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1.  Deep Brain Stimulation for Tourette’s Syndrome: The Case for Targeting the Thalamic Centromedian–Parafascicular Complex 
Tourette’s syndrome (TS) is a neurologic condition characterized by both motor and phonic tics and is typically associated with psychiatric comorbidities, including obsessive-compulsive disorder/behavior and attention-deficit hyperactivity disorder, and can be psychologically and socially debilitating. It is considered a disorder of the cortico–striato–thalamo–cortical circuitry, as suggested by pathophysiology studies and therapeutic options. Among these, deep brain stimulation (DBS) of the centromedian–parafascicular nucleus (CM-Pf) of the thalamus is emerging as a valuable treatment modality for patients affected by severe, treatment-resistant TS. Here, we review the most recent experimental evidence for the pivotal role of CM-Pf in the pathophysiology of TS, discuss potential mechanisms of action that may mediate the effects of CM-Pf DBS in TS, and summarize its clinical efficacy.
PMCID: PMC5102892  PMID: 27891112
Tourette; tics; DBS; centromedian–parafascicular; CM-Pf; thalamus
2.  Functional correlates of the therapeutic and adverse effects evoked by thalamic stimulation for essential tremor 
Brain  2016;139(8):2198-2210.
Thalamic deep brain stimulation (DBS) is an effective therapy for essential tremor. Gibson et al. use functional MRI to reveal patterns of activation that correlate with stimulation-induced therapeutic and adverse effects. Their results suggest that thalamic DBS controls tremor, and induces paraesthesias, through distal modulation of tremor-related network nodes.
Thalamic deep brain stimulation (DBS) is an effective therapy for essential tremor. Gibson et al. use functional MRI to reveal patterns of activation that correlate with stimulation-induced therapeutic and adverse effects. Their results suggest that thalamic DBS controls tremor, and induces paraesthesias, through distal modulation of tremor-related network nodes.
Deep brain stimulation is an established neurosurgical therapy for movement disorders including essential tremor and Parkinson’s disease. While typically highly effective, deep brain stimulation can sometimes yield suboptimal therapeutic benefit and can cause adverse effects. In this study, we tested the hypothesis that intraoperative functional magnetic resonance imaging could be used to detect deep brain stimulation-evoked changes in functional and effective connectivity that would correlate with the therapeutic and adverse effects of stimulation. Ten patients receiving deep brain stimulation of the ventralis intermedius thalamic nucleus for essential tremor underwent functional magnetic resonance imaging during stimulation applied at a series of stimulation localizations, followed by evaluation of deep brain stimulation-evoked therapeutic and adverse effects. Correlations between the therapeutic effectiveness of deep brain stimulation (3 months postoperatively) and deep brain stimulation-evoked changes in functional and effective connectivity were assessed using region of interest-based correlation analysis and dynamic causal modelling, respectively. Further, we investigated whether brain regions might exist in which activation resulting from deep brain stimulation might correlate with the presence of paraesthesias, the most common deep brain stimulation-evoked adverse effect. Thalamic deep brain stimulation resulted in activation within established nodes of the tremor circuit: sensorimotor cortex, thalamus, contralateral cerebellar cortex and deep cerebellar nuclei (FDR q < 0.05). Stimulation-evoked activation in all these regions of interest, as well as activation within the supplementary motor area, brainstem, and inferior frontal gyrus, exhibited significant correlations with the long-term therapeutic effectiveness of deep brain stimulation (P < 0.05), with the strongest correlation (P < 0.001) observed within the contralateral cerebellum. Dynamic causal modelling revealed a correlation between therapeutic effectiveness and attenuated within-region inhibitory connectivity in cerebellum. Finally, specific subregions of sensorimotor cortex were identified in which deep brain stimulation-evoked activation correlated with the presence of unwanted paraesthesias. These results suggest that thalamic deep brain stimulation in tremor likely exerts its effects through modulation of both olivocerebellar and thalamocortical circuits. In addition, our findings indicate that deep brain stimulation-evoked functional activation maps obtained intraoperatively may contain predictive information pertaining to the therapeutic and adverse effects induced by deep brain stimulation.
PMCID: PMC4958905  PMID: 27329768
functional MRI; deep brain stimulation; ventralis intermedius nucleus; thalamus; essential tremor
3.  Motor and non-motor circuitry activation induced by subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson’s disease patients: Intraoperative fMRI for DBS 
Mayo Clinic proceedings  2015;90(6):773-785.
