Erika K. Ross

Subthalamic Nucleus Deep Brain Stimulation Induces Motor Network BOLD Activation: Use of a High Precision MRI Guided Stereotactic System for Nonhuman Primates

BACKGROUND Functional magnetic resonance imaging (fMRI) is a powerful method for identifying in vivo network activation evoked by deep brain stimulation (DBS). OBJECTIVE Identify the global neural circuitry effect of subthalamic nucleus (STN) DBS in nonhuman primates (NHP). METHOD An in-house developed MR image-guided stereotactic targeting system delivered a mini-DBS stimulating electrode, and blood oxygenation level-dependent (BOLD) activation during STN DBS in healthy NHP was measured by combining fMRI with a normalized functional activation map and general linear modeling. RESULTS STN DBS significantly increased BOLD activation in the sensorimotor cortex, supplementary motor area, caudate nucleus, pedunculopontine nucleus, cingulate, insular cortex, and cerebellum (FDR < 0.001). CONCLUSION Our results demonstrate that STN DBS evokes neural network grouping within the motor network and the basal ganglia. Taken together, these data highlight the importance and specificity of neural circuitry activation patterns and functional connectivity.

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 Parkinsons disease, Huntingtons 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.

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 Alzheimers 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.

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.

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.

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.

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

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for medically refractory Parkinsons 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.

The Brain Initiative—Implications for a Revolutionary Change in Clinical Medicine via Neuromodulation Technology

Abstract Launched in April 2013, the goal of the White House Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is to catalyze the development of neurotechnology to provide new insights into the fundamental mechanisms of disease process. This ongoing international effort spans both the public and private sectors and has produced a number of specialized programs intended to facilitate partnerships between engineers, scientists, clinicians, industry, and regulatory agencies to translate new neuromodulation technologies into initial clinical studies. In this chapter, the history behind the launch of the BRAIN Initiative and the implications of the new BRAIN programs on the development of neuromodulation technologies are described.

Noninvasive neuromodulation in essential tremor demonstrates relief in a sham-controlled pilot trial: Neuromodulation for Essential Tremor

Although the precise mechanisms are uncertain, essential tremor (ET) is thought to be caused by tremulous activity within a central tremor neural network, which involves the ventral intermediate nucleus (VIM) of the thalamus. Clinical evidence supports targeting the VIM to treat tremor symptoms in ET with various methods. Previous studies have shown that electrical median nerve stimulation evokes activity within the VIM and other regions of the central tremor network. Based on these reports, we hypothesized that median and radial nerve stimulation at the wrist could reduce hand tremor. The objective of this study was to evaluate the efficacy of median and radial nerve stimulation as a noninvasive, nonpharmacological treatment to aid in the symptomatic relief of hand tremor in individuals with ET. Twenty-three blinded subjects were examined at a single site under an institutional review board-approved protocol (Fig. S1, Table S1). Subjects were randomized to treatment or sham groups. For stimulation, hydrogel electrodes were positioned on the wrist over the median and radial nerves (Fig. 1A; see Supporting Information). Efficacy was measured as the change in the Tremor Research Group’s Essential Tremor Rating Assessment Scale (TETRAS) Archimedes spiral drawing task following stimulation compared with prestimulation (Fig. 1B,C). The response in the treatment group was significant compared with both baseline and sham. In the treatment group, blinded rater scores significantly improved following stimulation (1.77 6 0.21) compared with prestimulation (2.77 6 0.22; P 5 0.01; Fig. 1D). This response was achieved without the risks of surgical or pharmacological intervention, such as the risk of hemorrhage or infection with DBS implantation, or side effects of ET medications, including the first-line therapies propranolol and primidone. In the sham group, scores did not change significantly following stimulation (2.37 6 0.22) compared with prestimulation (2.62 6 0.14; P 5 0.37; Fig. 1E). The response to treatment corresponded to an estimated hand tremor amplitude reduction of 60% 6 8.4% and was significantly greater in the treatment than in the sham group (P 5 0.02; Fig. 1F). Three subjects experienced transient redness and/or itchiness under the hydrogel electrodes that resolved without intervention. No unanticipated device effects occurred during the study. This was a pilot study with too few subjects for subanalyses of the effects of age, medication status, or medical history. Future studies should expand the subject count, investigate the response rate, repeatability, durability, and effects of chronic use, and add assessments of quality of life. This therapeutic approach was inspired by the idea that peripheral stimulation evokes central activity in brain regions such as the VIM, a thalamic target widely accepted to improve tremor with DBS. Although our data support this idea, other potential mechanisms are possible, including circuitry modulated in previous studies demonstrating tremor reduction by manipulation of peripheral sensory input. Future studies that are able to better characterize the precise mechanism may facilitate improvements to therapy. Nonetheless, this randomized, sham-controlled pilot study suggests that noninvasive neuroperipheral therapy may offer clinically meaningful symptomatic relief from hand tremor in ET with a favorable side effect profile compared with other available therapies.

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.