Proceedings of the Sixth Deep Brain Stimulation Think Tank Modulation of Brain Networks and Application of Advanced Neuroimaging, Neurophysiology, and Optogenetics

The annual deep brain stimulation (DBS) Think Tank aims to create an opportunity for a multidisciplinary discussion in the field of neuromodulation to examine developments, opportunities and challenges in the field. The proceedings of the Sixth Annual Think Tank recapitulate progress in applications of neurotechnology, neurophysiology, and emerging techniques for the treatment of a range of psychiatric and neurological conditions including Parkinson’s disease, essential tremor, Tourette syndrome, epilepsy, cognitive disorders, and addiction. Each section of this overview provides insight about the understanding of neuromodulation for specific disease and discusses current challenges and future directions. This year’s report addresses key issues in implementing advanced neurophysiological techniques, evolving use of novel modulation techniques to deliver DBS, ans improved neuroimaging techniques. The proceedings also offer insights into the new era of brain network neuromodulation and connectomic DBS to define and target dysfunctional brain networks. The proceedings also focused on innovations in applications and understanding of adaptive DBS (closed-loop systems), the use and applications of optogenetics in the field of neurostimulation and the need to develop databases for DBS indications. Finally, updates on neuroethical, legal, social, and policy issues relevant to DBS research are discussed

Previous, current, and future stereotactic EEG techniques for localising epileptic foci

INTRODUCTION: Drug-resistant focal epilepsy presents a significant morbidity burden globally, and epilepsy surgery has been shown to be an effective treatment modality. Therefore, accurate identification of the epileptogenic zone for surgery is crucial, and in those with unclear noninvasive data, stereoencephalography is required. AREAS COVERED: This review covers the history and current practices in the field of intracranial EEG, particularly analyzing how stereotactic image-guidance, robot-assisted navigation, and improved imaging techniques have increased the accuracy, scope, and use of SEEG globally. EXPERT OPINION: We provide a perspective on the future directions in the field, reviewing improvements in predicting electrode bending, image acquisition, machine learning and artificial intelligence, advances in surgical planning and visualization software and hardware. We also see the development of EEG analysis tools based on machine learning algorithms that are likely to work synergistically with neurophysiology experts and improve the efficiency of EEG and SEEG analysis and 3D visualization. Improving computer-assisted planning to minimize manual input from the surgeon, and seamless integration into an ergonomic and adaptive operating theater, incorporating hybrid microscopes, virtual and augmented reality is likely to be a significant area of improvement in the near future

Optogenetic Brain Interfaces

The brain is a large network of interconnected neurons where each cell functions as a nonlinear processing element. Unraveling the mysteries of information processing in the complex networks of the brain requires versatile neurostimulation and imaging techniques. Optogenetics is a new stimulation method which allows the activity of neurons to be modulated by light. For this purpose, the cell-types of interest are genetically targeted to produce light-sensitive proteins. Once these proteins are expressed, neural activity can be controlled by exposing the cells to light of appropriate wavelengths. Optogenetics provides a unique combination of features, including multimodal control over neural function and genetic targeting of specific cell-types. Together, these versatile features combine to a powerful experimental approach, suitable for the study of the circuitry of psychiatric and neurological disorders. The advent of optogenetics was followed by extensive research aimed to produce new lines of light-sensitive proteins and to develop new technologies: for example, to control the distribution of light inside the brain tissue or to combine optogenetics with other modalities including electrophysiology, electrocorticography, nonlinear microscopy, and functional magnetic resonance imaging. In this paper, the authors review some of the recent advances in the field of optogenetics and related technologies and provide their vision for the future of the field.United States. Defense Advanced Research Projects Agency (Space and Naval Warfare Systems Center, Pacific Grant/Contract No. N66001-12-C-4025)University of Wisconsin--Madison (Research growth initiative; grant 101X254)University of Wisconsin--Madison (Research growth initiative; grant 101X172)University of Wisconsin--Madison (Research growth initiative; grant 101X213)National Science Foundation (U.S.) (MRSEC DMR-0819762)National Science Foundation (U.S.) (NSF CAREER CBET-1253890)National Institutes of Health (U.S.) (NIH/NIBIB R00 Award (4R00EB008738)National Institutes of Health (U.S.) (NIH Director’s New Innovator award (1-DP2-OD002989))Okawa Foundation (Research Grant Award)National Institutes of Health (U.S.) (NIH Director’s New Innovator Award (1DP2OD007265))National Science Foundation (U.S.) (NSF CAREER Award (1056008)Alfred P. Sloan Foundation (Fellowship)Human Frontier Science Program (Strasbourg, France) (Grant No. 1351/12)Israeli Centers of Research Excellence (I-CORE grant, program 51/11)MINERVA Foundation (Germany