To test the hypothesis suggested by previous studies that subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with PD would affect the activity of both motor and non-motor networks, we applied intraoperative fMRI to patients receiving DBS.
Patients and Methods
Ten patients receiving STN DBS for PD underwent intraoperative 1.5T fMRI during high frequency stimulation delivered via an external pulse generator. The study was conducted between the dates of January 1, 2013 and September 30, 2014.
We observed blood oxygen level dependent (BOLD) signal changes (FDR<.001) in the motor circuitry, including primary motor, premotor, and supplementary motor cortices, thalamus, pedunculopontine nucleus (PPN), and cerebellum, as well as in the limbic circuitry, including cingulate and insular cortices. Activation of the motor network was observed also after applying a Bonferroni correction (p<.001) to our dataset, suggesting that, across subjects, BOLD changes in the motor circuitry are more consistent compared to those occurring in the non-motor network.
These findings support the modulatory role of STN DBS on the activity of motor and non-motor networks, and suggest complex mechanisms at the basis of the efficacy of this treatment modality. Furthermore, these results suggest that, across subjects, BOLD changes in the motor circuitry are more consistent compared to those occurring in the non-motor network. With further studies combining the use of real time intraoperative fMRI with clinical outcomes in patients treated with DBS, functional imaging techniques have the potential not only to elucidate the mechanisms of DBS functioning, but also to guide and assist in the surgical treatment of patients affected by movement and neuropsychiatric disorders.
PMCID: PMC4469128  PMID: 26046412
Deep Brain Stimulation (DBS); Functional Magnetic Resonance Imaging (fMRI); Subthalamic Nucleus; Parkinson Disease
4.  Dopamine Release in the Nonhuman Primate Caudate and Putamen Depends upon Site of Stimulation in the Subthalamic Nucleus 
The Journal of Neuroscience  2016;36(22):6022-6029.
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.
SIGNIFICANCE STATEMENT Electrical stimulation of deep structures of the brain, or deep brain stimulation (DBS), is used to modulate pathological brain activity. However, technological limitations and incomplete understanding of the therapeutic mechanisms of DBS prevent personalization of this therapy and may contribute to less-than-optimal outcomes. We have demonstrated that DBS coincides with changes in dopamine neurotransmitter release in the basal ganglia. Here we mapped relationships between DBS and changes in neurochemical activity. Importantly, this study shows that DBS-evoked dopamine release can be reduced or increased by refocusing the DBS on a slightly different stimulation site.
PMCID: PMC4887566  PMID: 27251623
caudate; deep brain stimulation; dopamine; fast-scan cyclic voltammetry; functional magnetic resonance imaging; subthalamic nucleus
5.  Toward sophisiticated basal ganglia neuromodulation: review on basal gaglia deep brain stimulation 
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.
PMCID: PMC4534367  PMID: 25684727
deep brain stimulation; striatum; subthalamic nucleus; globus pallidus; substantia nigra; electrochemistry; voltammetry; functional magnetic resonance imaging; pig; human
6.  Minimally invasive convection enhanced delivery of biologics into dorsal root ganglia: Validation in the pig model and prospective modeling in humans: Technical note 
Journal of neurosurgery  2014;121(4):851-858.
Dorsal root ganglia (DRG) are critical anatomical structures involved in nociception. Intraganglionic (IG) drug delivery is therefore an important route of administration for novel analgesic therapies. Although IG injection in large animal models is highly desirable for pre-clinical biodistribution and toxicology studies of new drugs, no method to deliver pharmaceutics into the DRG has been reported in any large species. The present study describes a minimally invasive technique of IG agent delivery in domestic swine, one of the most common large animal models. The technique utilizes computed tomography (CT) guidance for DRG targeting, and a custom-made injection assembly for convection-enhanced delivery (CED) of therapeutic agents directly into DRG parenchyma. The DRG were initially visualized by CT-myelogram to determine the optimal access route to the DRG. The subsequent IG injection consisted of three steps. First, a commercially available guide needle was advanced to a position dorso-lateral to the DRG, and the dural root sleeve was punctured, leaving the guide needle contiguous with, but not penetrating, the DRG. Second, the custom-made stepped stylet was inserted through the guide needle into the DRG parenchyma. Third, the stepped stylet was replaced by the custom-made stepped needle, which was used for the IG CED. Initial dye injections performed in pig cadavers confirmed the accuracy of DRG targeting under CT guidance. IG administration of adeno-associated virus in vivo resulted in a unilateral transduction of the injected DRG, with 33.5% DRG neurons transduced. Transgene expression was also found in the dorsal root entry zones at the corresponding spinal levels. The results thereby confirm the efficacy of CED by the stepped needle and a selectivity of DRG targeting. Imaging based modeling of the procedure in humans suggests that IG CED may be translatable to the clinical setting.
