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Background: Treatment of refractory bipolar disorder (BD) is extremely challenging. Deep brain stimulation (DBS) holds promise as an effective treatment intervention. However, we still understand very little about the mechanisms of DBS and its application on BD., Aim: The present study aimed to investigate the behavioural and neurochemical effects of ventral tegmental area (VTA) DBS in an animal model of mania induced by methamphetamine (m-amph)., Methods: Wistar rats were given 14 days of m-amph injections, and on the last day, animals were submitted to 20 min of VTA DBS in two different patterns: intermittent low-frequency stimulation (LFS) or continuous high-frequency stimulation (HFS). Immediately after DBS, manic-like behaviour and nucleus accumbens (NAc) phasic dopamine (DA) release were evaluated in different groups of animals through open-field tests and fast-scan cyclic voltammetry. Levels of NAc dopaminergic markers were evaluated by immunohistochemistry., Results: M-amph induced hyperlocomotion in the animals and both DBS parameters reversed this alteration. M-amph increased DA reuptake time post-sham compared to baseline levels, and both LFS and HFS were able to block this alteration. LFS was also able to reduce phasic DA release when compared to baseline. LFS was able to increase dopamine transporter (DAT) expression in the NAc., Conclusion: These results demonstrate that both VTA LFS and HFS DBS exert anti-manic effects and modulation of DA dynamics in the NAc. More specifically the increase in DA reuptake driven by increased DAT expression may serve as a potential mechanism by which VTA DBS exerts its anti-manic effects., (© 2024 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Tourette syndrome is a childhood-onset neuropsychiatric disorder characterized by intrusive motor and vocal tics that can lead to self-injury and deleterious mental health complications. While dysfunction in striatal dopamine neurotransmission has been proposed to underlie tic behaviour, evidence is scarce and inconclusive. Deep brain stimulation (DBS) of the thalamic centromedian parafascicular complex (CMPf), an approved surgical interventive treatment for medical refractory Tourette syndrome, may reduce tics by affecting striatal dopamine release. Here, we use electrophysiology, electrochemistry, optogenetics, pharmacological treatments and behavioural measurements to mechanistically examine how thalamic DBS modulates synaptic and tonic dopamine activity in the dorsomedial striatum. Previous studies demonstrated focal disruption of GABAergic transmission in the dorsolateral striatum of rats led to repetitive motor tics recapitulating the major symptom of Tourette syndrome. We employed this model under light anaesthesia and found CMPf DBS evoked synaptic dopamine release and elevated tonic dopamine levels via striatal cholinergic interneurons while concomitantly reducing motor tic behaviour. The improvement in tic behaviour was found to be mediated by D2 receptor activation as blocking this receptor prevented the therapeutic response. Our results demonstrate that release of striatal dopamine mediates the therapeutic effects of CMPf DBS and points to striatal dopamine dysfunction as a driver for motor tics in the pathoneurophysiology of Tourette syndrome., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Neurotransmitters, such as dopamine and serotonin, are responsible for mediating a wide array of neurologic functions, from memory to motivation. From measurements using fast scan cyclic voltammetry (FSCV), one of the main tools used to detect synaptic efflux of neurochemicals in vivo , principal component regression (PCR), has been commonly used to predict the identity and concentrations of neurotransmitters. However, the sensitivity and discrimination performance of PCR have room for improvement, especially for analyzing mixtures of similar oxidizable neurochemicals. Deep learning may be able to address these challenges. To date, there have been a few studies to apply machine learning to FSCV, but no attempt to apply deep learning to neurotransmitter mixture discrimination and no comparative study have been performed between PCR and deep learning methods to demonstrate which is more accurate for FSCV analysis so far. In this study, we compared the neurochemical identification and concentration estimation performance of PCR and deep learning in an analysis of FSCV recordings of catecholamine and indolamine neurotransmitters. Both analysis methods were tested on in vitro FSCV data with a single or mixture of neurotransmitters at the desired concentration. In addition, the estimation performance of PCR and deep learning was compared in incorporation with in vivo experiments to evaluate the practical usage. Pharmacological tests were also conducted to see whether deep learning would track the increased amount of catecholamine levels in the brain. Using conventional FSCV, we used five electrodes and recorded in vitro background-subtracted cyclic voltammograms from four neurotransmitters, dopamine, epinephrine, norepinephrine, and serotonin, with five concentrations of each substance, as well as various mixtures of the four analytes. The results showed that the identification accuracy errors were reduced 5-20% by using deep learning compared to using PCR for mixture analysis, and the two methods were comparable for single analyte analysis. The applied deep-learning-based method demonstrated not only higher identification accuracy but also better discrimination performance than PCR for mixtures of neurochemicals and even for in vivo testing. Therefore, we suggest that deep learning should be chosen as a more reliable tool to analyze FSCV data compared to conventional PCR methods although further work is still needed on developing complete validation procedures prior to widespread use.

