TheProject A Publicationof The MiamiProject To CureParalysis& The BuonicontiFund To CureParalysis The MiamiProject To CureParalysis Research ReviewResearch 2012 A Message from The Miami Project

his year has already been one of the most exciting Tto date in the history of The Miami Project to Cure Paralysis. Following approval from the FDA to initiate a Phase I Safety Trial in people with subacute (recent) spinal cord injury (SCI), Miami Project scientists and clinicians received ethics permission from the University of Miami Miller School of Medicine to begin enrollment for this important trial. In November we recruited our fi rst subject and in December successfully transplanted millions of his own Schwann cells into the injury. The operation went smoothly, and we are in the process of recruiting our next subjects. This critical dose escalation safety trial will provide a basis for future trials where subjects with chronic paralysis (those paralyzed for a year or more) will be treated with this novel cell therapy. These are very exciting times for The Miami Project scientifi c community as we continue to translate our discoveries into people to make a difference in their lives. We greatly appreciate the support of our donors and scientifi c colleagues who are helping to provide critical resources as we continue to move our investigations forward.

As previously mentioned, in the near future, we plan on A message from the extending these cell therapies to subjects with chronic SCI. Based on encouraging preclinical studies, it appears Chairman and the that Schwann cell transplantation also represents a Scientifi c Director logical cellular approach to repairing the nervous system years after the primary insult. To maximize our chances Barth Green, M.D.,F.A.C.S. of seeing improvements in chronically injured SCI subjects, we have initiated an exciting Boot Camp in The W. Dalton Dietrich, Ph.D. Miami Project that will help condition and train selected individuals to maximize their chances of having a good result with the cell therapies. Thus, a series of approaches including dietary considerations, conditioning regimens, and neurorehabilitation strategies are being combined to maximize improvements in function. The Miami Project has recently obtained a state-of-the-art eLegs robotic exoskeleton for walking and we are investigating its utility for rehabilitation, conditioning, or as a mobility device in people living with paralysis. We feel that Schwann cell transplantation and subsequent combination approaches, together with these conditioning and rehabilitation strategies, may be an exciting future therapeutic to make a meaningful difference to people living with the SCI.

The Miami Project is also beginning to work more closely with various biotech companies to help translate some of their products and discoveries to the paralysis population. A recent development is our work with Medtronics to test a state-of-the-art brain-machine interface to enhance upper extremity function in people with chronic cervical SCI. Brain signal processing and electrical monitoring equipment

2 The Project along with muscle stimulators will allow commands from the brain to be transmitted to upper extremity muscles to enhance motor function in selected subjects. New approaches for deep brain stimulation are also proving advantageous in promoting sensory and motor function in animal models of SCI and a clinical trial will begin this year targeting unresponsive pain in chronically injured individuals. Our ultimate goal will be to combine exciting biomedical and rehabilitation approaches with biological therapies to maximize repair and recovery processes.

The Miami Project scientists continue to receive new funding from various spinal cord foundations, as well as the National Institutes of Health and the Department of Defense (DoD). Many of the discoveries and clinical studies that we are testing in the civilian population are relevant to our military personnel who also have a high incidence of SCI and traumatic brain injury (TBI). Indeed, new DoD funding is currently supporting studies on the detrimental effects of repetitive concussion that may occur in individuals during various sporting events as well as in war situations throughout the world. A new multi-center therapeutic hypothermia trial is being initiated that will test for the fi rst time whether mild cooling prior to decompression surgery in patients with severe TBI can have dramatic effects on improving outcome. Again, these are excellent examples of how discoveries within The Miami Project are being successfully translated to our patient populations.

Currently, there are limited pharmacological agents that can be used to protect the injured spinal cord from secondary injury mechanisms. A variety of drug therapies have failed to show signifi cant benefi ts in the acute SCI populations. Our drug discovery program has identifi ed novel molecules and cell signaling pathways that promote axonal regeneration better than currently available agents. Miami Project scientists also continue to investigate the therapeutic effects of hypothermia in patients with acute cervical SCI. A total of 35 participants have now been treated with therapeutic hypothermia and current results appear to be extremely encouraging. Indeed, at one year following injury, a signifi cant percentage of conversion from complete paralysis to incomplete paralysis is being seen in the cooled population. Our scientists and clinicians are submitting multi- center trial grant applications to rigorously test the benefi ts of therapeutic hypothermia in this patient population as well.

We continue to concentrate on various quality of life issues that are important to people living with paralysis. Fertility problems in men living with SCI continue to be investigated and a new clinical trial testing a novel therapeutic target is being conducted. Another important quality of life issue involves the high incidence of neuropathic pain that is seen in our subjects living with paralysis. Clinical studies are underway to evaluate various factors that infl uence neuropathic pain. The Project continues to represent a unique scientifi c environment by which discovery, translational, and clinical research comes together with the ultimate goal of advancing new therapies to protect and promote recovery in our SCI population. This issue of our magazine covers all of our research endeavors and accomplishments during 2012 and highlights advances in many of our programs. These are indeed exciting times within The Miami Project, and we thank our friends, colleagues, and research participants for their long-term support and commitment to our research. 2013 is already turning out to be a special year, and we thank everyone for their support.

Sincerely,

Barth Green W. Dalton Dietrich, Ph.D. Co-Founder and Chairman, The Miami Project Scientifi c Director, The Miami Project to to Cure Paralysis Cure Paralysis Department of Neurological Surgery Kinetic Concepts Distinguished Chair in University of Miami Miller School of Medicine Neurosurgery Senior Associate Dean for Discovery Science Professor of Neurological Surgery, Neurology and Cell Biology and Anatomy University of Miami Miller School of Medicine

The Project 3 TABLE OF CONTENTS Project The A Publication of The Miami Project To Cure Paralysis & The Buoniconti Fund To Cure Paralysis Research Review 2012 2 Message from the Chairman, Dr. Barth A. Green and 6 Scientifi c Director, Dr. W. Dalton Dietrich 5 Fundraising, Administrative, and Scientifi c Support Staff

RESEARCH HIGHLIGHTS 6 Brain Stimulation RegenBase 11 8 10 Faculty Highlight 11 H.O.P.E.S 12 Hot Topics 13 Education Outreach 15 Summer Student Research 16 16 Combination Treatment for Pain 18 Research Funding

FEATURE ARTICLE 22 The “SCAR“ 22 24 Faculty Profi les 34 Gail F. Beach Memorial Lecture Series 35 New Faculty 36 Active Clinical Studies and Trials 37 Scientifi c Research Publications 2012 43 In Memoriam 35 On the Cover: Ultra microscope image of blood Editor & Contributor, Kim Anderson-Erisman, Ph.D. The Project is published biannually by The Miami Project to vessels inside the Managing Editor, Scott Roy Cure Paralysis, a Center of Excellence at the University of spinal cord that Graphic Editor, Robert Camarena Miami Leonard M. Miller School of Medicine. contribute to scar Contributors, Diana Berning, Danielle Cilien, Vance Lemmon, All contents ©2013. Reproduction in whole or in part without formation when Victor Pikov, Eva Widerstrom-Noga written permission is prohibited. The University of Miami is an damaged. Equal Opportunity/Affi rmative Action Employer. Photographs & Graphics, Robert Camarena, Jae Lee, Vance Lemmon, Melissa Carballosa-Gonzalez Privacy Policy: If you do not wish to receive The Project in the Website: www.themiamiproject.org future, please send your request to the address above or call Physical Address: Mailing Address: 305-243-7147. 1095 NW 14th Terrace, R-48 Post Offi ce Box 016960, R-48 Miami, FL 33136 Miami, FL 33101 Phone: 305-243-6001

4 The Project Miami Project Staff

The Miami Project scientifi c team is grateful for the dedication and hard work of the the fundraising, administrative, and scientifi c support staff. This incredible group of people spend countless hours providing direct clerical and administrative support to the research staff, and raising the precious private funds to support Miami Project research endeavors.

Fundraising, Administrative, and Scientifi c Support Staff Management

Marc A. Buoniconti Suzanne M. Sayfi e Diana C. Berning President Executive Director Center Administrator

Stephanie Sayfi e Aagaard Kim Anderson-Erisman, Ph.D. Teri I. Bendell Randy Carlson Director, Major Gifts, Director, Education Director, Web Services, Director, Finance Corporate Relations, Auction, and Database Marketing and Events

Randy L. Medenwald Scott P. Roy Francine Y. Schoen, MLS Kristin Wherry Director, Government Director, Public Relations Development Director, Director, Buoniconti Fund Relations and Communications Foundation Relations National Chapters

Jacqueline Manzano Marcela Ward Bill Sims Jon-Roi Vega Manager, Marketing Manager, Human Manager, Facilities and Senior Manager, Resources Operations Sponsored Programs

Support Staff Scientifi c Staff

Teresa Arcay Michele Kenny Alexander Marcillo, M.D. Rebecca Avshalom Anil Lalwani Post-doctoral Fellows 19 Morayma Barreto Maria-Jose Luna Graduate Students 20 Javier Burgos Jeremy Lytle Medical/Residents/Observerships 16 Robert Camarena Leonor Muros Undergraduate Students 55 Maria Chagoyen Maria Muniz Volunteers 22 Danielle Cilien Haley Pews Other students 11 Judith Cox Walters Carole Robbins Research Staff 73 Georgina Escobar Tim Saltsman Letitia Fisher Pablo Sanchez Evelyn Gomez Maria Serna Cynthia Jones Jacqueline Tommasino

The Project 5 Brain Stimulation

Brain Stimulation to Reduce Pain and Autonomic Problems

an electrical stimulation to the brain permanently reduce some debilitating symptoms of spinal cord injury C(SCI), such as pain and the episodes of high blood pressure called autonomic dysrefl exia? Dr. Ian Hentall and his collaborators, Drs. Jonathan Jagid, Eva Widerström-Noga, Alberto Martinez-Arizala, and Bruno Gallo, recently received funding from the Department of Defense to conduct a clinical trial to test this very question.

The basis for this clinical trial is rooted in Dr. Hentall’s pre-clinical research (funded in part by the Kleberg Foundation) as well as advances in the fi eld of deep brain stimulation (DBS). The fi gure below illustrates some of the pre-clinical evidence generated by Dr. Hentall. There is a region in the midbrain called the Periaquaductal Gray, or PAG, where

6 The Project Brain Stimulation

electrical stimulation triggers the release of pain relieving Our multi-disciplinary team will attempt to answer these molecules. Dr. Hentall has demonstrated that a few weeks questions. Dr. Hentall has partnered with neurosurgeon Dr. of stimulation in the PAG after SCI reduces pain sensitivity, Jonathan Jagid, who is very experienced with DBS surgery improves autonomic control of and technology. Dr. Jagid also the intestines and breathing, partners with neurologist and reduces the development of clinical neurophysiologist Dr. autonomic dysrefl exia, and Bruno Gallo, who will fi ne-tune enhances movement. These the stimulators on a monthly changes are likely a result of basis to adapt to the needs alterations in various cellular of each individual. Dr. Eva signaling pathways that enhance Widerström-Noga is an expert in growth in the damaged spinal SCI-induced pain and Dr. Alberto cord. The details of these Martinez-Arizala is head of the various experiments have been SCI Clinic at the Miami Veterans published in peer-reviewed Administration Hospital, and an scientifi c journals. expert in clinically managing secondary complications Deep brain stimulation (DBS) associated with living with SCI. Drs. Ian Hentall and Jonathan Jagid involves a surgical procedure With their collective expertise, a to implant a “brain pacemaker”. very well controlled trial can be The device sends different conducted to comprehensively patterns of electrical stimulation evaluate the usefulness of to a specifi c region of the brain DBS to manage pain and to interrupt pathways that are not potentially prevent the onset functioning correctly. Currently, of life threatening autonomic DBS is approved by the Food dysrefl exia. and Drug Administration (FDA) for use in individuals with The team has already obtained advanced Parkinson’s disease FDA approval to use the or essential tremor whose Medtronic Activa PC DBS device symptoms are inadequately in up to 12 participants in a controlled by medication. The Feasibility Clinical Investigation. electrode is placed deep in the This chart illustrates the low number of surgical The study is collaborative brain. This has been performed complications from Dr. Jagid’s DBS surgeries. between the University of in over 100,000 people and Miami and the Miami Veterans the procedure and technology Administration Hospital. The have been proven to be safe and effective. DBS has been group is in the process of obtaining ethical approval from used in the PAG in a few hundred people experiencing both institutions, after which enrollment will begin. The treatment-resistant chronic pain. Approximately 40 of end goals of the trial are to use DBS to (1) immediately those individuals had SCI. The results have been variable block ongoing or intermittent SCI pain without acute or because those trials were all done differently using long-term adverse reactions, (2) simultaneously reduce various stimulation patterns and targets, injury types, pain spontaneous or evoked autonomic dysrefl exia, and (3) symptoms, and durations of follow-up. So the question gradually lead to permanent improvements in pain and of whether DBS can effectively reduce SCI-induced pain autonomic symptoms of SCI. If the method works, it will remains unanswered, plus nobody seems to have looked be a fairly simple matter to go forward with further study at permanent benefi ts of this stimulation after SCI or at and eventual clinical application, since no further device symptoms other than pain. development or preclinical research would be required.

The Project 7 RegenBase

RegenBase a searchable, comprehensive information framework and knowledge base that will advance the fi eld of axon regeneration Deepthi Puram, Dusica Vidovic, Christopher Mader, Stephen Schürer, Uma Vempati, Ubbo Visser, Vance Lemmon, Hande Küçük, Saminda Abeyruwan, Caty Chung, Amar Koleti

he spinal cord injury (SCI) research Tcommunity, like other research communities, has been discussing the diffi culties of replicating important studies as well as challenges with identifying information in the research literature that can lead to novel therapeutic strategies. One way of attacking this problem is “RegenBase”, a knowledge base being developed at The Miami Project by Drs. Vance Lemmon and John Bixby and their University of Miami collaborators Drs. Stephan Schürer and Ubbo Visser. The overall goal of the program is to develop a searchable, comprehensive information framework and knowledge Dr. Vance Lemmon leading the meeting. base that will advance the fi eld of axon regeneration, thereby aiding the discovery of therapeutically relevant genes or drugs for future clinical trials. This project is being funded by a grant awarded in 2012 from the National Institute of Neurological Disease and Stroke at the National Institutes of Health (NIH). The specifi c goals of RegenBase are to:

1. Develop minimal information standards for in vitro studies of neurite growth and guidance 2. Develop minimal information standards for in vivo studies of nervous system regeneration and repair 3. Develop an ontology that defi nes key concepts and their relationships to describe knowledge about neuronal regeneration 4. Curate (fi nd, group, organize, share) information in the neuronal regeneration domain 5. Develop a searchable knowledge base in the neuronal regeneration domain

8 The Project RegenBase

Breakout group at the meeting in October, 2012: Tatsumi Hirata (National Institute of Genetics, Japan), Phil Popovich (Ohio State Univ, USA), Miguel Santiago-Medina (Univ. of Minn., USA), Takashi Namba (Nagoya Univ., Japan), Hiroyuki Kamiguchi (Brain Science Int., RIKEN, Japan), Ubbo Visser (Univ. of Miami, USA).

A special meeting held October 10-12, 2012 was focused Growth Experiment; MIAGE). Growth cones are at the on the fi rst 2 goals described above. The meeting was leading edge of growing neurites and are the “business called “Growth Cones and Axon Regeneration: Entering end”; they sense, move, integrate, and adapt to their local the Age of Informatics” and was funded by the National environment. Thus, understanding and controlling them Institute of Child Health and Human Development at the are key to successful regeneration. There were also NIH, the Japan Society for the Promotion of Sciences, presentations by the participants about their research. and The Miami Project. Invited participants were leading The next day involved discussing the minimal information scientists from the United States and Japan whose needed to describe animal experiments targeting research is focused on nervous system regeneration regeneration after SCI (Minimal Information about a Spinal and repair. The meeting comprised formal presentations Cord Injury experiment; MIASCI), as well as additional and breakout discussion sessions. With only 25 senior research talks. The last day featured research talks and scientists and 11 post-doctoral fellows and PhD students, a mentoring session for PhD students and Post-docs in the environment was ripe for collaboration. attendance.

