Resolution of tonic concentrations of highly similar neurotransmitters using voltammetry and deep learning.

With advances in our understanding regarding the neurochemical underpinnings of neurological and psychiatric diseases, there is an increased demand for advanced computational methods for neurochemical analysis. Despite having a variety of techniques for measuring tonic extracellular concentrations of neurotransmitters, including voltammetry, enzyme-based sensors, amperometry, and in vivo microdialysis, there is currently no means to resolve concentrations of structurally similar neurotransmitters from mixtures in the in vivo environment with high spatiotemporal resolution and limited tissue damage. Since a variety of research and clinical investigations involve brain regions containing electrochemically similar monoamines, such as dopamine and norepinephrine, developing a model to resolve the respective contributions of these neurotransmitters is of vital importance. Here we have developed a deep learning network, DiscrimNet, a convolutional autoencoder capable of accurately predicting individual tonic concentrations of dopamine, norepinephrine, and serotonin from both in vitro mixtures and the in vivo environment in anesthetized rats, measured using voltammetry. The architecture of DiscrimNet is described, and its ability to accurately predict in vitro and unseen in vivo concentrations is shown to vastly outperform a variety of shallow learning algorithms previously used for neurotransmitter discrimination. DiscrimNet is shown to generalize well to data captured from electrodes unseen during model training, eliminating the need to retrain the model for each new electrode. DiscrimNet is also shown to accurately predict the expected changes in dopamine and serotonin after cocaine and oxycodone administration in anesthetized rats in vivo. DiscrimNet therefore offers an exciting new method for real-time resolution of in vivo voltammetric signals into component neurotransmitters.

Anti-manic effect of deep brain stimulation of the ventral tegmental area in an animal model of mania induced by methamphetamine.

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.

Techniques for Measurement of Serotonin: Implications in Neuropsychiatric Disorders and Advances in Absolute Value Recording Methods.

Serotonin (5-HT) is a monoamine neurotransmitter in the peripheral, enteric, and central nervous systems (CNS). Within the CNS, serotonin is principally involved in mood regulation and reward-seeking behaviors. It is a critical regulator in CNS pathologies such as major depressive disorder, addiction, and schizophrenia. Consequently, in vivo serotonin measurements within the CNS have emerged as one of many promising approaches to investigating the pathogenesis, progression, and treatment of these and other neuropsychiatric conditions. These techniques vary in methods, ranging from analyte sampling with microdialysis to voltammetry. Provided this diversity in approach, inherent differences between techniques are inevitable. These include biosensor size, temporal/spatial resolution, and absolute value measurement capabilities, all of which must be considered to fit the prospective researcher's needs. In this review, we summarize currently available methods for the measurement of serotonin, including novel voltammetric absolute value measurement techniques. We also detail serotonin's role in various neuropsychiatric conditions, highlighting the role of phasic and tonic serotonergic neuronal firing within each where relevant. Lastly, we briefly review the present clinical application of these techniques and discuss the potential of a closed-loop monitoring and neuromodulation system utilizing deep brain stimulation (DBS).

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.

Deep brain stimulation alleviates tics in Tourette syndrome via striatal dopamine transmission.

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.

High frequency deep brain stimulation can mitigate the acute effects of cocaine administration on tonic dopamine levels in the rat nucleus accumbens.

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.

Software for near-real-time voltammetric tracking of tonic neurotransmitter levels in vivo.

Tonic extracellular neurotransmitter concentrations are important modulators of central network homeostasis. Disruptions in these tonic levels are thought to play a role in neurologic and psychiatric disease. Therefore, ways to improve their quantification are actively being investigated. Previously published voltammetric software packages have implemented FSCV, which is not capable of measuring tonic concentrations of neurotransmitters in vivo. In this paper, custom software was developed for near-real-time tracking (scans every 10 s) of neurotransmitters' tonic concentrations with high sensitivity and spatiotemporal resolution both in vitro and in vivo using cyclic voltammetry combined with dynamic background subtraction (M-CSWV and FSCAV). This software was designed with flexibility, speed, and user-friendliness in mind. This software enables near-real-time measurement by reducing data analysis time through an optimized modeling algorithm, and efficient memory handling makes long-term measurement possible. The software permits customization of the cyclic voltammetric waveform shape, enabling experiments to detect a specific analyte of interest. Finally, flexibility considerations allow the user to alter the fitting parameters, filtering characteristics, and size and shape of the analyte kernel, based on data obtained live during the experiment to obtain accurate measurements as experimental conditions change. Herein, the design and advantages of this near-real-time voltammetric software are described, and its use is demonstrated in in vivo experiments.

