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Last lecture to wrap the Neural Engineering course.

Hirak Parikh

on 15 October 2010

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Transcript of BME599_IntroToNeuralEngineeringWrap

special topics: NEURAL ENGINEERING 1. Overview of neural engineering

2.Basic anatomy and physiology, neural signals

3.Electrodes and recording

4.Neural interfaces

5.Brain’s responses to implantable devices Electrodes Cortical Neuroprostheses Neural Stimulation Brain's Response implantable devices Neural Anatomy and physiology

Understanding brain mechanisms, feedback loops
Cortical microcircuits
Deep Brain Stimulation mechanisms, pathways
Glial and tissue responses
Brain plasticity Applications Emerging Technologies Optogenetics Stimulation and DBS modifications Gaming, Consumer Research, Sensory enhancement 6.Neural stimulation

7.Blood brain barrier and drug delivery

8.Visual and Auditory Prostheses

9.Neuromodulation: Deep Brain Stimulation

10.Cortical neuroprostheses

11.Emerging technologies and applications and outlook Acute and chronic responses
Wireless devices basic knowledge underlying our understanding of
host response to implants is being challenged by recent findings
centered on the cellular and molecular biology of CNS response
to injury.

The glial scar, rich in reactive astrocytes, is generally considered
an inhibitory physical and biochemical barrier to axonal growth.

However, emerging studies indicate that reactive astrocytes can
play protective roles during the acute injury phase by aiding wound
healing, protecting and supporting neurons, and limiting secondary
damage due to uncontrolled infl ammation, demyelination
and tissue damage (Bush et al., 1999; Faulkner et al., 2004; Hertz
and Zielke, 2004; Okada et al., 2006; Renault-Mihara et al., 2008).

Moreover, depending on the structure of the scar tissue and the
molecules expressed by the reactive astrocytes, under some circumstances,
reactive astrocytes may support axonal outgrowth (Li
and Raisman, 1995; Sivron and Schwartz, 1995; Ridet et al., 1997). NPC transplants have indicated that
priming the cells toward the neuronal fate is required because NPCs
tend to remain undifferentiated or become glia in non-neurogenic
implant sites (Fricker et al., 1999; Sheen et al., 1999; Cao et al., 2001;
Han et al., 2002; Gao et al., 2006; Lepore et al., 2006) and this effect
is exacerbated in glial scar microenvironments (Cao et al., 2001,
2002; Faijerson et al., 2006). Inflammation is also known to infl uence
NPC response: mild acute infl ammation can induce neurogenesis
while uncontrolled and longer-term inflammation mediated by
large numbers of activated microglia can greatly reduce the number
of newborn neurons (Ekdahl et al., 2003; Butovsky et al., 2006). As
with the potential benefi cial roles of astrocytic and microglial cells,
our ever increasing understanding of how host and transplanted
NPCs respond in the implant environment has great promise to
yield potentially powerful mechanisms for improving long-term
device performance. New Findings about brain's response to injury Neural Stem Cells or neurogenesis Bioactive coatings, reducing mechanical
mismatch between the probe-brain interfaces

Webb et al. (2001) immobilized a neural cell adhesion molecule
(L1-NCAM) on glass substrates and showed in vitro that these bioactive
coatings attract primary CNS neurons and support neurite
outgrowth while repelling primary astrocytes, meningeal cells and
fi broblasts.