The fi rst day began with the concepts of minimal The information collected from the breakout sessions is information reporting and biomedical ontologies. These currently being used to develop proposals for minimal are important because the biology of axon regeneration information standards by faculty at The Miami Project. is complex, and sharing information across laboratories These will be circulated to the meeting participants and will requires that there be some degree of uniformity in next be distributed to the research community for feedback. reporting core data. The day progressed to identifi cation After a period of comment, the revised MIAGE and MIASCI of the minimum information needed to describe “petri standards wi ll be recommended to scientists and journal dish” experiments evaluating the migration and guidance editors and also used to incorporate information into the of growth cones (Minimal Information about an Axon evolving RegenBase knowledge base.

The Project 9 Faculty Spotlight Dr. James Guest

Dr. James Guest is an Associate Professor in the University of Miami department of Neurological Surgery and a faculty member of The Miami Project to Cure Paralysis. Dr. Guest hails from Canada; he earned his Bachelor’s and Medical degrees at the University of Alberta. He earned his PhD, however, here at the University of Miami with the late Dr. Richard Bunge in 1996. That’s when he started working with Schwann cells and pursuing pre-clinical studies to support their potential for clinical application.

Dr. Guest didn’t start out knowing this would be his calling, however. As a boy he was interested in science and participated in school science fairs, but as he went through high school his interests shifted towards political science, history, sports, and hands-on craftsman work. He actually started college thinking of becoming a lawyer, but after James D. Guest, MD, PhD, FRCS(C), FACS 2 years he decided it wasn’t for him and took some time off. He worked for a year at a chemical plant as a power to achieve neurolo gical recovery after acute and chronic engineer to make some travel money and then headed SCI. To do so he uses large animal models to increase across to Southeast Asia for 3 years as a volunteer with the relevance of the pre-clinical testing to address key UNICEF, the Red Cross, and other organizations. Those questions of effi cacy and safety. His pre-clinical research travels moved him and had a signifi cant impact on his in large animal models was critical in our Investigational future. For example, he spent a year working on the border New Drug application to the Food and Drug Administration of Thailand and Cambodia where he was trained to perform regarding transplantation of Schwann cells after sub-acute veterinary procedures on water buffalo – undoubtedly a SCI. His group uses advanced histological, behavioral, contributor to his success with large animal studies now. electrophysiologic, MRI, and ultrasound techniques. They Later he started doing wound care for children who had have worked on designing devices to deliver cells and lost limbs from mines or had limb abscesses. That was his therapeutics in a minimally injurious manner. Currently, initial exposure to using his hands for medical purposes they are testing the transplantation of autologous Schwann and he found it gratifying. After those experiences he cells and skin-derived precursor cells to repair tracts of made the decision to go into medical school with a view the injured spinal cord. In addition, they are testing the to working in less developed countries as a surgeon combination of cell transplantation, intensive rehabilitation, or infectious disease specialist. He has continued to and epidural electrical stimulation for safety and effi cacy in volunteer his time in developing countries, most recently chronic SCI models. in Haiti since the devastating earthquake in 2010 through Project Medishare. During neurosurgical training in Other areas of research Dr. Guest specializes in include Vancouver, he spent several months as the resident on studies of human post-mortem spinal cord tissue, intra- the acute spinal cord injury (SCI) unit and realized that operative human spinal cord conduction studies, research the available treatments did not repair the spinal cord, design for clinical trials, supervision of clinical trials, and and determined to use his career to develop restorative assessment of stem cell studies. He is Co-PI of our Phase treatments for SCI. I Schwann cell trial with Dr. Allan Levi and is the Site-PI for the North American Clinical Trials Network sponsored by Dr. Guest has been a faculty member at The Miami Project the Christopher and Dana Reeve Foundation. All-in-all, since 1999. His laboratory focuses on translational studies Dr. Guest is a well-rounded clinician scientist and a valued in cellular, molecular, and electrical stimulation strategies member of The Miami Project faculty.

10 The Project H.O.P.E.S. H.O.P.E.S.

Is hypothermia treatment good for more than traumatic spinal cord injury (SCI)?

ypothermia has been recommended since 2005 by the American Heart HAssociation Guidelines for CPR and Emergency Cardiovascular Care to use immediately after cardiac arrest. It also has a long history of research regarding traumatic brain injury (TBI). The pre-clinical research has demonstrated robust neuroprotection induced by therapeutic hypothermia. The clinical trials, however, evaluating therapeutic hypothermia after TBI have had mixed results. One of the problems appears to be that the variability across sustained TBIs may be even greater than the variability across SCI. Miami Project faculty members, Drs. Shoji Yokobori, Ross Bullock, Dalton Dietrich, and Helen Bramlett, and colleagues have been pursuing the question of whether there are subsets of TBI in which therapeutic hypothermia may be most effective. It appears that the presence of a subdural hematoma shortly after TBI may be a key factor. Image of acute subdural hematoma in the brain. What is a subdural hematoma? In simple terms, it is basically when a blood clot forms between the surface of the brain and the thin membrane surrounding the brain (the dura). These occur in about 20% of all severe TBI’s and are very life-threatening. When the subdural hematoma is large or associated with coma, neurosurgeons need to surgically open the skull (perform a craniotomy) and remove the hematoma/blood clot. The blood clot can reduce or stop blood fl ow to areas of the brain and when it is removed there is a high chance of a reperfusion injury occurring as the blood re-enters those regions of the brain. Drs. Yokobori, Bullock, Dietrich, and Bramlett have demonstrated in an animal model that inducing hypothermia prior to removing the blood clot can reduce the damage caused by reperfusion. The Miami Project is also now involved with H.O.P.E.S.

H.O.P.E.S. is a clinical trial testing HypOthermia for Patients requiring Evacuation of Subdural Hematoma. This is a multi-center collaboration between scientists in the United States and Japan. The sites are the University of Texas Houston, University of Miami, University of Pittsburg, and Nippon Medical Center in Japan. It will be a randomized controlled trial for individuals that have sustained a TBI plus developed an acute subdural hematoma that needs to surgically be removed. Cooling will be induced using a device similar to that we use when cooling people acutely after SCI. In addition to measuring functional and cognitive outcomes, they will also be measuring biomarkers. Look in our Fall 2012 PROJECT magazine for a great article on biomarkers! The end goal is to determine whether this subset of individuals with a severe TBI can benefi t from therapeutic management of their temperature during a necessary surgical procedure. This is another example of how the translational, multi-disciplinary research efforts of The Miami Cooling the brain before surgically removing a blood clot reduces the Project can truly help change medicine. volume of injured tissue.

The Project 11 Hot Topics

A highlight of research studies that have been accepted for publication recently in very HotTopics high profi le journals.

e want to take this opportunity to highlight a couple of research studies that have been accepted for publication Wrecently in high profi le journals.

Dr. Eva Widerström-Noga and colleagues recently published a study in the prominent journal PAIN identifying a signifi cant biomarker for severe neuropathic pain associated with spinal cord injury (SCI). The study used imaging of the brain on individuals living with SCI without neuropathic pain, with low-impact neuropathic pain, or high-impact neuropathic pain compared to pain-free able-bodied controls. The anterior cingulate cortex (ACC) is an area of the brain that has been found to be involved with integrating and modulating pain and affective distress. Dr. Widerström-Noga found that in individuals with SCI living with severe neuropathic pain that was impacting their psychological and social realm, there were m etabolite concentrations suggesting reduced neuronal activity and increased glial activity in the ACC. These fi ndings are supported by previous animal research of similar mechanisms contributing to neuropathic pain after SCI. Brain imaging can give us quantitative, objective measures of a qualitative, subjective experience such as pain. This is important because having such a biomarker can allow us to quantitatively evaluate pain severity and treatment effi cacy. The utility of this biomarker will need to be validated across different types of neuropathic pain phenotypes and tested in clinical trials targeting pain outcomes. Box highlights anterior cingulate cortex region of the human brain.

Pain (2012, doi: 10.1016/j.pain.2012.07.022) Metabolite Concentrations in the Anterior Cingulated Cortex Predict High Neuropathic Pain Impact After Spinal Cord Injury. Widerström-Noga E, Pattany PM, Cruz-Almeida Y, Felix ER, Perez S, Cardenas DD, Martinez-Arizala A.

Drs. John Bethea and Mark Nash and colleagues recently published a study in the PLoS ONE journal evaluating cardiovascular disease risk factor gene expression in a mouse model of chronic SCI and advanced age. As humans with SCI live longer, the prevalence of neuroendocrine/metabolic disorders and increased risk factors for cardiovascular disease is becoming well known. However, the biologic mechanisms leading to these disorders have not been well explored. The team demonstrated in this pre-clinical study that several genes involved in leptin resistance are activated in chronic SCI. Additionally, adipokine gene products are altered after SCI as well as with advanced age. Adipokine-mediated infl ammatory responses and leptin resistance can both contribute to altered energy metabolism, which can contribute to obesity, diabetes, and cardiovascular disease. These pre-clinical fi ndings are important in enabling us to begin understanding the mechanisms leading to risk factors that we know are present in the clinical population. The end goal would be to develop therapeutic measures to counteract the dysregulated mechanisms.

PLoS ONE (7(7): e41073. doi:10.1371/journal.pone.0041073) Alterations in Mouse Hypothalamic Adipokine Gene Expression and Leptin Signaling following Chronic Spinal Cord Injury and with Advanced Age. Bigford GE, Bracchi-Ricard VC, Nash MS, Bethea JR.

12 The Project Education Outreach

The “go to” source for information about spinal cord injury

The Miami Project believes that an important component of developing treatments for paralysis involves communication with the community.

he Education department, directed by Kim Anderson-Erisman, Ph.D., is responsible for Thelping thousands of our community members each year. The other valuable members of the department are Maria Chagoyen, Danielle Cilien, and Letitia Fisher. The department answers phone calls and emails to provide people with information about all of our research programs as well as provide information about injury prevention, clinical care referral, resources for living with paralysis, and advice about unproven therapies around the world. We also conduct numerous tours and lecturers about our research. The top graph to the left shows the total number of people reached each month during 2012 outreach activities. The Education department also assists all of The Miami Project clinical research faculty with recruitment for their clinical studies. The top graph to the right shows that during 2012, about 500 people were able to participate in our studies targeting chronic spinal cord injury (SCI). In addition, Dr. Anderson-Erisman created a comprehensive resource page on The Miami Project webpage to provide individuals with tools for staying healthy while living with paralysis, www.themiamiproject.org/stayinghealthy. This includes information about stretching, exercising, diet, nutrition, sports and leisure activities.

The Project 13 Education Outreach

Dr. Jae Lee speaking about scar tissue at the 2nd Open House; audience members during the 2nd Open House.

On February 18, 2012 the Education department hosted the 2nd Annual Miami Project Community Open House. We opened up our doors to the public for an afternoon packed full of information. The fi rst session was focused on basic science repair strategies for chronic SCI. Dr. Jae Lee spoke about scar tissue, Dr. Damien Pearse spoke about replacing dead cells, and Dr. Vance Lemmon spoke about long distance regeneration. This was followed by a session on clinical science relevant to chronic injury. Dr. Christine Thomas spoke about muscle spasticity, Dr. Eva Widerström-Noga spoke about neuropathic pain, and Dr. Justin Sanchez spoke about new strategies in brain machine interface technology. The fi nal component of the day was behind-the-scenes tours of three laboratories, including a cell culture lab, regeneration lab, and human exercise lab. There were over 125 community members in attendance and the event was a great success! The 3rd Annual Community Open House is scheduled for April 20, 2013.

The Education Department also participated in the 3rd Annual Brain Fair as well as Take Your Child to Work Day, hosted Disability Mentoring Day, had an educational booth at the National Neurotrauma Society annual meeting, and gave invited lectures to multiple SCI consumer groups. If you have questions, don’t hesitate to email us at mpinfo@ med.miami.edu or call us at 305-243-7108.

Audience members listening to Dr. Dalton Dietrich at the 2nd Open House.

14 The Project Student Research

Summer Student Research

major role of The Miami Project is to provide education Aand training for the next generation of neuroscientists. This aspect of The Miami Project’s mission is equally as important as conducting the research that will lead to treatmnts. Our long-term educational goal is to increase the number of scientists and laboratories working on paralysis research and central nervous system disorders Dr. Anderson with poster judge Dr. Brambilla, winner Caleb Pitcairn, and other judges Dr. Sanchez, Dr. Cowan, and Dr. Lee. around the world. Students and young scientists beginning their careers gain skills from The Miami Project’s state- of-the-art comprehensive research and academic environment. 5. Walking-like Movements Produced by Reinnervated Hindlimb Muscles in Response to Stimulation of The Miami Project Summer Student Research Fellowship Transplanted Embryonic Cells, Giselle Fontela is offered to a handful of stellar students each summer eager to work in the laboratory of a Miami Project faculty 6. Developing an Astrocyte-Specifi c Viral Expression System to Characterize Reactive Astrogliosis, Joaquin member. In 2012, the following students were awarded Jimenez this fellowship: Benjamin Bowe – Pearse lab; Chelsea Cosner – Sagen lab; Giselle Fontela – Thomas lab; Sopiko 7. Plasticity of Schwann Cell Morphology in Vitro, Julia Jimsheleishvili – Liebl lab; Caleb Pitcairn – Lemmon lab; White Nrithya Sundararaman – Bethea lab; Julia White – Monje lab. 8. Design of SHG/EM2 Construct to Alleviate Spinal Cord Injury Induced Pain, Karen Velarde, Leslie Seijo These 7 students plus 8 other exceptional summer students wrote an abstract about their specifi c research 9. Evaluation of [Ser1]-histogranin and ω-conotoxin project and presented a poster at the 2nd Miami Project MVIIA Combined Analgesic Effect, Luke McIntosh Summer Student Research Session on August 1, 2012. Caleb Pitcairn won the David Hovda Outstanding Student 10. Myelin Expression in the Brain of TNF Receptor Research Poster Award! Knockout Mice, Nrithya Sundararaman

Summer Student Research Projects: 11. MicroRNA Overexpression in Neurons in Culture, 1. Immunocytochemistry and Confocal Imaging of Whole Ryan Kowalsky Mount Nervous System Tissue, Benjamin Bowe 12. Rolipram Rescues Cognitive Impairments Resulting 2. Novel Therapeutic Applications of CGRP8-37 for SCI From Traumatic Brain Injury, Rosmery Santos Neuropathic Pain and Migraines, Chelsea Cosner 13. Examining the Association of Eph Receptors using 3. Attenuation of Spinal Cord Injury-induced Pain Bimolecular Fluorescence Complementation (BiFC), by Intraspinal Transplantation of Recombinant Sopiko Jimsheleishvili Neuroprogenitor Cells in Rats, Catherine Gordon 14. Repair of Post Spinal Cord Injury Respiratory 4. Investigation of mRNA-binding Protein Overexpression Dysfunction through Brainstem electrical stimulation, on Neurite Growth, Caleb Pitcairn Shreyans Patel

The Project 15 Combination Treatments

Do we need combination treatments for pain?

Post-doctoral fellow Stanislava Jergova with Dr. Jacqueline Sagen.

he Miami Project has a multi-disciplinary group of scientists that are all doing research to understand Tand better treat neuropathic pain. This kind of pain differs a lot from physiological pain we all know. For example, when we cut our fi nger it feels painful for a couple of days, but as the wound heals the pain goes away. Neuropathic pain stays much longer, often for years, and it responds poorly to pain-killer drugs. Spinal cord injury (SCI) induced neuropathic pain is an extremely complex problem. Pain is not just “all in the head”. There are biologic changes that occur in the spinal cord as a direct result of injury. So, aside from losing sensation after SCI, spontaneous and/or evoked pain can develop. Some of the changes we know occur after SCI to contribute to the development of pain are: 1. Neuronal hyperexcitability a. Receptor changes, eg. NMDA & other glutamate receptors, and ion channel changes, eg. Sodium channels b. Increased release of excitatory substances c. Loss of endogenous inhibitory tone (disinhibition; loss of GABA interneurons in spinal cord; altered descending inhibition) 2. Neuroplasticity a. Structural changes, e.g. sprouting and rearrangement of pain fi bers entering the spinal cord from the periphery 3. Pain “generator” in the brain and spinal cord 4. Glia activation (astrocytes and microglia)

16 The Project Combination Treatments

A decrease of GABA-labeled neu- rons in the spinal dorsal horn at the ipsilateral side after SCI. Fluorescent staining for GABA neurons (red) and all neurons (green). Cell bodies posi- tive for both markers appear orange (arrows).

