Interdisciplinary Research Frontiers: A Neurologist’s Perspective The negative impact of stroke on the health of our society is staggering. Approximately 750,000 Americans each year have a stroke. Nearly one-quarter of these strokes are fatal. Of the 5 million stroke survivors in the United States, 60% have residual deficits. The impact of stroke mandates that preventative and ... Features
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Features  |   April 01, 2007
Interdisciplinary Research Frontiers: A Neurologist’s Perspective
Author Notes
  • Scott Silliman, is associate professor of neurology, University of Florida (UF) College of Medicine, and director of the Comprehensive Stroke Program and the Neurology Resident Training Program at the UF Shands-Jacksonville (FL) Medical Center. Contact him at scott.silliman@jax.ufl.edu.
    Scott Silliman, is associate professor of neurology, University of Florida (UF) College of Medicine, and director of the Comprehensive Stroke Program and the Neurology Resident Training Program at the UF Shands-Jacksonville (FL) Medical Center. Contact him at scott.silliman@jax.ufl.edu.×
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Features   |   April 01, 2007
Interdisciplinary Research Frontiers: A Neurologist’s Perspective
The ASHA Leader, April 2007, Vol. 12, 19-20. doi:10.1044/leader.FTR4.12052007.19
The ASHA Leader, April 2007, Vol. 12, 19-20. doi:10.1044/leader.FTR4.12052007.19
The negative impact of stroke on the health of our society is staggering. Approximately 750,000 Americans each year have a stroke. Nearly one-quarter of these strokes are fatal. Of the 5 million stroke survivors in the United States, 60% have residual deficits.
The impact of stroke mandates that preventative and therapeutic interventions for stroke continue to evolve. This progress will open new interdisciplinary possibilities for PhD graduates in speech and language science because these scientists can play a key role in helping to develop biologically based interventions for recovery of speech, language, cognitive, and swallowing deficits following stroke.
To frame the context for new pathways, an overview of contemporary stroke treatments [PDF] that have developed over three fronts (primary prevention, secondary prevention, and acute intervention) is presented first. Contemporary treatments for stroke have evolved from discoveries that were made within the basic sciences. Deciphering biochemical pathways or physiologic processes leads to discoveries of potential therapies that augment or interfere with these processes and pathways. These potential therapies become accepted and approved treatments only after they have been proven to be effective in clinical trials.
Primary Prevention
Primary preventive therapies prevent a first stroke, such as aggressive control of risk factors like chronic hypertension and smoking. Targets of primary preventive therapies have been identified through epidemiologic studies. For example, the link between chronic hypertension and stroke was identified through population-based epidemiologic studies such as the Framingham Heart Study.
Specific interventions for primary stroke prevention are designed once the pathophysiologic impact of a risk factor has been deduced. Development of the angiotensin-converting enzyme (ACE) inhibitor class of antihypertensive medication, a class of drugs shown to reduce the risk of first stroke in patients with vascular risk factors, depended on the discovery that an aberrant renin-angiotensin system contributed to hypertension.
It has been recognized for several decades that certain heritable conditions, such as sickle cell anemia, are associated with stroke. Recent advances in technology allowed scientists to sequence the human genome, and decipher allelic variants (polymorphisms). The discovery in 2002 that a locus on chromosome 5 was associated with an increased risk of stroke in the Icelandic population signaled the start of a new era in primary stroke research-stroke/gene association research (Gretarsdottir et al., 2002).
Secondary Prevention
Secondary preventive therapies reduce the risk of a second stroke following an initial cerebrovascular event. Pharmacological approaches, such as antithrombotic drugs (e.g., aspirin, clopidogrel) and use of statin drugs to lower cholesterol levels are some of many secondary preventive therapies that physicians prescribe.
Development of these drugs occurred only after scientists deciphered physiologic pathways controlling thrombosis and cholesterol generation that interferes with these pathways. For example, the statin drug class comprises drugs that impede hepatic cholesterol generation, thus reducing cholesterol levels. Testing the hypothesis that a drug reduces the risk of secondary stroke required well-designed multi-center, placebo-controlled, randomized trials. The recent study on stroke prevention by aggressive reduction in cholesterol levels (SPARCL; Amerenco et al., 2006) was the first to demonstrate that a statin (atorvastatin) reduced the risk of a secondary stroke.
