Seungleal Paek

Nucleus Accumbens Deep Brain Stimulation Results in Insula and Prefrontal Activation: A Large Animal fMRI Study

Background Deep Brain Stimulation (DBS) of the nucleus accumbens (NAc) has previously been investigated clinically for the treatment of several psychiatric conditions, including obsessive-compulsive disorder and treatment resistant depression. However, the mechanism underlying the therapeutic benefit of DBS, including the brain areas that are activated, remains largely unknown. Here, we utilized 3.0 T functional Magnetic Resonance Imaging (fMRI) changes in Blood Oxygenation Level-Dependent (BOLD) signal to test the hypothesis that NAc/internal capsule DBS results in global neural network activation in a large animal (porcine) model Methods Animals (n = 10) were implanted in the NAc/internal capsule with DBS electrodes and received stimulation (1, 3, and 5 V, 130 Hz, and pulse widths of 100 and 500 µsec). BOLD signal changes were evaluated using a gradient echo-echo planar imaging (GRE-EPI) sequence in 3.0 T MRI. We used a normalized functional activation map for group analysis and applied general linear modeling across subjects (FDR<0.001). The anatomical location of the implanted DBS lead was confirmed with a CT scan Results We observed stimulation-evoked activation in the ipsilateral prefrontal cortex, insula, cingulate and bilateral parahippocampal region along with decrease in BOLD signal in the ipsilateral dorsal region of the thalamus. Furthermore, as the stimulation voltage increased from 3 V to 5 V, the region of BOLD signal modulation increased in insula, thalamus, and parahippocampal cortex and decreased in the cingulate and prefrontal cortex. We also demonstrated that right and left NAc/internal capsule stimulation modulates identical areas ipsilateral to the side of the stimulation Conclusions Our results suggest that NAc/internal capsule DBS results in modulation of psychiatrically important brain areas notably the prefrontal cortex, cingulate, and insular cortex, which may underlie the therapeutic effect of NAc DBS in psychiatric disorders. Finally, our fMRI setup in the large animal may be a useful platform for translational studies investigating the global neuromodulatory effects of DBS

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).

Frequency-dependent functional neuromodulatory effects on the motor network by ventral lateral thalamic deep brain stimulation in swine

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-subject study of swine. Low (10 Hz) and high (130 Hz) frequency stimulation was applied at 3, 5, and 7 V in the VL thalamus of normal swine (n = 5). We found that stimulation frequency and voltage combinations differentially modulated the 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.

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.

Implementation of a chronic unilateral intraparenchymal drug delivery system in a swine model

BACKGROUND 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 3.0T 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. RESULTS 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±420mm(3)). 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. CONCLUSION 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.

A novel re-attachable stereotactic frame for MRI-guided neuronavigation and its validation in a large animal and human cadaver model

OBJECTIVE Stereotactic frame systems are the gold-standard for stereotactic surgeries, such as implantation of deep brain stimulation (DBS) devices for treatment of medically resistant neurologic and psychiatric disorders. However, frame-based systems require that the patient is awake with a stereotactic frame affixed to their head for the duration of the surgical planning and implantation of the DBS electrodes. While frameless systems are increasingly available, a reusable re-attachable frame system provides unique benefits. As such, we created a novel reusable MRI-compatible stereotactic frame system that maintains clinical accuracy through the detachment and reattachment of its stereotactic devices used for MRI-guided neuronavigation. APPROACH We designed a reusable arc-centered frame system that includes MRI-compatible anchoring skull screws for detachment and re-attachment of its stereotactic devices. We validated the stability and accuracy of our system through phantom, in vivo mock-human porcine DBS-model and human cadaver testing. MAIN RESULTS Phantom testing achieved a root mean square error (RMSE) of 0.94  ±  0.23 mm between the ground truth and the frame-targeted coordinates; and achieved an RMSE of 1.11  ±  0.40 mm and 1.33  ±  0.38 mm between the ground truth and the CT- and MRI-targeted coordinates, respectively. In vivo and cadaver testing achieved a combined 3D Euclidean localization error of 1.85  ±  0.36 mm (p  <  0.03) between the pre-operative MRI-guided placement and the post-operative CT-guided confirmation of the DBS electrode. SIGNIFICANCE Our system demonstrated consistent clinical accuracy that is comparable to conventional frame and frameless stereotactic systems. Our frame system is the first to demonstrate accurate relocation of stereotactic frame devices during in vivo MRI-guided DBS surgical procedures. As such, this reusable and re-attachable MRI-compatible system is expected to enable more complex, chronic neuromodulation experiments, and lead to a clinically available re-attachable frame that is expected to decrease patient discomfort and costs of DBS surgery.

Multifunctional system for observing, measuring and analyzing stimulation-evoked neurochemical signaling

The ability to measure neurotransmitter activity using implanted electrochemical sensors offers researchers a potent technique for analyzing neural activity across specific neural circuitry. We have developed a wirelessly controlled device, WINCS Harmoni, to observe and measure neurotransmitter dynamics at up to four separate sensors, with high temporal and spatial resolution. WINCS Harmoni also incorporates a versatile neurostimulator that can be synchronized with electrochemical recording. The WINCS Harmoni platform is thus optimally suited for probing the neurochemical effects of neurostimulation, and may in turn enable the development of personalized therapies for multiple brain disorders.

Revolutionizing Causal Circuitry Neurostimulation Utilizing the Optogenetic Technique Through Advanced Microsystems Development

Optogenetics has recently emerged to become one of the most significant tools for in vivo causal analysis of neural networks. Developed through decades of pioneering work, the optogenetic toolbox has expanded utility to allow virtually total control over cellular actions. This article explores the emerging technologies that have been incorporated into making optogenetics a versatile technique in neuroscience research. Genetically engineered opsins continually evolve to directly activate or inhibit neuronal transmission with greater precision and functionality. A variety of light sources and fiber coupling methods employ unique photoactivation patterns and shapes. This article further explores the novel devices and systems that have been developed for the research setting and the technologies each system incorporates. These tethered systems, portable devices, and implantable microdevices have inherent benefits and detriments that are also discussed. Finally, emerging translational properties of optogenetics, particularly that for retinal pigmentosa, demonstrate how optogenetics may one day precipitate out of the research setting and into our healthcare practice.

Physiological Monitoring in Deep Brain Stimulation: Toward Closed-Loop Neuromodulation Therapies

Deep brain stimulation (DBS) is a widely used, efficacious neurosurgical treatment for neurological movement disorders. For example, electrical stimulation in the ventral intermediate thalamic nucleus drastically reduces tremor in patients with essential tremor. Likewise, stimulation in the subthalamic nucleus or the internal globus pallidus significantly attenuates tremor, rigidity, bradykinesia, and gait complications of Parkinson’s disease. Its application is now rapidly expanding to a wide variety of conditions including epilepsy, neuropsychiatric disorders, Tourette syndrome, Alzheimer’s disease, and intractable pain. However, the exact underlying therapeutic mechanisms of action of DBS remain unclear. Despite this lack of understanding, clinical utility of DBS cannot be underappreciated, and there is a great need for studies that can elucidate patient-specific optimization of DBS parameters and targets. This chapter explores recent approaches for studying the underlying mechanisms of action of DBS. Additionally, it discusses the limitations of current open-loop approaches to DBS and accentuates the importance of developing a smart closed-loop DBS system that can optimize therapeutic parameters in real time to individual patients and symptoms.