PMCID: PMC5065916  PMID: 24995785
Dorsal root ganglia; computed tomography; intraganglionic injection; convection enhanced delivery; gene therapy; pain
7.  Optical stimulation for restoration of motor function following spinal cord injury 
Mayo Clinic proceedings  2015;90(2):300-307.
Spinal cord injury (SCI) can be defined as a loss of communication between the brain and the body due to disrupted pathways within the spinal cord. While many promising molecular strategies have emerged to reduce secondary injury and promote axonal regrowth, there is still no effective cure and recovery of function remains limited. Functional electrical stimulation (FES) represents a strategy developed to restore motor function without the need for regenerating severed spinal pathways. Despite its technological success, however, FES has not been widely integrated into the lives of spinal cord injury survivors. In this review, we briefly discuss the limitations of existing FES technologies. Additionally, we discuss how optogenetics, a rapidly evolving technique used primarily to investigate select neuronal populations within the brain, may eventually be used to replace FES as a form of therapy for functional restoration following SCI.
PMCID: PMC4339262  PMID: 25659246
Optogenetics; spinal cord injury; functional electrical stimulation; sensorimotor; FES; SCI
8.  Frequency-dependent functional neuromodulatory effects on the motor network by ventral lateral thalamic deep brain stimulation in swine 
NeuroImage  2014;105:181-188.
Thalamic deep brain stimulation (DBS) is an FDA-approved neurosurgical treatment for medication-refractory essential tremor. Its therapeutic benefit is highly dependent upon stimulation frequency and voltage parameters. We investigated these stimulation parameter-dependent effects on neural network activation by performing functional magnetic resonance imaging (fMRI) during DBS of the ventral lateral (VL) thalamus and comparing the blood oxygenation level-dependent (BOLD) signals induced by multiple stimulation parameter combinations in a within-subjects study of swine. Low (10 Hz) and high (130 Hz) frequency stimulation was applied at 3, 5, and 7 volts in the VL thalamus of normal swine (n = 5). We found that stimulation frequency and voltage combinations differentially modulated brain network activity in the sensorimotor cortex, the basal ganglia, and the cerebellum in a parameter-dependent manner. Notably, in the motor cortex, high frequency stimulation generated a negative BOLD response, while low frequency stimulation increased the positive BOLD response. These frequency-dependent differential effects suggest that the VL thalamus is an exemplary target for investigating functional network connectivity associated with therapeutic DBS.
PMCID: PMC4316813  PMID: 25451479
Ventral lateral thalamus (VL Thalamus); Deep brain stimulation (DBS); Essential tremor (ET); Low frequency stimulation (LFS); High frequency stimulation (HFS); and fMRI
9.  A Diamond-Based Electrode for Detection of Neurochemicals in the Human Brain 
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. (Clinical trials # NCT01705301).
PMCID: PMC4791376  PMID: 27014033
diamond-based electrode; dopamine; deep brain stimulation (DBS); fast scan cyclic voltammetry (FSCV); carbon fiber microelectrode; neuromodulation
10.  Implementation of a Chronic Unilateral Intraparenchymal Drug Delivery System in a Swine Model 
Systemic delivery of pharmacologic agents has led to many significant advances in the treatment of neurologic and psychiatric conditions. However, this approach has several limitations, including difficulty penetrating the blood-brain barrier and enzymatic degradation prior to reaching its intended target. Here, we describe the testing of a system allowing intraparenchymal (IPa) infusion of therapeutic agents directly to the appropriate anatomical targets, in a swine model.
New Method
Five male pigs underwent 3.0 T magnetic resonance (MR) guided placement of an IPa catheter into the dorso-medial putamen, using a combined system of the Leksell Stereotactic Arc, a Mayo-developed MRI-compatible pig head frame, and a custom-designed Fred Haer Company (FHC) delivery system.
Our results show hemi-lateral coverage of the pig putamen is achievable from a single infusion point and that the volume of the bolus detected in each animal is uniform (1544±420mm3).