Neurochemical Concentration Prediction Using Deep Learning vs Principal Component Regression in Fast Scan Cyclic Voltammetry: A Comparison Study.

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.

Deep Brain Stimulation for Addictive Disorders-Where Are We Now?

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.

The development of ultra-high field MRI guidance technology for neuronavigation.

OBJECTIVE: Magnetic resonance imaging at 7T offers improved image spatial and contrast resolution for visualization of small brain nuclei targeted in neuromodulation. However, greater image geometric distortion and a lack of compatible instrumentation preclude implementation. In this report, the authors detail the development of a stereotactic image localizer and accompanying imaging sequences designed to mitigate geometric distortion, enabling accurate image registration and surgical planning of basal ganglia nuclei. METHODS: Magnetization-prepared rapid acquisition with gradient echo (MPRAGE), fast gray matter acquisition T1 inversion recovery (FGATIR), T2-weighted, and T2*-weighted sequences were optimized for 7T in 9 human subjects to visualize basal ganglia nuclei, minimize image distortion, and maximize target contrast-to-noise and signal-to-noise ratios. Extracranial spatial distortions were mapped to develop a skull-contoured image localizer embedded with spherical silicone fiducials for improved MR image registration and target guidance. Surgical plan accuracy testing was initially performed in a custom-developed MRI phantom (n = 5 phantom studies) and finally in a human trial. RESULTS: MPRAGE and T2*-weighted sequences had the best measures among global measures of image quality (3.8/4, p < 0.0001; and 3.7/4, p = 0.0002, respectively). Among basal ganglia nuclei, FGATIR outperformed MPRAGE for globus pallidus externus (GPe) visualization (2.67/4 vs 1.78/4, p = 0.008), and FGATIR, T2-weighted imaging, and T2*-weighted imaging outperformed MPRAGE for substantia nigra visualization (1.44/4 vs 2.56/4, p = 0.04; vs 2.56/4, p = 0.04; vs 2.67/4, p = 0.003). Extracranial distortion was lower in the head's midregion compared with the base and apex ( 1.17-1.33 mm; MPRAGE and FGATIR, p < 0.0001; T2-weighted imaging, p > 0.05; and T2*-weighted imaging, p = 0.013). Fiducial placement on the localizer in low distortion areas improved image registration (fiducial registration error, 0.79-1.19 mm; p < 0.0001) and targeting accuracy (target registration error, 0.60-1.09 mm; p = 0.04). Custom surgical software and the refined image localizer enabled successful surgical planning in a human trial (fiducial registration error = 1.0 mm). CONCLUSIONS: A skull-contoured image localizer that accounts for image distortion is necessary to enable high-accuracy 7T imaging-guided targeting for surgical neuromodulation. These results may enable improved clinical efficacy for the treatment of neurological disease.

Biomarkers for Deep Brain Stimulation in Animal Models of Depression.

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.

Cocaine increases stimulation-evoked serotonin efflux in the nucleus accumbens.

