Methods and system for recording human physiological signals from implantable leads during spinal cord stimulation.

Objectives: This article presents a method-including hardware configuration, sampling rate, filtering settings, and other data analysis techniques-to measure evoked compound action potentials (ECAPs) during spinal cord stimulation (SCS) in humans with externalized percutaneous electrodes. The goal is to provide a robust and standardized protocol for measuring ECAPs on the non-stimulation contacts and to demonstrate how measured signals depend on hardware and processing decisions. Methods: Two participants were implanted with percutaneous leads for the treatment of chronic pain with externalized leads during a trial period for stimulation and recording. The leads were connected to a Neuralynx ATLAS system allowing us to simultaneously stimulate and record through selected electrodes. We examined different hardware settings, such as online filters and sampling rate, as well as processing techniques, such as stimulation artifact removal and offline filters, and measured the effects on the ECAPs metrics: the first negative peak (N1) time and peak-valley amplitude. Results: For accurate measurements of ECAPs, the hardware sampling rate should be least at 8 kHz and should use a high pass filter with a low cutoff frequency, such as 0.1 Hz, to eliminate baseline drift and saturation (railing). Stimulation artifact removal can use a double exponential or a second-order polynomial. The polynomial fit is 6.4 times faster on average in computation time than the double exponential, while the resulting ECAPs' N1 time and peak-valley amplitude are similar between the two. If the baseline raw measurement drifts with stimulation, a median filter with a 100-ms window or a high pass filter with an 80-Hz cutoff frequency preserves the ECAPs. Conclusions: This work is the first comprehensive analysis of hardware and processing variations on the observed ECAPs from SCS leads. It sets recommendations to properly record and process ECAPs from the non-stimulation contacts on the implantable leads.

Transcutaneous Afferent Patterned Stimulation Therapy Reduces Hand Tremor for One Hour in Essential Tremor Patients.

Essential tremor (ET) patients often experience hand tremor that impairs daily activities. Non-invasive electrical stimulation of median and radial nerves in the wrist using a recently developed therapy called transcutaneous afferent patterned stimulation (TAPS) has been shown to provide symptomatic tremor relief in ET patients and improve patients' ability to perform functional tasks, but the duration of tremor reduction is unknown. In this single-arm, open-label study, fifteen ET patients performed four hand tremor-specific tasks (postural hold, spiral drawing, finger-to-nose reach, and pouring) from the Fahn-Tolosa-Marin Clinical Rating Scale (FTM-CRS) prior to, during, and 0, 30, and 60 min following TAPS. At each time point, tremor severity was visually rated according to the FTM-CRS and simultaneously measured by wrist-worn accelerometers. The duration of tremor reduction was assessed using (1) improvement in the mean FTM-CRS score across all four tasks relative to baseline, and (2) reduction in accelerometer-measured tremor power relative to baseline for each task. Patients were labeled as having at least 60 min of therapeutic benefit from TAPS with respect to each specified metric if all three (i.e., 0, 30, and 60 min) post-therapy measurements were better than that metric's baseline value. The mean FTM-CRS scores improved for at least 60 min beyond the end of TAPS for 80% (12 of 15, p = 4.6e-9) of patients. Similarly, for each assessed task, tremor power improved for at least 60 min beyond the end of TAPS for over 70% of patients. The postural hold task had the largest reduction in tremor power (median 5.9-fold peak reduction in tremor power) and had at least 60 min of improvement relative to baseline beyond the end of TAPS therapy for 73% (11 of 15, p = 9.8e-8) of patients. Clinical ratings of tremor severity were correlated to simultaneously recorded accelerometer-measured tremor power (r = 0.33-0.76 across the four tasks), suggesting tremor power is a valid, objective tremor assessment metric that can be used to track tremor symptoms outside the clinic. These results suggest TAPS can provide reductions in upper limb tremor symptoms for at least 1 h post-therapy in some patients, which may improve patients' ability to perform tasks of daily living.

Sources of off-target effects of vagus nerve stimulation using the helical clinical lead in domestic pigs.