As you can see, there are many mechanisms contributing in humans. They administered the drugs to the intrathecal to neuropathic pain. As a result, it may be more effective space on purpose, rather than oral or systemically, because to try to target multiple mechanisms at the same time fewer side effects occur when drugs are given intrathecally. with a combination approach. Dr. Jacqueline Sagen has Dr. Sagen’s lab found that the only combination that been doing just that; she performs basic science research resulted in a synergistic reduction of pain was the to determine and target multiple biologic mechanisms combination of Baclofen and ketamine. This, in effect, contributing to chronic neuropathic pain. She uses cell “quieted” the overactive excitatory neurons and “woke transplantation as well as drugs to target pain mechanisms up” the underactive inhibitory neurons to somewhat reset in animal models. The goal of combination treatments is the system. This suggests that these are good targets to to induce an effect that is better than when each treatment pursue therapeutically. is given separately. This is called additive. If the additive effect is better than expected, then it is called supra- Another way to deliver combination analgesic drugs additive or synergistic. In that situation the total dose of the locally to avoid systemic side effects is to use cells as combination might be lower than if given separately, which minipumps - either engineered cells capable of releasing would be a good thing because lower doses usually cause analgesic substances or endogenous cells converted fewer side effects. to release recombinant virus-encoding analgesics. As chronic neuropathic pain involves reduced inhibition and In 2009, Dr. Sagen’s laboratory demonstrated that enhanced excitation of neurons in the spinal cord, targeting acetaminophen, which acts in part by inhibiting the both of these mechanisms at the same time using cell or degradation of naturally occurring cannabinoids in the gene therapy may be a promising approach for long-term body, in combination with morphine or gabapentin pain reduction. Recently, Dr. Sagen’s lab has developed has a greater effectiveness (synergistic) on reducing pain recombinant neural stem cells that are able to release than either drug alone. Her lab also discovered that 2 an inhibitory neurotransmitter (GABA) and a peptide types of small proteins (peptides) derived from the marine antagonist of excitatory receptors (serine-histogranin). The cone snail were very effective when given in combination cells are therefore able to target both the inhibitory and at reducing pain responses in spinal injured animals. excitatory processes and restore the balance between These identifi ed promising targets are being utilized in the them. Injection of such cells into the spinal cord helped to generation of engineered cells and gene therapy vectors to reduce neuropathic pain symptoms in animals with SCI. produce sustained delivery of analgesic peptides for long- Dr. Sagen’s lab is currently working on several recombinant term pain alleviation. plasmids encoding genes from the marine cone snail that were found to be effective in the combination studies In 2012, her group focused on blocking hyperactive above. These will be ready to test in SCI pain models to excitatory receptors (using ketamine or histogranin) and fi nd out the best combination approaches to beat the pain. activating hypoactive inhibitory neurons (using baclofen One thing is clear, however, and that is that targeting just or muscimol) in the dorsal horn of the spinal cord. These one mechanism contributing to neuropathic pain is likely drugs were delivered separately or in combinations to the not going to be good enough. So, Dr. Sagen is forging intrathecal space, similar to how a “Baclofen pump” works down the right track with combination treatments.

The Project 17 Research Funding

Each year, Miami Project scientists seek funding for their research by submitting proposals to the National Institutes of Health, the premier scientifi c body in the United States, as well as other funding agencies and foundations.

Their scientifi c peers rate the merits of these proposed experiments in a highly competitive process and only the best are funded. The agencies and organizations listed below supported the Principal Investigator(s) and the scientifi c project(s) indicated during 2012.

Craig H. Neilsen Foundation Dr. Nancy Brackett (P.I.) -Infl ammasome Signaling and Sperm Cell Function -Improving Reproductive Function in Men with Spinal Cord Injury

Dr. Stanislava Jergova (P.I. – Post-doctoral Fellowship), Dr. Jacqueline Sagen (Sponsor) -Recombinant Stem Cell Therapy for Spinal Cord Injury Pain

Dr. Robert Keane (P.I.) -Infl ammasome Regulation Following Spinal Cord Injury

Dr. Daniel Liebl (P.I.) -A Novel Mechanism to Block Oligodendrocyte Cell Death Following SCI

Dr. Mark Nash (P.I.) -Effects of Salsalate Monotherapy on Prandial-Induced Vascular Infl ammation in Overweight Persons with SCI -Effects of Exercise on Prandial Lipemia and Fat Oxidation After Tetraplegia -A Model Community/Home-based Exercise Program for SCI Abramson Foundation Dr. Pantelis Tsoulfas (P.I.) Dr. Brian Noga (P.I.), Dr. Ian Hentall (Co-I.) -Neural Stem Cells for Spinal Cord Injury -Acute Facilitation of Walking After SCI Using Deep Brain Stimulation American Heart Association Scientifi c Development Grant Dr. Kevin Park (P.I.), Dr. Jae Lee (Co-I.) Dr. Juan Pablo De Rivero Vaccari (P.I.) -Novel Combinatorial Approaches to Promote Axon Regrowth -Activation of Rig-like Receptor Signaling after Focal Cerebral After Chronic SCI Ischemia Dr. Jacqueline Sagen (P.I.) Christopher & Dana Reeve Foundation -Utilizing Designer Genes to Alleviate Chronic SCI Pain Dr. Mary Bartlett Bunge (P.I.) -Studies of Schwann Cell Transplantation Dr. Eva Widerström-Noga (P.I.), Dr. Alberto Martinez-Arizala -Research Consortium on Spinal Cord Injury: Studies of (Co-I.) Schwann Cell Transplantation -Utility of Quantitative Sensory Testing in SCI-related Pain

Dr. James Guest (Center P.I.) Department of Defense (DOD) Defense Advanced -North American Clinical Trials Network Research Projects Agency (DARPA) Dr. Justin Sanchez (P.I.) Dr. Brian Noga (P.I.), Dr. Ian Hentall (Co-I.) -Tissue, Electrical, and Material Responses in Electrode -Therapeutic Potential of DBS for Improving Walking Failure Following Incomplete Spinal Cord Injury

18 The Project Research Funding

-Creating the Synthetic Brain Through Hybrid Computational Dr. Helen Bramlett (P.I.) and Biological Systems: Repairing and Replacing Neural -Pathophysiology of Polytrauma and Novel Treatment Networks Strategies -Responsive Neurorehabilitation Using an Advanced Brain Monitoring BCI Dr. M. Ross Bullock (P.I.) -Laboratory Studies to Evaluate Perfl uorocarbon in Models of Traumatic Brain Injury Department of Defense (DOD) Spinal Cord Injury Research Program of the Offi ce of the Congressionally Dr. W. Dalton Dietrich (P.I.), Dr. Helen Bramlett (Co-I.) Directed Medical Research Programs -Operation Brain Trauma Therapy Dr. W. Dalton Dietrich (P.I.), Dr. Michael Wang (Partner P.I.) -The Importance of Temperature in the Pathophysiology of -Biomarkers for Spinal Cord Injury-Related Medical Mild Repetitive Brain Injury Complications Dr. Jed Hartings (P.I.), Dr. M. Ross Bullock (Co-I.) Dr. W. Dalton Dietrich (P.I.), Dr. John Bixby (Co-I.), Dr. Jae Lee -Spreading Depressions as Secondary Insults after (Co-I.), Dr. Vance Lemmon (Co-I.), Dr. Daniel Liebl (Co-I.), Dr. Traumatic Injury to the Human Brain Kevin Park (Co-I.), Dr. Pantelis Tsoulfas (Co-I.) -Battlefi eld Exercise and Combat Related Spinal Cord Injury Dr. Frank Tortella (P.I.), Dr. M. Ross Bullock (Co-I.) -Treatment of Traumatic Brain Injury using the Dr. Jonathan Jagid, (P.I.), Dr. Ian Hentall (Co-I.), Dr. Alberto Neuroprotectant NNZ2566 Martinez-Arizala (Co-I.), Dr. Eva Widerström-Noga (Co-I.) -Treatment of Pain and Autonomic Dysrefl exia in Spinal Cord Department of Defense (DoD) United States Army Injury with Deep Brain Stimulation Medical Research Acquisition Activity Dr. W. Dalton Dietrich (P.I.), Dr. Helen Bramlett (Co-I.) Dr. Mark Nash (P.I.) -Operation Brain Trauma Therapy -Obesity/Overweight in Persons with Early and Chronic SCI: A Randomized, Multicenter, Controlled Lifestyle Intervention E. Matilda Ziegler Foundation for the Blind Dr. Kevin Park (P.I.) Dr. Kevin K. Park (P.I.) -Novel Combinatorial Approaches to Enhance Retinal -Novel Combinatory Approaches to Repair Visual System Ganglion Cell Survival and Axon Regeneration after Optic After Optic Nerve Damage Nerve Injury

Dr. Damien Pearse (P.I.) Florida Department of Transportation -Site-directed Nanotherapeutics to Abrogate Relapsing/ Dr. Gillian Hotz (P.I.) Remitting Multiple Sclerosis and Promote Remyelination -Safe Route to School-WalkSafe County Program Repair -Statewide WalkSafe Program and Tech Center -WalkSafe Miami-Dade Dr. Damien Pearse (P.I.), Dr. Mary Bartlett Bunge (Partner -WalkSafe Tool Kit P.I.), Dr. James Guest (Partner P.I.), Dr. Dalton Dietrich (Co- -BikeSafe Program I.) -Transportation Enhancement -Schwann Cell (SC) Implantation for SCI Repair: Optimization of Dosing, Long-Term Cell Persistence, and the International Collaboration on Repair Discoveries Evaluation of Toxicity and Tumorigenicity Dr. Rachel Cowan (Distinguished Visiting Scholar) -Measurement Properties of Wheelchair Propulsion Tests: Dr. Damien Pearse (P.I.), Dr. Howard Levene (Partner P.I.) Minimal Clinical Important Difference and Smallest Detectable -Translation of Novel PDE4 Inhibitors for the Treatment of Difference Acute Spinal Cord Injury International Spinal Research Trust Dr. Eva Widerström-Noga (P.I.), Dr. Kim Anderson-Erisman Dr. James Guest (Center P.I.) (Co-I.), Dr. Alberto Martinez-Arizala (Co-I.) -Comparison of Schwann Cells and Skin-derived Precursor -Experiences of Living with Persistent Pain After a Spinal Cells for Repair of Demyelination in the Primate Corticospinal Cord Injury Tract

KiDZ Neuroscience Center Department of Defense (DoD) Psychological Health Dr. Gillian Hotz (P.I.) and Traumatic Brain Injury Program of the Offi ce of -Accelerometer Study Congressionally Directed Medical Research Programs -Countywide Concussion Surveillance System

The Project 19 Research Funding

Medtronic Spinal and Biologics Dr. Suzanne Groah (P.I), Dr. Mark Nash (Co-I.) Dr. Barth Green (Co-I.) -Rehabilitation Research and Training Center on Secondary -Pivotal IDE Study of the Bryan Cervical Disc Prosthesis in Conditions in SCI the Treatment of Degenerative Disc Disease National Institute of Neurological Disorders & Stroke National Center for Medical Rehabilitation Research Dr. Coleen Atkins (P.I.) in the National Institute of Child Health and Human -Rehabilitation Strategies for Memory Dysfunction after Development and the National Institute of Neurological Traumatic Brain Injury Disorders and Stroke Dr. Christine Thomas (P.I.) Dr. Mary Bartlett Bunge (Co-P.I.), Dr. John Bethea (Co-P.I.), -Verifying Automatic Analysis of Muscle Spasms in Large Dr. Ian Hentall (Co-I.), Dr. Paula Monje (Co-I.), Dr. Kevin Datasets Park (Co-I.), Dr. Patrick Wood (Co-I.) -Cytological Studies of Developing and Mature Neurons National Football League Charities Medical Research Dr. Coleen Atkins (P.I.) Dr. John Bethea (P.I.), Dr. Roberta Brambilla (Co-I.) -The Effects of Mild Hyperthermia on Outcome after Mild -The Role of Astroglial-NF-kB in SCI Traumatic Brain Injury -Astrocytes Play a Critical Role in the Pathology of EAE

National Heart, Lung, and Blood Institute Dr. John Bixby (P.I.), Dr. Vance Lemmon (Co-I.) Dr. David Fuller (P.I.), Dr. Justin Sanchez (Co-I.) -Novel Compounds that Overcome Glial Inhibition of Axonal -Training Novel Host-Graft Circuits to Enhance Spinal Cord Regeneration Repair Dr. John Bixby (P.I.), Dr. Vance Lemmon (Co-P.I.), Dr. Jeff Dr. Stephan Schürer (P.I.), Dr. Vance Lemmon (Co-I.) Goldberg (Co-P.I.) -LINCS Information FramEwork (LIFE) to integrate and -Triazine-based Compounds to Promote Regeneration in Analyze Diverse Data Sets Optic Neuropathies

National Human Genome Research Institute Dr. Vance Lemmon (P.I.), Dr. John Bixby (P.I.), Dr. Stephan Dr. Vance Lemmon (P.I.) Schürer (P.I.) -Bioassay Ontology and Software Tools to Integrate and -Regenbase: A Searchable Database to Organize Analyze Diverse Data Sets Regeneration Knowledge via Ontologies

National Institute of Child Health & Human Development Dr. Jesse Brodkin (P.I.), Dr. Jacqueline Sagen (Sub- Dr. Edelle Field-Fote (P.I.), Dr. Diana Cardenas (Co-I.), Dr. contractor for Small Business Innovation Research award) Mark Nash (Co-I.) -Using a Multi-touch Screen to Automate Pain Assessment -Improving Hand and Arm Function in Individuals with SCI Dr. Ramon Diaz-Arastia (P.I.), Dr. M. Ross Bullock (Co-I.) Dr. Vance Lemmon (P.I.), Dr. John Bixby (Co-I.) -Phase II, Randomized Controlled Trial of Brain Tissue -Novel Gene Targets for CNS Axonal Regeneration Oxygen Monitoring

National Institute of Disability & Rehabilitation Research Dr. W. Dalton Dietrich (P.I.), Dr. Helen Bramlett (Co-I.) Dr. Diana Cardenas (P.I.), Dr. Rachel Cowan (Co-I.), Dr. -Mechanisms of Recovery Following Traumatic Brain Injury Mark Nash (Co-I.) -Effi cacy of Necrostatins on Post-traumatic Epilepsy (via -Spinal Cord Injury Model Systems American Recovery and Reinvestment Act)

Dr. Michael Boninger (P.I.), Dr. Kevin Dalal (Site P.I., Miami), Dr. W. Dalton Dietrich (P.I.), Dr. Helen Bramlett (Co-I.), Dr. Dr. Rachel Cowan (Site Co-P.I., Miami) Coleen Atkins (Co-I.) -Collaboration on Mobility Training -The Importance of Temperature on Infl ammation after TBI -Cyclic Nucleotide Regulation in Traumatic Brain Injury Dr. Mark Nash (P.I.) -Exercise Interventions for Spinal Cord Injured Adults with Dr. Robert Keane (P.I.) Obesity-related Secondary Disorders -Infl ammasome Regulation After Spinal Cord Injury

Dr. Mark Nash (P.I.), Dr. Kim Anderson-Erisman (Co-I.) Dr. Jae Lee (P.I.) -Sleep Disordered Breathing in Persons with Chronic -Role of Fibroblasts in Axon Regeneration After SCI Tetraplegia: Characterization and Intervention