In the face of a global epidemic of drug addiction, neglecting to develop new effective therapies will perpetuate the staggering human and economic costs of substance use. This review aims to summarize and evaluate the preclinical and clinical studies of deep brain stimulation (DBS) as a novel therapy for refractory addiction, in hopes to engage and inform future research in this promising novel treatment avenue. An electronic database search (MEDLINE, EMBASE, Cochrane library) was performed using keywords and predefined inclusion criteria between 1974 and 6/18/2021 (registered on Open Science Registry). Selected articles were reviewed in full text and key details were summarized and analyzed to understand DBS' therapeutic potential and possible mechanisms of action. The search yielded 25 animal and 22 human studies. Animal studies showed that DBS of targets such as nucleus accumbens (NAc), insula, and subthalamic nucleus reduces drug use and seeking. All human studies were case series/reports (level 4/5 evidence), mostly targeting the NAc with generally positive outcomes. From the limited evidence in the literature, DBS, particularly of the NAc, appears to be a reasonable last resort option for refractory addictive disorders. We propose that future research in objective electrophysiological (e.g., local field potentials) and neurochemical (e.g., extracellular dopamine levels) biomarkers would assist monitoring the progress of treatment and developing a closed-loop DBS system. Preclinical literature also highlighted the prefrontal cortex as a promising DBS target, which should be explored in human research., (© 2022. The Author(s).)

Objectives: Despite recent advances in depression treatment, many patients still do not respond to serial conventional therapies and are considered "treatment resistant." Deep brain stimulation (DBS) has therapeutic potential in this context. This comprehensive review of recent studies of DBS for depression in animal models identifies potential biomarkers for improving therapeutic efficacy and predictability of conventional DBS to aid future development of closed-loop control of DBS systems., Materials and Methods: A systematic search was performed in Pubmed, EMBASE, and Cochrane Review using relevant keywords. Overall, 56 animal studies satisfied the inclusion criteria., Results: Outcomes were divided into biochemical/physiological, electrophysiological, and behavioral categories. Promising biomarkers include biochemical assays (in particular, microdialysis and electrochemical measurements), which provide real-time results in awake animals. Electrophysiological tests, showing changes at both the target site and downstream structures, also revealed characteristic changes at several anatomic targets (such as the medial prefrontal cortex and locus coeruleus). However, the substantial range of models and DBS targets limits the ability to draw generalizable conclusions in animal behavioral models., Conclusions: Overall, DBS is a promising therapeutic modality for treatment-resistant depression. Different outcomes have been used to assess its efficacy in animal studies. From the review, electrophysiological and biochemical markers appear to offer the greatest potential as biomarkers for depression. However, to develop closed-loop DBS for depression, additional preclinical and clinical studies with a focus on identifying reliable, safe, and effective biomarkers are warranted., (Copyright © 2021 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Deep brain stimulation (DBS) is used to treat a wide array of neurologic conditions. However, traditional programming of stimulation parameters relies upon short term subjective observation of patient symptoms and undesired stimulation effects while in the clinic. To gain a more objective measure of the neuronal activity that contributes to patient symptoms and response to treatment, there is a clear need for a fully-implantable DBS system capable of chronically recording patient-specific electrophysiological biomarker signals over time. By providing an objective correlate of a patient's disease and response to treatment, this capability has the potential to improve therapeutic benefit while preventing undesirable side effects. Herein, the engineering and capabilities of the Percept PC, the first FDA-approved, fully-implantable DBS device capable of nearly-simultaneous electrophysiological recordings and stimulation, are discussed. The device's ability to chronically record local field potentials (LFPs) at implanted DBS leads was validated in patients with neurological disorders. Lastly, the electrophysiological activity correlates of clinically relevant patient-reported events are presented. While FDA approved for conditions such as Parkinson's disease, essential tremor, dystonia, obsessive-compulsive disorder, and epilepsy, chronic electrophysiological recordings in humans has broad applications within basic science and clinical practice beyond DBS, offering a wealth of information related to normal and abnormal neurophysiology within distinct brain areas., (Copyright © 2020. Published by Elsevier B.V.)

