Archives of Physical Medicine and Rehabilitation
Volume 88, Issue 5 , Pages 551-554, May 2007

Brain Injury Research: Lessons for Reinventing the Future. The 38th Zeiter Lecture

Presented in part to the Interagency Conference on Traumatic Brain Injury, March 11, 2006, Bethesda, MD; and to the American Academy of Physical Medicine and Rehabilitation, November 9, 2006, Honolulu, HI. The lecture is based in part from: Zafonte RD. Update on biotechnology for TBI rehabilitation. J Head Trauma Rehabil 2006;21:403-7.

  • Ross D. Zafonte, DO

      Affiliations

    • Corresponding Author InformationCorrespondence to Ross D. Zafonte, DO, University of Pittsburgh, UPMC Health System, 3471 Fifth Ave, Ste 201, Pittsburgh, PA 15215

University of Pittsburgh, UPMC Health System, Pittsburgh, PA.

Article Outline

Abstract 

Zafonte RD. Brain injury research: lessons for reinventing the future. The 38th Zeiter Lecture.

I discuss novel dynamics in brain injury medicine that will shape the field of physical medicine and rehabilitation over the next several years. I review the lessons from previous clinical trials and discuss how rapid biotechnologic changes will influence the lives of people with disabilities. This lecture focuses on prior paradigms and addresses lessons learned, novel strategies for reinvention (including person-specific therapies), conventional therapy programs, biomaterials and devices, cellular-based therapies, and potential therapeutic interventions.

Key Words: Brain injuries, Rehabilitation, Technology, medical

 

THE SPECIALTY OF PHYSICAL medicine and rehabilitation (PM&R) has had its share of visionary leaders—for example, Walter J. Zeiter, MD—who were bold enough to change the field. We must revisit our past in order to develop strategies for the future of our specialty. In this lecture, I will use the clinical care of, and research into, traumatic brain injury (TBI) as an exemplum of how we can reorganize the way we think about how we practice our particular specialty.

TBI is tiered into primary and secondary injuries. Primary injury occurs as a direct consequence of the injury (ie, subdural hematoma, contusion) while secondary injury exists as a cascade of processes that worsen after the initial injury. It is this series of interacting events that creates a complex and multifactorial disease process. These secondary injury components are a possible target for neuroprotective therapies.

This cascade of events has an impact on several pathways that influence both acute injury and recovery processes. Numerous acute care neuroprotective trials have been completed, yet many had been halted and others have failed to show efficacy for the primary outcome measure.1 The question remains, Why?

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The Past 

Preclinical studies using animal models have demonstrated the efficacy of various neuroprotective therapies. These animal studies have typically been performed with male, genetically pure, animals and have had with relatively proximal outcome measures such as lesion volumes. When these therapies have been used in clinical trials, they have failed to yield strong clinical dividends,2 and the results have been disappointing.3 Thus, we are now at a point at which no standard neuroprotective therapy has been developed.

Various agents have shown promise, but concerns about goals, trial design, or the measures used have slowed their successful development. Polyethylene glycol superoxide dismutase is a free-radical scavenger with a modest side-effect profile. A phase II trial of this agent by Muizelaar et al4 appeared to yield positive results but the definitive trial resulted in a negative finding for the primary measure.5 The investigators noted a 7.9% better outcome at 3 months postinjury. Perhaps this study asked for a differential outcome that was too robust and hence was too underpowered to show a small difference between groups. A small difference in outcome, however, may have meaning for the patients we serve and their families.

Several N-methyl-d-aspartate (NMDA) receptor antagonists have been tested in the treatment of acute head injury. These agents target a specific pathway and seek to ameliorate a portion of the excitotoxic process that follows TBI. No NMDA antagonist medication has yet been found efficacious in a terminal clinical trial for the primary outcome measure,2 and prior trials were stopped prematurely. For years, clinicians and researchers have focused on the role of corticosteroids in the treatment of trauma. The Corticosteroid Randomization After Significant Head injury (CRASH) study6 is the largest randomized trial of steroids for human TBI ever undertaken. The impact of intravenous steroids was evaluated in subjects with TBI who had Glasgow Coma Scale scores of 14 or lower. The study found no reduction in mortality, and in fact, reported an increase in the number of deaths at 2 weeks postinjury in the corticosteroid treatment group. Of note, mortality—even in the placebo groups—was higher than previous reports and the results of other recent steroid-based studies, such as with tirlizaid mesylate (a 21-amino steroid), showed no significant benefits. The tirlizaid mesylate study did have a randomization flaw because of a mismatch between groups, with subjects with more severe injuries being randomized to the treatment group. A recent phase III study7 of a proposed neuroprotective cannabinoid found that it had no significant beneficial effects.