Developed by He et al. (2007) with an immobilized
anti-inflammatory tridecapeptide, α-MSH, on silicon probes,
demonstrating diminished inflammation and gliosis

Cell-based bioactive coatings on neural probes have also been examined;
Schlosshauer et al. (2001) encapsulated rat Schwann cells within
a fibrin gel and placed the gel in contact with a slice of rat spinal
cord adhered to a neural probe. Bioactive Coatings Wireless Technologies to reduce tethering Wise et al. (2004) discusses a wide range of wireless implantable
devices that have been developed in recent years; hence a transition
from transcranial designs to intracranial device designs is feasible
if the latter can be shown to mitigate the tissue response, as suggested
by the work of Tresco and colleagues (Kim et al., 2004; Biran
et al., 2007). Neuroprosthetic engineers
have begun to explore this approach by incorporating microfl uidic
channels into devices (Chen et al., 1997, 2008; Lee et al., 2004;
Retterer et al., 2004; Takeuchi et al., 2005; Papageorgiou et al., 2006;
Mercanzini et al., 2008) or implementing surfaces modifi ed with
a controlled-release matrix loaded with drug (Klaver and Caplan,
2007; Winter et al., 2007b; Jun et al., 2008; Abidian and Martin,
2009; Jhaveri et al., 2009). Recent studies from the research group of
David Martin (Abidian and Martin, 2009; Abidian et al., 2009) have
elegantly illustrated the potential of multifunctional surface coatings
on neural probes Microfluidic channels, delivery of molecules Purcell, et al (2009)
We hypothesized that re-entry into the cell cycle may be associated with reactive gliosis surrounding neural prostheses, and that administration of a cell cycle inhibitor (flavopiridol) at the time of surgery would reduce this effect. We investigated the effects of flavopiridol on recording quality and impedance over a 28-day time period and conducted histology at 3 and 28 days post-implantation. Flavopiridol reduced the expression of a cell cycle protein (cyclin D1) in microglia surrounding probes at the 3-day time point. Impedance at 1 kHz was decreased by drug administration across the study period compared to vehicle controls. "Our finding that monkeys could learn to use virtually any motor cortex cell to control muscle stimulation—regardless of the cell’s original relation to wrist movement. Strategies based on decoding the activity of neural ensembles to obtain movement parameters or muscle activity depend on finding cells that modulate
sufficiently with the output variables during actual or imagined movements. Instead, arbitrary cells available on recording arrays could be brought under volitional control using biofeedback, substantially expanding the source of control signals for brain– machine interfaces." In vitro and in vivo experimental evidence has uncovered
a number of deep nuclei that may modulate epileptogenic
foci. In some cases, DBS at these sites has reduced
seizure frequency and/or severity in both animal and
human studies.
Direct control of seizures, especially in the
hippocampus also holds promise.

The design of automated
seizure detection devices and their clinical applications in
closed-loop stimulation research has arguably transformed
the field of AES. Challenge Topics from the NIH Translational Research

15-RR-101*Applied translational technology development. This program will support two-year applied translational projects to move advanced technologies from the prototype stage into the clinic. Novel, cost-effective tools for clinical care or clinical research will be modified, hardened, and tested. Interdisciplinary teams of technology developers, basic researchers and clinicians will address scientific and engineering problems associated with clinical applications of new technologies. Contact: Dr. Douglas Sheeley, 301-594-9762, sheeleyd@mail.nih.gov; NIDA Contact: Dr. Kris Bough, 301-443-9800, boughk@mail.nih.gov

15-NR-101*NIH Partners in Research Program: Pathways for Translational Research. This two year initiative will develop strategies for dissemination of interventions with demonstrated effectiveness for translation into clinical practice by teams of academic and community research partners. This initiative will provide the knowledge to more rapidly move scientific findings into communities to improve health. Contact: Dr. David Banks, 301-496-9558, Banksdh@mail.nih.gov

BBB – Drug delivery
15-NS-101* Manipulating the blood-brain-barrier to deliver CNS therapies for Mental/Nervous System Disorders. Neuroscience discoveries have led to promising therapeutic strategies for treatment of severe neurological disorders. However, the blood brain barrier presents a major hurdle to delivering potentially exciting agents such as RNA therapies, genes, critical enzymes, antibodies, other molecular entities, or cell therapies. The challenge is to develop potentially useful means of CNS drug targeting and delivery systems. Contact: Dr. Tom Jacobs, 301-496-1431, tj12g@nih.gov

