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Overview of Our Neuromodulation-Related Technologies

Seven core bioengineering projects are at various levels of development. Each neuromodulation-related project acts as a puzzle piece, facilitating development of a fundamental element of our novel 'nanotransponder' technology (U.S. Patents 8,788,033 and 9,302,114).

These biocompatible tiny devices are designed to be steered through an unstable epileptic brain circuit, and strategically 'parked' within it. Once parked or anchored, unique nano-sized components are designed to release focused and measured 'charge densities' to 'modulate' the epileptic network, and ultimately stabilize it.

Primary high-grade brain cancer cells are also being used as a target for assessing the capability of our nanotransponder components to destroy, or 'ablate' the cells by releasing damaging 'current-densities' or 'charge-densities'.

Our proof-of-principle demonstrating the viability of this technology is shown in the Figure to the left. Destruction of high-grade brain cancer (glioma) cells was imaged upon release of lethal current from nano-complexes (upper right micrograph), compared with intact viable glioma cells in a control well with uncharged nano-complexes (upper left micrograph). These nano-complexes were labelled with fluorescent probe molecules (seen in the lower 2 images to the left). Stored charge from these complexes was released after turning off an electric field used to charge the nano-components by a process called inductance. The core technology is composed of nano-sized biocompatible building blocks called carbon nanotubes (CNTs) (Harris et al, 2015). CNTs possess unique mechanical, chemical and electrical properties. Nano-components closely related to CNTs can store charge by inductance prior to releasing exquisitely-focused 'charge densities'. CNT electrical properties can be also employed as electrical bridges that are capable of extending the reach of stimulation therapy delivered from electrode contacts inserted into the brain (patent application PCT/US2014/62/088,170).

Each of the 7 core projects is summarized below.

PROJECT 1: Visualization of the Epileptic Circuit

The objective of Project 1 is to develop a computationally intensive system designed to facilitate visualization of intractable epileptic circuits in humans for interfacing direct neuromodulation therapy.

A computational workflow is evolving in our lab that models interfacing deep brain electrodes with abnormal brain circuits employing our innovative neurovisualization suite (see below). The generated model is then used as a navigation plan for implanting recently FDA-approved responsive direct brain stimulation therapy technology (NeuroPace, Inc) (Rossi et al, 2010). This fully implantable 'on-demand' stimulation therapy technology has been successfully used in a multi-center FDA-sponsored trial for detecting the electrical onset of a focal seizure, and stabilizing the seizure network by stimulating the seizure-generating brain source or pathway (Morrell et al, 2011).

Specifically, a novel depth electrode placement planning system (PCT/US2014/62/088,170) has been established in our laboratory for propagating current to distant epileptic tissue during direct neurostimulation therapy (NeuroPace, Inc). The system's goal is to predict, prior to implantation, optimal lead placement in cortical white matter for influencing the maximal extent of the epileptic circuit.

Our neurovisualization suite consists of 3 fundamental techniques for determining responsive neurostimulation depth lead placement in patients with two 'putatively independent' medically-resistant epileptic sources as follows:

1) Pre-implantation finite element modeling is used to predict the volume of cortical activation (VOCA). This model estimates the electric field and neural tissue influenced surrounding adjacent active depth contacts prior to implantation. The brain volume dataset is 'segmented' into compartments (grey matter, white matter and cerebrospinal fluid). These compartments demonstrate given characteristics that allow each to conduct electricity. Such a model takes into account anticipated stimulator settings that send stimulation into brain by way of the connected deep brain electrodes.