Moderate hypothermia treatment for severe TBI has been discussed for almost 6 decades. While preliminary data have suggested positive outcomes, and indeed several studies have shown such outcomes with cardiopulmonary arrest patients, a large multisite controlled trial failed to demonstrate efficacy in TBI patients.8 The initial study from the University of Pittsburgh did, however, demonstrate efficacy.9 Why did these differences occur and did a patient subgroup benefit? The trial by Clifton et al8 brings into focus the difficulty in standardizing multicenter trials because there was tremendous intersite variability in the acute care management and re-warming strategies; these variations may have played a significant role in the disparate findings. A subgroup analysis noted a potential benefit from hypothermia treatment among subjects who were 45 years of age or younger. The study also suggested that subjects who were already hypothermic at the time of admission also benefited from the treatment. Presently, a trial sponsored by the National Institutes of Health—the National Acute Brain Injury Study hyperthermia–II (NABIS-II)—is evaluating the role of moderate hypothermia treatment in a subgroup of subjects with severe TBI.

The use of practice guidelines appears to have an affect on the mortality rate and outcomes of people with TBI, thus making it even more challenging to detect differences. Both decreasing mortality and the decreasing rate of poor outcomes resulting from following the Brain Trauma Foundation guidelines10 for the treatment of acute severe head injury may be creating a benefit, but it may also be making more challenging the detection of differences resulting from innovative therapies.

In a review of TBI clinical trials, Narayan et al11 advocated for strong preclinical models and a wide window of opportunity. They also advocated for an understanding of population differences; I believe that this is a key component of the future of acute and postacute care. Careful consideration should be given to understanding genetic and biologic factors involved in the actual injury and recovery processes. Researchers should pay more attention to the adequacy of study design and/or be less preoccupied with obtaining a major effect (“hitting a home run”) than in achieving incremental improvement (the proverbial “single”).

Thus, can any drug that targets a singular mechanism be globally effective? Some researchers and clinicians have advocated using “sloppy drugs” (those that target multiple mechanisms), while others have called for incremental use of a medication cocktail to enhance neuroprotection and limit secondary injury. Of interest is a recent phase II trial by Wright et al12 of a relatively sloppy drug with multiple mechanisms of action. They studied progesterone and found it to be safe, noting a trend for better outcomes.

Postacute studies have verified many of the same concerns and they have been limited in their scope. We have learned that there is no effective treatment for the long-term prophylaxis of posttraumatic seizures.13 Few studies14 have optimally evaluated in a standardized fashion therapy treatment regimes or interventions. Postacute pharmacologic studies15 have been criticized because of their small sample sizes and limited outcome measures. Several agents have shown promise, however. In a double-blind randomized controlled trial with 34 TBI patients who received methylphenidate, Whyte et al16 noted improved visual processing speed, but whether this relates to improved long-term outcomes is as yet unclear.

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Conventional Care 

We still do not have a clear understanding of the role of conventional therapy. Because some data suggest that too early an intervention may damage an organism, issues regarding the timing of therapeutic intervention and its appropriate withdrawal are key to the future of rehabilitation care. We also need to define the proper dosing for various therapeutic interventions and how some of the interventions can be augmented or inhibited by strategies that we now use.14

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The Future: The Need to Reinvent— Restorative Medicine and the Biology of Recovery 

Clearly, in brain injury medicine, and perhaps even in the entire field of PM&R, we must consider our future options. Using a scientific approach, we can lead the way in developing new biotechnologies. If we understand the mechanisms of recovery, we can create novel ways to enhance the recovery process. By thinking “outside the box” and challenging prior paradigms we can help design new ways to care for our patients. Examples exist in fields such as neurosurgery and otolaryngology that have reinvented themselves by designing new methods or innovations to solve long-standing problems. I believe such thinking will be critical as PM&R seeks to move forward in both musculoskeletal and rehabilitative arenas. A focus on the biology of recovery will have profound implications for our field.17 We have the opportunity to review the entire postacute continuum and its biologic links, including wellness and aging prevention.

