Evolution of optogenetic microdevices

Implementation of optogenetic techniques is a recent addition to the neuroscientists\u27 preclinical research arsenal, helping to expose the intricate connectivity of the brain and allowing for on-demand direct modulation of specific neural pathways. Developing an optogenetic system requires thorough investigation of the optogenetic technique and of previously fabricated devices, which this review accommodates. Many experiments utilize bench-top systems that are bulky, expensive, and necessitate tethering to the animal. However, these bench-top systems can make use of power-demanding technologies, such as concurrent electrical recording. Newer portable microdevices and implantable systems carried by freely moving animals are being fabricated that take advantage of wireless energy harvesting to power a system and allow for natural movements that are vital for behavioral testing and analysis. An investigation of the evolution of tethered, portable, and implantable optogenetic microdevices is presented, and an analysis of benefits and detriments of each system, including optical power output, device dimensions, electrode width, and weight is given. Opsins, light sources, and optical fiber coupling are also discussed to optimize device parameters and maximize efficiency from the light source to the fiber, respectively. These attributes are important considerations when designing and developing improved optogenetic microdevices

Oxycodone-induced dopaminergic and respiratory effects are modulated by deep brain stimulation

Introduction: Opioids are the leading cause of overdose death in the United States, accounting for almost 70,000 deaths in 2020. Deep brain stimulation (DBS) is a promising new treatment for substance use disorders. Here, we hypothesized that VTA DBS would modulate both the dopaminergic and respiratory effect of oxycodone.Methods: Multiple-cyclic square wave voltammetry (M-CSWV) was used to investigate how deep brain stimulation (130 Hz, 0.2 ms, and 0.2 mA) of the rodent ventral segmental area (VTA), which contains abundant dopaminergic neurons, modulates the acute effects of oxycodone administration (2.5 mg/kg, i.v.) on nucleus accumbens core (NAcc) tonic extracellular dopamine levels and respiratory rate in urethane-anesthetized rats (1.5 g/kg, i.p.).Results: I.V. administration of oxycodone resulted in an increase in NAcc tonic dopamine levels (296.9 ± 37.0 nM) compared to baseline (150.7 ± 15.5 nM) and saline administration (152.0 ± 16.1 nM) (296.9 ± 37.0 vs. 150.7 ± 15.5 vs. 152.0 ± 16.1, respectively, p = 0.022, n = 5). This robust oxycodone-induced increase in NAcc dopamine concentration was associated with a sharp reduction in respiratory rate (111.7 ± 2.6 min−1 vs. 67.9 ± 8.3 min−1; pre- vs. post-oxycodone; p < 0.001). Continuous DBS targeted at the VTA (n = 5) reduced baseline dopamine levels, attenuated the oxycodone-induced increase in dopamine levels to (+39.0% vs. +95%), and respiratory depression (121.5 ± 6.7 min−1 vs. 105.2 ± 4.1 min−1; pre- vs. post-oxycodone; p = 0.072).Discussion: Here we demonstrated VTA DBS alleviates oxycodone-induced increases in NAcc dopamine levels and reverses respiratory suppression. These results support the possibility of using neuromodulation technology for treatment of drug addiction

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

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

Deep brain stimulation for treatment-resistant depression

INTRODUCTIONDeep brain stimulation (DBS) has emerged as an alternative, reversible, nonablative neuromodulatory treatment for severely refractory major depressive disorder (MDD) and bipolar depression (BD). In the past decade, DBS for mood disorders has been reported in small case series, and it remains largely investigational. For those patients who do not receive therapeutic benefit from other available treatment options, including pharmacotherapy, psychotherapy, and electroconvulsive therapy, DBS holds promise [1, 2]. In general, DBS is believed to work by modulating the cortico-striato-thalamo-cortical (CSTC) circuits (see Fig. 11.1). The CSTC and its associative limbic and motor circuits have been implicated in the pathogenesis of MDD and BD. Various DBS targets have been examined for treatment-resistant depression (TRD) including the subgenual cingulate gyrus, ventral capsule/ventral striatum, nucleus accumbens, inferior thalamic peduncle, lateral habenula and the medial forebrain bundle. Still, many important clinical questions remain, including: (1) what is the most appropriate, effective and therapeutically consistent target, (2) what are the optimal stimulation parameters, and (3) what are the progressive mechanisms of action and how can recovery be optimized over time? This chapter will review reported clinical trials of DBS for MDD and BD, describing rationale for target selection, reported efficacy, clinical applicability and hypothesized mechanisms of action

Differential corticosteroid receptor regulation of mesoaccumbens dopamine efflux during the peak and nadir of the circadian rhythm : a molecular equilibrium in the midbrain?