Objective . Stereotactic technology enables fine navigation to small structures in the human body. While current stereotactic systems facilitate accurate targeting, they are mechanically cumbersome and limited in scope. Here, we hypothesized that a stereotactic system could be developed with a reduced footprint while maintaining broad targeting capabilities in order to improve versatility in frame placement location and surgical workflow. Approach . We designed a stereotactic system around the center-of-arc principle, with mechanical properties that would enable a compact design and ample targeting and trajectory maneuverability. To examine the opportunity for a low-cost rapidly-deployable system we developed two fabrication variants, one using three dimensional (3D)-printing and the other using conventional machining. Mechanical and image-guided accuracies were tested in phantom studies using magnetic resonance imaging (MRI) and computed tomography. Using human cadaver head specimens, we assessed the system's surgical workflow and its ability to reliably and accurately implant electrodes in deep brain stimulation (DBS) surgery. Main results . We developed a small 7.7 × 5.4 cm 2 device platform that rigidly mounts to curvilinear bone and supports the attachment of surgical instrumentation. Attachment of two surgical instruments, an imaging localizer and a compact targeting device, demonstrated successful MRI-guided intervention in phantom studies with a vector error of 1.79 ± 0.41 mm. Evaluation of the 3D-printed system for DBS surgery confirmed ease of device platform attachment and instrument functionality, as well as demonstrated a surgical targeting accuracy of 1.83 ± 0.15 mm. In addition, we found the surgical time to be 78.3 ± 5.4 min for bilateral electrode implantation. Significance . We developed a light and compact stereotactic system whose accuracy is on par with those used clinically. This technology is suitable for clinical translation and its flexibility in positioning will seamlessly expand the capabilities for stereotaxy to treat a wide range of conditions, both within neurosurgery and beyond., (© 2020 IOP Publishing Ltd.)

The development of closed-loop deep brain stimulation (DBS) systems represents a significant opportunity for innovation in the clinical application of neurostimulation therapies. Despite the highly dynamic nature of neurological diseases, open-loop DBS applications are incapable of modifying parameters in real time to react to fluctuations in disease states. Thus, current practice for the designation of stimulation parameters, such as duration, amplitude, and pulse frequency, is an algorithmic process. Ideal stimulation parameters are highly individualized and must reflect both the specific disease presentation and the unique pathophysiology presented by the individual. Stimulation parameters currently require a lengthy trial-and-error process to achieve the maximal therapeutic effect and can only be modified during clinical visits. The major impediment to the development of automated, adaptive closed-loop systems involves the selection of highly specific disease-related biomarkers to provide feedback for the stimulation platform. This review explores the disease relevance of neurochemical and electrophysiological biomarkers for the development of closed-loop neurostimulation technologies. Electrophysiological biomarkers, such as local field potentials, have been used to monitor disease states. Real-time measurement of neurochemical substances may be similarly useful for disease characterization. Thus, the introduction of measurable neurochemical analytes has significantly expanded biomarker options for feedback-sensitive neuromodulation systems. The potential use of biomarker monitoring to advance neurostimulation approaches for treatment of Parkinson's disease, essential tremor, epilepsy, Tourette syndrome, obsessive-compulsive disorder, chronic pain, and depression is examined. Further, challenges and advances in the development of closed-loop neurostimulation technology are reviewed, as well as opportunities for next-generation closed-loop platforms.

Background and Objectives: Deep brain stimulation (DBS) of the thalamus is a promising therapeutic alternative for treating medically refractory Tourette syndrome (TS). However, few human studies have examined its mechanism of action. Therefore, the networks that mediate the therapeutic effects of thalamic DBS remain poorly understood., Methods: Five participants diagnosed with severe medically refractory TS underwent bilateral thalamic DBS stereotactic surgery. Intraoperative fMRI characterized the blood oxygen level-dependent (BOLD) response evoked by thalamic DBS and determined whether the therapeutic effectiveness of thalamic DBS, as assessed using the Modified Rush Video Rating Scale test, would correlate with evoked BOLD responses in motor and limbic cortical and subcortical regions., Results: Our results reveal that thalamic stimulation in TS participants has wide-ranging effects that impact the frontostriatal, limbic, and motor networks. Thalamic stimulation induced suppression of motor and insula networks correlated with motor tic reduction, while suppression of frontal and parietal networks correlated with vocal tic reduction. These regions mapped closely to major regions of interest (ROI) identified in a nonhuman primate model of TS., Conclusions: Overall, these findings suggest that a critical factor in TS treatment should involve modulation of both frontostriatal and motor networks, rather than be treated as a focal disorder of the brain. Using the novel combination of DBS-evoked tic reduction and fMRI in human subjects, we provide new insights into the basal ganglia-cerebellar-thalamo-cortical network-level mechanisms that influence the effects of thalamic DBS. Future translational research should identify whether these network changes are cause or effect of TS symptoms.