20 The Project Research Funding

Dr. Allan Levi (P.I.) The Hearsts Foundation -Transplantation of Autologous Schwann Cells for the Repair Dr. James Guest (P.I.) of Segmental Peripheral Nerve Defects -Pivotal Pre-Clinical Studies for Transplantation of Schwann Cells in Chronic Spinal Cord Injury Dr. Daniel Liebl (P.I.) -Ephrins Regulate Stem Cell Proliferation following Traumatic The Karl Kirchgessner Foundation Brain Injury Dr. Kevin Park (P.I.) -Regulation of Synaptic Formation and Effi cacy Following -Developing PTEN shRNA-mediated Combinatorial Traumatic Brain Injury Approaches to Improve Optic Nerve Regeneration Dr. Andrew Maudsley (P.I.), Dr. Eva Widerström-Noga (Co-I.) -Volumetric MRSI Evaluation of Traumatic Brain Injury The Pew Charitable Trusts Dr. Kevin Park (P.I.) Dr. Brian Noga (P.I.), Dr. Ian Hentall (Co-I.) -Visual System Repair Following Optic Nerve Damage -Control of Spinal Locomotor Activity by Monoamines University of Miami Stanley J. Glaser Foundation Dr. Michael Norenberg (P.I.), Dr. John Bethea (Co-I.) Dr. Coleen Atkins (P.I.) -NF-kappaB in Astrocyte Swelling/Brain Edema Associated -Rehabilitation Strategies for Cognitive Disabilities after with Acute Liver Failure Traumatic Brain Injury

Dr. Damien Pearse (P.I.), Dr. Mary Bartlett Bunge (Co-I.), Dr. Dr. Kevin Park (P.I.) Brian Noga (Co-I.), Dr. Patrick Wood (Co-I.) -Repairing Optic Nerve Damage -Axon Regeneration: Synergistic Actions of the MAPK and Cyclic AMP Pathways Veterans Administration Biological Laboratory Research and Development Dr. Damien Pearse (P.I.) Dr. Helen Bramlett (P.I.) -Therapeutic Targeting of Intracellular Mechanisms Involved -Novel Treatment Strategies for Targeting Post-Traumatic in Glial Scar Formation Epilepsy

Dr. Jacqueline Sagen (P.I.) Veterans Administration Rehabilitation Research and -Potent Analgesic Conopeptides for Treatment of Chronic Development Spinal Cord Injury Pain Dr. Robert Jackson (P.I.), Dr. Diana Cardenas (Co-I.) -Rehabilitation of IPF Patients: Effects of Exercise and Dr. Justin Sanchez (P.I.) Oxidant Stress -Neural Correlates of Tourette Syndrome Wings for Life Foundation Dr. Christine Thomas (P.I.) Dr. Damien Pearse (P.I.) -Muscle Function in Human Cervical Spinal Cord Injury -Transcriptional Activation of Endogenous and Exogenous -Rescue of Denervated Muscle Neural Precursor Cells for SCI Repair

Dr. Grace Zhai (P.I.), Dr. Pantelis Tsoulfas (Co-I.) State of Florida Brain and Spinal Cord Injury -Mechanisms of Neuronal Maintenance and Protection Program and Red Light Camera Fund -These two state funds contribute to several Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation research programs within The Miami Project to Dr. Ian Hentall (P.I.) Cure Paralysis -Trophic Brainstem Stimulation for Autonomic Dysfunction after Spinal Cord Injury

State of Florida James and Esther King Biomedical Research Program Dr. John Bixby (P.I.), Dr. Murray Blackmore (Co-I.), Dr. Vance Lemmon (Co-I.) -Combination Therapy in SCI: Proof of Concept for New Compounds and Candidate Genes

The Project 21 Scar Tissue

The“SCAR ...“ what is it, really?

e all hear about scar tissue and how much of a barrier it is to repairing the chronically Winjured spinal cord, but what is it really and how do we overcome it? Dr. Jae Lee joined The Miami Project faculty in 2010 focused on answering this very question. Scar tissue begins to develop around the injury site several weeks after the injury occurs and continues to change for several months, possibly years. It is initially the body’s natural effort to enclose the injury site to prevent it from getting bigger. This is actually important because scientists have shown that if you disrupt the formation of the scar, the injury site “spreads out” and interferes with some of the Figure 1: Image of a mouse spinal cord injury showing the astroglial scar and severed axons from the spontaneous recovery cortex (red) and brainstem (green). that occurs over time. However, once the scar is formed it becomes an inhibitory barrier to axon regeneration. The fi gure above illustrates this very well. Corticospinal axons are colored red; these are axons whose cell bodies are located in the cortex of the brain and they are very important for directing voluntary control of skilled movements. Serotonergic axons are colored green; these are axons from cell bodies largely located in the midbrain and brainstem and they are important for many types of movements, including locomotion. The fi gure clearly demonstrates that these axons are still present long after the spinal cord injury (SCI) has occurred, but they cannot move past the scarred injury site.

The main component of the scar that you tend to hear about has to do with cells called astrocytes (colored blue in the fi gure above). Sometimes the scar will be referred to as the astroglial scar, or glial scar for short, because astrocytes are a type of glial cell. Glial cells are sometimes called the “glue” of the nervous system, but they do more than just hold everything together. After an injury to the spinal cord, glial cells are involved with removing dead cells and walling off the injury. However, astrocytes are not the only component of scar tissue. Dr. Lee

22 The Project Scar Tissue

has been focusing on the fi brotic scar as well, which is in the interior of the injury site (see fi gure to the right). The fi brotic scar is made up of chemicals released by a type of cell called a fi broblast. The chemicals released by fi broblasts give structure to tissue and are important in normal wound healing processes of the skin. Dr. Lee was one of the fi rst to show evidence that these fi broblasts enter the spinal cord from the microscopic blood vessels within the cord that get damaged during the injury. Since a major function of fi broblasts is to release a chemical called fi bronectin, Dr. Lee’s group has been investigating the role of fi bronectin at the injury site. While fi bronectin is not expressed in the normal central nervous system (CNS = the brain and spinal cord), it is expressed at high levels Figure 2:The fi brotic scar (green) fi lls the injury site while surrounded by the astroglial scar. after SCI. Interestingly, even though the fi bronectin is released by the fi broblast cells, Dr. Lee’s recent results indicate that another type are immune cells and these results suggest that the of cell, the macrophage, may be primarily responsible immune response after injury may also play an important for the assembly of fi bronectin into a matrix at the injury role in formation of the fi brotic scar. In non-CNS tissue, site, which results in the fi brotic scar. Macrophage cells fi bronectin is involved in a wide range of activities important to maintaining the body, but its role in the fi brotic scar after SCI is not clear. It is clear, however, that axons cannot grow through it. In 2012 Dr. Lee received a fi ve-year grant from the National Institutes of Health on the role of fi broblasts in axon regeneration after SCI and he is planning on submitting a similar fi ve-year grant application on the fi bronectin story sometime in 2013. Understanding the scar is critical to overcoming it as an inhibiting barrier to axonal regeneration. The Miami Project strives to have a comprehensive approach to the complex problem of repairing SCI and is happy to have Dr. Lee contributing so signifi cantly to ultimately overcoming the scar. Dr. Jae Lee (center) with post-doctoral fellow Cynthia Soderblum (left) and graduate student Yunjiao Zhu (right).

The Project 23 Faculty Profiles The Miami Project To Cure Paralysis Faculty Profi les The faculty of The Miami Project are a talented multidisciplinary team. In the following Profi les, each faculty member describes their specifi c research focus and highlights of recent progress.

W. DALTON DIETRICH, PH.D. Scientifi c Director Kinetic Concepts Distinguished Chair in Neurosurgery Senior Associate Dean for Discovery Science Professor, Departments of Neurological Surgery, Neurology, and Cell Biology & Anatomy Neuroprotection and Improved Recovery of Function following Central Nervous System (CNS) Trauma My research interest is the pathobiology and treatment of CNS injury in both the acute and chronic setting. Animal models of cerebral ischemia, and brain and spinal cord trauma are utilized to investigate the mechanisms of tissue injury. The ultimate goal is to target specifi c injury processes for pharmacological intervention, including the addition of growth factors, to promote circuit plasticity, regeneration, and recovery of function.

BARTH A. GREEN, M.D., F.A.C.S. Co-Founder Professor and Chairman, Department of Neurological Surgery Translational Interventions Over the recent years my research efforts have mainly involved taking the cutting edge basic neuroscience work product and data created by our Miami Project team from the bench to our UM affi liated clinics and hospitals. A good example of such translational research efforts has included the use of modest hypothermia for neuroprotection both in cases of acute spinal cord injury (SCI) and for use in the operating room for patients undergoing high risk spinal cord surgery. I am also privileged to be able to collaborate with The Miami Project cellular transplantation programs and have been working on projects involving adult mesenchymal stem cells as well as being part of the major effort transforming our successful Schwann cell laboratory model into clinical trials. Another area of clinical interest and research includes the diagnosis and treatment of Chiari I malformation with and without syringomyelia. Each of these projects involves collaborations with Miami Project basic and clinical researchers as well as the faculty from the Department of Neurological Surgery and several other collaborating departments and Centers of Excellence at the University of Miami Miller School of Medicine.

24 The Project Faculty Profiles

MARY BARTLETT BUNGE, PH.D. Christine E. Lynn Distinguished Professor in Neuroscience Professor, Departments of Cell Biology, Neurological Surgery, and Neurology Development of Combination Strategies to Repair the Injured Spinal Cord The goal in my laboratory is to foster regeneration of axons across and beyond a SCI. To improve regeneration of axons, we are investigating reducing the accumulation of proteoglycans (molecules that inhibit axonal growth), improving survival of transplanted Schwann cells (SCs), and genetically engineering SCs before transplantation to improve their neurotrophic factor- secreting capability or neurons to enhance their ability to regenerate axons after injury. We pay particular attention to the interface between the SC implant and the host spinal cord.

JOHN R. BETHEA, PH.D. Professor, Departments of Microbiology & Immunology and Neurological Surgery Immunological Consequences of SCI and the Development of Neuroprotective Strategies In my laboratory we are studying SCI and diseases of the nervous system such as Multiple Sclerosis (MS) to try to understand the cellular and molecular mechanisms that contribute to astrogliosis and secondary neuronal cell death. To this end, my laboratory has two main research objectives. Firstly, we are studying the neuro-infl ammatory response that occurs following SCI and, secondly, we are developing novel therapies for SCI and diseases of the CNS.

JOHN BIXBY, PH.D. Professor, Departments of Molecular & Cellular Pharmacology and Neurological Surgery Vice Provost for Research

VANCE LEMMON, PH.D. Walter G. Ross Distinguished Chair in Developmental Neuroscience Professor, Department of Neurological Surgery High Content Screening and Functional Genomics of the Nervous System Our laboratory has developed methods to test thousands of genes or chemicals in hundreds of thousands of neurons each week and obtain quantitative information about cell morphology and gene expression. This “high throughput” capability allows us to tackle questions about development and regeneration using systems biology approaches. The Lemmon-Bixby lab has several ongoing projects related to axon regeneration. One project is based on the observation that young CNS neurons have a greater regenerative capacity than old CNS neurons (collaboration with Dr. Jeff Goldberg). We have identifi ed a family of developmentally regulated transcription factors (proteins that bind DNA and turn on or off scores of genes) that is very important in axon regeneration. Another project is to test the roles of known signaling proteins called kinases. In this screen we have tested hundreds of kinases by overexpression and have also tested a few hundred kinase inhibitors, many of which strongly promote neurite growth in vitro. The data from this screen are allowing us to begin to build models of neuronal signaling networks underlying axon regeneration. A third project is based on the observation that peripheral sensory neurons initiate a genetic program appropriate for axonal regeneration after injury. Our laboratory is combining next-generation sequencing with cell-based phenotypic screening to identify genes and microRNAs that are part of this genetic program.

The Project 25 Faculty Profiles

M. ROSS BULLOCK, M.D., PH.D. Professor, Department of Neurological Surgery Director, Clinical Neurotrauma Preclinical Mechanistic and Neuroprotection Research in Traumatic Brain Injury (TBI) and Clinical Trials, and Neuromonitoring Techniques in the Injured Brain We have recently obtained two year funding from the Department of Defense to evaluate the neuroprotective effect of Perfl uorocarbons in four rodent models of TBI (penetrating brain injury, closed TBI with secondary hypoxia, tissue culture with stretch injury, and mechanistic and safety studies). These oxygen carriers have shown benefi t in previous studies involving fl uid percussion injury and subdural hematoma models. We are also evaluating hypothermia neuroprotection, in humans and animals, using novel biomarkers as surrogate indicators of possible benefi t.

DIANA CARDENAS, M.D., M.H.A. Professor and Chair, Department of Rehabilitation Medicine Chief of Service & Medical Director, Department of Rehabilitation Medicine Pain Interventions and Prevention of Urinary Tract Infections The goals of my research are to help fi nd therapeutic interventions that improve recovery, reduce secondary conditions, and create a better life for persons with SCI and other conditions that impair physical or cognitive function. Currently, my research focus is in the areas of neuropathic pain and neurogenic bladder management.

EDELLE C. FIELD-FOTE, PH.D., P.T. Professor, Departments of Physical Therapy and Neurological Surgery Motor Restoration after Spinal Cord Injury The studies in the Neuromotor Rehabilitation Research Laboratory cross the boundaries of basic neurophysiology and neurorehabilitation. We apply principles of neuroplasticity and motor learning to understand how interventions can be optimized and combined to promote best recovery of functio n. Some of our rehabilitation studies focus on recovery of hand and arm function, while others are aimed at walking function.

ROBERT W. KEANE, PH.D. Professor, Department of Physiology & Biophysics Regulation of Innate Immunity after CNS Trauma Innate immunity is the fi rst line of defense against pathogens and host-derived signals of cellular stress. My research focuses on investigating mechanisms that direct normal innate immunity and its dysregulation in CNS injury and disease, including (1) agonists and activation mechanisms of infl ammasomes, (2) regulatory mechanisms that potentiate or limit infl ammasome activation after injury, and (3) emerging links between innate immunity and Alzheimer’s disease.

26 The Project Faculty Profiles

ALLAN D. LEVI, M.D., PH.D., F.A.C.S.Professor, Departments of Neurological Surgery, Orthopedics, and Rehabilitation Medicine Chief of Neurospine Service, Jackson Memorial Hospital/Chief of Neurosurgery, University of Miami Hospital Cellular Transplantation Strategies after SCI/Systemic Hypothermia after Acute SCI My clinical research interests currently focus on developing cellular transplantation strategies to repair injuries within both the human CNS and PNS. I am Co-PI on our autologous human Schwann cells (ahSC) trial, which represents a fi rst-in-man dose escalation study of ahSC for individuals with sub-acute thoracic SCI. Hypothermia continues to show promise in a variety of acute CNS injuries. There are various factors that need to be considered with systemic cooling of the SCI patient, including methods of cooling, window from injury to initiation, duration and depth of hypothermia, rate of re-warming, etc. I am the PI of our trial studying systemic hypothermia induced via an intravascular catheter and continued for 48 hours after acute cervical SCI.

DANIEL J. LIEBL, PH.D. Professor, Department of Neurological Surgery Director, Neuroscience Graduate Program Molecular Mechanisms that Regulate Cellular Dysfunction and Death Following CNS Injury, and Mechanisms to Promote Regeneration and Recovery The goal of my laboratory is to identify the mechanisms that lead to CNS pathophysiology and its regenerative potential. We focus on a family of molecules, called eprhins and Eph receptors, which play important roles in the developing, regenerating, and injured nervous systems. Specifi cally, we are interested in areas of adult neurogenesis, neuroprotection, apoptotic cell death, synaptic plasticity, regeneration, and therapeutic strategies. Overall, our approach is to develop novel strategies to minimize CNS damage and maximize regeneration/tissue repair, which can be best achieved through a comprehensive mechanistic approach.

MARK S. NASH, PH.D., F.A.C.S.M. Professor, Departments of Neurological Surgery, Rehabilitation Medicine, and Kinesiology & Sports Sciences Physiological Assessment of Secondary Complications Following SCI: Electrical Stimulation, Cardiometabolic & Vascular Physiology, Cardioendocrine Pathology, and Exercise & Dietary Biochemistry One of the enduring goals of The Miami Project has been to test and then translate strategies that optimize health of persons with SCI. A signifi cant target for this strategy has focused on physical activity to lessen secondary risks of SCI associated with physical deconditioning. We also examine complementary themes to validate exercise prescription after SCI, identify optimal dietary composition, and use of prescription and non-prescription agents that reduce hazards of fasting and postprandial lipid disorders, dysglycemia, and vascular infl ammatory stress.