Acute Interventions
Acute interventional therapies are those treatments administered near the time a stroke occurs to minimize brain damage induced by the cerebrovascular event. Intravenous tissue plasminogen activator (tPA) was the first approved interventional therapy for stroke and must be administered within three hours of symptom onset for it to be effective. Recipients of this drug are 50% less likely to have moderate or severe deficits from their stroke.
Clinical use of this drug followed many years of scientific study. Tissue plasminogen activator, a chemical produced by cells that line arterial walls, rapidly dissolves thrombi that can occlude arteries—including cerebrovascular arteries. The U.S. Food and Drug Administration approval of the clinical use of this drug for stroke in 1996 occurred decades after its discovery as an enzyme involved in hemostasis. The time delay between discovery and approval was related to scientific investigations in the basic sciences (e.g., gene sequencing, recombinant gene technology, animal models of stroke) and clinical sciences (e.g. dose escalation studies, phase II safety studies, phase III efficacy study) that had to occur in order for tPA to be mass-produced, dosed, and administered appropriately to humans.
Post-Acute Interventions
The next frontier in stroke therapeutics centers on the development of post-acute interventional therapies, an area with many interdisciplinary research opportunities. These recovery-enhancing therapies, which may be pharmacological or device-based, such as neurostimulation, are administered days to weeks after a stroke occurs. To develop post-interventional stroke therapies, scientific discoveries must be translated into practical applications. As with primary, secondary, and acute interventional therapies, discoveries typically begin in a laboratory with basic research, then progress to the clinical level.
Undoubtedly, the development of safe, effective, post-stroke interventions will require interconnection among many scientific disciplines. The field of genetics likely will play an important role, as evidence is emerging that genetic factors play a role in recovery from stroke. For example, a recently published study concluded that a sibling history of stroke was associated with a greater likelihood of stroke survivors having a National Institute of Health Stroke Scale score > 5 (Meschia et al., 2006).
This finding suggests that heritable factors may contribute to infarct size and/or the neurobiologic mechanisms underlying brain reorganization following stroke. Neuroimaging parameters such as lesion size, location, and functional mapping will help to select patients for interventions and guide placement of devices that augment recovery. In the multi-center Everest study, which is examining the safety and efficacy of a cortical stimulator for recovery of post-stroke arm weakness, functional magnetic resonance imaging (fMRI) is being used to identify the cortical area that has taken over control of wrist/hand movement from the damaged brain area. The cortical stimulator is being placed over the motor activating site.
Research Expertise in Post-Acute Stroke Management
Speech-language scientists can play a key role in helping to develop biologically based post-acute interventions for recovery of speech, language, cognitive, and swallowing deficits following stroke. Curricula that prepare PhD students in the speech and language sciences may need to be redesigned to incorporate fields of study that have not been part of traditional doctoral coursework. The new PhD will need to have a basic understanding of key sciences, such as those mentioned above, to assist with the development of post-acute interventions.
For example, coursework in genetics that incorporates topics such as modes of gene transmission, influence of polymorphisms on phenotypes, and types of scientific genetic analyses (e.g., linkage analysis) may be appropriate areas of expertise. Basic training in MRI interpretation and in pharmacologic principles, such as dose response, drug metabolism, and the blood-brain barrier, may also be warranted. Education in these fields will allow those seeking a PhD to become more familiar with paradigms that may affect recovery from stroke and enhance their role and stature as members of research teams.
Becoming Members of Translational Research Teams
A more efficient and productive way to bring scientific discoveries to stroke patients is to make the traditional bench-to-bedside approach to research a two-way street. In this approach, called translational research, basic scientists provide clinicians with new tools for use in patients and for assessment of their impact, and clinical researchers make novel observations about the nature and progression of disease that often stimulate basic investigations. (For further information on translational research, see the National Institutes of Health [2006] Roadmap for Medical Services; for an example of a translational science approach that incorporates expertise from neuroscience and language science, see Shaywitz, Mody, & Shaywitz [2006]).
An example of current translational research in stroke is the field of biomarkers, which are peripheral (serologic) markers of central nervous system injury derived from cellular elements within brain tissue. Ultimately, biomarkers might assist with diagnosis and acute management of stroke. Basic scientists discover the biomarkers and techniques for measuring them but depend on clinicians for subtyping stroke mechanisms and defining stroke location and size. Translational research can be a powerful process that may lead to devices, drugs, and bedside therapies that enhance recovery when utilized in the post-acute phase of stroke. PhD graduates in the communication sciences and disorders will have the opportunity to participate on these translational teams if they receive the appropriate academic and research preparation.
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April 2007
Volume 12, Issue 5