There has been significant progress in understanding the role of neurotransmitters in normal and pathologic brain function. However, preclinical trials aimed at improving therapeutic interventions do not take advantage of real-time in vivo neurochemical changes in dynamic brain processes such as disease progression and response to pharmacologic, cognitive, behavioral, and neuromodulation therapies. This is due in part to a lack of flexible research tools that allow in vivo measurement of the dynamic changes in brain chemistry. Here, we present a research platform, WINCS Harmoni, which can measure in vivo neurochemical activity simultaneously across multiple anatomical targets to study normal and pathologic brain function. In addition, WINCS Harmoni can provide real-time neurochemical feedback for closed-loop control of neurochemical levels via its synchronized stimulation and neurochemical sensing capabilities. We demonstrate these and other key features of this platform in non-human primate, swine, and rodent models of deep brain stimulation (DBS). Ultimately, systems like the one described here will improve our understanding of the dynamics of brain physiology in the context of neurologic disease and therapeutic interventions, which may lead to the development of precision medicine and personalized therapies for optimal therapeutic efficacy.

Introduction: Deep brain stimulation (DBS) is a circuit-based treatment shown to relieve symptoms from multiple neurologic and neuropsychiatric disorders. In order to treat the memory deficit associated with Alzheimer's disease (AD), several clinical trials have tested the efficacy of DBS near the fornix. Early results from these studies indicated that patients who received fornix DBS experienced an improvement in memory and quality of life, yet the mechanisms behind this effect remain controversial. It is known that transmission between the medial limbic and corticolimbic circuits plays an integral role in declarative memory, and dysfunction at the circuit level results in various forms of dementia, including AD. Here, we aimed to determine the potential underlying mechanism of fornix DBS by examining the functional circuitry and brain structures engaged by fornix DBS., Methods: A multimodal approach was employed to examine global and local temporal changes that occur in an anesthetized swine model of fornix DBS. Changes in global functional activity were measured by functional MRI (fMRI), and local neurochemical changes were monitored by fast scan cyclic voltammetry (FSCV) during electrical stimulation of the fornix. Additionally, intracranial microinfusions into the nucleus accumbens (NAc) were performed to investigate the global activity changes that occur with dopamine and glutamate receptor-specific antagonism., Results: Hemodynamic responses in both medial limbic and corticolimbic circuits measured by fMRI were induced by fornix DBS. Additionally, fornix DBS resulted in increases in dopamine oxidation current (corresponding to dopamine efflux) monitored by FSCV in the NAc. Finally, fornix DBS-evoked hemodynamic responses in the amygdala and hippocampus decreased following dopamine and glutamate receptor antagonism in the NAc., Conclusions: The present findings suggest that fornix DBS modulates dopamine release on presynaptic dopaminergic terminals in the NAc, involving excitatory glutamatergic input, and that the medial limbic and corticolimbic circuits interact in a functional loop., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This review presents state-of-the-art knowledge about the roles of the basal ganglia (BG) in action-selection, cognition, and motivation, and how this knowledge has been used to improve deep brain stimulation (DBS) treatment of neurological and psychiatric disorders. Such pathological conditions include Parkinson's disease, Huntington's disease, Tourette syndrome, depression, and obsessive-compulsive disorder. The first section presents evidence supporting current hypotheses of how the cortico-BG circuitry works to select motor and emotional actions, and how defects in this circuitry can cause symptoms of the BG diseases. Emphasis is given to the role of striatal dopamine on motor performance, motivated behaviors and learning of procedural memories. Next, the use of cutting-edge electrochemical