2a) Propagation of stimulation therapy through actual brain pathways is simulated prior to electrode implantation using the VOCA model positioned in a special MRI sequence, called diffusion tensor imaging (DTI). DTI is the foundation of our second fundamental technique, called subtraction post-ictal diffusion tensor imaging (spiDTI) developed in our lab (See Figure to left, reproduced with permission, Rossi et al, 2010). SpiDTI facilitates visualization of the path taken by the seizure. Water temporarily diffusing, or leaking out of white matter pathways after the seizure ends (during the post-ictal period) can be imaged. SpiDTI of activated white matter pathways can be overlaid onto transient blood flow patterns captured by SPECT technology. Ictal SPECT imaging captures seizure-onset related transient blood flow changes occurring in grey matter (not white matter). In other words, spiDTI can 'connect the SPECT dots' for visualizing the seizing brain circuit. The spiDTI shown here was acquired prior to depth electrode implantation. A post-ictal, or post-seizure' DTI scan was acquired immediately following a seizure in a patient that did not generalize secondarily. This brain scan was subtracted from a baseline DTI scan. The resulting signal represents a change in the so-called fractional anisotropy (FA), or change in the directionality of water diffusion leaking from axons. Notice the maximal change in FA seen as a crescent-like signal in the left paramesial temporal region and corpus callosum. Again, the spiDTI visualization technique likely demonstrates remnants of the seizure propagation pathway through the brain. The blue sphere represents a pre-implantation positioning model of the 'therapeutic electric field' surrounding a cylindrical depth electrode connected to a NeuroPace stimulator.

2b) Our electrode placement planning dataset generated by our workflow is actually a brain computer interface (BCI) blueprint for the surgeon. A trial is currently being developed in our lab in collaboration with the RUSH Department of Neurosurgery for evolving our electrode placement plan into a dynamic intra-operative electrode placement planning system. Specifically, a dataset containing multiple layers of visualization data (including a technology called magnetoencephalography (MEG)) will be imported into an operating room (OR) navigation system. A dominant data layer includes a so-called 'activation function' (Cendejas Zaragoza, Byrne & Rossi, 2015). Our goal for this project is to fully develop the ability to rapidly visualize, while the patient is in the OR, NeuroPace deep brain electrode placement with real-time updating of modelled activated brain circuit maps. The trial will compare our dynamic depth lead placement planning dataset coupled with a Medtronic StealthStation & Samsung-NeuroLogica intraoperative CT scanner (BodyTom), versus an established O-arm X-ray Surgical Planning System (Medtronic), shown in the figure to the left. Our system, once fully deployed, will rapidly update the intra-operative visualization of anticipated excited (red) and inhibited (blue) brain pathways prior to activating the implanted stimulation generator (IPG). Such near-real time intra-operative visualization is necessary for potentially repositioning the NeuroPace depth leads to optimally connect with critical neural pathways. This study will contribute to the momentum crucial for evolving present and future neuromodulation-focused BCI technologies.

3) Validation of the predicted stimulated anatomical targets and final implanted electrode placement is determined several months post-implantation using a unique brain scan protocol developed in our laboratory, called subtracted activated SPECT (SAS) (Rossi et al, 2005; Rossi & Cendejas Zaragoza, 2015). White matter pathways are used like 'on-ramps' such that axons can propagate electrical current distant from the source of stimulation. SAS validates the ability to connect with predicted on-ramps, or white matter pathways. SAS imaging is described as follows: An implanted investigational direct cortical neurostimulator (NeuroPace, Inc) is used to deliver focal stimulation WITHOUT causing a focal seizure, also known as an after-discharge (AD). Radiotracer is injected at the onset of delivering stimulation to identify grey matter-related transient blood flow changes, both near and distant from the stimulated electrode contacts. Pre-implantation, the modeling system can predict white matter connectivity and potential side-effects to stimulation. Post-implantation, SAS is used to validate focal blood flow changes throughout the brain caused by sending neurostimulation therapy through white matter pathways. This workflow demonstrates the feasibility of planning patient-specific deep brain electrode placement for sending electrical current strategically through the patient's epileptic circuit (or brain circuit of interest).

