HMRI Researcher Takes Strokes Against Stroke

One of the most distressing and challenging forms of neural injury is stroke.  Also commonly called "brain attack," stroke affects the nervous system - one of the most important systems of the body, yet also the most vulnerable to injury and possessing the least capacity for recovery from the injury.  Stroke is the third leading medical cause of death in the USA, the main cause of long-term disability among adults, and costs more than $70 billion annually in health care. About 30% of stroke victims are permanently disabled with a variety of severe impairments, including memory loss, vision, speech, motor control, voiding and sexual dysfunction.  Intervention, prevention and rehabilitation methods to date have been insufficient to substantially reduce the number of strokes and alleviate their permanent side effects.

Recently, Panya Steve Manoonkitiwongsa, Ph.D., of HMRI's Neural Engineering Laboratory described the nature of stroke, its complications and various treatments.  He and his research colleagues are focusing on developing safe and effective therapeutic methods that would significantly improve existing forms of stroke recovery.

Stroke injury can be broadly viewed as two types:  hemorrhagic and ischemic.  Both involve lack of oxygen to the brain. Hemorrhagic stroke occurs when blood vessels rupture and the blood oozes out of the vasculature (the blood vessels), causing the brain areas that normally receive blood from those hemorrhaged vessels - with the vital oxygen and nutrients they carry - to suffocate.  Lack of blood (oxygen) to brain cells for just four minutes or less can permanently damage the cells.  Hemorrhage further complicates the disease by pooling blood in the brain.  Ischemic stroke, on the other hand, occurs when something in the blood vessel blocks the flow of blood; consequently, the blood stops flowing or its flow through the vessel is diminished.  This leads to suffocation of the brain and damage to the brain cells.  Most of the stroke incidences in the USA are ischemic strokes.  Thus, most of the studies conducted in stroke research have addressed the biological problems and clinical treatments of ischemic stroke.  

Current treatment choices   

According to Dr. Manoon, the best intervention methods currently available "serve merely to restore blood flow and/or reduce the probability of further stroke injuries. Physical therapy commonly constitutes the rehabilitation process for the afflicted patient."    Common non-invasive (that is, non-surgical) treatments for stroke include administering a variety of drugs to achieve several objectives:

thrombolysis - opens up the blood vessels that have been blocked

anticoagulation - thins the blood and reduces the probability of more blockage of the blood vessel

antihypertension - reduces blood pressure to avoid hemorrhage of the weakened blood vessels, or injury to the brain.

antiplatelet - reduces inflammation-related events so as to minimize the probability of further blockage of the blood vessel.

Thrombolysis is the treatment that is administered immediately to a patient when brought to the hospital or clinic to open up blocked blood vessels and restore blood flow to the brain.  It involves infusion of tissue plasminogen activator (tPA) and is currently the only Food & Drug Administration (FDA)-approved procedure.  This therapy is very limited in its application and effectiveness.  It must be given within three hours from the onset of stroke, or hemorrhage may occur.  The patient must not be on medications that could weaken the blood vessels, nor have any disease or abnormalities that could cause the weakening of the blood vessels.  This treatment merely serves to restore blood flow but not to protect the brain cells (neurons) from injury and death.  Furthermore, administration of tPA to the patient, in itself, could damage the neurons.

Improving the odds

Unless the neurons that are damaged in stroke are preserved or protected from death, recovery can take a long time, if the patient recovers at all.  Thus, stroke specialists agree that neuroprotection - that is, administering  substances that would help preserve or protect the neurons - should be included with the tPA thrombolytic treatment.  These would not only protect the neurons and reduce brain injury caused by the ischemic stroke, but also compensate for the adverse effects of tPA on the neurons. Several researchers worldwide are also proposing angiogenesis: treating stroke by causing the brain to make more blood vessels.  The logic is that, by inducing the formation of more blood vessels in the brain, more blood would flow to the brain area that suffered the injury.  The increased blood flow would, therefore, help relieve the oxygen deprivation in the brain.  Some propose that a single agent that could provide both neuroprotection and angiogenesis would appear to be the most promising.  

Of the various chemicals tested through the years that are both neuroprotective and increase the formation of blood vessels, few have captured more attention than vascular endothelial growth factor (VEGF). This substance accomplishes both things, but also has several negative side effects.  One of the major side effects of this chemical is to cause the blood vessels to become permeable, or porous, so that blood fluids and substances in the blood leak out of the blood vessels into the brain.  Thus, though VEGF may create new blood vessels in the brain, it can also cause the blood vessels that are already in the brain to become leaky.  Even the new blood vessels that are formed are also permeable.  It is, therefore, unclear whether VEGF could safely and effectively be used to cause neuroprotection and angiogenesis in the brain at the same time.

Manoonkitiwongsa and his colleagues have conducted experiments to determine whether neuroprotection and angiogenesis by VEGF necessarily occur together.  Their data, published in the June 24 Journal of Cerebral Blood Flow and Metabolism, reveal that neuroprotection and angiogenesis maybe inversely related.  That is, VEGF may be neuroprotective only as long as angiogenesis does not occur.  When angiogenesis is significantly induced, VEGF no longer protects the brain, and creating more vessels may inflict further injury to the brain and worsen the consequences of stroke.  They believe that VEGF could be a strong candidate for stroke therapy when used for neuroprotection, but that induction of angiogenesis by VEGF should be avoided by controlling the dosage.  "Our data are very preliminary," says Manoonkitiwongsa.  "More dosages need to be tested to confirm our hypothesis." 