techniques in animal and human studies of BG functioning under normal and disease conditions is discussed. Finally, functional neuroimaging studies are reviewed; these works have shown the relationship between cortico-BG structures activated during DBS and improvement of disease symptoms., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) thalamic nuclei has been considered an option for treating Tourette syndrome. Using a large animal DBS model, this study was designed to explore the network effects of CM-Pf DBS., Methods: The combination of DBS and functional magnetic resonance imaging is a powerful means of tracing brain circuitry and testing the modulatory effects of electrical stimulation on a neuronal network in vivo. With a within-subjects design, we tested the proportional effects of CM and Pf DBS by manipulating current spread and varying stimulation contacts in healthy pigs (n = 5)., Results: Our results suggests that CM-Pf DBS has an inhibitory modulating effect in areas that have been suggested as contributing to impaired sensory-motor and emotional processing. The results also help to define the differential neural circuitry effects of the CM and Pf with evidence of prominent sensorimotor/associative effects for CM DBS and prominent limbic/associative effects for Pf DBS., Conclusions: Our results support the notion that stimulation of deep brain structures, such as the CM-Pf, modulates multiple networks with cortical effects. The networks affected by CM-Pf stimulation in this study reinforce the conceptualization of Tourette syndrome as a condition with psychiatric and motor symptoms and of CM-Pf DBS as a potentially effective tool for treating both types of symptoms., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Object: Conventional deep brain stimulation (DBS) devices continue to rely on an open-loop system in which stimulation is independent of functional neural feedback. The authors previously proposed that as the foundation of a DBS "smart" device, a closed-loop system based on neurochemical feedback, may have the potential to improve therapeutic outcomes. Alterations in neurochemical release are thought to be linked to the clinical benefit of DBS, and fast-scan cyclic voltammetry (FSCV) has been shown to be effective for recording these evoked neurochemical changes. However, the combination of FSCV with conventional DBS devices interferes with the recording and identification of the evoked analytes. To integrate neurochemical recording with neurostimulation, the authors developed the Mayo Investigational Neuromodulation Control System (MINCS), a novel, wirelessly controlled stimulation device designed to interface with FSCV performed by their previously described Wireless Instantaneous Neurochemical Concentration Sensing System (WINCS)., Methods: To test the functionality of these integrated devices, various frequencies of electrical stimulation were applied by MINCS to the medial forebrain bundle of the anesthetized rat, and striatal dopamine release was recorded by WINCS. The parameters for FSCV in the present study consisted of a pyramidal voltage waveform applied to the carbon-fiber microelectrode every 100 msec, ramping between -0.4 V and +1.5 V with respect to an Ag/AgCl reference electrode at a scan rate of either 400 V/sec or 1000 V/sec. The carbon-fiber microelectrode was held at the baseline potential of -0.4 V between scans., Results: By using MINCS in conjunction with WINCS coordinated through an optic fiber, the authors interleaved intervals of electrical stimulation with FSCV scans and thus obtained artifact-free wireless FSCV recordings. Electrical stimulation of the medial forebrain bundle in the anesthetized rat by MINCS elicited striatal dopamine release that was time-locked to stimulation and increased progressively with stimulation frequency., Conclusions: Here, the authors report a series of proof-of-principle tests in the rat brain demonstrating MINCS to be a reliable and flexible stimulation device that, when used in conjunction with WINCS, performs wirelessly controlled stimulation concurrent with artifact-free neurochemical recording. These findings suggest that the integration of neurochemical recording with neurostimulation may be a useful first step toward the development of a closed-loop DBS system for human application.