Objective: Clinical data suggest that efficacious vagus nerve stimulation (VNS) is limited by side effects such as cough and dyspnea that have stimulation thresholds lower than those for therapeutic outcomes. VNS side effects are putatively caused by activation of nearby muscles within the neck, via direct muscle activation or activation of nerve fibers innervating those muscles. Our goal was to determine the thresholds at which various VNS-evoked effects occur in the domestic pig­an animal model with vagus anatomy similar to human­using the bipolar helical lead deployed clinically. Approach: Intrafascicular electrodes were placed within the vagus nerve to record electroneurographic (ENG) responses, and needle electrodes were placed in the vagal-innervated neck muscles to record electromyographic (EMG) responses. Main results: Contraction of the cricoarytenoid muscle occurred at low amplitudes (~0.3 mA) and resulted from activation of motor nerve fibers in the cervical vagus trunk within the electrode cuff which bifurcate into the recurrent laryngeal branch of the vagus. At higher amplitudes (~1.4 mA), contraction of the cricoarytenoid and cricothyroid muscles was generated by current leakage outside the cuff to activate motor nerve fibers running within the nearby superior laryngeal branch of the vagus. Activation of these muscles generated artifacts in the ENG recordings that may be mistaken for compound action potentials representing slowly conducting Aδ-, B-, and C-fibers. Significance: Our data resolve conflicting reports of the stimulation amplitudes required for C-fiber activation in large animal studies (>10 mA) and human studies (<250 µA). After removing muscle-generated artifacts, ENG signals with post-stimulus latencies consistent with Aδ- and B-fibers occurred in only a small subset of animals, and these signals had similar thresholds to those that caused bradycardia. By identifying specific neuroanatomical pathways that cause off-target effects and characterizing the stimulation dose-response curves for on- and off-target effects, we hope to guide interpretation and optimization of clinical VNS.

Functional vagotopy in the cervical vagus nerve of the domestic pig: implications for the study of vagus nerve stimulation.

OBJECTIVE: Given current clinical interest in vagus nerve stimulation (VNS), there are surprisingly few studies characterizing the anatomy of the vagus nerve in large animal models as it pertains to on-and off-target engagement of local fibers. We sought to address this gap by evaluating vagal anatomy in the pig, whose vagus nerve organization and size approximates the human vagus nerve. APPROACH: Here we combined microdissection, histology, and immunohistochemistry to provide data on key features across the cervical vagus nerve in a swine model, and compare our results to other animal models (mouse, rat, dog, non-human primate) and humans. MAIN RESULTS: In a swine model we quantified the nerve diameter, number and diameter of fascicles, and distance of fascicles from the epineural surface where stimulating electrodes are placed. We also characterized the relative locations of the superior and recurrent laryngeal branches of the vagus nerve that have been implicated in therapy limiting side effects with common electrode placement. We identified key variants across the cohort that may be important for VNS with respect to changing sympathetic/parasympathetic tone, such as cross-connections to the sympathetic trunk. We discovered that cell bodies of pseudo-unipolar cells aggregate together to form a very distinct grouping within the nodose ganglion. This distinct grouping gives rise to a larger number of smaller fascicles as one moves caudally down the vagus nerve. This often leads to a distinct bimodal organization, or 'vagotopy'. This vagotopy was supported by immunohistochemistry where approximately half of the fascicles were immunoreactive for choline acetyltransferase, and reactive fascicles were generally grouped in one half of the nerve. SIGNIFICANCE: The vagotopy observed via histology may be advantageous to exploit in design of electrodes/stimulation paradigms. We also placed our data in context of historic and recent histology spanning multiple models, thus providing a comprehensive resource to understand similarities and differences across species.

An Injectable Neural Stimulation Electrode Made from an In-Body Curing Polymer/Metal Composite.

Implanted neural stimulation and recording devices hold vast potential to treat a variety of neurological conditions, but the invasiveness, complexity, and cost of the implantation procedure greatly reduce access to an otherwise promising therapeutic approach. To address this need, a novel electrode that begins as an uncured, flowable prepolymer that can be injected around a neuroanatomical target to minimize surgical manipulation is developed. Referred to as the Injectrode, the electrode conforms to target structures forming an electrically conductive interface which is orders of magnitude less stiff than conventional neuromodulation electrodes. To validate the Injectrode, detailed electrochemical and microscopy characterization of its material properties is performed and the feasibility of using it to stimulate the nervous system electrically in rats and swine is validated. The silicone-metal-particle composite performs very similarly to pure wire of the same metal (silver) in all measures, including exhibiting a favorable cathodic charge storage capacity (CSCC ) and charge injection limits compared to the clinical LivaNova stimulation electrode and silver wire electrodes. By virtue of its simplicity, the Injectrode has the potential to be less invasive, more robust, and more cost-effective than traditional electrode designs, which could increase the adoption of neuromodulation therapies for existing and new indications.