Our next-generation electrode placement planning system will immediately benefit neuromodulation-related BCI technologies for both the treatment of refractory focal-onset epilepsy and movement disorders. Our first generation depth electrode placement planning system (Rossi et al, 2010) is shown below. A second generation depth lead planning system (not shown) is now in the implementation phase (Cendejas Zaragoza et al, 2015). The system's computationally-intensive modelling of a pre-operative blueprint for brain-electrode interface planning will continue to evolve (Zaragoza, Hondorp & Rossi, 2013). The development of our dynamic OR planning system (described above in 2b) will set the stage for modelling 'nano-electrode' positioning in epileptic brain networks. Such dynamic nanotransponder positioning will provide the capability of strategically shaping electrical bridges for optimally connecting extensive epileptic circuits.

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PROJECT 2: Mechanized Direct Drug-Delivery Using an 'On-Demand Inhibitory Feedback' System

The core aim of Project 2 was to develop a mechanized inhibitory feedback system to augment direct stimulation therapy with on-demand pulsatile direct anti-epileptic drug (AED) delivery.

The platform employed a self-sustained focal-onset epilepsy rat model (Mangubat & Rossi, 2010; Mangubat et al, 2015). Our investigator-initiated study was funded by an industry sponsor (Johnson & Johnson Pharma). The dual drug delivery-recording/stimulating microprobe was developed for us in collaboration with NeuroNexus Technologies (Ann Arbor, MI).

The 'bench top-to-practice' goal of this preclinical project was to augment stabilization of a bihemispheric epileptic brain circuit in freely moving rats using a combined automated pharmaceutical and electrical current delivery system. In other words, 'on-demand' brain stimulation therapy that automatically senses epileptic patterns and then delivers direct brain stimulation was connected in tandem with responsive nano-bolused delivery of a novel neuromodulator, carisbamate. Both therapies were concurrently delivered at critical nodes in an extensive, but well-delineated epileptogenic network. See Mangubat et al, 2015 for details.

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PROJECT 3: AED Delivery Using Biocompatible Nano-carriers

The objective of Project 3 is to develop magnetic field-guided delivery of AED encapsulated in charged biocompatible nano-carriers.

Below is an animation simulating an electric field generated by a matrix of stimulating electrodes. Our goal is to guide nano-electrodes (composed of a CNT backbone) through brain for shuttling drug molecules while delivering focused non-damaging charge densities to stabilize epileptic circuits, or damaging charge densities for destroying cancer cells.

The nano-carrier complexes can target tissue receptors by surfing through brain in an induced magnetic field. Preliminary preclinical experiments are in progress.

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PROJECT 4: Biocompatible Carbon Nanotube-Ligand Complexes

Project 4 is a project that crosses disciplines to synthesize biocompatible carbon nanotube-ligand complexes to target high-grade glioma cells.

This project was funded by philanthropy within the RUSH Department of Neurosurgery. In addition, a microelectrode company (NeuroNexus Technologies) in collaboration with our laboratory since 2008 has developed a hybrid recording/stimulating & drug delivery microelectrode for use in rodents (see Project 2). A prototype electrode array is anticipated to guide diagnostic molecules linked to radiolabeled semi-conducting carbon nanotube carriers through a magnetic field for the treatment of brain cancer as developed and imaged in our lab (See below).

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PROJECT 5: Nano-Switch to Aid Delivery of Charges to Neoplastic Cells

The core objective of Project 5 begins with data generated from project 4. A carbon nanotube nano-switch will be fully developed for delivering focused charge using nano-capacitors. These innovative nanosized devices will be capable of ablating high-grade cancer cells, as well as potentially stabilizing the epileptic micro-network.

The microelectrode technology developed in project 4 is being employed in this project as a delivery system for biosensor-nanocapacitor complexes. This system will facilitate targeting cancer cells growing in living rat brains. We currently have a patent for this technology at RUSH (originally submitted in 9/2009, revised in 9/2010, and awarded in 7/2014).

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PROJECT 6: RFID MEMS Technology for Transmitting Data

Project 6 is designed to develop sensor-enabled radiofrequency identification (RFID) micro-electromechanical systems (MEMS) technology for transmitting data reflecting changes in the micro-environment. Two subprojects (6a & 6b) compose the core of project 6. Project 6a describing RFID MEMS technology is not described further at this time.