Comparison with Existing Method
The IPa infusion system is designed to isolate the intracranial catheter from bodily-induced forces while delivering drugs and molecules into the brain tissue by convection-enhanced delivery, with minimal-to-no catheter track backflow.
This study presents an innovative IPa drug delivery system, which includes a sophisticated catheter and implantable pump designed to deliver drugs and various molecules in a precise and controlled manner with limited backflow. It also demonstrates the efficacy of the delivery system, which has the potential to radically impact the treatment of a wide range of neurologic conditions. Lastly, the swine model used here has certain advantages for translation into clinical applications.
PMCID: PMC4564994  PMID: 24486877
Chronic Drug Delivery System; Intraparenchymal Catheter; Blood Brain Barrier; Central Nervous System; Swine Model
11.  Mood Stability in Parkinson’s Disease Status Post Deep Brain Stimulation: A 6-Month Prospective Follow-up Study 
Psychosomatics  2013;55(5):478-484.
Deep brain stimulation (DBS) for Parkinson’s disease (PD) has been associated with psychiatric adverse effects (PAEs) including anxiety, depression, mania, psychosis and suicide. The purpose of this study was to evaluate safety of DBS in a large PD clinical practice.
Patients approved for surgery by Mayo Clinic DBS clinical committee participated in a 6 month prospective naturalistic follow-up study. In addition to the Unified Parkinson’s Disease Rating Scale (UPDRS), stability and psychiatric safety was measured using: Beck Depression Inventory (BDI-II), Hamilton Depression Rating Scale (HAMD-17), and Young Mania Rating scale (YMRS). Outcomes were compared in PD patients with past psychiatric history to PD patients with no comorbid psychiatric history.
Forty-nine of 54 patients completed the study. Statistically significant 6-month baseline to endpoint improvement was found in motor and mood scales. No significant differences were found in psychiatric outcomes based on presence or absence of psychiatric comorbidity.
Our study suggests PD patients with a history of psychiatric comorbidity can safely respond to DBS with no greater risk of PAE occurrence. A multi-disciplinary team approach including careful psychiatric screening ensuring mood stabilization and psychiatric follow-up should be viewed as standard of clinical care to optimize psychiatric outcome in the course of DBS treatment.
PMCID: PMC4063889  PMID: 24360528
12.  Wireless control of intraspinal microstimulation in a rodent model of paralysis 
Journal of neurosurgery  2014;123(1):232-242.
Despite a promising outlook, existing intraspinal microstimulation (ISMS) techniques for restoring functional motor control after spinal cord injury are not yet suitable for use outside a controlled laboratory environment. Thus, successful application of ISMS therapy in humans will require the use of versatile chronic neurostimulation systems. The objective of this study was to establish proof of principle for wireless control of ISMS to evoke controlled motor function in a rodent model of complete spinal cord injury.
The lumbar spinal cord in each of 17 fully anesthetized Sprague-Dawley rats was stimulated via ISMS electrodes to evoke hindlimb function. Nine subjects underwent complete surgical transection of the spinal cord at the T-4 level 7 days before stimulation. Targeting for both groups (spinalized and control) was performed under visual inspection via dorsal spinal cord landmarks such as the dorsal root entry zone and the dorsal median fissure. Teflon-insulated stimulating platinum-iridium microwire electrodes (50 μm in diameter, with a 30- to 60-μm exposed tip) were implanted within the ventral gray matter to an approximate depth of 1.8 mm. Electrode implantation was performed using a free-hand delivery technique (n = 12) or a Kopf spinal frame system (n = 5) to compare the efficacy of these 2 commonly used targeting techniques. Stimulation was controlled remotely using a wireless neurostimulation control system. Hindlimb movements evoked by stimulation were tracked via kinematic markers placed on the hips, knees, ankles, and paws. Postmortem fixation and staining of the spinal cord tissue were conducted to determine the final positions of the stimulating electrodes within the spinal cord tissue.
The results show that wireless ISMS was capable of evoking controlled and sustained activation of ankle, knee, and hip muscles in 90% of the spinalized rats (n = 9) and 100% of the healthy control rats (n = 8). No functional differences between movements evoked by either of the 2 targeting techniques were revealed. However, frame-based targeting required fewer electrode penetrations to evoke target movements.
Clinical restoration of functional movement via ISMS remains a distant goal. However, the technology presented herein represents the first step toward restoring functional independence for individuals with chronic spinal cord injury.