15-DA-105Manipulating the blood-brain barrier to deliver CNS therapies for mental/nervous system disorders. Substance abuse has been shown to impact the neurological, behavioral, and neurocognitive consequences of HIV infection. A variety of strategies, including use of antiretroviral, anti-inflammatory, and/or neuroprotective therapeutics, have been proposed as potential treatments for neuroAIDS, but delivery of potentially effective agents across the blood-brain barrier remains a hurdle. This initiative is aimed at developing potentially useful CNS drug targeting and delivery systems that will be effective in the context of substance abuse. Contact: Dr. Diane Lawrence, 301-443-1470, lawrencedi@nida.nih.gov

15-DA-111 Manipulating the blood-brain barrier to deliver CNS therapies for mental/nervous system disorders. Methods to deliver peptide/peptidomimetic drugs to CNS, develop drugs that pass blood brain barrier but do not pass through the placental barrier, use of nanotechnology based methodologies for CNS delivery, methods to deliver drugs only through placental barrier but do not cross the BBB, innovative in-vitro models to predict BBB and placental barrier. Contact: Dr. Rao S. Rapaka, 301-435-1304, Rr82u@nih.gov

Feedback-Controlled Drug Delivery Systems 13-EB-103
Current drug delivery technologies allow controlled dosing but are limited in that they don't respond to actual biological status so there is no feedback loop. To address this, a transformation that shifts the current controlled release paradigm from passive (one drug at a single dose over time) to a “smart” active delivery system that includes sensing and biofeedback is needed. Proposals are sought to create smart, active biomaterials that respond to physiological/pathological stimuli by delivering a drug only when necessary and that can be turned off when the stimulus changes with the overall goal of optimizing treatment outcomes. Contact: Dr. Lori Henderson, 301-451-4778, hendersonlori@mail.nih.gov Breakthrough technologies for neuroscience
06-NS-103 Breakthrough technologies for neuroscience.
Advances in basic neuroscience are often catalyzed by the development of breakthrough technologies that allow interrogation of nervous system function (e.g. patch clamp recording from single cells, optical imaging, multi-channel recording arrays, fluorescent dyes to image cell types and intracellular processes, etc.). The challenge is to develop new technologies with the potential to enable basic neuroscientists to make future quantum leaps in understanding nervous system development and function. Contact: Dr. Edmund Talley, 301-496-1917, talleye@ninds.nih.gov

15-MH-110Understanding the mechanism of action of deep brain stimulation. Conduct basic and clinical research on the mechanism of action of deep brain stimulation. Studies should be relevant to its use in the treatment of mental disorders. This initiative will also establish a registry of clinical data, electrode targeting, and device settings which will be available for analysis and meta-analysis. Contact: Dr. Steven J. Zalcman, 301-443-1692, szalcman@mail.nih.gov

06-NS-104 Developing and validating assistive neuro-technologies.
The burden of illness of neurological disorders could be reduced by enabling technologies that reduce functional disability in patients with severe motor or sensory loss. For example, these would include technologies that improve ambulation, upper extremity dexterity, swallowing, or neural control of prostheses. Contact: Dr. Naomi Kleitman, 301-496-1447, nk85q@nih.gov

13-NS-101 Developing novel biomaterials to interfaces with neural activity.
The burden of neurological illness could be advanced by development of smart biomaterials that enable interfacing with the nervous system to restore function and decrease disability. These might include biomaterials that allow more effective neural-computer interfaces, scaffolds to improve repair of injured nerve or spinal cord as well as neurotransmission across damage nerve or cord. Contact: Dr. Joe Pancrazio, 301-496-1447, jp439m@nih.gov