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The Next Generation of Physiatry: Therapeutic Options 

Perhaps most important to the field of PM&R is the training of the next generation of physiatrists. Physicians entering physiatry today will find the practice landscape changed by biologic therapies and discoveries such as no previous generations ever experienced. Thus, we are entering an era of functional biologic physiatry. Understanding one’s own biologic factors and their role in the recovery process will carry important implications for the field of PM&R. Through an understanding of the more sophisticated and refined biologic behavior patterns, we can integrate our patients’ psychosocial and biologic profiles into our therapeutic regimes in a more seamless manner. It is likely that not every therapy will work for every person. Thus, understanding specific genetic and biologic factors that influence the recovery process is critical. A more refined appreciation of such factors will permit us to design more effective acute and postacute therapies. Work at the University of Pittsburgh has shown sex-based differences for biomarkers of oxidative stress injury after TBI.18 Genetic factors may affect recovery and it will be important to examine the relationship between genetic polymorphism and therapy (or an enriched environment).19 Using either novel imaging techniques or biochemical markers of injury to further define the extent and type of injury will be key in the future. There is the potential of developing a set of markers that can help us design and refine our patients’ therapy, throughout the sphere of physiatric practice.

Bioscaffolds are unique structural tools that provide a framework to enhance tissue healing. These novel substrates use active biologic tissues and permit these biologic structures to grow within a cocoon of a polymer-like network. Bioscaffold therapy has been used to enhance wound healing and has even been used to heal skeletal and heart muscle.20 Such therapy offers great promise for those with central or peripheral neurologic disorders and may have an important role in musculoskeletal care.

Neurotrophic factors can enhance the growth of neuronal tissue and enhance arborization and include factors such as brain-derived neurotrophic factor and nerve growth factors; these factors, and others, appear to have a significant role in synaptogenesis, plasticity, and cell survival. They are also critical in the process of neuron differentiation.21 There is clearly activity-dependent release of these neurotrophins and these factors play a role in protein synthesis in dendrites, thus enhancing outgrowth. A significant portion of restorative science will begin to focus on the proper delivery, method of delivery, and timing of delivery of these agents.

Cellular-based therapies are in our future, yet they remain controversial. Stem cells are pluripotential cells that differentiate into numerous specific cellular subtypes, including nerve, bone, or other tissues.22 The mechanism of stem cell facilitation and its efficacy as a potential tool in musculoskeletal and neurologic disease is not clear. Questions remain as to whether these cells act via direct replacement and proliferation or as a trophic support for the region, enhancing the milieu and encouraging endogenous processes. Stem cell therapy may also help us create a therapeutic environment, making surrounding tissue easier to manipulate and enhancing regeneration. Research using animal models has suggested that there is an attenuation of behavioral deficits and motor deficits after stem cell transplantation. Where, when, and how they repair lost neuronal connections and neural networks remains unclear, however. In addition, we must further clarify how these cells interact with activity, experience, and pharmacologic enhancement.

In a 2005 published study,23 a human cell implantation trial for those with stroke was completed. The researchers employed human N2 tera cells derived from teratocarcinoma to perform a human cellular implantation study. The study cells were implanted in stroke volunteers with residual motoric deficits. Several major findings were striking. The neurons were found at the graft site and they appeared permanently postmitotic. Although functional improvements in a small population study did not appear to be statistically significant, there was a trend for visual processing and executive function enhancement via a mechanism that is as yet unclear.

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Technology for Future Care 

Medicine is replete with novel companies employing biologic implantable devices for almost every extremity and disorder. The exact long-term benefit of many of these devices is not clear; however, such devices will become more common. Cortical stimulation has been advocated as a means to enhance recovery for those with focal motor weakness, as well as those with dystonia, motor control disorders, and of course Parkinson’s disease. Vagus nerve stimulation appears to diminish both epilepsy and resistant depression. The interaction among stimulatory therapy, classical therapy, and these devices is another venue for future research. Transcranial magnetic stimulation (TMS) allows us to direct magnetic current into the brain to create both an evaluative and therapeutic enviornment.24 TMS technology may help us map and understand further the parameters of recovery. It may also be employed as a therapeutic intervention for those with motor disorders and, perhaps, with neurocognitive disorders.

Nanotechnology will be important in the future of rehabilitation care; these engineered materials carry a functional size of less than 100 nanometers. Not only is the technology at the smallest functional level of organization but also some aspect of the material or device can be manipulated or controlled via physical or chemical signaling means. The technology is small enough to allow us to study cellular communication and signaling, and to reorganize the interaction between devices and human being. Nanotechnology will help us evaluate how neurons or muscles respond to chemical and physical forces and how subcellular stimuli work within a neuron. They are a potentially important route for drug testing as well as an evaluation tool for the optimal therapeutic environment and neuroprotection. Nanotechnology may also help us refine elements of drug transport, enhancing blood-brain barrier crossing, and opening up new venues for therapy delivering medications.25 By being employed for long-term implantation devices, nanoparticles may help enhance cellular integration and limit the chronic immune response. Nanobots are nanometer-sized robots that can be programmed to deliver on-site cellular therapy, and manipulation of muscle groups. These agents may also play a role in neural recovery and neural regeneration by limiting secondary toxins and serving as scavengers of unwanted materials postinjury.