On mapping epilepsy : magneto- and electroencephalographic characterizations of epileptic activities

Epilepsy is one of the most common neurological disorder, affecting up to 10 individuals per 1000 persons. The disorder have been known for several thousand years, with the first clinical descriptions dating back to ancient times. Nonetheless, characterization of the dynamics underlying epilepsy remains largely unknown. Understanding these patophysiological processes requires unifying both a neurobiological perspective, as well as a technically advanced neuroimaging perspective. The incomplete insight into epilepsy dynamics is reflected by the insufficient treatment options. Approximately 30% of all patients do not respond to anti-epileptic drugs (AEDs) and thus suffers from recurrent seizures despite adequate pharmacological treatments. These pharmacoresistant patients often undergo epilepsy surgery evaluations. Epilepsy surgery aims to resect the part of the brain that generates the epileptic seizure activity (seizure onset zone, SOZ). Nonetheless, up to 50% of all patients relapse after surgery. This can be due to incomplete mapping of both the SOZ and of other structures that might be involved in seizure initiation and propagation. Such cortical and subcortical structures are collectively referred to as the epileptic network. Historically, epilepsy was considered to be either a generalized disorder involving the entire brain, or a highly localized, focal, disorder. The modern technological development of both structural and functional neuroimaging has drastically altered this view. This development has made significant contributions to the now prevailing view that both generalized and focal epilepsies arise from more or less widespread pathological network pathways. Visualization of these pathways play an important role in the presurgical planning. Thus, both improved characterization and understanding of such pathways are pivotal in improvement of epilepsy diagnostics and treatments. It is evident that epilepsy research needs to stand on two legs: Both improved understanding of pathological, neurobiological and neurophysiological process, and improved neuroimaging instrumentation. Epilepsy research do not only span from visualization to understanding of neurophysiological processes, but also from cellular, neuronal, microscopic processes, to dynamical, large-scale network processes. It is well known that neurons involved in epileptic activities exhibit specific, pathological firing patterns. Genetic mutations resulting in neuronal ion channel defects can cause severe, and even lethal, epileptic syndromes in children, clearly illustrating a role for neuron membrane properties in epilepsy. However, cellular processes themselves cannot explain how epileptic seizures can involve, and propagate across, large cortical areas and generate seizure-specific symptomatologies. A strict cellular perspective can neither explain epilepsy-associated pathological interactions between larger distant regions in between seizures. Instead, the dynamical effects of cellular synchronization across both mesoscopic and macroscopic scales also need to be considered. Today, the only means to study such effects in human subjects are by combinations of neuroimaging modalities. However, as all measurement techniques, these exhibit individual limitations that affect the kind of information that can be inferred from these. Thus, once more we reach the conclusion that epilepsy research needs to rest upon both a neurophysiological/neurobiological leg, and a technical/instrumentational leg. In accordance with this necessity of a dual approach to epilepsy, this thesis covers both neurophysiological aspects of epileptic activity development, as well as functional neuroimaging instrumentation development with focus on epileptic activity detection and localization. Part 1 (neurophysiological part) is concerned with the neurophysiological dynamical changes that underlie development of so called interictal epileptiform discharges (IEDs) with special focus on the role of low-frequency oscillations. To this aim, both conventional magnetoencephalography (MEG) and intracranial electroencephalography (iEEG) with neurostimulation is analyzed. Part 2 (instrumentation part) is concerned with development of cutting-edge, novel on-scalp magnetoencephalography (osMEG) within clinical epilepsy evaluations and research with special focus on IEDs. The theses cover both modeling of osMEG characteristics, as well as the first-ever osMEG recording of a temporal lobe epilepsy patient

Multi-Modal Neuroimaging Analysis and Visualization Tool (MMVT)

Sophisticated visualization tools are essential for the presentation and exploration of human neuroimaging data. While two-dimensional orthogonal views of neuroimaging data are conventionally used to display activity and statistical analysis, three-dimensional (3D) representation is useful for showing the spatial distribution of a functional network, as well as its temporal evolution. For these purposes, there is currently no open-source, 3D neuroimaging tool that can simultaneously visualize desired combinations of MRI, CT, EEG, MEG, fMRI, PET, and intracranial EEG (i.e., ECoG, depth electrodes, and DBS). Here we present the Multi-Modal Visualization Tool (MMVT), which is designed for researchers to interact with their neuroimaging functional and anatomical data through simultaneous visualization of these existing imaging modalities. MMVT contains two separate modules: The first is an add-on to the open-source, 3D-rendering program Blender. It is an interactive graphical interface that enables users to simultaneously visualize multi-modality functional and statistical data on cortical and subcortical surfaces as well as MEEG sensors and intracranial electrodes. This tool also enables highly accurate 3D visualization of neuroanatomy, including the location of invasive electrodes relative to brain structures. The second module includes complete stand-alone pre-processing pipelines, from raw data to statistical maps. Each of the modules and module features can be integrated, separate from the tool, into existing data pipelines. This gives the tool a distinct advantage in both clinical and research domains as each has highly specialized visual and processing needs. MMVT leverages open-source software to build a comprehensive tool for data visualization and exploration.Comment: 29 pages, 10 figure

Getting the best outcomes from epilepsy surgery.