JACQUELINE SAGEN, PH.D., M.B.A. Professor, Department of Neurological Surgery Cellular Implants for the Alleviation of Chronic Pain and CNS Injury Our laboratory explores novel and more effective strategies in the therapeutic management of chronic pain. Our recent research is focused on (1) identifi cation of more effective analgesic agents and combinations for alleviating pain using SCI models and (2) development of emerging therapeutic interventions, including cell transplantation and gene therapy, which have the potential to provide long-term alleviation in people with intractable pain, overcoming the need for repeated pharmacologic administration.

The Project 27 Faculty Profiles

CHRISTINE K. THOMAS, PH.D. Professor, Department of Neurological Surgery Neuromuscular Weakness, Fatigue, Spasms, and Regeneration Our laboratory is currently asking two main questions regarding SCI. First, in studies on people with SCI, we want to understand how well involuntary contractions of paralyzed muscles (spasms) are managed by exercise or by taking baclofen, a drug that is commonly used to control spasticity. Second, in our animal studies, we are exploring how to replace neurons that die because of SCI. Neuron death is common at the injury site and results in severe muscle weakness.

GILLIAN A. HOTZ, PH.D. Research Professor, Department of Neurological Surgery Director, KiDZ Neuroscience Center Director, Concussion, WalkSafeTM & BikeSafeTMPrograms Neurocognitive Defi cits and Injury Prevention As a behavioral neuroscientist my clinical interests have always been investigating the neurocognitive defi cits of those individuals that have sustained a traumatic and acquired brain injury. I have co-authored two neurocognitive tests, The Brief Test of Head Injury for adults and the Pediatric Test of Brain Injury for children. My research has also focused on injury prevention, preventing brain and spinal cord injuries in children, and I have developed the WalkSafe program, which has been shown to decrease the number of elementary school age children that get hit by cars, and now the BikeSafe program to educate middle school age children on bicycle safety skills. As the Director of the Concussion Program we have a comprehensive countywide concussion care program including neurologic evaluation, neuroimaging, neuropharmacological management, and neuropsychological testing using ImPACT, a computerized neurocognitive screening measure.

PATRICK M. WOOD, PH.D. Research Professor, Department of Neurological Surgery Changes in the Molecular and Biological Properties of Human Schwann Cells Schwann cells have shown promise in animal studies in promoting recovery from SCI. We have developed protocols that allow the generation, from a small biopsy of human peripheral nerve, of large numbers of a person’s own Schwann cells that can be transplanted back into their injured spinal cord. Effi cient growth of human Schwann cells in culture requires the addition of recombinant neuregulin and the cAMP enhancer forskolin. To better understand the effects of these reagents on Schwann cells, we are performing basic research to determine the mechanisms by which neuregulin and cAMP enhancers promote interaction between axons and Schwann cells, including axon-induced proliferation and the formation of myelin sheaths.

HELEN M. BRAMLETT, PH.D. Associate Professor, Department of Neurological Surgery The Pathophysiology and Treatment of CNS Injury The focus of my neurotrauma laboratory is to investigate both acute and long-term consequences of brain and spinal cord trauma. My current research interests are on the pathophysiology of TBI and SCI with an emphasis on the pathogenesis of progressive white matter damage as well as the benefi ts of therapeutic hypothermia. My laboratory is also investigating mechanistic events leading to the development of posttraumatic epilepsy. Additionally, my current work is also focusing on complex traumatic brain injury models that mimic polytrauma as this type of injury has become more prevalent in combat areas.

28 The Project Faculty Profiles

JAMES D. GUEST, M.D., PH.D., F.A.C.S., F.R.C.S.(C) Associate Professor, Department of Neurological Surgery Translation Studies in Cellular, Molecular, and Electrical Stimulation Strategies to Achieve Neurological Recovery After Acute and Chronic SCI The central aim of our group is to achieve translation of therapeutic studies from animal models to early stage human trials. To this end we use some large animal models to increase the relevance of the pre-clinical testing to address key questions of effi cacy and safety. The emphasis is on conducting testing of therapeutics to emulate human application as fully as possible. We design devices to deliver cells and therapeutics in a minimally injurious manner. Currently, we are testing the transplantation of autologous Schwann cells and skin-derived precursor cells to repair tracts of the injured spinal cord. In addition we are testing the combination of cell transplantation, intensive rehabilitation, and epidural electrical stimulation for safety and effi cacy.

DAMIEN D. PEARSE, PH.D. Associate Professor, Department of Neurological Surgery Exploration and Translation of Therapeutic Strategies to Repair the Injured Spinal Cord and Brain My laboratory focuses on several key aspects of CNS injury repair, including (1) the utility and clinical translation of exogenous and endogenously harnessed cell therapeutics (particularly when used in combinatory approaches), (2) understanding the role of, and developing therapies for, altered cyclic AMP (adenylyl cyclase, phosphodiesterases, and PKA) and MAPK signaling in neurons and glia after CNS injury, (3) the use of nanotherapeutics for multifunctional and site- directed gene/drug targeting to the injured CNS, and (4) the application of methodologies for improved imaging of axonal regeneration and cell integration within the injured CNS such as 3D ultramicroscopy and diffusion tensor imaging.

JUSTIN C. SANCHEZ, PH.D. Associate Professor, Department of Biomedical Engineering Director, Neuroprosthetics Research Group Neuroprosthetics and Neural Engineering The goals of my research are to develop brain-machine interfaces (BMI) to restore communication and movement control to people with neurological impairments. The approach is to use technology to directly interact with the central and peripheral nervous system, interpret the internal coding of brain activity for intent, and send commands to bionic devices to trigger movements. The laboratory uses electrophysiological and neural computational tools to seamlessly interface these devices with the nervous system. I am interested in developing combined therapies (technology with rehabilitation and repair) to personalize therapeutic approaches for people living with disabilities.

PANTELIS TSOULFAS, M.D. Associate Professor, Departments of Neurological Surgery and Cell Biology & Anatomy Neurotrophins: Specifi city of Action My laboratory is interested in two areas of neurobiology that are signifi cant for developing new strategies for spinal cord injury repair. Over the past years, we have worked to modify neurotrophins that are better suited for use in SCI. We are also interested in understanding the processes involved in maintaining and differentiating neural stem cells.

The Project 29 Faculty Profiles

MICHAEL Y. WANG, M.D., F.A.C.S. Associate Professor, Departments of Neurological Surgery and Rehabilitation Medicine Spinal Cord Injury Outcomes My primary research has been in the investigation of SCI Outcomes. I work with Miami Project researchers Drs. Allan Levi and Barth Green in studying the clinical effects of Hypothermia. Currently, a multi-center randomized, prospective study on the effects of hypothermia in SCI is planned. In addition, I am studying the clinical application of SCI biomarkers to predict the effects of both injuries as well as therapeutic interventions with Drs. Dalton Dietrich and Ross Bullock.

KIM ANDERSON-ERISMAN, PH.D. Research Associate Professor, Department of Neurological Surgery Director of Education Translational Investigations for Chronic SCI My research focuses on translational investigations and bridging the gap between basic science, clinical science, and the public community living with SCI. I recently completed a multi-center clinical study evaluating the reliability and validity of the Spinal Cord Independence Measure in the US healthcare setting. My current projects focus on 1) aging related changes in bladder health after SCI and 2) determining the minimum amount of exercise and locomotor training required for clinical trials targeting chronic SCI.

NANCY L. BRACKETT, PH.D., H.C.L.D. Research Associate Professor, Departments of Neurological Surgery and Urology Male Fertility following SCI Our research is focused on understanding and improving impairments to male fertility which occur following SCI. A major aim is to determine the cause of impaired semen quality in men with SCI. Our recent evidence indicates that the problem is related to the seminal plasma. Our current research is investigating infl ammatory factors, including semen cytokine levels, as contributors to the problem. Our ultimate goal is to develop therapies to normalize semen quality in men with SCI, so that chances of biological fatherhood are increased.

IAN D. HENTALL, PH.D. Research Associate Professor, Department of Neurological Surgery Brainstem Infl uences on Neurotrauma Our research is centered on the general idea that serotonin-containing brainstem neurons infl uence natural repair processes following brain or spinal cord injury. We study in rats how these brainstem (raphé) neurons respond during injury, how raphé activity infl uences restorative molecular mechanisms in damaged regions, and how recovery from SCI or TBI is improved by prolonged electrical stimulation of these nuclei or of their input areas. The procedure of deep brain stimulation has potential for treating early of chronic injury in man.

30 The Project Faculty Profiles

ALBERTO MARTINEZ-ARIZALA, M.D. Clinical Associate Professor, Departments of Neurology, Neurological Surgery, and Orthopaedics & Rehabilitation Pathophysiology and Treatment of Secondary Complications in SCI My research interests focus on common complications that are seen following SCI: pain, spasticity, syringomyelia, and tethered cord syndrome. My interests include investigating the basis for the development of the different spasticity and pain profi les in the spinal cord injured population and to study potential novel treatments for those conditions.

BRIAN R. NOGA, PH.D. Research Associate Professor, Department of Neurological Surgery Brain and Spinal Mechanisms Controlling Walking Our long-term goal is to develop and optimize treatments for SCI based on transmitter enhancement strategies that include deep brain stimulation, delivery of neurotransmitters or similarly acting drugs, or transplantation of cells secreting these substances. Of the many possible neurotransmitter candidates that could be used for this purpose, monoamines hold particular promise. We have concentrated our recent research effort on understanding the role monoamines play in the control of walking in normal and injured spinal cord.

EVA WIDERSTRÖM-NOGA, D.D.S., PH.D. Research Associate Professor, Departments of Neurological Surgery, Rehabilitation Medicine, Neuroscience Program, and Health Scientist Veterans Affairs SCI-related Neuropathic Pain Phenotypes and Biomarkers My research program is focused on the identifi cation of clinical correlates of underlying mechanisms of neuropathic pain associated with neurological trauma in order to facilitate the translation of basic research fi ndings into treatments tailored to specifi c mechanisms. We are also examining the personal experiences of people living with chronic pain and SCI. My research program is highly collaborative and includes extensive interdisciplinary protocols for a multimodal evaluation of pain symptoms and its psychosocial impact, quantitative assessment of neurological function, and biomarkers including non-invasive brain imaging and genetic polymorphism.

COLEEN ATKINS, PH.D. Assistant Professor, Department of Neurological Surgery Developing Novel Therapies for TBI and SCI The research in my laboratory focuses on developing novel therapeutic interventions for TBI and SCI. The research goal of my laboratory is to enhance rehabilitation and recovery by manipulating synaptic plasticity at specifi c levels of the neuroaxis following TBI and SCI. We have found that specifi c synaptic plasticity signaling pathways are altered after TBI and we are currently using pharmacotherapies to target those pathways to improve behavioral recovery after TBI.

The Project 31 Faculty Profiles

JAE K. LEE, PH.D. Assistant Professor, Department of Neurological Surgery Neutralizing Inhibitors of Axon Regeneration; Stimulating Plasticity The long term research goal in my laboratory is to elucidate the mechanisms of cellular interactions in the injured adult spinal cord that creates an environment inhibitory to axonal growth. Currently, we know which cells can produce what types of inhibitory molecules, but we need a better understanding of how these cells interact and the relative signifi cance of the different inhibitory molecules they produce in order to identify an effective therapeutic target to treat SCI and related neurological disorders.

HOWARD B. LEVENE, M.D., PH.D. Assistant Professor, Department of Neurological Surgery Schwann Cell Transplantation after SCI One proposed therapy for SCI is to introduce cells to the injury site to help repair, restore, or support existing neurons. My research focuses on a large animal model to study the effect and behavior of transplanted autologous Schwann cells. I have been involved in the refi nement of this animal model. This approach allows for the scientifi c study of the behavior of implanted cells and generates the groundwork for clinical trials. Research utilizing this model is done in collaboration with clinicians and scientists at the Miami Project such as Drs. Guest, Solano, Pearse, Wood, Bunge, and many more.

KEVIN K. PARK, PH.D. Assistant Professor, Department of Neurological Surgery Intrinsic Mechanisms of Axon Regeneration My lab is interested in understanding the neuron’s intrinsic mechanisms that account for failure of axon regeneration in the CNS. Previously, I and others have identifi ed several key proteins that block axon regeneration, which are present in mature CNS neurons. In my current research, I will further extend my fi ndings in order to better understand the mechanisms governing robust axon regeneration and also to explore the potential of developing therapeutic strategies for SCI and other neurodegenerative conditions.

ROBERTA BRAMBILLA, PH.D. Research Assistant Professor, Department of Neurological Surgery Modulation of the Immune Response in Neurologic Disease The main focus of my research has been to understand the role of neuroinfl ammation in the pathophysiology of neurodegenerative disorders (e.g., SCI and MS), with a specifi c interest in the contribution of the astrocytes, a type of glial cell that represents the most abundant cell population in the nervous system. Currently, my laboratory is developing two specifi c lines of research in the area of neuroimmunology, which focus on (1) investigating the role of tumor necrosis factor in the processes of demyelination and remyelination and (2) investigating the occurrence of neuropathic pain associated with MS.

32 The Project Faculty Profiles

RACHEL E. COWAN, PH.D. Research Assistant Professor, Department of Neurological Surgery Enhancement and Preservation of Maximal Transfer and Wheelchair Propulsion Ability Our fi rst focus is defi ning what levels of fi tness and ‘skill’ are required to independently perform transfers to and from the bed, car, shower, and ground and if these are different for various levels of SCI. Our second focus is defi ning how changes in fi tness and wheelchair confi guration can meaningfully reduce the effort required to propel a manual wheelchair and how these changes may differ by level of SCI.

JUAN PABLO DE RIVERO VACCARI, PH.D. Research Assistant Professor, Department of Neurological Surgery Underlying Mechanisms of the Innate Immune Response and Contributions to Various CNS Diseases My research focuses on understanding early infl ammatory events in CNS trauma and neurodegenerative diseases. Currently, my laboratory is focusing on the effects of pattern recognition receptor (PRR)-activation after SCI and neurodegenerative diseases such as Alzheimer’s disease.

PAULA V. MONJE, PH.D. Research Assistant Professor, Department of Neurological Surgery Molecular Signals Controlling Schwann Cell Proliferation and Differentiation In Vitro Methods to Enhance the Schwann Cell’s Potency for CNS Repair My laboratory studies basic aspects of Schwann cell biology and their use in transplantation for CNS regeneration. Specifi cally, we are investigating the role of cAMP and growth factors in the reciprocal interactions between Schwann cells and neurons underlying the regulation of Schwann cell proliferation and myelination, as well as the initiation of Schwann cell dedifferentiation after injury. Our lab works intensively towards refi ning the use and developing new cell culture methods for the growth and assessment of function of both human and rodent Schwann cells. One important goal is to improve the quality of cultured adult Schwann cells for an intended use in clinical trials.

The Project 33 Gail F. Beach Memorial Lecture Series

Gail F. Beach Memorial Lecture Series

he Miami Project has brought many renowned neuroscientists from around the world to our campus as part of TThe Gail F. Beach Memorial Visiting Lectureship Series. The lectureship series is dedicated to Gail F. Beach, a schoolteacher and person with SCI, whose generosity and foresight provides outstanding educational opportunities for The Miami Project researchers and our neuroscience colleagues at the University of Miami.

January 9, 2013 September 5, 2012 Dwight E. Bergles, PhD Randall T. Moon, PhD The Johns Hopkins University - Baltimore, MD University of Washington School of Medicine - Seattle, WA “Regenerative Capabilities of Oligodendrocyte Progenitors “Wnt/beta Catenin Signaling in Acute Injury and Chronic in the Adult CNS” Disease”

November 7, 2012 Leigh R. Hochberg, MD, PhD Brown University - Providence, RI “Intracortically-Based Brain-Computer Interfaces: Turning Thought into Action”

Dr. Dwight Bergles with host Dr. Roberta Brambilla.