PMCID: PMC4457704  PMID: 25479124
intraspinal microstimulation; functional electrical stimulation; spinal cord injury; diagnostic and operative techniques
13.  High frequency stimulation of the subthalamic nucleus evokes striatal dopamine release in a large animal model of human DBS neurosurgery 
Neuroscience letters  2010;475(3):136-140.
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 (1–7 V) increases in evoked dopamine release exhibited a sigmoidal pattern attaining a plateau between 5 to 7 V of stimulation, while frequency-dependent dopamine release exhibited a linear increase from 60 to 120 Hz and attained a plateau thereafter (120–240 Hz). 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 (120–180 Hz). 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.
PMCID: PMC2874873  PMID: 20347936
Deep brain stimulation; Dopamine release; Fast-scan cyclic voltammetry; Pig brain; Subthalamic nucleus; Parkinson’s disease
14.  Centromedian-Parafascicular Deep Brain Stimulation Induces Differential Functional Inhibition of the Motor, Associative, and Limbic Circuits in Large Animals 
Biological psychiatry  2013;74(12):917-926.
Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) thalamic nuclei has been considered an option for treating Tourette syndrome (TS). Using a large animal DBS model, this study was designed to explore the network effects of CM-Pf DBS.
The combination of 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. Using a with-in 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).
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.
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 TS as a condition with psychiatric and motor symptoms and of CM-Pf DBS as a potentially effective tool for treating both types of symptoms.
PMCID: PMC3910443  PMID: 23993641
Deep brain stimulation (DBS); Tourette syndrome; centromedian; parafascicular; functional magnetic resonance imaging (fMRI); swine model; neural circuitry
15.  Development of the Mayo Investigational Neuromodulation Control System: toward a closed-loop electrochemical feedback system for deep brain stimulation 
Journal of neurosurgery  2013;119(6):1556-1565.
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).
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.
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.
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.
PMCID: PMC4001796  PMID: 24116724
deep brain stimulation; dopamine; fast scan cyclic voltammetry; wireless device; functional neurosurgery
16.  Dopamine measurement during prolonged deep brain stimulation: a proof-of-principle study of paired pulse voltammetry 
Deep Brain Stimulation (DBS) has been effective in treating various neurological and psychiatric disorders; however, its underlying mechanism hasn’t been completely understood. Fast scan cyclic voltammetry (FSCV) is a valuable tool to elucidate underlying neurotransmitter mechanisms of DBS, due to its sub-second temporal resolution and direct identification of analytes. However, since DBS-like high frequency stimulation evokes neurotransmitter release as well as extracellular pH shift, it is hard to isolate the neurotransmitter signal from the complex environment. Here we demonstrate the efficacy of a modified FSCV technique, Paired Pulse Voltammetry (PPV), in detecting dopamine (DA) release in the caudate nucleus during long-term electrical stimulation of the medial forebrain bundle (MFB) in the rat.
Unlike traditional FSCV applying a single triangular waveform, PPV employs a binary waveform with a specific time gap (2.2 ms) in between the comprising pulses. DA measurement was performed with a carbon fiber microelectrode placed in the caudate nucleus and a twisted bipolar stimulating electrode in the MFB. PPV data was collected with the Wireless Instantaneous Neurochemical Concentration Sensing System (WINCS).
Using PPV, the detection of DA was evident throughout the long-term stimulation (5 minutes); however, without PPV, in vivo environmental changes including pH shift eventually obscured the characteristic oxidation current of DA at 0.6V.
These results indicate that PPV can be a valuable tool to accurately determine DA dynamics in a complex in vivo environment during long-term electrical stimulation.
PMCID: PMC3969747  PMID: 24688801
Deep Brain Stimulation (DBS); Fast Scan Cyclic Voltammetry (FSCV); Paired Pulse Voltammetry (PPV); Dopamine (DA); Medial Forebrain Bundle (MFB)
17.  The Nucleus Accumbens as a Potential Target for Central Poststroke Pain 
Mayo Clinic Proceedings  2012;87(10):1025-1031.