They recently submitted a grant proposal to the National Institutes of Health for the purposes of 1) deciphering the relationship between neuroprotection and angiogenesis by VEGF and 2) characterizing the alterations in the brain exposed to the various doses of VEGF.  Once these are precisely identified, and the mechanisms responsible for the relationships are elucidated, they hope to resolve whether neuroprotection and angiogenesis by VEGF can concurrently and safely be used as treatment methods for stroke.

Neural Engineering Laboratory director Doug McCreery, Ph.D., said of this project, "Their research will provide significant and critical knowledge and bridge an important gap in our current understanding of stroke treatment."

Prevention helps too

Education about stroke prevention encourages reducing risk through healthful living - e.g. cessation of smoking and consumption of intoxicants, sufficient exercise, proper diet, weight control, sugar control and stress management.  However, "at-risk" behaviors do not change quickly. The fact is, many of the general public do smoke, consume alcohol to excess, pursue sedentary work or activities for much of the time, do not exercise regularly, do not control their caloric intake, and are subjected to the mental and psychological stresses of everyday life. Furthermore, as a person advances in age, the brain and its blood vessels become weaker and more susceptible to stroke.  With the more sedentary lifestyle that comes with advancing age, its probability increases further.

The lifetime costs of therapy and medication per person are estimated to be $200,000 for hemorrhagic stroke and $100,000 for ischemic stroke.  Inpatient hospital costs alone average about $30,000 per admission for hemorrhagic stroke and $10,000 for ischemic stroke.  These expenses are in addition to physician services and other costs.

Statistics show that more than 500,000 stroke episodes occur in the USA each year of which one-third are fatal.  In 2002 alone, more than 700,000 strokes occurred in the USA, of which approximately 500,000 were first-ever strokes and 200,000 were recurrent strokes.  If the age-specific rates of stroke remain unchanged from 2002 to 2025, the overall number of strokes in the USA will increase from approximately 700,000 in 2002 to 1,136, 000 in 2025.

NIH Grant will Support Studies of Bladder Dysfunction Resulting from Stroke

The National Institutes of Health awarded an $800,000 three-year research grant to Victor Pikov, Ph.D., of Huntington Medical Research Institutes' Neural Engineering Department.  Dr. Pikov is studying the problem of stroke-related incontinence.  His project, "Functional Microstimulation of the Lumbosacral Spinal Cord," explores using electrical stimulation to activate neurons in the spinal cord to restore bladder control following stroke.

Pikov proposes using low-frequency electrical stimulation to create a stroke-like incontinence.  The "virtual" stroke will inhibit the ability of lumbosacral spinal cord nerves to control the bladder.  "Electrical stimulation in the spinal cord to restore voiding is a new area of research," says Dr. Pikov.  "Only two other labs in the world  are doing what we do at HMRI, but we have the advantage.  We're using arrays of electrodes, rather than individual electrodes."

For the past 30 years, HMRI's Neural Engineering program has been at the forefront of neural prosthesis research to produce safe, effective microstimulation to control the nervous system.  In this case the implant, when activated, will produce symptoms of incontinence by applying repetitive electrical stimulation directly to the individual bladder neurons of the spinal cord.  Pikov's simulation of incontinence is repeatable and reversible, and done without lesions or injury.  The hoped-for result would be the development of an implantable array of electrodes controlling bladder function without any further need for invasive surgery or drug treatment.

Stroke is the third leading cause of death in the United States and is the main cause of long-term disability among adults.  Many people develop bladder dysfunction soon after suffering a stroke.  A likely explanation is that a stroke reduces the brain's ability to inhibit the activity of spinal cord nerves involved in bladder contraction, resulting in incontinence.  Currently, routine management of bladder dysfunction after stroke includes catheterization and drug treatment.  Both have a significant risk of side effects such as urinary tract infections and urinary retention. 

Victor Pikov, Ph.D. was awarded the HMRI-Caltech Boswell Fellowship in 2000.  The Boswell Fellowship, endowed by the James G. Boswell Foundation, supports postdoctoral scientists in joint research at Caltech and HMRI.  He brings a background in neuroanatomy, immunohistochemisty and bladder physiology to the Neural Engineering laboratory.  Born in Ukraine, he studied physiology at Kiev State University, received a B.A. cum laude in Biopsychology at Vassar College.  He received his Ph.D. in Cell Biology from Georgetown University.  Other members of the Neural Engineering team contributing to these studies include program director Douglas McCreery, Ph.D., Xindong Liu, Ph.D., and Leo Bullara.  Their efforts have the potential to substantially improve the future quality of life for stroke patients. 

National Institutes of Health Awards Grant for Migraine Research

The National Institutes of Health has awarded a four-year $1.4 million grant for migraine headache research to the Huntington Medical Research Institutes' Molecular Neurology Laboratory, directed by Michael Harrington, M.B., ChB., FRCP.

HMRI scientists have recruited volunteer study participants from the San Gabriel Valley for research aimed at understanding the biochemistry of migraine. They  measure the chemical composition of spinal fluid and blood, using powerful new mass spectrometry instruments combined with human genome information, to identify thousands of molecules in each sample.

It is estimated that 30 million Americans suffer from migraine.  Sufferers are exceptionally sick during migraine attacks, with pain affecting the muscles of the back of the head and neck.  The HMRI scientists have identified components that change during attacks, between attacks, and what differs between migraine sufferers and those not troubled by headaches.  Early results have revealed changes in molecules involved in many brain processes, including oxidation, blood vessel reactivity, pain and sleep.

Dr. Harrington hopes to learn whether these chemical changes in the brain affect a predisposition to migraine, and so lead to better intervention and personalized treatment for individual sufferers.

The project also receives funding from the Norris, Glide and Hezlep Family foundations, and from Thermo Finnigan, a medical technologies company in Palo Alto.