Although dopamine is the most implicated neurotransmitter in the mediation of the pathophysiology of addiction, animal studies show serotonin also plays a vital role. Cocaine is one of the most common illicit drugs globally, but the role of serotonin in its mechanism of action is insufficiently characterized. Consequently, we investigated the acute effects of the psychomotor stimulant cocaine on electrical stimulation-evoked serotonin (phasic) release in the nucleus accumbens core (NAcc) of urethane-anesthetized (1.5 g/kg ip) male Sprague-Dawley rats using N-shaped fast-scan cyclic voltammetry (N-FSCV). A single carbon fiber microelectrode was first implanted in the NAcc. Stimulation was applied to the medial forebrain bundle using 60 Hz, 2 ms, 0.2 mA, 2-s biphasic pulses before and after cocaine (2 mg/kg iv) was administered. Stimulation-evoked serotonin release significantly increased 5 min after cocaine injection compared with baseline (153 ± 21 nM vs. 257 ± 12 nM; P = 0.0042; n = 5) but was unaffected by saline injection (1 mL/kg iv; n = 5). N-FSCV's selective measurement of serotonin release in vivo was confirmed pharmacologically via administration of the selective serotonin reuptake inhibitor escitalopram (10 mg/kg ip) that effectively increased the signal in a separate group of rats (n = 5). Selectivity to serotonin was further confirmed in vitro in which dopamine was minimally detected by N-FSCV with a serotonin to dopamine response ratio of 1:0.04 (200 nM of serotonin:1 µM dopamine ratio; P = 0.0048; n = 5 electrodes). This study demonstrates a noteworthy influence of cocaine on serotonin dynamics, and confirms that N-FSCV can effectively and selectively measure phasic serotonin release in the NAcc.NEW & NOTEWORTHY Serotonin plays a vital role in drug addiction. Here, using N-shaped fast-scan cyclic voltammetry, we demonstrated the effect of cocaine on the phasic release of serotonin at the nucleus accumbens core. To the best of our knowledge, this has not previously been elucidated. Our results not only reinforce the role of serotonin in the mechanism of action of cocaine but also help to fill a gap in our knowledge and provide a baseline for future studies in cocaine addiction.

Tonic Serotonin Measurements In Vivo Using N-Shaped Multiple Cyclic Square Wave Voltammetry.

Here, we present the development of a novel voltammetric technique, N-shaped multiple cyclic square wave voltammetry (N-MCSWV) and its application in vivo. It allows quantitative measurements of tonic extracellular levels of serotonin in vivo with mitigated fouling effects. N-MCSWV enriches the electrochemical information by generating high dimensional voltammograms, which enables high sensitivity and selectivity against 5-hydroindoleacetic acid (5-HIAA), dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), histamine, ascorbic acid, norepinephrine, adenosine, and pH. Using N-MCSWV, in combination with PEDOT:Nafion-coated carbon fiber microelectrodes, a tonic serotonin concentration of 52 ± 5.8 nM (n = 20 rats, ±SEM) was determined in the substantia nigra pars reticulata of urethane-anesthetized rats. Pharmacological challenges with dopaminergic, noradrenergic, and serotonergic synaptic reuptake inhibitors supported the ability of N-MCSWV to selectively detect tonic serotonin levels in vivo. Overall, N-MCSWV is a novel voltammetric technique for analytical quantification of serotonin. It offers continuous monitoring of changes in tonic serotonin concentrations in the brain to further our understanding of the role of serotonin in normal behaviors and psychiatric disorders.

Feasibility of Applying Fourier Transform Electrochemical Impedance Spectroscopy in Fast Cyclic Square Wave Voltammetry for the In Vivo Measurement of Neurotransmitters.

We previously reported on the use of fast cyclic square wave voltammetry (FCSWV) as a new voltammetric technique. Fourier transform electrochemical impedance spectroscopy (FTEIS) has recently been utilized to provide information that enables a detailed analytical description of an electrified interface. In this study, we report on attempts to combine FTEIS with FCSWV (FTEIS-FCSWV) and demonstrate the feasibility of FTEIS-FCSWV in the in vivo detection of neurotransmitters, thus giving a new type of electrochemical impedance information such as biofouling on the electrode surface. From FTEIS-FCSWV, three new equivalent circuit element voltammograms, consisting of charge-transfer resistance (Rct), solution-resistance (Rs), and double-layer capacitance (Cdl) voltammograms were constructed and investigated in the phasic changes in dopamine (DA) concentrations. As a result, all Rct, Rs, and Cdl voltammograms showed different DA redox patterns and linear trends for the DA concentration (R2 > 0.99). Furthermore, the Rct voltammogram in FTEIS-FCSWV showed lower limit of detection (21.6 ± 15.8 nM) than FSCV (35.8 ± 17.4 nM). FTEIS-FCSWV also showed significantly lower prediction errors than FSCV in selectivity evaluations of unknown mixtures of catecholamines. Finally, Cdl from FTEIS-FCSWV showed a significant relationship with fouling effect on the electrode surface by showing decreased DA sensitivity in both flow injection analysis experiment (r = 0.986) and in vivo experiments. Overall, this study demonstrates the feasibility of FTEIS-FCSWV, which could offer a new type of neurochemical spectroscopic information concerning electrochemical monitoring of neurotransmitters in the brain, and the ability to estimate the degree of sensitivity loss caused by biofouling on the electrode surface.