Although deep brain stimulation (DBS) has been found to be efficacious for some chronic pain syndromes, its usefulness in patients with central poststroke pain (CPSP) has been disappointing. The most common DBS targets for pain are the periventricular gray region (PVG) and the ventralis caudalis of the thalamus. Despite the limited success of DBS for CPSP, few alternative targets have been explored. The nucleus accumbens (NAC), a limbic structure within the ventral striatum that is involved in reward and pain processing, has emerged as an effective target for psychiatric disease. There is also evidence that it may be an effective target for pain. We describe a 72-year-old woman with a large right hemisphere infarct who subsequently experienced refractory left hemibody pain. She underwent placement of 3 electrodes in the right PVG, ventralis caudalis of the thalamus, and NAC. Individual stimulation of the NAC and PVG provided substantial improvement in pain rating. The patient underwent implantation of permanent electrodes in both targets, and combined stimulation has provided sustained pain relief at nearly 1 year after the procedure. These results suggest that the NAC may be an effective DBS target for CPSP.
PMCID: PMC3498057  PMID: 22980165
CPSP, central poststroke pain; DBS, deep brain stimulation; ECT, electroconvulive therapy; ICL, intercommissural line; MCS, motor cortex stimulation; NAC, nucleus accumbens; PFC, prefrontal cortex; PVG, periventricular gray region; VC, ventralis caudalis of the thalamus
18.  Underlying Neurobiology and Clinical Correlates of Mania Status-Post Subthalamic Nucleus Deep Brain Stimulation in Parkinson’s disease: A Review of the Literature 
Deep brain stimulation (DBS) is a novel and effective surgical intervention for refractory Parkinson’s disease (PD).
We review the current literature to identify the clinical correlates associated with STN DBS-induced hypomania/mania in PD patients.
Ventromedial electrode placement has been most consistently implicated in the induction of STN DBS-induced mania. There is some evidence of symptom amelioration when electrode placement is switched to a more dorsolateral contact. Additional clinical correlates may include unipolar stimulation, higher voltage (>3 V), male patients and/or early onset PD.
STN DBS-induced psychiatric adverse events emphasize the need for comprehensive psychiatric presurgical evaluation and follow-up in PD patients. Animal studies and prospective clinical research, combined with advanced neuroimaging techniques, are needed to identify clinical correlates and underlying neurobiological mechanism(s) of STN DBS-induced mania. Such working models would serve to further our understanding of the neurobiological underpinnings of mania and contribute valuable new insight towards development of future DBS mood stabilization therapies.
PMCID: PMC3570815  PMID: 22450620
Parkinson’s disease; mania; subthalamic nucleus (STN); deep brain stimulation (DBS)
19.  Wireless Fast-Scan Cyclic Voltammetry to Monitor Adenosine in Patients With Essential Tremor During Deep Brain Stimulation 
Mayo Clinic Proceedings  2012;87(8):760-765.
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.
PMCID: PMC3538486  PMID: 22809886
CFM, carbon fiber microelectrode; DBS, deep brain stimulation; ET, essential tremor; FSCV, fast-scan cyclic voltammetry; MRI, magnetic resonance imaging; VIM, ventral intermediate nucleus of the thalamus
20.  High frequency stimulation abolishes thalamic network oscillations: an electrophysiological and computational analysis 
Journal of neural engineering  2011;8(4):046001.
Deep Brain Stimulation (DBS) of thalamus has been demonstrated to be an effective for treatment of epilepsy. To investigate mechanism of action of thalamic DBS, we examined the effects of high frequency stimulation (HFS) on spindle oscillations in thalamic brain slices from ferrets. We recorded intracellular and extracellular electrophysiological activity in the nucleus Reticularis thalami (nRt) and in thalamocortical relay (TC) neurons in the lateral geniculate nucleus, stimulated the slice using a concentric bipolar electrode, and recorded the level of glutamate within the slice. HFS (100 Hz) of TC neurons generated excitatory post-synaptic potentials (EPSPs), increased the number of action potentials in both TC and nRt neurons, reduced the input resistance, increased the extracellular glutamate concentration, and abolished spindle wave oscillations. High frequency stimulation of the nRt also suppressed spindle oscillations. In both locations, HFS was associated with significant and persistent elevation in extracellular glutamate levels and suppressed spindle oscillations for many seconds after the cessation of stimulation. We simulated HFS within a computational model of the thalamic network, and HFS also disrupted spindle wave activity, but the suppression of spindle activity was short-lived. Simulated HFS disrupted spindle activity for prolonged periods of time only after glutamate release and glutamate-mediated activation of a hyperpolarization-activated current (Ih) were incorporated into the model. Our results suggest that the mechanism of action of thalamic DBS as used in epilepsy may involve the prolonged release of glutamate, which in turn modulates specific ion channels such as Ih, decreases neuronal input resistance, and abolishes thalamic network oscillatory activity.