We believe that assistive technology carries an important and underappreciated role for people with disability, especially those with brain injury. It is important to define a more comprehensive understanding of the technologic needs, and the potential benefits of these technologies to people with TBI and other disabilities. Our personalized joystick allows people with motor control disorders to control a powered wheelchair because the joystick does not permit marked deviation from a planned course.26, 27 This system permits improved wheelchair mobility for those with the most severe motor disturbance. Critical to the development of cognitive assistive technology is an ability to tailor the technologic needs to the person being served. Such individualized care will allow people to function at the highest possible level.

Presently, most robot technology development has focused on motor control and developing. One of our local projects employs robots in virtual reality to provide a rehabilitation-by-distortion environment.28 This potential therapeutic concept uses virtual reality and perceptual-based gapping phenomena to enhance motor control for those with long-term significant motor deficit. Thus by fooling the system we may be able to increase motor capacity. In addition the role of so-called helper robots will be central to the future care of the elders and those with disabilities. Neuroprosthetics may be injectable microstimulators working at the neuromuscular level. They have the potential with radiofrequency control to enhance motor movement, to correct foot drop, or even to prevent skin lesions; potential therapeutic benefit may also involve central motor control with predictive equations allowing for robotic control of prosthetic devices.29 The key to this future is understanding sensory feedback in order to optimize central and peripheral control and functional utilization.30

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Questioning What We Know 

In any further reinvention, we must understand whether what we do and believe is really true. Some of our strongest beliefs may need to evolve and paradigms of the past are often paradigms of failure. Because it appears that our practices may not always be optimal, we must question how we practice and look for basic and clinical evidence behind our beliefs. Some clinical examples may illustrate this idea. We had been taught to employ high-calorie diets for those post-trauma. What kind of early and late dietary regimes are optimal for those with severe TBI? What if the proportions of and type of calories that the patient should receive differ greatly from traditional convention? Some research suggests that we could be enhancing the inflammatory process by providing high-calorie diets laced with high carbohydrate.31 Can this impact on a patient’s outcome, length of stay, and recovery process? Our postacute pharmacologic belief systems have been predicated on a series of small studies and beliefs in an empirical set of dos and don’ts. It appears that at least in the animal literature pharmacologic agents, both in the acute and postacute stages can be linked to outcome after TBI. We have been told that haloperidol, at least in the postacute setting, has a negative impact on outcome. However, it appears that we need to understand “windows of opportunity” in a physiologic sense. Therapies that may have a negative role at one point in time may be neutral or positive at another period in time. Millbrandt et al32 evaluated haloperidol use among mechanically ventilated persons in an intensive care unit (ICU) setting. Millbrandt noted a lower hospital mortality among those treated with haloperidol early in their ICU course. While this study has limitations, it raises questions and suggests a possible therapeutic window when haloperidol may serve as a cytokine suppressant, and then another window, perhaps during rehabilitation, where it may have relatively negative effects on chronic recovery.

More recently, many physiatrists have turned to atypical antipsychotics for the treatment of agitation post TBI. As a field, we have done this without substantial evidence that the agents are safer or better than this chronic haloperidol. In a recent animal study,33 our group demonstrated that risperidone (Risperdal) acts like haloperidol, with both medications producing a potential long-term negative effect on the recovery model. Further study in animal models is needed to define the safety of other agents after TBI.

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Conclusions 

The future of PM&R is exciting because it is filled with the potential to further define the specific parameters of injury and to employ biotechnology in patient care. We need to return to our scientific roots and to begin to forge new thinking about the biology of recovery. We physiatrists need to be bold enough to reinvent our approach to patients and their care.

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References 

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 Supported by the National Institute on Disability and Rehabilitation Research (grant no. H133P70013-00) and the National Institutes of Health (grant no. 1UO1HD42678-02).

 No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated.

PII: S0003-9993(07)00176-1

doi:10.1016/j.apmr.2007.02.039

Archives of Physical Medicine and Rehabilitation
Volume 88, Issue 5 , Pages 551-554, May 2007

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