Development and validation of a rapidly deployable CT-guided stereotactic system for external ventricular drainage: preclinical study.

External ventricular drainage (EVD) is an emergency neurosurgical procedure to decrease intracranial pressure through a catheter mediated drainage of cerebrospinal fluid. Most EVD catheters are placed using free hands without direct visualization of the target and catheter trajectory, leading to a high rate of complications- hemorrhage, brain injury and suboptimal catheter placement. Use of stereotactic systems can prevent these complications. However, they have found limited application for this procedure due to their long set-up time and expensive hardware. Therefore, we have developed and pre-clinically validated a novel 3D printed stereotactic system for rapid and accurate implantation of EVD catheters. Its mechanical and imaging accuracies were found to be at par with clinical stereotactic systems. Preclinical trial in human cadaver specimens revealed improved targeting accuracy achieved within an acceptable time frame compared to the free hand technique. CT angiography emulated using cadaver specimen with radio-opaque vascular contrast showed vessel free catheter trajectory. This could potentially translate to reduced hemorrhage rate. Thus, our 3D printed stereotactic system offers the potential to improve the accuracy and safety of EVD catheter placement for patients without significantly increasing the procedure time.

Cocaine-Induced Changes in Tonic Dopamine Concentrations Measured Using Multiple-Cyclic Square Wave Voltammetry in vivo.

For over 40 years, in vivo microdialysis techniques have been at the forefront in measuring the effects of illicit substances on brain tonic extracellular levels of dopamine that underlie many aspects of drug addiction. However, the size of microdialysis probes and sampling rate may limit this technique's ability to provide an accurate assessment of drug effects in microneural environments. A novel electrochemical method known as multiple-cyclic square wave voltammetry (M-CSWV), was recently developed to measure second-to-second changes in tonic dopamine levels at microelectrodes, providing spatiotemporal resolution superior to microdialysis. Here, we utilized M-CSWV and fast-scan cyclic voltammetry (FSCV) to measure changes in tonic or phasic dopamine release in the nucleus accumbens core (NAcc) after acute cocaine administration. Carbon-fiber microelectrodes (CFM) and stimulating electrodes were implanted into the NAcc and medial forebrain bundle (MFB) of urethane anesthetized (1.5 g/kg i.p.) Sprague-Dawley rats, respectively. Using FSCV, depths of each electrode were optimized by determining maximal MFB electrical stimulation-evoked phasic dopamine release. Changes in phasic responses were measured after a single dose of intravenous saline or cocaine hydrochloride (3 mg/kg; n = 4). In a separate group, changes in tonic dopamine levels were measured using M-CSWV after intravenous saline and after cocaine hydrochloride (3 mg/kg; n = 5). Both the phasic and tonic dopamine responses in the NAcc were augmented by the injection of cocaine compared to saline control. The phasic and tonic levels changed by approximately x2.4 and x1.9, respectively. These increases were largely consistent with previous studies using FSCV and microdialysis. However, the minimal disruption/disturbance of neuronal tissue by the CFM may explain why the baseline tonic dopamine values (134 ± 32 nM) measured by M-CSWV were found to be 10-fold higher when compared to conventional microdialysis. In this study, we demonstrated phasic dopamine dynamics in the NAcc with acute cocaine administration. M-CSWV was able to record rapid changes in tonic levels of dopamine, which cannot be achieved with other current voltammetric techniques. Taken together, M-CSWV has the potential to provide an unprecedented level of physiologic insight into dopamine signaling, both in vitro and in vivo, which will significantly enhance our understanding of neurochemical mechanisms underlying psychiatric conditions.

