Epilepsy & Behavior 15 (2009) 120–122

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Epilepsy & Behavior

journal homepage: www.elsevier .com/locate /yebeh

Technological Approaches to the Scientific Explorations of Epilepsy and Behavior

The future of neurotechnology innovation

Zack LynchNeurotechnology Industry Organization, 315 30th Street, San Francisco, CA 94131, USA

a r t i c l e i n f o a b s t r a c t

Article history:Received 23 March 2009Accepted 23 March 2009Available online 25 April 2009

Keywords:NeurotechnologyNeuromodulationOptogeneticsNeuroimagingStem cellsBlood brain barrierNanowiresEconomic burdenNeurological diseasePsychiatric illness

1525-5050/$ - see front matter � 2009 Elsevier Inc. Adoi:10.1016/j.yebeh.2009.03.030

E-mail address: zack@neurotechindustry.org

Advances across several areas of neurotechnology research including stem cells treatments, new imagingtechnologies, drug delivery technologies and novel neuromodulation platforms promise to accelerate thedevelopment of treatments and cures for brain-related illnesses.

� 2009 Elsevier Inc. All rights reserved.

1. Introduction

Neurological diseases and psychiatric illnesses account for morehospitalizations, long-term care, and chronic suffering than nearlyall other health conditions combined. Beyond the untold humansuffering, the annual economic burden of brain-related illnesseshas reached more than $1 trillion in the United States [1].

Critical unmet medical needs remain in almost every area ofbrain and nervous system disorders, including: Alzheimer’s dis-ease, addiction, anxiety, depression, epilepsy, multiple sclerosis,obesity, pain, Parkinson’s disease, sensory disorders, spinal cord in-jury, stroke, schizophrenia, sleep disorders, and traumatic braininjury.

An increasing awareness of this growing economic problem andthe corresponding market opportunity of nearly 2 billion peopleworldwide are stimulating both public and private funding in neu-rotechnology including new drugs, medical devices, and diagnos-tics for brain and peripheral nervous system disorders. Recentadvances in neuroscience have dramatically expanded our under-standing of the basic biological and behavioral components ofbrain-related illnesses.

In particular, an increasing number of neurotransmitters, neu-rotransmitter receptors, ion channels, and other proteins criticalfor normal brain functioning have been identified and character-ized [2,3], genetically engineered animal models have improved

ll rights reserved.

target validation [4] and neuroimaging techniques have made iteasier to study what occurs in the injured and healthy brain [5].

Although great strides have been made over the past decade,technological advances across several areas of research and devel-opment hold promise for the development of even more efficacioustreatments and, for the first time, cures for brain and peripheralnervous system disorders. These areas include stem cell treat-ments, new imaging technologies, drug delivery technologies,and novel neuromodulation platforms.

2. Stem cells and neuroregeneration

The brain has extremely limited capabilities to repair itself, butnew strategies are emerging to improve the brain’s ability toregenerate lost neurons and to facilitate the incorporation of im-planted stem cells into brain circuitry.

There are currently at least eight private and three public com-panies developing neuroregeneration cell transplant therapies.More than $450 million in venture funding has been invested incompanies working on cell replacement and stem cell therapiesfor brain and spinal cord disorders.

There are significant challenges to overcome when consideringthe use of implanted cells for neurological diseases. For example,inducing a cell to differentiate into a skin cell or a liver cell is likelyto be easier than inducing it to form precise connections with an-other area of the brain. The chemical signals for forming the appro-priate connections in the brain may be present only during certain

Z. Lynch / Epilepsy & Behavior 15 (2009) 120–122 121

times of development [6]. Additionally, the character and connec-tions of these new cells must be stable. Despite these complexities,stem cell therapies offer the potential for outright cures to someneurological diseases.

Recently, we have seen progress in bringing these treatmentsinto human trials. A California company has been in clinical testingof fetal stem cells to treat Batten’s disease since 2005 and expectsto complete their Phase I study in early 2009. In December 2008,they received FDA approval to begin trials in a second disorder,Pelizaeus–Merzbacher disease (PMD), a fatal brain disorder that af-fects mainly young children. In February 2009, the first embryonicstem cell trial for spinal cord injury treatment was also approved.These are slow and precautious steps, centering on untreatable dis-orders, but cell-based therapeutic candidates for amyotrophic lat-eral sclerosis, Parkinson’s disease, Alzheimer’s disease, and strokewill soon follow.

3. Neuroimaging and disease treatment

Brain and nervous system illnesses are exceptionally difficult toresearch and diagnose, partly because changes in the local environ-ment of the brain are difficult to assess within the confines of theskull. Although diagnostic tests for diseases like cancer and diabe-tes are common and can use samples from blood, urine, or tissue,diagnostic tests for many brain-related illnesses are only beginningto emerge.

Neuroimaging is revolutionizing the diagnosis and treatment ofbrain-related illness. It is difficult to imagine treating patients withbrain tumors, cerebrovascular disorders, or epilepsy without cur-rent imaging tools. Several decades of neuroimaging research havecontributed enormously to our understanding of structural andfunctional differences in people with neurological and psychiatricdisorders.