Neurosurgery is an underutilized treatment that can potentially cure drug-refractory epilepsy. Careful, multidisciplinary presurgical evaluation is vital for selecting patients and to ensure optimal outcomes. Advances in neuroimaging have improved diagnosis and guided surgical intervention. Invasive electroencephalography allows the evaluation of complex patients who would otherwise not be candidates for neurosurgery. We review the current state of the assessment and selection of patients and consider established and novel surgical procedures and associated outcome data. We aim to dispel myths that may inhibit physicians from referring and patients from considering neurosurgical intervention for drug-refractory focal epilepsies. Ann Neurol 2018;83:676-690

Cortical Dynamics Underlying Seizure Mapping and Control

In one-third of epilepsy patients, antiepileptic drugs do not effectively control seizures, leaving resective surgery as the primary treatment option. In the absence of discrete focal lesions, long-term outcome after surgery is modest and often associated with side effects. In many cases, surgery cannot be performed due to the lack of a discrete region generating seizures. For these reasons, new therapeutic technologies have been developed to treat drug-resistant epilepsy with electrical stimulation. These devices are promising, but the efficacy of first-generation implants has been limited. The work in this thesis aims to advance current approaches to seizure monitoring and control by developing better hardware and building the foundational knowledge behind the cortical dynamics underlying seizure generation, propagation and neural stimulation. In this thesis, I first develop new technologies that sample local field potentials on the cortical surface with high spatial and temporal resolutions. These devices capture complex spatiotemporal patterns of epileptiform activity that are not detected on current clinical electrodes. By adding stimulation functionalities to these arrays, we position them as an ideal candidate for responsive, therapeutic neurostimulation. Next, I explore the effect of direct electrical stimulation in the cortex by recording responses with high spatial resolution on the surface and within the cortical laminae. The findings detail the capabilities and limitations of electrical stimulation as a means of modulating seizures. Finally, I use the same three-dimensional recording paradigm in feline neocortex to investigate the genesis and propagation of epileptiform activity in an isolated, chemically-induced epilepsy model. These experiments demonstrate that important circuit elements involved in seizure propagation are found deeper in the cortex and are not reflected in surface recordings. My investigations also present potential stimulation strategies to more effectively disrupt the spread of seizures in the neocortex. It is my hope that the results of this work will inform future technologies to better detect and prevent seizures, ultimately improving the lives of drug-resistant epilepsy patients through the next generation of implantable devices

Development and application of inhibitory luminopsins for the treatment of epilepsy

Optogenetics has shown great promise as a direct neuromodulatory tool for halting seizure activity in various animal models of epilepsy. However, light delivery into the brain is still a major practical challenge that needs to be addressed before future clinical translation is feasible. Not only does light delivery into the brain require surgically implanted hardware that can be both invasive and restrictive, but it is also difficult to illuminate large or complicated structures in the brain due to light scatter and attenuation. We have bypassed the challenges of external light delivery by directly coupling a bioluminescent light source (a genetically encoded Renilla luciferase) to an inhibitory opsin (Natronomonas halorhodopsin) as a single fusion protein, which we term an inhibitory luminopsin (iLMO). iLMOs were developed and characterized in vitro and in vivo using intracellular recordings, multielectrode arrays, and behavioral testing. iLMO2 was shown to generate hyperpolarizing outward currents in response to both external light and luciferase substrate, which was sufficient to suppress action potential firing and synchronous bursting activity in vitro. iLMO2 was further shown to suppress single-unit firing rate and local field potentials in the hippocampus of anesthetized and awake animals. Finally, expression of iLMO was scaled up to multiple structures of the basal ganglia to modulate rotational behavior of freely moving animals in a hardware-independent fashion. iLMO2 was further utilized to acutely suppress focal epileptic discharges induced by intracerebral injection of bicuculline and generalized seizures resulting from systemic administration of pentylenetetrazol. Inhibitory luminopsins have enabled the possibility of optogenetic inhibition of neural activity in a non-invasive and hardware-independent fashion. This work increases the versatility, scalability, and practicality of utilizing optogenetic approaches for halting seizure activity in vivo.Ph.D