Project 6b is designed as a workbench for establishing a proof-of-concept to better understand the limitations of a patient with epilepsy to non-invasively interfere with the progression of a seizure. The strategy involves consciously replaying a particular baseline interictal scalp EEG signature initially acquired during an integrated simple cognitive or motor-skill task. The attention of the subject is cue-driven (e.g., focusing on a computer monitor while thinking about moving a displayed block, or generating a sound, etc). The task is custom-designed to engage brain circuitry shared by the patient's own seizure network.
The goal is to interfere with the progression of the seizure onset. We have developed signal processing algorithms to control a wireless/rechargeable self-contained EEG telemetry helmet. In addition, feasibility testing of prototype micro-electromechanical system (MEMS) components can be performed using this workbench to facilitate moving these principles to the nano-scale. For example, the system incorporates the principles of inductive recharging of the helmet-based battery. This principle will be used to repolarize the nano-capacitor developed in Project 5. This work was partly funded by the Danny Did Foundation. An IRB-approved trial is currently in progress at RUSH to assess the prototype system in both adults and children with refractory epilepsy.

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PROJECT 7: Synaptic Transponder Nano-Device Technology

The above fundamental elements, once developed, will be used to complete what is essentially project 7. This project is the primary outcome objective of the translational bioengineering research initiative. Nanotransponder technology is a game-changing tool that will potentially contribute toward understanding cutting-edge questions addressing information processing in the brain. That is, nanotransponders as 'injectants', strategically delivered into brain pathways of interest, will provide the ability to measure brain activity at the level of a single neuron. In addition, it will facilitate capturing information processing that occurs throughout large populations of communicating neural networks. Problems ranging from epilepsy and brain cancer, to memory-encoding (e.g., grid & place cells/networks in the entorhinal cortex and hippocampus encoding maps of the spatial environment (Hafting et al, 2005)), can be better understood and manipulated with this technology. As importantly, future directions for this novel tool include bridging damaged CNS regions as in stroke, brain trauma and paralysis. As a result, the measurable outcome for this particular future application will include potential restoration of information processing between critical brain regions bridging severed connections in the CNS.

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A. 'On-demand', or Closed-Loop Stimulation Therapy

Preparatory research to attain the above objective is essential. Delivery of treatment stimulation contingent on detection of the ictal-onset at the epileptic source presents as the next generation of implantable technologies directed toward containing epileptic brain circuits. Such strategies are crucial in individuals with medically intractable focal-onset epilepsy where surgical options are minimal or non-existent. The described strategy is known as closed-loop neurostimulation therapy. Recently approved responsive neurostimulation (RNS, NeuroPace, Inc) therapy technology, as well as the most recent vagal nerve stimulation (VNS) pulse generator (Model 106, Cyberonics, Inc) capitalize on closed-loop sensing strategies. The latter technology senses seizure-onset associated heart rate accelerations compared to the patient's baseline heart rate trending. These effective devices are stepping stones toward creating even more sophisticated micro- and nano-electromechanical systems for optimizing neuromodulation therapies.

B. Nanoparticle Drug Carriers

Although promising as a next-generation treatment strategy, direct brain drug delivery is currently limited to positive convection pressure and diffusion kinetics near the tip of the catheter. The action of directly applied modulating drug can be enhanced with biocompatible and degradable charged nanocarriers (Rossi, 2012). Such complexes can be potentially shuttled in a directed manner by the electric field generated at intracranial electrodes used to deliver stimulation therapy. Nanoscale devices are somewhere from 10 to ten thousand times smaller than human cells. They are similar in size to large biological molecules (biomolecules) such as enzymes and receptors. Their small size allows nanoscale carriers to readily interact with biomolecules on both the surface of cells and inside of the cells. Nanoparticles smaller than 50 nm can easily enter most cells, while those smaller than 20 nm can move out of the blood vessels as they circulate through the body.