The combination of deep brain stimulation (DBS) and functional MRI (fMRI) is a powerful means of tracing brain circuitry and testing the modulatory effects of electrical stimulation on a neuronal network in vivo. The goal of this study was to trace DBS-induced global neuronal network activation in a large animal model by monitoring the blood oxygenation level-dependent (BOLD) response on fMRI. We conducted DBS in normal anesthetized pigs, targeting the subthalamic nucleus (STN) (n=7) and the entopeduncular nucleus (EN), the non-primate analog of the primate globus pallidus interna (n=4). Using a normalized functional activation map for group analysis and the application of general linear modeling across subjects, we found that both STN and EN/GPi DBS significantly increased BOLD activation in the ipsilateral sensorimotor network (FDR<0.001). In addition, we found differential, target-specific, non-motor network effects. In each group the activated brain areas showed a distinctive correlation pattern forming a group of network connections. Results suggest that the scope of DBS extends beyond an ablation-like effect and that it may have modulatory effects not only on circuits that facilitate motor function but also on those involved in higher cognitive and emotional processing. Taken together, our results show that the swine model for DBS fMRI, which conforms to human implanted DBS electrode configurations and human neuroanatomy, may be a useful platform for translational studies investigating the global neuromodulatory effects of DBS., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Essential tremor is often markedly reduced during deep brain stimulation simply by implanting the stimulating electrode before activating neurostimulation. Referred to as the microthalamotomy effect, the mechanisms of this unexpected consequence are thought to be related to microlesioning targeted brain tissue, that is, a microscopic version of tissue ablation in thalamotomy. An alternate possibility is that implanting the electrode induces immediate neurochemical release. Herein, we report the experiment performing with real-time fast-scan cyclic voltammetry to quantify neurotransmitter concentrations in human subjects with essential tremor during deep brain stimulation. The results show that the microthalamotomy effect is accompanied by local neurochemical changes, including adenosine release., (Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Subthalamic nucleus deep brain stimulation (STN DBS) ameliorates motor symptoms of Parkinson's disease, but the precise mechanism is still unknown. Here, using a large animal (pig) model of human STN DBS neurosurgery, we utilized fast-scan cyclic voltammetry in combination with a carbon-fiber microelectrode (CFM) implanted into the striatum to monitor dopamine release evoked by electrical stimulation at a human DBS electrode (Medtronic 3389) that was stereotactically implanted into the STN using MRI and electrophysiological guidance. STN electrical stimulation elicited a stimulus time-locked increase in striatal dopamine release that was both stimulus intensity- and frequency-dependent. Intensity-dependent (1-7V) increases in evoked dopamine release exhibited a sigmoidal pattern attaining a plateau between 5 and 7V of stimulation, while frequency-dependent dopamine release exhibited a linear increase from 60 to 120Hz and attained a plateau thereafter (120-240Hz). Unlike previous rodent models of STN DBS, optimal dopamine release in the striatum of the pig was obtained with stimulation frequencies that fell well within the therapeutically effective frequency range of human DBS (120-180Hz). These results highlight the critical importance of utilizing a large animal model that more closely represents implanted DBS electrode configurations and human neuroanatomy to study neurotransmission evoked by STN DBS. Taken together, these results support a dopamine neuronal activation hypothesis suggesting that STN DBS evokes striatal dopamine release by stimulation of nigrostriatal dopaminergic neurons., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Thalamic deep brain stimulation (DBS) is proven therapy for essential tremor, Parkinson's disease and Tourette's syndrome. We tested the hypothesis that high-frequency electrical stimulation results in local thalamic glutamate release. Enzyme-linked glutamate amperometric biosensors were implanted in anesthetized rat thalamus adjacent to the stimulating electrode. Electrical stimulation was delivered to investigate the effect of frequency, pulse width, voltage-controlled or current-controlled stimulation, and charge balancing. Monophasic electrical stimulation-induced glutamate release was linearly dependent on stimulation frequency, intensity and pulse width. Prolonged stimulation evoked glutamate release to a plateau that subsequently decayed back to baseline after stimulation. Glutamate release was less pronounced with voltage-controlled stimulation and not present with charge balanced current-controlled stimulation. Using fixed potential amperometry in combination with a glutamate bioprobe and adjacent microstimulating electrode, the present study has shown that monophasic current-controlled stimulation of the thalamus in the anesthetized rat evoked linear increases in local extracellular glutamate concentrations that were dependent on stimulation duration, frequency, intensity and pulse width. However, the efficacy of monophasic voltage-controlled stimulation, in terms of evoking glutamate release in the thalamus, was substantially lower compared to monophasic current-controlled stimulation and entirely absent with biphasic (charge balanced) current-controlled stimulation. It remains to be determined whether similar glutamate release occurs with human DBS electrodes and similar charge balanced stimulation. As such, the present results indicate the importance of evaluating local neurotransmitter dynamics in studying the mechanism of action of DBS.

In this study, fixed potential amperometry was used to examine several pathways by which Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) or dopamine axons within the dorsal forebrain bundle (DFB) release striatal dopamine, thus potentially providing therapeutic benefits for Parkinson's Disease patients. In urethane anesthetized mice, electrical stimulations (20 monophasic pulses at 50 Hz every 30 sec) were applied to the STN or DFB while infusing the local anesthetic lidocaine (4%) into the substantia nigra compacta (SNc) or pedunculopontine tegmental nucleus (PPT). Findings suggest that DFB stimulation activates ascending SNc dopamine axons, while STN stimulation evokes striatal dopamine release directly via excitatory glutamatergic inputs to SNc dopamine cells and indirectly via excitatory cholinergic/glutamatergic STN-PPT-SNc pathways.