15-NS-103 Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease.
Entry into the NINDS translational research program requires evidence that a new therapeutic approach is efficacious in an animal or cell model of a neurological disease. The NINDS seeks grants to conduct research that establishes proof-of-concept sufficient to initiate a preclinical therapeutic development effort. Contact: Dr. Jill Heemskerk, 301-496-1779, jh440o@nih.gov 06-DA-102Tool Development for the Neurosciences. Tools that unambiguously identify, manipulate, and report from neurons in vivo and in vitro are needed to help us understand interactions within neural circuits, to examine the functions of types of neurons that are derived from different brain regions, and to determine how selective and conditional silencing or activation of individual neurons or groups of similar neurons may alter functional outcomes, including behavior. This methodology can contribute greatly to the identification of real-time responses to drugs of abuse or to therapeutic interventions, and can play a key role in helping us understand endogenous neuroprotective mechanisms and the repair of frank brain damage or neural dysfunction as a result of drug abuse. Contact: Dr. Nancy Pilotte, 301-435-1317, npilotte@nih.gov

13-DK-103Scaffolds, biomatrices, smart materials. Examples: Development of novel biomaterials, scaffolds, and biomatrices that may modulate cellular behavior, differentiation, and engraftment to optimize cellular replacement therapies and tissue engineering; Development of smart biomaterials, implantable biohybrids matrices or membranes that may release bioactive agents that promote vascularization, innervation, or inhibit the inflammatory/fibrotic response thus improving biocompatibility and durability. Contact: Dr. Guillermo Arreaza, 301-594-4724, arreazag@mail.nih.gov. 06-HD-101*Improved interfaces for prostheses to improve rehabilitation outcomes. Mechanical design and control algorithms for prosthetic limbs have seen remarkable advances recently. Still lacking, however, are robust interfaces for these limbs to both the brain and the skeleton. The foci of this challenge will be to improve functional rehabilitation outcomes by 1) developing or refining control interfaces that can utilize signals from cerebral cortex to drive the latest generation of arm prostheses; 2) developing or refining methods for anchoring prosthetic arms directly into residual bone without risk of infection; and 3) incorporating these technologies into standard rehabilitation practices to improve patient quality of life. These improvements in prosthetic limbs could potentially provide enhanced functionality for recipients while reducing the time and cost of rehabilitation efforts. Contact: Dr. Michael Weinrich, 301-402-0832, weinricm@mail.nih.gov.

06-MH-103New technologies for neuroscience research. Develop technologies for neuroscience research that are software-based, (e.g., informatics tools, implementation of data analytic algorithms), hardware-based (e.g., instrumentation or devices), or biology-based (e.g., driven by conditional gene expression or The battery-operated device, made by Medtronic, is implanted under the skin of the abdomen and then attached to two insulated wires that are sutured to the stomach wall.[1]

The IGS sends painless electric pulses to the stomach, inducing an early and lasting sensation of “fullness,” possibly by regulating the gut hormones responsible for appetite.[1,2] The IGS is used in combination with diet and lifestyle modifications.[2] Buszaki, Science 2004 According to a market research study from Neurotech Reports, the worldwide neuromodulation device industry will grow from $3.0 billion in 2008 to $4.5 billion in 2010. Neurotech Reports projects a compound annual growth rate of 26 percent in the industry.

The size of the treatment population is enormous. Just imagine the following statistics for a handful of disorders:

• Epilepsy: 40-50 million patients worldwide
• Migraine: 26 million in the U.S. alone
• Spinal cord injuries: 250,000 in the U.S.
• Parkinson disease: 1.5 million in the U.S.
• Urinary incontinence: 13 million adults in the U.S.

To date, neuromodulation has barely scratched the surface of these vast populations. As technologies continue to develop and physician training and adoption increase, the likelihood of neuromodulation therapies touching people’s lives will increase exponentially. Optogenetics SleepWake Circuitry Next generation optrodes DBS for epilesy Ecog electrode hybrid electrode melting, silk electrode theta oscillation and spiking activity interaction hypothesized cortical microcircuit (Martin 2004) Laminar activity in motor cortex Mortiz et al, 2007
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