For example, PET scans have been shown to be 93% accurate indetecting Alzheimer’s disease about 3 years before the conven-tional diagnosis of ‘‘probable Alzheimer’s” [7]. Imaging now offersinsights into the mechanisms of action of drugs used to treatschizophrenia and the causal mechanisms that may be at the rootof many disorders [8]. Diagnosis of mental illness and differentialtreatment selection is one of the most difficult aspects of psychiat-ric treatment, yet this is where neuroimaging will add tremendousvalue in the years ahead.

On the neurofeedback front, a private company, in conjunctionwith Stanford University, is using real-time functional MRI (rtfMRI)to train patients in pain management techniques by monitoringthe ongoing activity of their brains. Within a 13-minute session,patients can learn to control activity in different parts of their brainand alter their sensitivity to painful stimuli, allowing them to bet-ter control pain. Patients watched their brain’s level of activity asseen by rtfMRI and were trained to decrease pain intensity throughmental exercises, such as focusing on a part of the body where theydid not have pain. In years to come, rtfMRI has the potential to addan entirely new treatment option for a whole host of brain-relatedillnesses including depression, addiction, and dementia.

4. Crossing the blood–brain barrier

Dozens of private companies are currently developing or com-mercializing neurodrug delivery methods and devices that willbring life to old and new compounds alike. These technologiesinclude:

� Implantable devices: Implantable pumps bypass the blood–brain barrier (BBB) and deliver highly accurate amounts of drugsto specific sites in the brain or spinal cord.

� Expression systems: A French company is circumventing theBBB using encapsulated cell technology (ECT), a polymerimplant containing cells that provide continuous, long-termrelease of the therapeutic protein to the brain or eye [9].

� Receptor-mediated transport: Receptors that transport nutrientsto the brain from the blood can be tricked into transporting ther-apeutic chemicals, peptides, and proteins across the BBB. Insu-lin, transferrin, and lipoproteins, for example, cross the BBB byfacilitated transport, and can be combined with therapeutic pro-teins or other molecules to promote access to the brain [10].

� Cell-penetrating peptides: During the past decade, several argi-nine-rich peptides have been described, such as SynB vectors,which allow for intracellular delivery and BBB transport [11].The mechanism for this transport is unknown. A Swiss companyis using cell-penetrating peptides to develop treatments forstroke and myocardial infarction.

� Focused ultrasound: Some research shows that focused ultra-sound can temporarily open the BBB in a targeted area for a win-dow of time [12]. A seed stage company is working tocommercialize this technology and improve it for use in humans.

� Nanoparticle formulations: Nanoparticle formulations refer totherapeutics encapsulated in nanoscale particles that can passthe BBB [13]. Although there is great interest in using nanotech-nology to improve neuropharmaceutical delivery to the brain, itwill take some time to overcome challenges of this platform,including the need for intravenous delivery, manufacturing,and clearance by the liver.

5. Novel neuromodulation platforms

Adaptation of pacemaker technology has led to major advancesin neurodevice development, allowing for stimulation of discretebrain areas and nerves for the treatment of Parkinson’s, essentialtremor, epilepsy, and even obsessive–compulsive disorder. Noveldevice platforms for neuromodulation will allow for less invasiveand more responsive therapies in the future.

Optogenetics, for example, is an emerging field combining op-tics and genetics to probe neural circuits on the millisecond timescale [14]. In early development, delivery of genes tied to cell-spe-cific promoters has been used to make certain neurons light sensi-tive. Then highly targeted light-emitting hardware such asfiberoptics is used to activate or deactivate that specific cell type.One startup in this area is developing an optogenetic neuromodu-lation system that may one day enable the blind to see. Leveragingthis technology will yield entirely new levels of control over spe-cific cell types in the brain, making it possible to treat illnesses thatemerge as a result of malfunctioning neuronal circuits.

Another exciting example of the future of neurodevice develop-ment relates to the development of conducting polymer nano-wires, which will make it possible to monitor and modulateindividual brain cells. The wires can be threaded through the circu-latory system into the brain, without the need for invasive brainsurgery. They do not block normal blood flow or interfere withthe exchange of gases and nutrients through the blood vessel walls.

Looking forward, it will be possible to connect an entire array ofnanowires to a catheter tube that could then be guided throughthe circulatory system into the brain. Once there, the wires wouldbranch out into tinier blood vessels until they reached specific loca-tions. Each nanowire would then be used to record the electricalactivity of a single nerve cell or small groups of them. Nanowire sen-sors could greatly improve doctors’ ability to pinpoint damage frominjury and stroke, localize the epileptogenic zone(s) of seizures, anddetect the presence of tumors and other brain abnormalities. Beyondthat, nanowires that could deliver electrical impulses have the po-tential to transform the entire field of neuromodulation, dramati-cally expanding the potential scope of treatable conditions.

122 Z. Lynch / Epilepsy & Behavior 15 (2009) 120–122

When looked at separately, each of these technological innova-tions will dramatically improve disease diagnosis and therapeuticeffectiveness. But looking at them separately is a mistake. Tounderstand the breakthrough treatments that will truly transformneuromedicine in the years to come, we need to consider what willemerge as the new technologies converge and create multiplier ef-fects with each other, thus opening up entirely new avenues fortreating and curing the brain-related illnesses that impact the dailylives of so many across the planet.

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