Corticosteroid receptor modulation of mesoaccumbens dopamine neurotransmission is believed to be a key neurobiological mechanism mediating the effects of stress in addiction. Importantly, nucleus accumbens (NAc) subregions (core and shell) are reported to respond differentially to fluctuating basal levels of glucocorticoids, with dopaminergic responses in the core of the NAc being somewhat impervious to fluctuating levels of glucocorticoids relative to the shell. To investigate the corticosteroid receptor mechanisms mediating basal dopamine efflux in the core of the NAc, we have used chronoamperometry in combination with stearate-modified graphite paste electrodes in urethane anesthetized male Long–Evans rats during the peak and nadir of the circadian cycle. Blockade of ventral tegmental area low-affinity glucocorticoid (GR) or high-affinity mineralocorticoid (MR) receptors with mifepristone (1 μg/μl) or spironolactone (0.2 μg/μl), respectively, indicated that endogenous phase-dependent corticosteroid receptor activation (GRs during peak; MRs during nadir) facilitated extracellular NAc dopamine efflux. Conversely, the alternate receptor\u27s actions appeared inhibitory at these time points (MRs during peak; GRs during nadir). Pharmacological activation of either the GR or MR with corticosterone (2 μg/μl) or aldosterone (0.2 μg/μl), respectively, potentiated NAc dopamine efflux, irrespective of circadian phase. Together, these data suggest that dominant corticosteroid receptor activation stimulates tonic mesoaccumbens dopamine transmission, enabling MRs and GRs to differentially maintain basal NAc dopamine release over the course of the circadian cycle. This points to an important molecular mechanism through which relatively stable NAc core dopamine extracellular levels could be maintained in the face of fluctuating corticosterone circadian rhythms

A miniature closed-loop deep brain stimulation device

This paper presents a miniature light-weight closed-loop deep brain stimulation (DBS) device that delivers on-demand stimulation current pulses by monitoring and analysing local field potentials. The device includes monitoring and DBS units, each designed and fabricated on a separate small round circuit board. The closed-loop DBS device has been successfully validated by injecting a pre-recorded neural signal into its input, and collecting and analysing its output. The monitoring unit has an amplification gain of 113 dB in frequency range of 0.7-50 Hz. The DBS unit gives on-demand stimulation current pulses of duration 90 μs, frequency 130 Hz, and amplitude 200 μ. The total weight of the device including a 3V coin battery is 1.41 g. The diameter of the device is 11.4 mm. This portable head-mountable device is suitable for use in pre-clinical trials with small laboratory animals

A miniature energy harvesting rectenna for operating a head-mountable deep brain stimulation device

This paper presents design, implementation, and evaluation of a miniature rectenna for energy harvesting applications. The rectenna produces DC power from a distant microwave energy transmitter. The generated DC power is then utilized to operate a head-mountable deep brain stimulation device. The rectenna consists of a miniature three-layer planar inverted-F antenna and a Schottky-diode-based bridge rectifier. The antenna has a volume of π × 6 × 1.584 mm3, a resonance frequency of 915 MHz with a simulated bandwidth of 18 MHz (907-925 MHz), and a measured bandwidth of 18 MHz (910-928 MHz) at the return loss of -10 dB. A dielectric substrate of FR-4 of εr = 4.5 and δ = 0.02 is used for simulation and fabrication of the antenna and the rectifier due to its low cost. An L-section impedance matching circuit is employed between the antenna and the rectifier to reduce the mismatch loss. The impedance matching circuit operates as a low-pass filter eliminating higher order harmonics. A deep brain stimulation device is successfully operated by the rectenna at a distance of 20 cm away from a microwave energy transmitter of power 26.77 dBm. The motivation of this paper includes creation of a deep brain stimulation device that operates indefinitely without a battery. From the application standpoint, the developed energy harvesting rectenna facilitates long-term deep brain stimulation of laboratory animals for preclinical research investigating neurological disorders