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.

Tourette syndrome is a childhood-onset neuropsychiatric disorder characterized by intrusive motor and vocal tics that can lead to self-injury and deleterious mental health complications. While dysfunction in striatal dopamine neurotransmission has been proposed to underlie tic behaviour, evidence is scarce and inconclusive. Deep brain stimulation (DBS) of the thalamic centromedian parafascicular complex (CMPf), an approved surgical interventive treatment for medical refractory Tourette syndrome, may reduce tics by affecting striatal dopamine release. Here, we use electrophysiology, electrochemistry, optogenetics, pharmacological treatments and behavioural measurements to mechanistically examine how thalamic DBS modulates synaptic and tonic dopamine activity in the dorsomedial striatum. Previous studies demonstrated focal disruption of GABAergic transmission in the dorsolateral striatum of rats led to repetitive motor tics recapitulating the major symptom of Tourette syndrome. We employed this model under light anaesthesia and found CMPf DBS evoked synaptic dopamine release and elevated tonic dopamine levels via striatal cholinergic interneurons while concomitantly reducing motor tic behaviour. The improvement in tic behaviour was found to be mediated by D2 receptor activation as blocking this receptor prevented the therapeutic response. Our results demonstrate that release of striatal dopamine mediates the therapeutic effects of CMPf DBS and points to striatal dopamine dysfunction as a driver for motor tics in the pathoneurophysiology of Tourette syndrome. [ABSTRACT FROM AUTHOR]

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. postoxycodone; 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. [ABSTRACT FROM AUTHOR]

Cocaine's addictive properties stem from its capacity to increase tonic extracellular dopamine levels in the nucleus accumbens (NAc). The ventral tegmental area (VTA) is a principal source of NAc dopamine. To investigate how high frequency stimulation (HFS) of the rodent VTA or nucleus accumbens core (NAcc) modulates the acute effects of cocaine administration on NAcc tonic dopamine levels multiple-cyclic square wave voltammetry (M-CSWV) was used. VTA HFS alone decreased NAcc tonic dopamine levels by 42%. NAcc HFS alone resulted in an initial decrease in tonic dopamine levels followed by a return to baseline. VTA or NAcc HFS following cocaine administration prevented the cocaine-induced increase in NAcc tonic dopamine. The present results suggest a possible underlying mechanism of NAc deep brain stimulation (DBS) in the treatment of substance use disorders (SUDs) and the possibility of treating SUD by abolishing dopamine release elicited by cocaine and other drugs of abuse by DBS in VTA, although further studies with chronic addiction models are required to confirm that. Furthermore, we demonstrated the use of M-CSWV can reliably measure tonic dopamine levels in vivo with both drug administration and DBS with minimal artifacts. [ABSTRACT FROM AUTHOR]

Background: The ventral tegmental area (VTA), containingmesolimbic andmesocortical dopaminergic neurons, is implicated in processes involving reward, addiction, reinforcement, and learning, which are associated with a variety of neuropsychiatric disorders. Electrical stimulation of the VTA or the medial forebrain bundle and its projection target the nucleus accumbens (NAc) is reported to improve depressive symptoms in patients affected by severe, treatment-resistant major depressive disorder (MDD) and depressive-like symptoms in animal models of depression. Here we sought to determine the neuromodulatory effects of VTA deep brain stimulation (DBS) in a normal large animal model (swine) by combining neurochemical measurements with functional magnetic resonance imaging (fMRI). Methods: Animals (n=8 swine) were implanted with a unilateral DBS electrode targeting the VTA. During stimulation (130 Hz frequency, 0.25 ms pulse width, and 3 V amplitude), fMRI was performed. Following fMRI, fast-scan cyclic voltammetry in combination with carbon fiber microelectrodes was performed to quantify VTA-DBS-evoked dopamine release in the ipsilateral NAc. In a subset of swine, the blood oxygen level-dependent (BOLD) percent change evoked by stimulation was performed at increasing voltages (1, 2, and 3 V). Results: A significant increase in VTA-DBS-evoked BOLD signal was found in the following regions: the ipsilateral dorsolateral prefrontal cortex, anterior and posterior cingulate, insula, premotor cortex, primary somatosensory cortex, and striatum. A decrease in the BOLD signal was also observed in the contralateral parahippocampal cortex, dorsolateral and anterior prefrontal cortex, insula, inferior temporal gyrus, and primary somatosensory cortex (Bonferroni-corrected < 0.001). During neurochemical measurements, stimulation time-locked changes in dopamine release were recorded in the NAc, confirming that mesolimbic dopaminergic neurons were stimulated by DBS. In the parametric study, BOLD signal changes were positively correlated with stimulation amplitude. Conclusions: In this study, the modulation of the neural circuitry associated with VTA-DBS was characterized in a large animal. Our findings suggest that VTA-DBS could affect the activity of neural systems and brain regions implicated in reward, mood regulation, and in the pathophysiology of MDD. In addition, we showed that a combination of fMRI and electrochemically-based neurochemical detection platform is an effective investigative tool for elucidating the circuitry involved in VTA-DBS. [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]