February 13, 2012 William David Richardson, PhD, FLS, FMedSci University of London – United Kingdom “Myelin Dynamics in Healthy Adult Mice”

Dr. Leigh Hochberg with Dr. Justin Sanchez. March 6, 2013 Jeffrey Milbrandt, MD, PhD December 5, 2012 Washington University School of Medicine - St. Louis, David S. K. Magnuson, PhD Missouri University of Louisville – Louisville, KY “Demystifying Axonal Degeneration: New Therapeutic “Directing Spinal Cord Plasticity: Activity-Dependent Gain Targets Provide Hope for Peripheral Neuropathy” and Loss of Locomotor Function after Injury” April 3, 2013 Bruce D. Trapp, PhD The Cleveland Clinic Foundation - Cleveland, Ohio “Pathogenesis of Neurological Disability in Multiple Sclerosis”

May 1, 2013 Hongjun Song, PhD Johns Hopkins University School of Medicine - Baltimore, MD “Circuit Mechanisms Regulating Adult Neural Stem Cells Dr. Mark Nash with guest lecturer Dr. David Magnuson. and Neurogenesis”

34 The Project New Faculty

New Faculty – Rachel E. Cowan, Ph.D.

he Miami Project is proud to have a new junior faculty member join our team in 2012, Dr. Rachel Cowan. Dr. Cowan’s Tcurrent research focus is on enhancement and preservation of maximal transfer and wheelchair propulsion ability in individuals with spinal cord injury (SCI). Her training has centered on understanding and infl uencing human performance. At the University of North Carolina Wilmington she earned a Bachelor’s degree in physical education with an emphasis on athletic training rather than the typical emphasis on teaching. She then went on to obtain her Master’s degree at Wake Forest University focused on learning how to use exercise and fi tness to delay or reverse effects of chronic disease in people over the age of fi fty. From there she moved up to Pennsylvania and got her PhD in rehabilitation science and technology focusing on wheelchair biomechanics in people with SCI at the University of Pittsburgh . Dr. Cowan came to The Miami Project in 2008 to complete a post-doctoral fellowship in our applied physiology lab studying fi tness levels in people with different levels of SCI.

Dr. Rachel Cowan instructing Frank Diaz on using the wheelchair treadmill.

Aside from her formal training, she also “dabbles” in computer programming. She is highly skilled in a program called MATLAB, which is a platform for writing custom solutions for data collection, data extraction, and data analysis. This is very important for large data sets with several confounding variables that could potentially infl uence outcome. Furthermore, Dr. Cowan is a blossoming statistics wiz! This is a great asset because she helps us consider new ways to design clinical studies, particularly because SCI has so much variability between people with the “same” injury.

What really drives Rachel Cowan though is the fact that she has a spinal cord injury herself. The reality of experiencing and living with an SCI cannot be taught in any books. The core of that drive centers around the frustrations associated with obtaining appropriate SCI healthcare, equipment, services, etc. that enable people with SCI to successfully resume life. Dr. Cowan funnels those frustrations into making a difference. To that end, her research tends to focus on providing evidence that will support changing policy. In effect, she tries to generate research that is useful immediately, for clinicians, individuals with SCI, other researchers, engineers, or companies, rather than many years down the road.

What you might not know about Dr. Cowan is that she is an avid snow skier! Her outlook on life is to explore and try new things. This ranges from sports to foods to locations. For several years after her SCI she was terrifi ed of traveling on her own because of her SCI, but now has it down to a science after some tough love in graduate school! Welcome, Dr. Cowan, to The Miami Project faculty!

TheThe ProjectProject 35 Active Clinical The Miami Project clinical researchers currently have 17 research Studies and Trials studies available for people who have had a spinal cord injury for at least 1 year. They are investigating questions regarding exercise science, rehabilitation training, pain, male fertility, spasticity, sleep problems, and neuroprosthetics.

The Miami Project also has 13 clinical trials ongoing or in the planning stages to test interventional repair or neuroprotective strategies for spinal cord injury or traumatic brain injury. It has never been a more exciting time!

Clinical Studies

Clinical Trials

36 The Project Scientific Publications Scientifi c Published studies that Publications have passed the test of peer review are the benchmark of scientifi c progress. Listed here are the 2012 research publications by Miami Project scientists and colleagues.

Aarabi B, Harrop JS, Tator CH, Alexander M, Dettori JR, Benglis DM, Trimble B, Bullock R (2012) Past, Present, and Future Grossman RG, Fehlings MG, Mirvis SE, Shanmuganathan K, Developments of Intracranial Monitoring in Traumatic Brain Injury. Zacherl KM, Burau KD, Frankowski RF, Toups E, Shaffrey CI, In, Le Roux, Levine, Kofke (eds). Neurocritical care. Blackwell. Guest JD, Harkema SJ, Habashi NM, Andrews P, Johnson MM, Rosner MK (2012) Predictors of Pulmonary Complications in Berrocal YA, Almeida, VW, Gupta R, Levi AD (In press) Blunt Traumatic Spinal Cord Injury. J Neurosurg Spine. 17(1 Transplantation of Autologous Schwann Cells Within a NeuraGen Suppl):38-45. Tube for the Repair of Large Segmental Peripheral Nerve Defects. J Neurosurg. Adamczak S, Dale G, de Rivero Vaccari JP, Bullock MR, Dietrich WD, Keane RW (2012) Infl ammasome Proteins in Cerebrospinal Bigford GE, Bracchi-Ricard VC, Nash MS, Bethea JR (2012) Fluid of Brain-Injured Patients as Biomarkers of Functional Alterations in Mouse Hypothalamic Adipokine Gene Expression Outcome. J Neurosurg. 117(6):1119-1125. and Leptin Signaling Following Chronic Spinal Cord Injury and With Advanced Age. PLoS One. 7(7):e41073. Adelson PD, Pineda J, Bell MJ, Abend NS, Berger RP, Giza CC, Hotz G, Wainwright MS; Pediatric TBI Demographics and Clinical Bigford GE, Chaudhry NS, Keane RW Holohean AM (2012) Assessment Working Group (2012) Common Data Elements for 5-Hydroxytryptamine 5HT2C Receptors Form a Protein Complex Pediatric Traumatic Brain Injury: Recommendations From the with N-methyl-D-aspartate GluN2A Subunits and Activate Working Group on Demographics and Clinical Assessment. J Phosphorylation of Src Protein to Modulate Motoneuronal Neurotrauma. 29(4):639-653. Depolarization. J Bio Chem. 287(14):11049-11059. Ahmad FU, Bullock MR (2012) Chronic Subdural Hematomas: Blackmore MG, Wang Z, Lerch JK, Motti D, Zhang YP, Shields CB, Current Treatment. World Neurosurg. 77(1):49-50. Lee JK, Goldberg JL, Lemmon VP, Bixby JL (2012) Krüppel-like Factor 7 Engineered for Transcriptional Activation Promotes Axon Ahmad FU, Madhavan K, Trombly R, Levi AD (2012) Anterior Regeneration in the Adult Corticospinal Tract. Proc Natl Acad Sci. Thigh Compartment Syndrome and Local Myonecrosis After 109(19):7517-7522. Posterior Spine Surgery on a Jackson Table. World Neurosurg. 78(5):553.e5-8. Boninger ML, Cowan RE (2012) Why Do We Need Improved Mo- Ahmad F, Sherman JD, Wang MY (2012) Percutaneous Trans- bility Technology? J Neuroeng Rehabil. 9:16. Facet Screws for Supplemental Posterior Cervical Fixation. World Neurosurg. 78(6):716.e1-4. Boninger ML, Cowan RE, Fregly BJ (2012) Structures Promoting Research, Training, and Technology Transfer in Mobility: Lessons Ahmad FU, Wang MY, Levi AD (In press) Hypothermia for Learned from a Visit to European Centers. J Neuroeng Rehabil. Acute Spinal Cord Injury – A review – Invited Submission. World 9:19. Neurosurg. Brambilla R, Couch Y, Lambertsen KL (In press) The Effect of Atkins CM, Cepero ML, Kang Y, Liebl DJ, Dietrich WD (In Stroke on Immune Function. Mol Cell Neurosci. press) Effects of Early Rolipram Treatment on Histopathological Outcome After Controlled Cortical Impact Injury in Mice. Neurosci Brambilla R, Dvoriantchikova G, Barakat D, Ivanov D, Bethea JR, Lett. Shestopalov VI (2012) Transgenic Inhibition of Astroglial NF-kB Protects From Optic Nerve Damage and Retinal Ganglion Cell Atkins CM, Kang Y, Furones C, Truettner JS, Alonso OF, Dietrich Loss in Experimental Optic Neuritis. J Neuroinfl ammation. 9:213. WD (2012) Post-injury Treatment with Rolipram Increases Hemorrhage a fter Traumatic Brain Injury. J Neurosci Res. 90(9):1861-71.

The Project 37 Scientific Publications

Bramlett HM, Dietrich WD (2012) The Effects of Posttraumatic Carballosa Gonzalez MM, Blaya MO, Alonso OF, Bramlett HM Hypothermia on Diffuse Axonal Injury Following Parasagittal Fluid PH D, Hentall ID (In press) Midbrain Raphe Stimulation Improves Percussion Brain Injury in Rats. Ther Hypo Temp Man. 2:14-23. Behavioral and Anatomical Recovery from Fluid-Percussion Brain Injury. J Neurotrauma. Bregy A, Nixon R, Lotocki G, Alonso OF, Atkins CM, Tsoulfas P, Bramlett HM, Dietrich WD (2012) Posttraumatic Hypothermia Celigoj FA, Ibrahim E, Aballa TC, Lynne CM, Brackett NL (2012) Increases Doublecortin Expressing Neurons in the Dentate Gyrus Semen Quality in Men who Sustained a Spinal Cord Injury During after Traumatic Brain Injury in the Rat. Exp Neurol. 233(2):821-8. the Prepubertal Period. J Urol. 188(2):521-525. Brophy G, Gillman C, Bullock R (In press) Pharmacokinetics of Cyclosporin A in Adults with Traumatic Brain Injury. Pharmacology. Cowan RE, Callahan MK, Nash MS (2012) The 6-Min Push Test is Reliable and Predicts Low Fitness in Spinal Cord Injury. Med Sci Bryce TN, Biering-Sørensen F, Finnerup NB, Cardenas DD, Sports Exerc. 44(10):1993-2000. Defrin R, Ivan E, Lundeberg T, Norrbrink C, Richards JS, Siddall P, Stripling T, Treede RD, Waxman SG, Widerström-Noga E, Cowan RE, Fregly BJ, Boninger ML, Chan L, Rodgers MM, Re- Yezierski RP, Dijkers M (2012) International Spinal Cord Injury inkensmeyer DJ (2012) Recent Trends in Assistive Technology for Pain Classifi cation: Part 1. Background and Description. March Mobility. J Neuroeng Rehabil. 9:20. 6-7, 2009. Spinal Cord. 50(6):413-417. Cowan RE, Ginnity KL, Kressler J, Nash MS (2012) Assessment Bryce TN, Biering-Sørensen F, Finnerup NB, Cardenas DD, of the Talk Test and Rating of Perceived Exertion for Exercise In- Defrin R, Ivan E, Lundeberg T, Norrbrink C, Richards JS, Siddall tensity Prescription in Persons With Paraplegia. Top Spinal Cord P, Stripling T, Treede RD, Waxman SG, Widerström-Noga E, Inj Rehabil. 18(3):212–219. Yezierski RP, Dijkers M (2012) International Spinal Cord Injury Pain (ISCIP) Classifi cation: Part 2. Initial Validation Using Cowan RE, Nash MS, Anderson KD (In press) Exercise Participa- Vignettes. Spinal Cord. 50(6):404-412. tion Barrier Prevalence and Association with Exercise Participa- tion Status in Individuals with Spinal Cord Injury. Spinal Cord. Buchser W, Collins M, Garyantes T, Guha R, Haney S, Lemmon V, Li Z, Trask OJ (2012) Assay Guidance Manual: Cowan RE, Nash MS, Anderson KD (2012) Perceived Exercise Assay Development Guidelines for Image-Based High Content Barriers and Odds of Exercise Participation Among Persons Screening, High Content Analysis and High Content Imaging. With SCI Living in High-Income Households. Top Spinal Cord Inj Eli Lilly & Company and the National Center for Advancing Rehabil 18(2):126–127. Translational Sciences. PMID: 22553861 http://www.ncbi.nlm.nih. gov/books/NBK53196/ Cruz-Almeida Y, Felix ER, Martinez-Arizala A, Widerström-Noga EG (2012) Decreased Spinothalamic and Dorsal Column Medial Buchser WJ, Smith RP, Pardinas JR, Haddox CL, Hutson T, Moon Lemniscus-Mediated Function is Associated with Neuropathic L, Hoffman SR, Bixby JL, Lemmon VP (2012) Peripheral Nervous Pain After Spinal Cord Injury. J Neurotrauma. 20;29(17):2706-15. System Genes Expressed in Central Neurons Induce Growth on Inhibitory Substrates. PLoS One. 7(6):e38101. Dahl G, Keane RW (2012) Pannexin: From Discovery to Bedside in 11±4 Years? Brain Res. 1487:150-159. Bullock MR (2012) Editorial: Neurosurgical Presence. J De Rivero Vaccari JP, Sawaya ME, Brand F 3rd, Nusbaum Neurosurg. 117(3):597-598; discussion 598. BP, Bauman AJ Bramlett HM, Dietrich WD, Keane RW (2012) Caspase-1 Level is Higher in the Scalp in Androgenetic Alopecia. Bunge MB, Pearse DD (2012) Response to the Report, “ A Re- Dermatol Surg. 38(7 Pt 1):1033-1039. Assessment of a Combinatiorial Treatment Involving Schwann Cell Transplants and Elevation of Cyclic AMP on Recovery of Dai J, Dala JS, Thakar S, Henkemeyer M, Lemmon VP, Harunaga Motor Function Following Thoracic Spinal Cord Injury in Rats” by JS, Schlatter MC, Buhusi M, Maness PF (2012) EphB Regulates Sharp et al. (this volume). Exp Neurol. 233(2):645-648. L1 Phosphorylation During Retinocollicular Mapping. Mol Cell Neurosci. 50(2):201-210. Bunge MB, Wood PM (2012) Realizing the Maximum Potential of Schwann Cells to Promote Recovery From Spinal Cord Injury. De Rivero Vaccari JP, Bastien D, Yurcisin G, Pineau I, Dietrich Handb Clin Neurol. 109:523-540. WD, De Koninck Y, Keane RW, Lacroix S (2012) P2X4 Receptors Infl uence Infl ammasome Activation After Spinal Cord Injury. J Burns PB, Kressler J, Nash MS (2012) Physiological Responses Neurosci. 32(9):3058-3066. to ‘Exergaming’ after Spinal Cord Injury. Top Spinal Cord Inj Rehabil. 18(4):331-339. De Rivero Vaccari JP, Minkiewicz J, Wang X, De Rivero Vaccari JC, German R, Marcillo AE, Dietrich WD, Keane RW (2012) Cahill KS, Levi AD, Cummock MD, Liao W, Wang MY (In press) A Astrogliosis Involves Activation of Retinoic Acid-Inducible Gene- Comparison of Acute Hospital Charges After Tubular versus Open Like Signaling in the Innate Immune Response After Spinal Cord Microdiskectomy. World Neurosurg. Injury. Glia. 60(3):414-421.

Cahill KS, Martinez JL, Wang MY, Vanni S, Levi AD (2012) De Rivero Vaccari JP, Sawaya ME, Brand F 3rd, Nusbaum Motor Nerve Injuries Following the Minimally Invasive Lateral BP, Bauman AJ Bramlett HM, Dietrich WD, Keane RW (2012) Transpsoas Approach. J Neurosurg Spine. 17(3):227-231. Caspase-1 Level is Higher in the Scalp in Androgenetic Alopecia. Dermatol Surg. 38(7 Pt 1):1033-1039. Cahill KS, Wang MY (In press) Airport Screening and Spinal Implants. World Neurosurg. Dididze M, Green BA, Dalton Dietrich W, Vanni S, Wang MY, Levi Cahill KS, Wang MY (2012) Cost Effectiveness of Lumbar Fusion AD (In press) Systemic Hypothermia in Acute Cervical Spinal Improves with Time. Neurosurgery. 70(2):N21 Cord Injury: A Case-Controlled Study. Spinal Cord.

Cahill KS, Wang MY (2012) Evaluating the Accuracy of Robotic Dietrich WD, Levi A, Green B (2012) ICU and Intra-Operative Assistance in Spine Surgery. Temperature Management. Therapeutic Hypothermia and Neurosurgery. 71(2):N20-21. Temperature Management. 2(1):2-5.

