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Neurochemical recording techniques have expanded our understanding of the pathophysiology of neurological disorders, as well as the mechanisms of action of treatment modalities like deep brain stimulation (DBS). DBS is used to treat diseases such as Parkinson’s disease, Tourette syndrome, and obsessive-compulsive disorder, among others. Although DBS is effective at alleviating symptoms related to these diseases and improving the quality of life of these patients, the mechanism of action of DBS is currently not fully understood. A leading hypothesis is that DBS modulates the electrical field potential by modifying neuronal firing frequencies to non-pathological rates thus providing therapeutic relief. To address this gap in knowledge, recent advances in electrochemical sensing techniques have given insight into the importance of neurotransmitters, such as dopamine, serotonin, glutamate, and adenosine, in disease pathophysiology. These studies have also highlighted their potential use in tandem with electrophysiology to serve as biomarkers in disease diagnosis and progression monitoring, as well as characterize response to treatment. Here, we provide an overview of disease-relevant neurotransmitters and their roles and implications as biomarkers, as well as innovations to the biosensors used to record these biomarkers. Furthermore, we discuss currently available neurochemical and electrophysiological recording devices, and discuss their viability to be implemented into the development of a closed-loop DBS system.

The combination of electrophysiology and electrochemistry acquisition methods using a single carbon fiber microelectrode (CFM) in the brain has enabled more extensive analysis of neurochemical release, neural activity, and animal behavior. Predominantly, analog CMOS (Complementary Metal Oxide Semiconductor) switches are used for these interleaved applications to alternate the CFM output between electrophysiology and electrochemistry acquisition circuitry. However, one underlying issue with analog CMOS switches is the introduction of transient voltage artifacts in recorded electrophysiology signals resulting from CMOS charge injection. These injected artifacts attenuate electrophysiology data and delay reliable signal observation after every switch actuation from electrochemistry acquisition. Previously published attempts at interleaved electrophysiology and electrochemistry were able to recover reliable electrophysiology data within approximately 10-50 ms after switch actuation by employing various high-pass filtering methods to mitigate the observed voltage artifacts. However, high-pass filtering of this nature also attenuates valuable portions of the local-field potential (LFP) frequency range, thus limiting the extent of network-level insights that can be derived from in vivo measurements. This paper proposes a solution to overcome the limitation of charge injection artifacts that affect electrophysiological data while preserving important lower-frequency LFP bands. A voltage follower operational amplifier was integrated before the CMOS switch to increase current flow to the switch and dissipate any injected charge. This hardware addition resulted in a 16.98% decrease in electrophysiology acquisition delay compared to circuitry without a voltage follower. Additionally, single-term exponential modeling was implemented in post-processing to characterize and subtract remaining transient voltage artifacts in recorded electrophysiology data. As a result, electrophysiology data was reliably recovered 3.26 ± 0.22 ms after the beginning of the acquisition period (a 60% decrease from previous studies), while also minimizing LFP attenuation. Through these advancements, coupled electrophysiology and electrochemistry measurements can be conducted at higher scan rates while retaining data integrity for a more comprehensive analysis of neural activity and neurochemical release. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for medically refractory Parkinson's disease. Although DBS has recognized clinical utility, its biologic mechanisms are not fully understood, and whether dopamine release is a potential factor in those mechanisms is in dispute. We tested the hypothesis that STN DBS-evoked dopamine release depends on the precise location of the stimulation site in the STN and the site of recording in the caudate and putamen. We conducted DBS with miniature, scaled-to-animal size, multicontact electrodes and used functional magnetic resonance imaging to identify the best dopamine recording site in the brains of nonhuman primates (rhesus macaques), which are highly representative of human brain anatomy and circuitry. Real-time stimulation-evoked dopamine release was monitored using in vivo fast-scan cyclic voltammetry. This study demonstrates that STN DBS-evoked dopamine release can be reduced or increased by redirecting STN stimulation to a slightly different site. [ABSTRACT FROM AUTHOR]

Opiates, like other addictive drugs, elevate forebrain dopamine levels and are thought to do so mainly by inhibiting GABA neurons near the ventral tegmental area (VTA), in turn leading to a disinhibition of dopamine neurons. However, cholinergic inputs from the laterodorsal (LDT) and pedunculopontine (PPT) tegmental nucleus to the VTA and substantia nigra (SN) importantly contribute, as either LDT or PPT lesions strongly attenuate morphine-induced forebrain dopamine elevations. Pharmacological blockade of muscarinic acetylcholine receptors in the VTA or SN has similar effects. M5 muscarinic receptors are the only muscarinic receptor subtype associated with VTA and SN dopamine neurons. Here we tested the contribution of M5 muscarinic receptors to morphine-induced dopamine elevations by measuring nucleus accumbens dopamine efflux in response to intra-VTA morphine infusion using in vivo chronoamperometry. Intra-VTA morphine increased nucleus accumbens dopamine efflux in urethane-anesthetized wildtype mice starting at 10 min after infusion. These increases were absent in M5 knockout mice and were similarly blocked by pre-treatment with VTA scopolamine in wildtype mice. Furthermore, in wildtype mice electrical stimulation of the PPT evoked an initial, short-lasting increase in striatal dopamine efflux, followed 5 min later by a second prolonged increase in dopamine efflux. In M5 knockout mice, or following systemic pre-treatment with scopolamine in wildtype mice, the prolonged increase in striatal dopamine efflux was absent. The time course of increased accumbal dopamine efflux in wildtype mice following VTA morphine was consistent with both the prolonged M5-mediated excitation of striatal dopamine efflux following PPT electrical stimulation and accumbal dopamine efflux following LDT electrical stimulation. Therefore, M5 receptors appear critical for prolonged PPT excitation of dopamine efflux and for dopamine efflux induced by intra-VTA morphine. [ABSTRACT FROM AUTHOR]