Deep brain stimulation (DBS), a surgical technique to treat certain neurologic and psychiatric conditions, relies on pre-determined stimulation parameters in an open-loop configuration. The major advancement in DBS devices is a closed-loop system that uses neurophysiologic feedback to dynamically adjust stimulation frequency and amplitude. Stimulation-driven neurochemical release can be measured by fast-scan cyclic voltammetry (FSCV), but existing FSCV electrodes rely on carbon fiber, which degrades quickly during use and is therefore unsuitable for chronic neurochemical recording. To address this issue, we developed durable, synthetic boron-doped diamond-based electrodes capable of measuring neurochemical release in humans. Compared to carbon fiber electrodes, they were more than two orders-of-magnitude more physically-robust and demonstrated longevity in vitro without deterioration. Applied for the first time in humans, diamond electrode recordings from thalamic targets in patients (n = 4) undergoing DBS for tremor produced signals consistent with adenosine release at a sensitivity comparable to carbon fiber electrodes. [ABSTRACT FROM AUTHOR]

Background Functional magnetic resonance imaging (fMRI) is a powerful method for identifying in vivo network activation evoked by deep brain stimulation (DBS). Objective Identify the global neural circuitry effect of subthalamic nucleus (STN) DBS in nonhuman primates (NHP). Method An in-house developed MR image-guided stereotactic targeting system delivered a mini-DBS stimulating electrode, and blood oxygenation level-dependent (BOLD) activation during STN DBS in healthy NHP was measured by combining fMRI with a normalized functional activation map and general linear modeling. Results STN DBS significantly increased BOLD activation in the sensorimotor cortex, supplementary motor area, caudate nucleus, pedunculopontine nucleus, cingulate, insular cortex, and cerebellum (FDR < 0.001). Conclusion Our results demonstrate that STN DBS evokes neural network grouping within the motor network and the basal ganglia. Taken together, these data highlight the importance and specificity of neural circuitry activation patterns and functional connectivity. [ABSTRACT FROM AUTHOR]

The precise mechanism whereby continuous high-frequency electrical stimulation of the subthalamic nucleus ameliorates motor symptoms of Parkinson's disease is unknown. We examined the effects of high-frequency stimulation of regions dorsal to and within the subthalamic nucleus on dopamine efflux in the striatum of urethane-anaesthetized rats using constant potential amperometry. Complementary extracellular electrophysiological studies determined the activity of subthalamic nucleus neurons in response to similar electrical stimulation of the subthalamic nucleus. High-frequency stimulation of the subthalamic nucleus increased action potential firing in the subthalamic nucleus only during the initial stimulation period and was followed by a cessation of firing over the remainder of stimulation. Electrical stimulation of the subthalamic nucleus with 15 pulses elicited stimulus-time-locked increases in striatal dopamine efflux with maximal peak effects occurring at 50 Hz frequency and 300 µA intensity. Extended subthalamic nucleus stimulation (1000 pulses at 50 Hz; 300 µA) elicited a similar peak increase in striatal dopamine efflux that was followed by a relatively lower steady-state elevation in extracellular dopamine over the course of stimulation. In contrast, extended stimulation immediately adjacent and dorsal to the subthalamic nucleus resulted in an 11-fold greater increase in dopamine efflux that remained elevated over the course of the stimulation. Immunohistochemical staining for tyrosine hydroxylase revealed catecholaminergic fibers running immediately dorsal to and through the subthalamic nucleus. Taken together, these results suggest that enhanced dopamine release within the basal ganglia may be an important mechanism whereby high-frequency stimulation of the subthalamic nucleus improves motor symptoms of Parkinson's disease. [ABSTRACT FROM AUTHOR]