38 The Project Scientific Publications

Ditunno JF, Cardenas DD, Formal C, Dalal K (2012) Advances Ghosh M, Tuesta LM, Puentes R, Patel S, Melendez K, El in the Rehabilitation Management of Acute Spinal Cord Injury. Maarouf A, Rutishauser U, Pearse DD (2012) Extensive Cell Handb Clin Neurol. 109:181-195. Migration, Axon Regeneration, and Improved Function with Polysialic Acid-Modifi ed Schwann Cells After Spinal Injury. Glia. Eaton MJ, Berrocal Y, Wolfe SQ, Widerstrom-Noga E (2012) 60(6):979-992. Review of the History and Current Status of Cell-Transplant Approaches for the Management of Neuropathic Pain. Pain Res Groah SL, Nash MS, Ward EA, Libin A, Mendez AJ, Burns PA, Treat. 2012:263972. Elrod M, Hamm LF (2012) Cardiometabolic Risk Clustering in Spinal Cord Injury: Results of Exploratory Factor Analysis. J El Maarouf A, Moyo-Lee Yaw D, Lindhout T, Pearse DD, Cardiopul Rehabil Prev. 31(2):73–80. Wakarchuk W, Rutishauser U (2012) Enzymatic Engineering of Polysialic Acid on Cells in Vitro and in Vivo using a Purifi ed Grossman RG, Frankowski RF, Burau KD, Toups EG, Crommett Bacterial Polysialyltransferase. J Bio Chem. 287(39):32770- JW, Johnson MM, Fehlings MG, Tator CH, Shaffrey CI, Harkema 32779. SJ, Hodes JE, Aarabi B, Rosner MK, Guest JD, Harrop JS (2012) Incidence and Severity of Acute Complications After Spinal Cord Farhat HI, Hood B, Bullock MR (2012) A Tangential Gunshot Injury. J Neurosurg Spine. 17(1 Suppl):119-28. Wound to the Head: Case Report and Review of the Literature. J Emerg Med. 43(2):e111-114. Grumbles RM, Almeida VW,Casella GT, Wood PM, Hemstapat K, Thomas CK (2012) Motoneuron Replacement for Reinnervation Fehlings MG, Wilson JR, Frankowski RF, Toups EG, Aarabi of Skeletal Muscle in Adult Rats. J Neuropathol Exp B, Harrop JS, Shaffrey CI, Harkema SJ, Guest JD, Tator CH, Neurol.71(10):921-930. Burau KD, Johnson MW, Grossman RG (2012) Riluzole for the Treatment of Acute Traumatic Spinal Cord Injury: Rationale for Guest, J (2012) Towards Ttreating Spinal Cord Injury in ‘Patients’: and Design of the NACTN Phase I Clinical Trial. J Neurosurg One Step at a Time. Brain. 11:3202-3205. Spine. 17(1 Suppl):151-156. Guest J, Harrop J, Aarabi B, Grossman B, Fawcett J, Fehlings Fernandez, A,O’phelan,K, Bullock R (In press) Traumatic Brain M, Tator C (2012) Optimization of the Decision-Making Process Injury: Evidence Based Medicine, Diagnosis, Treatment and for the Selection of Therapeutics to Undergo Clinical Testing for Complications. In: Textbook on Neurocritical Care, 2nd Edition, Spinal Cord Injury in the North American Clinical Trials Network. J Springer. Neurosurgery Spine. 17(1):94-101. Field-Fote EE (2012) An Impact Factor for JNPT! J Neurol Phys Hama AT, Broadhead A, Lorrain DS, Sagen J (2012) The Ther. 36(4):157-158. Antinociceptive Effect of the Asthma Drug Ibudilast in Rat Models of Peripheral and Central Neuropathic Pain. J Neurotrauma. Field-Fote EE (2012) Measuring Up to Our Full Potential: 29(3):600-610. Physical Therapy at the EDGE of Best Clinical Practice. J Neurol Phys Ther. 36(3):113-114. Hama A, Sagen J (2012) Combination Drug Therapy for Pain following Chronic Spinal Cord Injury. Pain Res Treat. Field-Fote EC (2012) Refl ecting on the Future. J Neurol Phys 2012:840486. Ther. 36(1):1-2. Hama A, Sagen J (2012) Combinations of Intrathecal Gamma- Field-Fote E, Ness LL, Ionno M (2012) Vibration Elicits Amino-Butyrate Receptor Agonists and N-methyl-d-aspartate Involuntary, Step-Like Behavior in Individuals with Spinal Cord Receptor Antagonists in Rats with Neuropathic Spinal Cord Injury Injury. Neurorehabil Neural Repair. 26(7):861-869. Pain. Eur J Pharmacol. 15;683(1-3):101-108. Flora G, Joseph G, Patel S, Singh A, Bleicher D, Barakat DJ, Harrop J, Guest J (In press) Cell-Based Therapies for Spinal Louro J, Fenton S, Garg M, Bunge MB, Pearse DD (In press) Cord Injury: What Does the Neurosurgeon Need to Know? Combining Neurotrophin Transduced Schwann Cells and Neurosurgery Quarterly. Rolipram to Promote Functional Recovery from Spinal Cord Injury. Cell Transplant. Harrop JS, Hashimoto R, Norvell D, Raich A, Aarabi B, Grossman RG, Guest JD, Tator CH, Chapman J, Fehlings MG (2012) Fode M, Krogh-Jespersen S, Brackett NL, Ohl DA, Lynne Evaluation of Clinical Experience Using Cell-Based Therapies CM, Sønksen J (2012) Male Sexual Dysfunction and Infertility in Patients with Spinal Cord Injury: A Systematic Review. J Associated with Neurological Disorders. Asian J Androl. 14(1):61- Neurosurg Spine. 17(1 Suppl):230-246. 68. Hentall ID, Gonzalez MM (2012) Promotion of Recovery from Frenkel MB, Cahill KS, Javahary RJ, Zacur G, Green BA, Levi Thoracic Spinal Cord Contusion in Rats by Stimulation of AD (In press) Fusion Rates in Multi-Level Anterior Cervical Medullary Raphe Or its Midbrain Input. Neurorehabil Neural Discectomy with Allograft and Instrumentation With and Without Repair. 26(4):374-384. the Use of Recombinant Human Bone Morphogenetic Protein. J Neurosurg Spine. Hill CE, Brodak DM, Bunge MB (2012) Dissociated Predegenerated Peripheral Nerve Transplants for Spinal Cord Gámez Sazo RE, Maenaka K, Gu W, Wood PM, Bunge MB Injury Repair: A Comprehensive Assessment of Their Effects on (2012) Fabrication of Growth Factor- and Extracellular Matrix- Regeneration and Functional Recovery Compared to Schwann Loaded, Gelatin-Based Scaffolds and Their Biocompatibility Cell Transplants. J Neurotrauma. 29:2226-2243. with Schwann Cells and Dorsal Root Ganglia. Biomaterials. 33(33):8529-8539. Hosier H, Groah SL, Libin AV, Tinsley E, Burns P, Nash MS (2012) Cardiometabolic Risk Profi les in Pre- Versus Ghosh M, Gracia-Castillo D, Aguirre V, Golshani R, Atkins CM, Postmenopausal Women With Spinal Cord Injury: Preliminary Bramlett HM, Dietrich WD, Pearse DD (2012) Proinfl ammatory Findings. Top Spinal Cord Inj Rehabil. 18(4):322–322. Cytokine Regulation of Cyclic AMP-Phosphodiesterase 4 Signaling in Microglia In Vitro and Following CNS Injury. Glia. Hood BH, Smith JS, Hamilton DK, Dididze M, Shaffrey CL, Levi 60(12):1839-59. AD (In press) The Use of Allograft and Recombinant Human Bone Morphogenetic Protein for Instrumented Atlanto-Axial Fusions. World Neurosurgery.

The Project 39 Scientific Publications

Hotz G, Cohn SM, Russ WB (2012) Re: Annual Pediatric Kressler J, Cowan RE, Ginnity KL, Nash MS (2012) Subjective Pedestrian Education Does Not Improve Pedestrian Behavior. J Measures of Exercise Intensity to Gauge Substrate Partitioning in Trauma Acute Care Surg. 72(4):1118-1119. Persons With Paraplegia. Top Spinal Cord Inj Rehabil. 18(3):205– 211. Hotz GA, Moyenda ZB, Bitar J, Bitar M, Ford HR, Green BA, Andrews DM, Ginzburg E (2012) Developing a Trauma Critical Lee JK, Zheng B (2012) Role of Myelin-Associated Inhibitors in Care and Rehab Hospital in Haiti: A Year After the Earthquake. Axonal Repair After Spinal Cord Injury. Exp Neurol. 235(1):33-42. Am J Disaster Med. 7(4):273-279. Lee JW, Jergova S, Furmanski O, Gajavelli S, Sagen J (2012) Hu Y, Park KK, Yang L, Wei X, Yang Q, Cho KS, Thielen P, Lee Predifferentiated GABAergic Neural Precursor Transplants for AH, Cartoni R, Glimcher LH, Chen DF, He Z (2012) Differential Alleviation of Dysesthetic Central Pain Following Excitotoxic Spinal Effects of Unfolded Protein Response Pathways on Axon Injury- Cord Injury. Front Physiol.3:167. Induced Death of Retinal Ganglion Cells. Neuron. 73(3):445-452. Lerch JK, Bixby JL, Lemmon VP (2012) Isoform Diversity and its Hurtado A, Marcillo A, Frydel B, Bunge MB, Bramlett HM, Dietrich Importance for Axon Regeneration. Neuropathology. 32(4):420- WD (2012) Anti-CD11d Monoclonal Antibody Treatment for Rat 431. Spinal Cord Compression Injury. Exp Neurol. 233(2):606-611. Lerch JK, Kuo F, Motti D, Morris R, Bixby JL, Lemmon VP (2012) Iremashvili V, Brackett NL, Lynne, CM (2012) Impact of Spinal Isoform Diversity and Regulation in Peripheral and Central Neurons Cord Injury. In: Male Infertility. Contemporary Clinical Approaches, Revealed Through RNA-Seq. PLoS One. 7(1):e30417. Andrology, ART & Antioxicants. S Parekattil and A Agarwal (Eds), Springer, NY, 337-348. Levene HB, Wang MY, Green BA (2012) Spinal Cord Trauma. In: Manual of intensive care medicine 7th Edition. Irwin RS, Rippe JM, Iremashvili VV, Brackett NL, Ohl DA, Sonksen J, Lynne CM (In eds. Lippincott Williams & Wilkins. Boston, MA. press) Fertility Management in Spinal Cord Injury and Ejaculatory Dysfunction. In: Male Infertility Practice. B Rizk, N Aziz, A Agarwal, Li L, Park IM, Brockmeier A, Chen B, Seth S, Francis JT, Sanchez E Sabanegh (Eds.), Editions ESKA, Paris. JC, Principe JC (In press) Adaptive Inverse Control of Neural Spatiotemporal Spike Patterns With a Reproducing Kernel Hilbert Jagid J, Harris L, Bullock R (In press) Traumatic Intraparenchyma Space (RKHS) Framework. IEEE Trans Neural Syst Rehabil Eng. Hematoma-Lobectomy. In: Neurosurgical Tricks of the Trade. Elsevier. Li L, Park IM, Seth S, Sanchez JC, Principe JC (2012) Functional Connectivity Dynamics Among Cortical Neurons: A Dependence Jergova S, Hentall ID, Gajavelli S, Varghese MS, Sagen J (2012) Analysis. IEEE Trans Neural Syst Rehabil Eng. 20(1):18-30. Intraspinal Transplantation of GABAergic Neural Progenitors Attenuates Neuropathic Pain in Rats: A Pharmacologic and Neurophysiological Evaluation. Exp Neurol. 234(1):39-49. Lu Y, Wang MY (2012) Neural Stem Cell Grafts for Complete Spinal Cord Injury. Neurosurgery. 71(6):N13-5. Jo S, Kalló Bardóczi Z, Arrojo e Drigo R, Zeöld A, Liposits Z, Oliva A, Lemmon VP, Bixby JL, Gereben B, Bianco AC (2012) Luo X, Park KK (2012) Neuron-Intrinsic Inhibitors of Axon Neuronal Hypoxia Induces Hsp40-Mediated Nuclear Import of Regeneration: PTEN and SOCS3. Int Rev Neurobiol. 105:141-173. Type 3 Deiodinase as an Adaptive Mechanism to Reduce Cellular Metabolism. J Neurosci. 32(25):8491-8500. Madhavan, K, Benglis D, Wang M, Vanni S, Lebwohl N, Green BA, Levi AD (In press) The Use of Modest Systemic Hypothermia Johnstone AL, Reierson GW, Smith RP, Goldberg JL, Lemmon After Iatrogenic Spinal Cord Injury During Surgery. Therapeutic VP, Bixby JL (2012) A Chemical Genetic Approach Identifi es Hypothermia and Temperature Management. Piperazine Antipsychotics as Promoters of CNS Neurite Growth on Inhibitory Substrates. Mol Cell Neurosci. 50(2):125-135. Maggio DM, Chatzipanteli K, Masters N, Patel SP, Dietrich WD, Pearse DD (2012) Acute Molecular Perturbation of Inducible Nitric Kathiresan AS, Ibrahim E, Aballa TC, Attia GR, Lynne CM, Oxide Synthase with an Antisense Approach Enhances Neuronal Brackett NL (2012) Anejaculatory Infertility Due to Multiple Preservation and Functional Recovery After Contusive Spinal Cord Sclerosis. Andrologia. 44(Suppl 1):833-835. Injury. J Neurotrauma. 29(12):2244-2249. Kathiresan AS, Ibrahim E, Modh R, Aballa TC, Lynne CM, Maling N, Hashermiyoon R, Foote KD, Okun MS, Sanchez JC Brackett NL (2012) Semen Quality in Ejaculates Produced (2012) Increased Thalamic Gamma Band Activity Correlates with by Masturbation in Men with Spinal Cord Injury. Spinal Cord. Symptom Relief following Deep Brain Stimulation in Human with 50(12):891-894. Tourette’s Syndrome. PLoS One. 7(9):e44215. Khalessi AA, Zada G, Wang MY, Calland JF (2012) Introduction: Manzano GR, Casella G, Wang MY, Vanni S, Levi AD (2012) A Quality Process Improvement and the Neurosurgeon. Neurosurg Prospective Randomized Trial Comparing Expansile Cervical Focus. 33(5):Introduction. Laminoplasty and Cervical Laminectomy and Fusion for Multilevel Cervical Myelopathy. Neurosurgery. 70(2):264-277. Kishimoto T, Itoh K, Umekage M, Tonosaki M, Yao T, Fukui K, Lemmon VP, Fushiki S (In press) Downregulation of L1 Perturbs Manzano GR, Casella G, Wang M, Vanni, Levi AD (2012) Reply Neuronal Migration and Alters the Expression of Transcription to Editor – A Prospective Randomized Trial Comparing Expansile Factors in Murine Neocortex. J Neurosci Res. Cervical Laminoplasty and Cervical Laminectomy and Fusion for Multilevel Cervical Myelopathy. Neurosurgery. 71(2):E521-522. Kitagawa RS, Bullock MR (In press) Lessons From the DECRA Study. World Neurosurg. Marcillo A, Frydel B, Bramlett HM, Dietrich WD (2012) A Reassessment of P2X7 Receptor Inhibition as a Neuroprotective Kocsis JD, Bunge MB (In press) Transplantation of Schwann Strategy in Rat Models of Contusion Injury. Exp Neurol. 233(2):687- Cells and Olfactory Ensheathing Cells as a Therapeutic Strategy 692. in Spinal Cord Injury. In: Textbook of Neural Repair and Rehabilitation (Eds, ME Selzer et al.).