PMCID: PMC3155385  PMID: 21623007
high frequency stimulation (HFS); deep brain stimulation (DBS); spindle oscillations
21.  Swine Model for Translational Research of Invasive Intracranial Monitoring 
Epilepsia  2011;52(6):e49-e53.
Focal cortical epilepsy is currently most effectively studied in humans. However, improvement in cortical monitoring and investigational device development is limited by lack of an animal model mimicking human acute focal cortical epileptiform activity under epilepsy surgery conditions. Therefore, we assessed the swine model for translational epilepsy research. Swine were used due to their cost effectiveness, convoluted cortex, and comparative anatomy similar to humans. Focal subcortical injection of benzyl-penicillin produced clinical seizures correlating with epileptiform activity demonstrating temporal and spatial progression. Swine were evaluated under 5 different anesthesia regimens. Of the 5 regimens, conditions similar to human intraoperative anesthesia, including continuous fentanyl with low dose isoflorane, was the most effective for eliciting complex, epileptiform activity after benzyl-penicillin injection. The most complex epileptiform activity (spikes, and high frequency activity) was then repeated reliably in 9 animals, utilizing 14 swine total. There were 20.1 ± 10.8 (95% CI: 11.8–28.4) epileptiform events with greater than 3.5 hertz activity occurring per animal. Average duration of each event was 46.3 ± 15.6 (95% CI: 44.0 to 48.6) seconds, ranging from 20 to 100 seconds. In conclusion, the acute swine model of focal cortical epilepsy surgery provides an animal model mimicking human surgical conditions with a large brain, gyrated cortex, and is relatively cheap among animal models. Therefore, we feel this model provides a valuable, reliable, and novel platform for translational studies of implantable hardware for intracranial monitoring.
PMCID: PMC3116097  PMID: 21627648
Epilepsy; Animal Model; Electroencephalography; Swine; Pig; Translational Research
22.  A Drude model analysis of conductivity and free carriers in boron-doped diamond films and investigations of their internal stress and strain 
Journal of materials science  2014;49(16):5782-5789.
Boron-doped diamond (BDD) has seen a substantial increase in interest for use as electrode coating material for electrochemistry and studies of deep brain stimulation mechanism. In this study, we present an alternative method for determining important characteristics, including conductivity, carrier concentration, and time constant, of such material by the signature of Drude-like metallic behavior in the far-infrared (IR) spectral range. Unlike the direct determination of conductivity from the four-point probe method, using far-IR transmittance provides additional information, such as whether the incorporation of boron results in a large concentration of carriers or in inducing defects in the diamond lattice. The slightly doped to medium-doped BDD samples that were produced using chemical vapor deposition and analyzed in this work show conductivities ranging between 5.5 and 11 (Ω cm)−1. Different growth conditions demonstrate that increasing boron concentration results in an increase in the carrier concentration, with values between 7.2 × 1016 and 2.5 × 1017 carriers/cm3. Addition of boron, besides leading to a decrease in the resistivity, also resulted in a decrease in the time constant, limiting BDD conductivity. Investigations, by confocal Raman mapping, of the induced stress in the material due to interaction with the substrate or to the amount of doping are also presented and discussed. The induced tensile stress, which was distributed closer to the film-substrate interface decreased slightly with doping.
PMCID: PMC4199101  PMID: 25328245
Journal of neurosurgery  2010;113(3):656-665.
We previously reported the development of a Wireless Instantaneous Neurotransmitter Concentration System (WINCS) for measuring dopamine and suggested that this technology may be useful for evaluating deep brain stimulation (DBS)-related neuromodulatory effects on neurotransmitter systems. WINCS supports fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM) for real-time, spatially resolved neurotransmitter measurements. The FSCV parameters used to establish WINCS dopamine measurements are not suitable for serotonin, a neurotransmitter implicated in depression, because they lead to CFM fouling and a loss of sensitivity. Here, we incorporate into WINCS a previously described N-shaped waveform applied at a high scan rate to establish wireless serotonin monitoring.
FSCV optimized for the detection of serotonin consisted of an N-shaped waveform scanned linearly from a resting potential of, in V, +0.2 to +1.0, then to −0.1 and back to +0.2 at a rate of 1000 V/s. Proof of principle tests included flow injection analysis and electrically evoked serotonin release in the dorsal raphe nucleus of rat brain slices.