Nanoparticles as drug carriers were first described (by Speiser and co-workers) in the 1970s. At about the same time, the term 'nano-technology' was coined by Norio Taniguchi (Taniguchi, 1974). Since then, a considerable amount of work on nanoparticles has been carried out in the field of drug/gene delivery. Some of these nanomedicines have already entered clinical trials, or even reached regulatory approval as a drug product. Drugs or other biologically active molecules are dissolved, entrapped, encapsulated in the nanoparticles, chemically attached to the biocompatible polymers, or adsorbed to their surface. The selection of the appropriate method for preparing drug-loaded nanoparticles depends on the physico-chemical properties of the polymer and the drug. As importantly, treatment efficacy is dependent on the brain compartments as well as tissue and flow properties in which these nanocarriers are directed.

Future directions for overcoming limitations of positive convection delivery include potentially steering nanocarrier-based therapeutic molecules through dense pathological tissue employing electrical, or magnetic fields. Such electromagnetic fields may themselves demonstrate an additive or synergistic effect on quieting potentially extensive epileptogenic brain circuits.

As the molecular underpinnings of neuromodulation evolve, and innovative technologies are realized, the most effective system will not be based on a single method. Instead, it is likely that a combination of sophisticated technologies will be optimally integrated with the individual's brain circuits of interest.

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1. Zaragoza L, Hondorp B, Rossi MA. Comparing isotropic and anisotropic brain conductivity modeling: Planning optimal depth-electrode placement in white matter for direct stimulation therapy in an epileptic circuit. Proc COMSOL Conf 2013;1-13.

2. Cendejas Zaragoza L, Byrne R, Rossi MA. Pre-implant modeling of electrode lead implant sites for predicting the extent of cortical activation during direct neurostimulation therapy. Neurological Research 2015. (accepted).

3. Harris TJ, Eng M, Wakeman DR, Huston TR, Rossi MA. An Assessment of the Cytotoxicity Relative to Purity and Concentration of Functionalized Single Wall Carbon Nanotubes on Human Astrocytes in vitro. Advanced Healthcare Materials 2015. (submitted).

4. Harris TJ, Cendejas Zaragoza L, Rossi MA. Carbon nanotube density augmenting the volume of activation during direct neurostimulation therapy. AES Abstr 2015. (accepted).

5. Mangubat EZ, Rossi MA. On-demand pulsatile delivery of carisbamate concurrent with closed-loop direct neurostimulation therapy in a selfsustained limbic status epilepticus (SSLSE) rat model. AES Abstr 2010;3.064.

6. Mangubat EZ, Kellogg R, Harris T, Rossi MA. On-demand pulsatile delivery of carisbamate concurrent with closed-loop direct neurostimulation therapy in a focal-Onset Epilepsy Rat Model. J Neurosurgery 2015; (in press) DOI: 10.3171/2015.1.JNS14946.

7. Rossi MA. Targeting anti-epileptic drug therapy without collateral damage: Nanocarrier-based drug delivery. Epilepsy Currents 2012;12(5):199-200.

8. Rossi MA, Stebbins G, Murphy C, Greene D, Brinker S, Sarcu D, Tenharmsel A, Stoub T, Stein MA, et al. Predicting white matter targets for direct neurostimulation therapy. Epilepsy Res 2010;91(2-3):176-186.

9. Rossi MA, Hoeppner TJ, Kanner, AM, Byrne R, Balabanov A, Palac S, Smith MC. Noninvasive presurgical estimation of cortical activation for optimizing intracranial electrode placement for responsive neurostimulation in refractory epilepsy. Epilepsia 2005;s8:335, Abstr 3.169.

10. Rossi MA. Energy-Releasing Carbon Nanotube Transponders. U.S. Patent 8,788,033 filed September 2009, and issued July 22, 2014.

11. Rossi MA, Cendejas Zaragoza L (Provisional Patent Application #62/088,170) Electrode Placement Planning System and Use Thereof.

12.Taniguchi N. On the basic concept of nano-technology. Proc Intl Conf Eng. Tokyo 1974;Part II:18-23.

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