40 The Project Scientific Publications

Mawhinney LJ, de Rivero Vaccari JP, Alonso OF, Jimenez CA, Prasad A, Xue QS, Sankar V, Nishida T, Shaw G, Streit WJ, Furones C, Moreno WJ, Lewis MC, Dietrich WD, Bramlett HM Sanchez JC (2012) Comprehensive Characterization and Failure (2012) Isofl urane/Nitrous Oxide Anesthesia Induces Increases in Modes of Tungsten Microwire Arrays in Chronic Neural Implants. J NMDA Receptor Subunit NR2B Protein Expression in the Aged Neural Eng. 9(5):056015. Rat Brain. Brain Res. 1431:23-34. Rammo RA, DeFazio MV, Bullock MR (2012) Management of Max JE, Wilde EA, Bigler ED, Macleod M, Vasquez AC, Schmidt Migrating Intracranial Bullets: Lessons Learned from Surviving an AT, Chapman SB, Hotz G, Yang TT, Levin HS (2012) Psychiatric AK-47 Bullet Through the Lateral Brainstem. World Neurosurg. Disorders After Pediatric Traumatic Brain Injury: A Prospective, 77(3-4):591.e19-24. Longitudinal, Controlled Study. J Neuropsychiatry Clin Neurosci. 24(4):427-436. Reinkensmeyer DJ, Bonato P, Boninger ML, Chan L, Cowan RE, Fregly BJ, Rodgers MM (2012) Major Trends in Mobility Technology Max JE, Wilde EA, Bigler ED, Thompson WK, MacLeod M, Research and Development: Overview of the Results of the NSF- Vasquez AC, Merkley TL, Hunter JV, Chu ZD, Yallampalli R, WTEC European Study. J Neuroeng Rehabil. 9:22. Hotz G, Chapman SB, Yang TT, Levin HS (2012) Neuroimaging Correlates of Novel Psychiatric Disorders After Pediatric Saigal G, Quencer R, Guest JD, Cristescu MM, Lebwohl N (In Traumatic Brain Injury. J Am Acad Child Adolesc Psychiatry. press) Vertebral Body Osteolysis Following the Use of Bone 51(11):1208-1217. Morphogenetic Protein in Spinal Surgery: A Mimicker of Infection. J Neuroradiol. McMahon P, Dididze M, Levi AD (2012) Incidental Durotomy After Spinal Surgery: A Prospective Study in an Academic Institution. J Sakurai A, Atkins CM, Alonso OF, Bramlett HM, Dietrich WD Neurosurg Spine. 14(1):30-36. (2012) Mild Hyperthermia Worsens the Neuropathological Damage Associated with Mild Traumatic Brain Injury in Rats. J Neurotrauma. Morton PD, Johnstone JT, Ramos AY, Liebl DJ Bunge MB, Bethea 29(2):313-21. JR (2012) Nuclear Factor –ĸB Activation in Schwann Cells Regulates Regeneration and Remyelination. Glia. 60(4):639-650. Sanchez J, Lytton W, Carmena J, Principe J, Fortes J, Barbour R, Francis J (2012) Dynamically Repairing and Replacing Neural Motti D, Bixby JL, Lemmon VP (2012) MicroRNAs and Neuronal Networks: Using Hybrid Computational and Biological Tools. IEEE Development. Semin Fetal Neonatal Med. 17(6):347-352. Pulse. 3(1):57-9. Mummidisetty CK, Bohórquez J, Thomas CK (2012) Automatic Saraf Lavi E, Levi AD, Schallert E, Brown AD, Norenberg MD Analysis of EMG During Clonus. J Neuroscience Methods. 204(1): (2012) MRI of Intraneural Perineurioma of the Brachial Plexus. 35-43. Radiology Case Reports. 7(1):649. Nash MS, Cowan RE (2012) “Spinal Cord Injury.” Encyclopedia Schaal SM, Garg MS, Ghosh M, Lovera L, Lopez M, Patel M, of Lifestyle Medicine and Health. Ed. James M. Rippe, MD. Louro J, Patel S, Tuesta L, Chan WM, Pearse DD (2012) The Thousand Oaks, CA: SAGE, 2012. 2642-47. SAGE Reference Therapeutic Profi le of Rolipram, PDE Target and Mechanism of Online. Web. 29 Feb. 2012. Action as a Neuroprotectant Following Spinal Cord Injury. PLoS One. 7(9):e43634. Nash MS, Cowan RE, Kressler J (2012) Evidence-Based and Heuristic Approaches for Customization of Care in Slepak TI, Salay LD, Lemmon VP, Bixby JL (2012) Dyrk Cardiometabolic Syndrome After Spinal Cord Injury. J Spinal Cord Kinases Regulate Phosphorylation of Doublecortin, Cytoskeletal Med. 35(5):278-292. Organization, and Neuronal Morphology. Cytoskeleton (Hoboken). 69(7):514-527. Nelersa CM, Barreras H, Runko E, Richard J, Shi Y, Glass SJ, Bixby JL, Lemmon VP, Liebl DJ (2012) High-Content Analysis Sparrow N, Manetti ME, Bott M, Fabianac T, Petrilli A, Bates ML, of Proapoptotic EphA4 Dependence Receptor Functions Using Bunge MB, Lambert S, Fernandez-Valle C (2012) The Actin- Small-Molecule Libraries. J Biomol Screen. 17(6):785-795. Severing Protein Cofi lin is Downstream of Neuregulin Signaling and is Essential for Schwann Cell Myelination. J Neurosci. 32(15):5284- Ohl DA, Fode M, Brackett NL, Lynne CM, Sønksen J (In 5297. press) The Use of Ejaculation Induction Procedures in Cancer Patients. In: Preservation in Men with Cancer. J Mulhall (Ed.). Steeves JD, Lammertse DP, Kramer JL, Kleitman N, Kalsi-Ryan Cambridge University Press, Cambridge. S, Jones L, Curt A, Blight AR, Anderson KD (2012) Outcome Measures for Acute/Subacute Cervical Sensorimotor Complete Okun MS, Foote KD, Wu SS, Ward HE, Bowers D, Rodriguez (AIS-A) Spinal Cord Injury during a Phase 2 Clinical Trial. Top RL Malaty IA, Goodman WK, Gilbert DM, Walker HC, Mink JW, Spinal Cord Inj Rehabil. 18(1):1-14. Merritt S, Morishita T, Sanchez JC (2012) A Trial of Scheduled Deep Brain Stimulation for Tourette Syndrome: Moving Away Streit W, Xue QS, Prasad A, Sankar V, Knott E, Dyer A, Reynolds From Continuous Deep Brain Stimulation Paradigms. Arch Neurol. J, Nishida T, Shaw G, Sanchez J (2012) Electrode Failure: Tissue, 8:1-10. Electrical, and Material Responses. IEEE Pulse. 3(1):30-33. Tator CH, Hashimoto R, Raich A, Norvell D, Fehlings MG, Harrop Oliva AA Jr, Kang Y, Furones C, Alonso OF, Bruno O, Dietrich WD, JS, Guest J, Aarabi B, Grossman R. Translational Potential of Atkins CM (2012) Phosphodiesterase Isoform-Specifi c Expression Preclinical Trials of Neuroprotection through Pharmacotherapy for Induced by Traumatic Brain Injury. J Neurochem. 123: 1019-1029. Spinal Cord Injury. J Neurosurgery Spine. 17(1):157-229. Oliva AA Jr, Kang Y, Sanchez-Molano J, Furones C, Atkins Theus MH Richard J, Liebl DJ (2012) Reproducible Expansion CM (2012) STAT3 Signaling after Traumatic Brain Injury. J and Characterization of Mouse Neural Stem/Progenitor Cells in Neurochem. 120(5):710-20. Adherent Cultures Derived From the Adult Subventricular Zone. Curr Protoc Stem Cell Biol. Chapter 2 Unit 2D.8. Prasad A, Sanchez JC (2012) Quantifying Long-Term Microelectrode Array Functionality Using Chronic In Vivo Titus DJ, Furones C, Kang Y, Atkins CM (In press) Age-Dependent Impedance Testing. J Neural Eng. 9(2):026028. Alterations in cAMP Signaling Contribute to Synaptic Plasticity Defi cits Following Traumatic Brain Injury. Neuroscience.

The Project 41 Scientific Publications

Tomura S, de Rivero Vaccari JP, Keane RW Bramlett HM, Dietrich Widerström-Noga E, Pattany PM, Cruz-Almeida Y, Felix ER, WD (2012) Effects of Therapeutic Hypothermia on Infl ammasome Perez S, Cardenas DD, Martinez-Arizala A (In press) Metabolite Signaling After Traumatic Brain Injury. J Cereb Blood Flow Metab. Concentrations in the Anterior Cingulated Cortex Predict High 32(10):1939-1947. Neuropathic Pain Impact After Spinal Cord Injury. Pain. Tran MD, Furones-Alonso O, Sanchez-Molano J, Bramlett Williams RR, Bunge MB (2012) Schwann Cell Transplantation: A HM (2012) Trauma-Induced Expression of Astrocytic Repair Strategy for Spinal Cord Injury? Prog Brain Res. 201:295- Thrombospondin-1 is Regulated by P2 Receptors Coupled to 312. Protein Kinase Cascades. Neuroreport. 23(12):721-726. Williams RR, Pearse DD, Tresco PA, Bunge MB (2012) The Assessment of Adeno-Associated Vectors as Potential Intrinsic Vempati UD, Przydzial MJ, Chung C, Abeyruwan S, Mir A, Saku- Treatments for Brainstem Axon Regeneration. J Gene Med. rai K, Visser U, Lemmon VP, Schürer SC (2012) Formalization, 14(1):20-34. Annotation and Analysis of Diverse Drug and Probe Screening Assay Datasets Using the BioAssay Ontology (BAO). PLoS One. Wilson JR, Grossman RG, Frankowski RF, Kiss A, Davis AM, 7(11):e49198 Kulkarni AV, Harrop JS, Aarabi B, Vaccaro A, Tator CH, Dvorak M, Shaffrey CI, Harkema S, Guest JD, Fehlings MG (2012) A Wallace DM, Ross BH, Thomas CK (2012) Characteristics of Clinical Prediction Model for Long-Term Functional Outcome After Lower Extremity Clonus After Human Cervical Spinal Cord Injury. Traumatic Spinal Cord Injury Based on Acute Clinical and Imaging J Neurotrauma. 29(5):915-924. Factors. J Neurotrauma. 29(13):2263-2271. Wang MY (2012) Adrenal Insuffi ciency Following Spinal Cord Yokobori S, Gajavelli S, Mondello S, Mo-Seaney J, Bramlett Injury: An Underrecognized Cause of Hemodynamic Instability. HM, Dietrich WD, Bullock MR (In press) Neuroprotective Effect World Neurosurg. 78(3-4):252. of Preoperatively Induced Mild Hypothermia as Determined by Biomarkers and Histopathological Estimation in a Rat Subdural Wang MY (2012) Bone Morphogenic Protein Use in the “Off- Hematoma Decompression Model. J Neurosurg. Label” Setting: Is it Appropriate? World Neurosurg. 78(6):617. Zhang X, Ibrahim E, de Rivero Vaccari JP, Lotocki G, Aballa Wang MY (2012) Cervical Spine Injuries: How Much Imaging is TC, Dietrich WD, Keane RW, Lynne CM, Brackett NL (In press) Necessary? World Neurosurg. pii: S1878-8750(12)01211-9. Involvement of the Infl ammasome in Abnormal Semen Quality of Men with Spinal Cord Injury. Fertil Steril. Wang MY (In press) Improvement of Sagittal Balance and Lumbar Lordosis Following Less Iinvasive Adult Spinal Deformity Surgery Zhang Y, Liu J, Yao S, Li F, Xin L, Lai M, Bracchi-Ricard V, Xu H, with Expandable Cages and Percutaneous Instrumentation. J Yen W, Meng W, Liu S, Yang L, Karmally S, Liu J, Zhu H, Gordon Neurosurg Spine. J, Khalili K, Srinivasan S, Bethea JR, Mo X, Hu (2012) Nuclear Factor kappa B Signaling Initiates Early Differentiation of Neural Wang MY (2012) Metal-on-Metal Lumbar Total Disc Arthroplasty: Stem Cells. Stem Cells. 30(3):5010-5024. Ready for Prime Time? World Neurosurg. 78(3-4):247. Zijdewind I, Gant K, Bakels R, Thomas CK (2012) Do Additional Wang MY (2012) Navigation for Spinal Surgery: Why Hasn’t It Inputs Change Maximal Voluntary Motor Unit Firing Rates After Become the Accepted Standard? World Neurosurg. pii: S1878- Spinal Cord Injury? Neurorehabil Neural Repair. 26(1):58-67. 8750(12)01210-7. Zijdewind I, Thomas CK (2012) Firing Patterns of Spontaneously Wang MY (2012) Percutaneous Iliac Screws for Minimally Active Motor Units in Spinal Cord-Injured Subjects. J Physiol. Invasive Spinal Deformity Surgery. Minim Invasive Surg. 590(Pt 7): 1683-1697. 2012:173685. Wang MY, Lerner J, Lesko J, McGirt MJ (2012) Acute Hospital Costs After Minimally Invasive Versus Open Lumbar Interbody Fusion: Data From a US National Database With 6106 Patients. J Spinal Disord Tech. 25(6):324-328. Wang MY, Madhavan K (2012) Mini-Open Pedicle Subtraction Osteotomy: Surgical Technique. World Neurosurg. pii: S1878- 8750(12)01101-1. To fi nd links to the abstracts and Wang MY, Williams S, Mummaneni PV, Sherman JD (In press) Minimally Invasive Percutaneous Iliac Screws: Initial 24 Case complete scientifi c publications Experience With CT Confi rmation. J Spinal Discord Tech. listed here, visit the Research Wang X, de Rivero Vaccari JP, Wang H, Diaz P, German R, Marcillo AE, Keane RW (2012) Activation of the Nuclear Factor Publications section of our E2-related Factor 2/Antioxidant Response Element Pathway is Neuroprotective After Spinal Cord Injury. J Neurotrauma. website at www.themiamiproject. 29(5):936-945. org/researchpublications Widerström-Noga, EG (In press) Central Pain, Outcome Measures in Clinical Trials. In: Encyclopedic Reference of Pain, 2nd edition (Robert F. Schmidt / William D. Willis eds.) Springer- Verlag, Heidelberg, Germany. Widerström-Noga, EG (2012) Multidimensional Clinical Pain Phenotypes After Spinal Cord Injury. Pain Management. 2(5):1-12.

42 The Project In Memoriam Mary June Eaton, Ph.D.

Mary June Eaton, Ph.D. In Memoriam

The Miami Project and spinal cord injury (SCI) research community recently lost an excellent scientist and dear friend, Dr. Mary June Eaton.

Signifi cance of her work

Dr. Eaton’s research involved the use of molecular biology techniques and investigation of various cell lines for the treatment of the consequences of SCI. Her research included work on neuronal and chromaffi n rat cell lines that secrete neurotransmitters such as serotonin (5HT), GABA, galanin, and catecholamines, as well as the neurotrophin BDNF and the opioid peptide met-enkephalin. One major goal of her research was to examine the potential of these cell lines to act like biologic “minipumps” to secrete molecules to alleviate neuropathic and neurogenic pain in rodent models of tonic, peripheral, and central spinal injury by transplanting these cells into the spinal cord. Having served in the army herself as a nurse, she felt a strong commitment to use her research to fi nd a way to help wounded soldiers with spinal cord injuries and neuropathic pain conditions.

Working with her

Dr. Eatons’s scientifi c and philosophical view was to move successful basic research to clinical applications for human medical problems “as quickly as possible”. She also applied this principle to all her work in the sense that she was always a step ahead and well organized. Working with her was therefore both inspiring and very productive. Although her work was pre-clinical, she was very aware and appreciative of all the clinical aspects of neuropathic pain that individuals with SCI face.

Mary as a person

Mary was a very creative and interesting individual. She approached life with the same energy as her work. She used her spare time to take fl ying lessons and to scuba dive among other things. She was also very interested in photography and making sculptures and jewelry. She was the type of person who never focused on the negative; rather, she always looked forward, which was one of her greatest strengths. Mary June Eaton, Ph.D., is greatly missed by her many friends and colleagues.

The Project 43 The Project Non-Profi t PO Box 016960, R-48 Organization U.S. Postage Miami, FL 33101 PAID Miami, Florida Permit 438

We’ve Begun The Miami Project to Cure Paralysis Doctors Perform First FDA Approved Schwann Cell Transplantation On Spinal Cord Injured Patient