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.

Understanding the different effects of fouling mechanisms on working and reference electrodes in fast-scan cyclic voltammetry for neurotransmitter detection.

Fast-scan cyclic voltammetry (FSCV) is a widely used technique for detecting neurotransmitters. However, electrode fouling can negatively impact its accuracy and sensitivity. Fouling refers to the accumulation of unwanted materials on the electrode surface, which can alter its electrochemical properties and reduce its sensitivity and selectivity. Fouling mechanisms can be broad and may include biofouling, the accumulation of biomolecules on the electrode surface, and chemical fouling, the deposition of unwanted chemical species. Despite individual studies discussing fouling effects on either the working electrode or the reference electrode, no comprehensive study has been conducted to compare the overall fouling effects on both electrodes in the context of FSCV. Here, we examined the effects of biofouling and chemical fouling on the carbon fiber micro-electrode (CFME) as the working electrode and the Ag/AgCl reference electrode with FSCV. Both fouling mechanisms significantly decreased the sensitivity and caused peak voltage shifts in the FSCV signal with the CFME, but not with the Ag/AgCl reference electrode. Interestingly, previous studies have reported peak voltage shifts in FSCV signals due to the fouling of Ag/AgCl electrodes after implantation in the brain. We noticed in a previous study that energy-dispersive spectroscopy (EDS) spectra showed increased sulfide ion concentration after implantation. We hypothesized that sulfide ions may be responsible for the peak voltage shift. To test this hypothesis, we added sulfide ions to the buffer solution, which decreased the open circuit potential of the Ag/AgCl electrode and caused a peak voltage shift in the FSCV voltammograms. Also, EDS analysis showed that sulfide ion concentration increased on the surface of the Ag/AgCl electrodes after 3 weeks of chronic implantation, necessitating consideration of sulfide ions as the fouling agent for the reference electrodes. Overall, our study provides important insights into the mechanisms of electrode fouling and its impact on FSCV measurements. These findings could inform the design of FSCV experiments, with the development of new strategies for improving the accuracy and reliability of FSCV measurements in vivo.

Clinical evaluation of a stereotactic system for single-stage deep brain stimulation surgery under general anesthesia: technical note.

OBJECTIVE: Conventional frame-based stereotactic systems have circumferential base frames, often necessitating deep brain stimulation (DBS) surgery in two stages: intracranial electrode insertion followed by surgical re-preparation and pulse generator implantation. Some patients do not tolerate awake surgery, underscoring the need for a safe alternative for asleep DBS surgery. A frame-based stereotactic system with a skull-mounted "key" in lieu of a circumferential base frame received US FDA clearance. The authors describe the system's application for single-stage, asleep DBS surgery in 8 patients at their institution and review its workflow and technical considerations. METHODS: Eight patients underwent DBS lead insertion and IPG implantation in a single surgical preparation under general anesthesia using the system. Postoperative CT imaging confirmed lead placement. RESULTS: Eight patients underwent implantation of 15 total leads targeting the ventral intermediate nucleus (4 patients), globus pallidus internus (GPi; 3 patients), and subthalamic nucleus (STN; 1 patient). Intraoperative microelectrode recording was conducted for GPi and STN targets. Postoperative CT imaging revealed a mean ± SD radial error of 1.24 ± 0.45 mm (n = 15 leads), without surgical complications. CONCLUSIONS: The stereotactic system facilitated safe and effective asleep, single-stage DBS surgery, maintaining traditional lead accuracy standards.

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.

Micromagnetic Stimulation (µMS) Controls Dopamine Release: An in vivo Study Using WINCS Harmoni.