An anthocyanin-enriched extract from strawberries delays disease onset and extends survival in the hSOD1G93A mouse model of amyotrophic lateral sclerosis.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting from the death of motor neurons in the brain, brain stem, and spinal cord. Several processes such as oxidative stress, neuroinflammation, and neuronal apoptosis, contribute to disease progression. Anthocyanins are flavonoid compounds derived from fruits and vegetables that possess antioxidant, anti-inflammatory, and anti-apoptotic abilities. Thus, these unique compounds may provide therapeutic benefit for the treatment of ALS. METHODS: We used the G93A mutant human SOD1 (hSOD1G93A) mouse model of ALS to assess the effects of an anthocyanin-enriched extract from strawberries (SAE) on disease onset and progression. Mice were administered SAE orally beginning at 60 days of age until end-stage such that mice received 2 mg/kg/day of the extract's primary anthocyanin constituent. Clinical indices of disease were assessed until mice were sacrificed at end-stage. Histopathological indices of disease progression were also evaluated at 105 days of age. RESULTS: hSOD1G93A mice supplemented with SAE experienced a marked (∼17 day) delay in disease onset and a statistically significant (∼11 day) extension in survival in comparison to their untreated mutant counterparts. Additionally, SAE-treated hSOD1G93A mice displayed significantly preserved grip strength throughout disease progression. Histopathological analysis demonstrated that SAE supplementation significantly reduced astrogliosis in spinal cord, and preserved neuromuscular junctions (NMJs) in gastrocnemius muscle. DISCUSSION: These data are the first to demonstrate that anthocyanins have significant potential as therapeutic agents in a preclinical model of ALS due to their ability to reduce astrogliosis in spinal cord and preserve NMJ integrity and muscle function. Therefore, further study of these compounds is warranted in additional preclinical models of ALS and other neurodegenerative diseases.

Detection of Norepinephrine in Whole Blood via Fast Scan Cyclic Voltammetry.

Bioelectronic Medicines is an emerging field that capitalizes on minimally-invasive technology to stimulate the autonomic nervous system in order to evoke therapeutic biomolecular changes at the end-organ. The goal of Bioelectronic Medicines is to realize both 'precision and personalized' medicine. 'Precise' stimulation of neural circuitry creates biomolecular changes targeted exactly where needed to maximize therapeutic effects while minimizing off-target changes associated with side-effects. The therapy is then 'personalized' by utilizing implanted sensors to measure the biomolecular concentrations at, or near, the end-organ of interest and continually adjusting therapy to account for patient-specific biological changes throughout the day. To realize the promise of Bioelectronic Medicines, there is a need for minimally invasive, real-time measurement of biomarkers associated with the effects of autonomic nerve stimulation to be used for continuous titration of therapy. In this study we examine the feasibility of using fast scan cyclic voltammetry (FSCV) to measure norepinephrine levels, a neurochemical relevant to end-organ function, directly from blood. FSCV is a well-understood method for measuring electroactive neurochemicals in the central nervous system with high temporal and high spatial resolution that has yet to be adapted to the study of the autonomic nervous system. The results demonstrate that while detecting the electroactive neurochemical norepinephrine in blood is more challenging than obtaining the same FSCV measurements in a buffer solution due to biofouling of the electrode, it is feasible to utilize a minimally invasive FSCV electrode to obtain neurochemical measurements in blood.

A Cystine-Rich Whey Supplement (Immunocal®) Provides Neuroprotection from Diverse Oxidative Stress-Inducing Agents In Vitro by Preserving Cellular Glutathione.

Oxidative stress is a principal mechanism underlying the pathophysiology of neurodegeneration. Therefore, nutritional enhancement of endogenous antioxidant defenses may represent a viable treatment option. We investigated the neuroprotective properties of a unique whey protein supplement (Immunocal®) that provides an essential precursor (cystine) for synthesis of the endogenous antioxidant, glutathione (GSH). Primary cultures of rat cerebellar granule neurons (CGNs), NSC34 motor neuronal cells, or HT22 hippocampal cells were preincubated in medium containing Immunocal and then subsequently treated with agents known to induce oxidative stress. Immunocal protected CGNs against neurotoxicity induced by the Bcl-2 inhibitor, HA14-1, the nitric oxide donor, sodium nitroprusside, CuCl2, and AlCl3. Immunocal also significantly reduced NSC34 cell death due to either H2O2 or glutamate and mitigated toxicity in HT22 cells overexpressing ß-amyloid1-42. The neuroprotective effects of Immunocal were blocked by inhibition of γ-glutamyl-cysteine ligase, demonstrating dependence on de novo GSH synthesis. These findings indicate that sustaining GSH with Immunocal significantly protects neurons against diverse inducers of oxidative stress. Thus, Immunocal is a nutritional supplement worthy of testing in preclinical animal models of neurodegeneration and in future clinical trials of patients afflicted by these diseases.