Automatic and Reliable Quantification of Tonic Dopamine Concentrations In Vivo Using a Novel Probabilistic Inference Method.

Dysregulation of the neurotransmitter dopamine (DA) is implicated in several neuropsychiatric conditions. Multiple-cyclic square-wave voltammetry (MCSWV) is a state-of-the-art technique for measuring tonic DA levels with high sensitivity (<5 nM), selectivity, and spatiotemporal resolution. Currently, however, analysis of MCSWV data requires manual, qualitative adjustments of analysis parameters, which can inadvertently introduce bias. Here, we demonstrate the development of a computational technique using a statistical model for standardized, unbiased analysis of experimental MCSWV data for unbiased quantification of tonic DA. The oxidation current in the MCSWV signal was predicted to follow a lognormal distribution. The DA-related oxidation signal was inferred to be present in the top 5% of this analytical distribution and was used to predict a tonic DA level. The performance of this technique was compared against the previously used peak-based method on paired in vivo and post-calibration in vitro datasets. Analytical inference of DA signals derived from the predicted statistical model enabled high-fidelity conversion of the in vivo current signal to a concentration value via in vitro post-calibration. As a result, this technique demonstrated reliable and improved estimation of tonic DA levels in vivo compared to the conventional manual post-processing technique using the peak current signals. These results show that probabilistic inference-based voltammetry signal processing techniques can standardize the determination of tonic DA concentrations, enabling progress toward the development of MCSWV as a robust research and clinical tool.

The development of an implantable deep brain stimulation device with simultaneous chronic electrophysiological recording and stimulation in humans.

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.

Brain Metabolic Changes with Longitudinal Transcutaneous Afferent Patterned Stimulation in Essential Tremor Subjects.

Background: Non-invasive peripheral nerve stimulation, also referred to as transcutaneous afferent patterned stimulation (TAPS), reduces hand tremor in essential tremor (ET) subjects. However, the mechanism of action of TAPS is unknown. Here, we investigated changes in brain metabolism over three months of TAPS use in ET subjects. Methods: This was an interventional, open label, single group study enrolling 5 ET subjects. They received 40 minutes of TAPS treatment twice daily for 90 days. Brain metabolic activity and tremor severity were measured using 18F-fluorodeoxyglucose (FDG) PET/CT, and the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS), respectively, at baseline and after 90 days. Tremor power and frequency was measured before and after all TAPS sessions using an onboard three-axis accelerometer. Results: FDG PET/CT revealed areas of hypermetabolism in ipsilateral cerebellar hemisphere and hypometabolism in contralateral cerebellar hemisphere following 90 days of TAPS treatment, compared to day one (uncorrected p value <0.05). Paired pre-post kinematic measurements over 90 days showed significantly decreased tremor power (p < 0.0001) but no change in tremor frequency. The TETRAS score on day 1 decreased from 6.5 ± 2.5 to 4.1 ± 1.8 following TAPS (p = 0.05). The pre-post TETRAS scores on day 90: 4.9 ± 1.5 and 4.1± 1 were lower than pre-TAPS TETRAS score on day 1 (p = 0.14 and 0.05, respectively). Conclusions: Our results suggest that longitudinal TAPS of the median and radial nerves modulates brain metabolism in areas instrumental to motor coordination and implicated in ET. Clinically, TAPS reduced tremor power, but had no effect on tremor frequency. This study paves the way for comprehensive studies in larger cohorts to further elucidate the mechanism of TAPS. Highlights: Non-invasive peripheral nerve stimulation, also referred to as transcutaneous afferent patterned stimulation (TAPS), reduces hand tremor in essential tremor subjects. Longitudinal TAPS therapy alters cerebellar metabolism, which can be a cause or consequence of tremor reduction. Cerebellar-premotor region connectivity may play a role in the anti-tremor effects of TAPS.

A compact stereotactic system for image-guided surgical intervention.

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 cm2device 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.