Flow cell injection analysis demonstrated that the N waveform applied at a scan rate of 1000 V/s significantly reduced serotonin fouling of the CFM, relative to that observed with FSCV parameters for dopamine. In brain slices, WINCS reliably detected sub-second serotonin release in the dorsal raphe nucleus evoked by local high-frequency stimulation.
WINCS supported high-fidelity wireless serotonin monitoring by FSCV at a CFM. In the future such measurements of serotonin in large animal models and in humans may help to establish the mechanism of DBS for psychiatric disease.
PMCID: PMC2946368  PMID: 20415521
5-HT; Deep brain stimulation; Neuromodulation; Neurotransmitters; Serotonin; Voltammetry
24.  Deep Brain Stimulation Results in Local Glutamate and Adenosine Release: Investigation into the Role of Astrocytes 
Neurosurgery  2010;67(2):367-375.
Several neurologic disorders are treated with deep brain stimulation; however, the mechanism underlying its ability to abolish oscillatory phenomena associated with diseases as diverse as Parkinson's and epilepsy remain largely unknown. In this study we sought to investigate the role of specific neurotransmitters in deep brain stimulation (DBS) and determine the role of non-neuronal cells in its mechanism of action.
We used the ferret thalamic slice preparation in vitro, which exhibits spontaneous spindle oscillations, in order to determine the effect of high-frequency stimulation on neurotransmitter release. We then performed experiments using an in vitro astrocyte culture to investigate the role of glial transmitter release in HFS-mediated abolishment of spindle oscillations.
In this series of experiments we demonstrated that glutamate and adenosine release in ferret slices was able to abolish spontaneous spindle oscillations. The glutamate release was still evoked in the presence of the Na+ channel blocker tetrodotoxin (TTX), but was eliminated with the vesicular H+-ATPase inhibitor, bafilomycin, and the calcium chelator, BAPTA-AM. Furthermore, electrical stimulation of purified primary astrocytic cultures was able to evoke intracellular calcium transients and glutamate release, and bath application of BAPTA-AM inhibited glutamate release in this setting.
These results suggest that vesicular astrocytic neurotransmitter release may be an important mechanism by which DBS is able to achieve clinical benefits.
PMCID: PMC2919357  PMID: 20644423
astrocytes; adenosine; deep brain stimulation; glia; glutamate; high frequency stimulation
25.  Development of intraoperative electrochemical detection: wireless instantaneous neurochemical concentration sensor for deep brain stimulation feedback 
Neurosurgical focus  2010;29(2):E6.
Deep brain stimulation (DBS) is effective when there appears to be a distortion in the complex neurochemical circuitry of the brain. Currently, the mechanism of DBS is incompletely understood; however, it has been hypothesized that DBS evokes release of neurochemicals. Well-established chemical detection systems such as microdialysis and mass spectrometry are impractical if one is assessing changes that are happening on a second-to-second time scale or for chronically used implanted recordings, as would be required for DBS feedback. Electrochemical detection techniques such as fast-scan cyclic voltammetry (FSCV) and amperometry have until recently remained in the realm of basic science; however, it is enticing to apply these powerful recording technologies to clinical and translational applications. The Wireless Instantaneous Neurochemical Concentration Sensor (WINCS) currently is a research device designed for human use capable of in vivo FSCV and amperometry, sampling at subsecond time resolution. In this paper, the authors review recent advances in this electrochemical application to DBS technologies. The WINCS can detect dopamine, adenosine, and serotonin by FSCV. For example, FSCV is capable of detecting dopamine in the caudate evoked by stimulation of the subthalamic nucleus/substantia nigra in pig and rat models of DBS. It is further capable of detecting dopamine by amperometry and, when used with enzyme linked sensors, both glutamate and adenosine. In conclusion, WINCS is a highly versatile instrument that allows near real-time (millisecond) detection of neurochemicals important to DBS research. In the future, the neurochemical changes detected using WINCS may be important as surrogate markers for proper DBS placement as well as the sensor component for a “smart” DBS system with electrochemical feedback that allows automatic modulation of stimulation parameters. Current work is under way to establish WINCS use in humans.
PMCID: PMC2939376  PMID: 20672923
deep brain stimulation; dopamine; adenosine; serotonin; fast-scan cyclic voltammetry; amperometry; electrochemistry

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