Neurostimulation Devices for the Treatment of Neurologic Disorders.

Rapid advancements in neurostimulation technologies are providing relief to an unprecedented number of patients affected by debilitating neurologic and psychiatric disorders. Neurostimulation therapies include invasive and noninvasive approaches that involve the application of electrical stimulation to drive neural function within a circuit. This review focuses on established invasive electrical stimulation systems used clinically to induce therapeutic neuromodulation of dysfunctional neural circuitry. These implantable neurostimulation systems target specific deep subcortical, cortical, spinal, cranial, and peripheral nerve structures to modulate neuronal activity, providing therapeutic effects for a myriad of neuropsychiatric disorders. Recent advances in neurotechnologies and neuroimaging, along with an increased understanding of neurocircuitry, are factors contributing to the rapid rise in the use of neurostimulation therapies to treat an increasingly wide range of neurologic and psychiatric disorders. Electrical stimulation technologies are evolving after remaining fairly stagnant for the past 30 years, moving toward potential closed-loop therapeutic control systems with the ability to deliver stimulation with higher spatial resolution to provide continuous customized neuromodulation for optimal clinical outcomes. Even so, there is still much to be learned about disease pathogenesis of these neurodegenerative and psychiatric disorders and the latent mechanisms of neurostimulation that provide therapeutic relief. This review provides an overview of the increasingly common stimulation systems, their clinical indications, and enabling technologies.

Non-clinical and Pre-clinical Testing to Demonstrate Safety of the Barostim Neo Electrode for Activation of Carotid Baroreceptors in Chronic Human Implants.

The Barostim neo™ electrode was developed by CVRx, Inc.to deliver baroreflex activation therapy (BAT)™ to treat hypertension and heart failure. The neo electrode concept was designed to deliver electrical stimulation to the baroreceptors within the carotid sinus bulb, while minimizing invasiveness of the implant procedure. This device is currently CE marked in Europe, and in a Pivotal (akin to Phase III) Trial in the United States. Here we present the in vitro and in vivo safety testing that was completed in order to obtain necessary regulatory approval prior to conducting human studies in Europe, as well as an FDA Investigational Device Exemption (IDE) to conduct a Pivotal Trial in the United States. Stimulated electrodes (10 mA, 500 µs, 100 Hz) were compared to unstimulated electrodes using optical microscopy and several electrochemical techniques over the course of 27 weeks. Electrode dissolution was evaluated by analyzing trace metal content of solutions in which electrodes were stimulated. Lastly, safety testing under Good Laboratory Practice guidelines was conducted in an ovine animal model over a 12 and 24 week time period, with results processed and evaluated by an independent histopathologist. Long-term stimulation testing indicated that the neo electrode with a sputtered iridium oxide coating can be stimulated at maximal levels for the lifetime of the implant without clinically significant dissolution of platinum or iridium, and without increasing the potential at the electrode interface to cause hydrolysis or significant tissue damage. Histological examination of tissue that was adjacent to the neo electrodes indicated no clinically significant signs of increased inflammation and no arterial stenosis as a result of 6 months of continuous stimulation. The work presented here involved rigorous characterization and evaluation testing of the neo electrode, which was used to support its safety for chronic implantation. The testing strategies discussed provide a starting point and proven framework for testing new neuromodulation electrode concepts to support regulatory approval for clinical studies.

Needle Decompression of Tension Pneumothorax with Colorimetric Capnography.