Objective: Research into the role of neurotransmitters in regulating normal and pathologic brain functions has made significant progress. Yet, clinical trials that aim to improve therapeutic interventions do not take advantage of the in vivo changes in the neurochemistry that occur in real time during disease progression, drug interactions or response to pharmacological, cognitive, behavioral, and neuromodulation therapies. In this work, we used the WINCS Harmoni tool to study the real time in vivo changes in dopamine release in rodent brains for the micromagnetic neuromodulation therapy. Approach: Although still in its infancy, micromagnetic stimulation (µMS) using micro-meter sized coils or microcoils (µcoils) has shown incredible promise in spatially selective, galvanic contact free and highly focal neuromodulation. These µcoils are powered by a time-varying current which generates a magnetic field. As per Faraday's Laws of Electromagnetic Induction, this magnetic field induces an electric field in a conducting medium (here, the brain tissues). We used a solenoidal-shaped µcoil to stimulate the medial forebrain bundle (MFB) of the rodent brain in vivo. The evoked in vivo dopamine releases in the striatum were tracked in real time by carbon fiber microelectrodes (CFM) using fast scan cyclic voltammetry (FSCV). Results: Our experiments report that µcoils can successfully activate the MFB in rodent brains, triggering dopamine release in vivo. We further show that the successful release of dopamine upon micromagnetic stimulation is dependent on the orientation of the µcoil. Furthermore, varied intensities of µMS can control the concentration of dopamine releases in the striatum. Significance: This work helps us better understand the brain and its conditions arising from a new therapeutic intervention, like µMS, at the level of neurotransmitter release. Despite its early stage, this study potentially paves the path for µMS to enter the clinical world as a precisely controlled and optimized neuromodulation therapy.

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.

Enhanced Dopamine Sensitivity Using Steered Fast-Scan Cyclic Voltammetry.

Fast-scan cyclic voltammetry (FSCV) is a technique for measuring phasic release of neurotransmitters with millisecond temporal resolution. The current data are captured by carbon fiber microelectrodes, and non-Faradaic current is subtracted from the background current to extract the Faradaic redox current through a background subtraction algorithm. FSCV is able to measure neurotransmitter concentrations in vivo down to the nanomolar scale, making it a very robust and useful technique for probing neurotransmitter release dynamics and communication across neural networks. In this study, we describe a technique that can further lower the limit of detection of FSCV. By taking advantage of a "waveform steering" technique and by amplifying only the oxidation peak of dopamine to reduce noise fluctuations, we demonstrate the ability to measure dopamine concentrations down to 0.17 nM. Waveform steering is a technique to dynamically alter the input waveform to ensure that the background current remains stable over time. Specifically, the region of the input waveform in the vicinity of the dopamine oxidation potential (∼0.6 V) is kept flat. Thus, amplification of the input waveform will amplify only the Faradaic current, lowering the existing limit of detection for dopamine from 5.48 to 0.17 nM, a 32-fold reduction, and for serotonin, it lowers the limit of detection from 57.3 to 1.46 nM, a 39-fold reduction compared to conventional FSCV. Finally, the applicability of steered FSCV to in vivo dopamine detection was also demonstrated in this study. In conclusion, steered FSCV might be used as a neurochemical monitoring tool for enhancing detection sensitivity.

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.

Symptom-specific differential motor network modulation by deep brain stimulation in Parkinson's disease.

OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established neurosurgical treatment for the motor symptoms of Parkinson's disease (PD). While often highly effective, DBS does not always yield optimal therapeutic outcomes, and stimulation-induced adverse effects, including paresthesia, muscle contractions, and nausea/lightheadedness, commonly occur and can limit the efficacy of stimulation. Currently, objective metrics do not exist for monitoring neural changes associated with stimulation-induced therapeutic and adverse effects. METHODS: In the present study, the authors combined intraoperative functional MRI (fMRI) with STN DBS in 20 patients with PD to test the hypothesis that stimulation-induced blood oxygen level-dependent signals contained predictive information concerning the therapeutic and adverse effects of stimulation. RESULTS: As expected, DBS resulted in blood oxygen level-dependent activation in myriad motor regions, including the primary motor cortex, caudate, putamen, thalamus, midbrain, and cerebellum. Across the patients, DBS-induced improvements in contralateral Unified Parkinson's Disease Rating Scale tremor subscores correlated with activation of thalamic, brainstem, and cerebellar regions. In addition, improvements in rigidity and bradykinesia subscores correlated with activation of the primary motor cortex. Finally, activation of specific sensorimotor-related subregions correlated with the presence of DBS-induced adverse effects, including paresthesia and nausea (cerebellar cortex, sensorimotor cortex) and unwanted muscle contractions (caudate and putamen). CONCLUSIONS: These results suggest that DBS-induced activation patterns revealed by fMRI contain predictive information with respect to the therapeutic and adverse effects of DBS. The use of fMRI in combination with DBS therefore may hold translational potential to guide and improve clinical stimulator optimization in patients.