical devices is rapidly evolving, and whilst there is a lot of interest in this area, widespread adoption has not yet been achieved due to several remaining technological hurdles. However, the significant therapeutic benefits offered by this technology mean that this will be an active area for research for years to come.

An Electrocorticography Device with an Integrated Microfluidic Ion Pump for Simultaneous Neural Recording and Electrophoretic Drug Delivery In Vivo

“…These efforts will be aided by the fact that the device design presented here can readily incorporate alternative ion bridge materials to expand the library of deliverable drugs . Likewise, the incorporation of additional backend electronics can enable closed loop feedback and control such that the µFIP can respond automatically to the input from the recording sites and/or other onboard biosensors . Future research will focus on remaining technological and scientific challenges including developing new ion bridge materials, validating the long‐term efficacy and stability of µFIP ECoG devices and investigating the therapeutic capabilities in appropriate disease models.…”

“…[27,35] Likewise, the incorporation of additional backend electronics can enable closed loop feedback and control such that the µFIP can respond automatically to the input from the recording sites and/or other onboard biosensors. [20,[36][37][38] Future research will focus on remaining technological and scientific challenges including developing new ion bridge materials, validating the long-term efficacy and stability of µFIP ECoG devices and investigating the therapeutic capabilities in appropriate disease models. We anticipate that these efforts will enable µFIP ECoG devices to be introduced to the clinic within a decade.…”

Biomarker-driven feedback control of synthetic biology systems for next-generation personalized medicine

“…In addition, real-time electroencephalogram (EEG) measurements of the slow oscillation rhythm of the brain were used for closed-loop auditory in-phase stimulation during sleep to improve declarative memory in humans ( Ngo et al, 2013 ). Closed-loop neuromodulation based on biomarkers of pathological activity ( Paz et al, 2013 ) or mitochondrial function ( Adams et al, 2018 ) could offer substantial clinical benefits in comparison to open-loop deep-brain stimulation in Parkinson’s and seizure patients. Integrating electrical neurological devices in a closed-loop with designer cell implants is currently a challenging task, but has the potential to overcome the drawbacks of cellular and mechanical therapies and to enable the treatment of highly complex neurological diseases in the future.…”

A Fully Implantable Wireless Bidirectional Neuromodulation System for Mice

“…The need for closed-loop approaches in clinical applications has long been recognized [1][2][3]. Recent indications under active research include spinal cord injury [4,5], psychiatric disorders and neurodegenerative diseases [6,7], bladder dysfunction [8], diabetes management [9], hypertension [10], and pain relief [11]. In some applications, the closed-loop algorithm is relatively simple, e.g.…”