BACKGROUND: The success of needle decompression for tension pneumothorax is variable, and there are no objective measures assessing effective decompression. Colorimetric capnography, which detects carbon dioxide present within the pleural space, may serve as a simple test to assess effective needle decompression. METHODS: Three swine underwent traumatically induced tension pneumothorax (standard of care, n = 15; standard of care with needle capnography, n = 15). Needle thoracostomy was performed with an 8-cm angiocatheter. Similarly, decompression was performed with the addition of colorimetric capnography. Subjective operator assessment of decompression was recorded and compared with true decompression, using thoracoscopic visualization for both techniques. Areas under receiver operating curves were calculated and pairwise comparison was performed to assess statistical significance (P < .05). RESULTS: The detection of decompression by needle colorimetric capnography was found to be 100% accurate (15 of 15 attempts), when compared with thoracoscopic assessment (true decompression). Furthermore, it accurately detected the lack of tension pneumothorax, that is, the absence of any pathologic/space-occupying lesion, in 100% of cases (10 of 10 attempts). Standard of care needle decompression was detected by operators in 9 of 15 attempts (60%) and was detected in 3 of 10 attempts when tension pneumothorax was not present (30%). True decompression, under direct visualization with thoracoscopy, occurred 15 of 15 times (100%) with capnography, and 12 of 15 times (80%) without capnography. Areas under receiver operating curves were 0.65 for standard of care and 1.0 for needle capnography (P = .002). CONCLUSIONS: Needle decompression with colorimetric capnography provides a rapid, effective, and highly accurate method for eliminating operator bias for tension pneumothorax decompression. This may be useful for the treatment of this life-threatening condition.

WINCS Harmoni: Closed-loop dynamic neurochemical control of therapeutic interventions.

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

Chemical basis for the disparate neuroprotective effects of the anthocyanins, callistephin and kuromanin, against nitrosative stress.

Oxidative and nitrosative stress are major factors in neuronal cell death underlying neurodegenerative disease. Thus, supplementation of antioxidant defenses may be an effective therapeutic strategy for diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. In this regard, treatment with nutraceutical antioxidants has garnered increasing attention; however, the differential neuroprotective effects of structurally similar nutraceuticals, which may affect their suitability as therapeutic agents, has not been directly examined. In this study we compare the ability of two anthocyanins, callistephin (pelargonidin-3-O-glucoside) and kuromanin (cyanidin-3-O-glucoside) to protect cerebellar granule neurons from damage induced by either oxidative or nitrosative stress. These anthocyanins differ by the presence of a single hydroxyl group on the B-ring of kuromanin, forming a catechol moiety. While both compounds protected neurons from oxidative stress induced by glutamate excitotoxicity, a stark contrast was observed under conditions of nitrosative stress. Only kuromanin displayed the capacity to defend neurons from nitric oxide (NO)-induced apoptosis. This protective effect was blocked by addition of Cu, Zn-superoxide dismutase, indicating that the neuroprotective mechanism is superoxide dependent. Based on these observations, we suggest a unique mechanism by which slight structural variances, specifically the absence or presence of a catechol moiety, lend kuromanin the unique ability to generate superoxide, which acts as a scavenger of NO. These findings indicate that kuromanin and compounds that share similar chemical characteristics may be more effective therapeutic agents for treating neurodegenerative diseases than callistephin and related (non-catechol) compounds.

Dopamine Release in the Nonhuman Primate Caudate and Putamen Depends upon Site of Stimulation in the Subthalamic Nucleus.

UNLABELLED: 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.

Anterior Thalamic Deep Brain Stimulation: Functional Activation Patterns in a Large Animal Model.

BACKGROUND: Deep brain stimulation (DBS) of the anterior thalamic nucleus (ATN) exerts its effects by modulating neural circuits involved in seizures. However, these networks remain incompletely characterized. OBJECTIVE: Investigate the effects of ATN DBS on network activity in a large animal model using 3-T fMRI. METHODS: Anesthetized swine underwent ATN DBS using stimulation parameters applied in the Stimulation of the Anterior Thalamus for the Treatment of Epilepsy (SANTE) trial. Stimulation amplitude, frequency, and temporal paradigm were varied and the resulting blood oxygen level-dependent signal was measured. RESULTS: ATN DBS resulted in activation within temporal, prefrontal, and sensorimotor cortex. An amplitude-dependent increase in cluster volume was observed at 60 Hz and 145 Hz stimulation. CONCLUSION: ATN DBS in swine induced parameter-dependent activation in cortical regions including but not limited to the Papez circuit. These findings may hold clinical implications for treatment of epilepsy in patients with temporal or extratemporal seizure foci.

Fornix deep brain stimulation circuit effect is dependent on major excitatory transmission via the nucleus accumbens.

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

Toward sophisticated basal ganglia neuromodulation: Review on basal ganglia 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.