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Timeline:
A quarter-century
of progress
Using depth electrodes to record brain activity, neurosurgeons are able
to locate and remove the tissue responsible for epilepsy while leaving
critical brain regions unharmed. Yale scientists are now refining the
procedure, using magnetic resonance imaging to reach the same outcome
faster and less invasively. The sequence of images at left shows the process
by which the electrode data are compared to three-dimensional MR data
during development of the new system.
The new Magnetic Resonance Research Center includes a 4-tesla magnet for
human studies that can pinpoint functional activities in areas as narrow
as 500 micrometers.
Center directors Rothman, left, and Constable, right, and collaborator
Duncan.
Sally and Bennett Shaywitz have used functional MRI to measure differences
in brain activity between groups of children with and without dyslexia.
Colored areas in the images highlight locations in the brain where there
is a marked difference in function in the two groups.
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High Resolution
The opening of a new Magnetic Resonance Research Center gives Yale expanded
capabilities for advancing imaging science and disease understanding.
Improving epilepsy treatment is just one focus.
By Marc Wortman
Amy Taylor (not her real name), a 30-something mother of two with a palm-size
opening in her skull, tries to muster a smile as she sits up in a bed
in the epilepsy monitoring unit at Yale-New Haven Hospital. A grid of
depth electrodes penetrates the lumpy wet crown of her exposed neocortex.
More than a dozen wires lead to a computer waiting to register the electrical
firing patterns of the next in what has become a regular but unpredictable
series of epileptic seizures.
The medications she has been taking for more than a decade no longer
control those seizures, which are the result of temporal lobe epilepsy.
She cannot work or drive, and rarely leaves home anymore. She will remain
in the unit for up to 10 days, until enough data have been collected to
localize the source of the malfunction in her brain. Electrical stimulation
will also be fed into the electrodes while she undergoes a battery of
tests to determine the precise location of critical language, movement
and sensory areas.
Despite her present misery, she is fortunate. Hers is the only
type of chronic brain disease that can be cured with surgery. But only
the results of the tests will reveal whether she is a candidate for treatment.
Two to three patients each month undergo intracranial surgery for
the type of testing Taylor underwent at Yale as a first step toward surgery
to cure her epilepsy. The Epilepsy Education Association estimates that
20,000 Americans with intractable seizures could be cured with surgery,
yet each year only 500 undergo the procedure. Fear and expense keep many
patients away. Altogether, the procedure can cost more than $120,000.
Using new imaging technologies, Yale scientists hope to make the choice
of surgery far less frightening and more economical. A multifaceted team
of engineers, linguists, physicists, neurologists, neuroscientists, applied
mathematicians, computer scientists and neurosurgeons is refining methods
for applying emerging magnetic resonance imaging (MRI) and spectroscopy
(MRS) technologies to epilepsy. If they succeed, sometime within the next
five years they will be able to locate the seizure focal point in a patient’s
brain and map out areas of brain function in less than three hours—a
tiny fraction of the 10 days Taylor spent under observation—and
without opening the skull. Just eliminating that part of the surgical
process will reduce both the total cost of epilepsy surgery by up to 40
percent and a source of enormous fear for patients.
The Yale investigators’ ambitions run well beyond that. They
hope that sometime within the coming decade temporal lobe epilepsy will
be curable without any surgery at all. According to Taylor’s neurosurgeon,
Dennis D. Spencer, M.D., HS ’76, “It all hinges on our being
able to use magnetic resonance imaging machinery to measure what’s
happening in the human brain.”
New windows, new insights
Spencer, director of the Epilepsy Surgery Program at Yale and chair of
the Department of Neurosurgery, already relies on MR studies to help guide
him when he operates. The possibilities for developing treatment methods
that, according to Spencer, “will put me out of business”
depend on studies under way at Yale’s Magnetic Resonance Research
Center (MRRC). Already one of the world’s leading scientific research
programs of its kind, the MRRC received a major boost last winter with
the opening of its new home in the 457,000-square-foot Anlyan Center for
Medical Research and Education.
The MRRC’s 50-member staff, along with six multiton magnets
supported by banks of computers, relocated from the Fitkin Memorial Pavilion
basement to more than double the space in a two-story facility in the
Anlyan Center (See The Big Move, Winter 2003). On the upper floor
of the new facility, faculty and administrative offices surround a large,
light-filled open work space with computer workstations at its center.
The facility has 40 networked computers dedicated to analyzing data produced
by its magnets. At the computers, students and other investigators manipulate
images of organs and graphic displays of data and develop algorithms to
model the behavior of parts of atoms within cells.
For the faculty and staff, the new quarters represent the increasing
importance of imaging technology to biomedical science and health care—and
a big boost for morale. Director Douglas L. Rothman, Ph.D., professor
of diagnostic radiology, notes that this is the first time he has had
a window in his office since he came to Yale as a graduate student in
1985. More important than what he can see out the window is what the new
facility will enable imaging scientists to see at the molecular level.
“This,” he says, “is one of the best facilities in the
world now.”
On the floor below, the MRRC houses eight magnets, including two
newly purchased systems. The MRRC maintains three animal and tissue research
systems, including a soon-to-be-installed 11.75-tesla animal magnet, able
to measure changes in animal metabolism at the molecular level. (A tesla,
named for radio-engineering pioneer Nikola Tesla, is a measurement of
the strength of a magnet’s field.) The center also houses three
human systems, including a new 4-tesla functional MRI (fMRI) system in
the W.M. Keck High Field Magnetic Resonance Laboratory that can pinpoint
functional activity in an area as small as 500 micrometers across. That
is half a millimeter, about the size of the fundamental information processing
units in the human brain (often referred to as cortical columns).
The state-of-the-art, $3.7 million human magnet was paid for in
part through a $1 million grant from the W.M. Keck Foundation. There are
also empty bays waiting for eventual installation of two additional magnets.
All of the MRRC bays are encased within 11 inches—nearly 2 million
pounds—of steel and copper to shield out even the most minute radio
signals, which could wash out reception by the ultrasensitive magnets,
and to contain their magnetic fields.
The new magnets have already dramatically improved what investigators
will be able to visualize. Studies of the central nervous system will
benefit particularly from the magnets’ higher sensitivity. “They
allow us to look at fundamental neuronal processing units, which we could
not do with our previous equipment,” says Rothman. For instance,
tissue that causes epileptic seizures can now be studied to determine
precisely how metabolic processes critical to normal neuronal activity
have malfunctioned, information crucial to the development of new treatment
methods.
Seeing deeper
MRI and MRS studies in many fields at Yale, including reading and dyslexia,
substance abuse, diabetes, mental illness and cardiovascular medicine,
are providing methods for tracking down disease mechanisms and leading
to novel forms of treatment. Basic science research at the MRRC is contributing
to a new understanding of fundamental physiological mechanisms such as
how energy is metabolized in the brain, heart and muscles. MR physicists
at the center have also expanded the understanding of the underlying physical
principles of MRI and MRS.
The MRRC is both a core center serving the research needs of the
entire university and the primary research space for seven Yale faculty.
These faculty have primary or secondary appointments in the Section of
Biomedical Imaging in the Department of Diagnostic Radiology, which was
formed to synergize the expertise of the imaging research groups at the
School of Medicine. About 50 separate grants, totaling nearly $35 million
and representing 50 faculty members in 13 different departments, rely
upon the MRRC. The center itself is supported by fees from those grants
and $7 million in direct research grants to faculty in the Section of
Biomedical Imaging. The section is linked to the Department of Biomedical
Engineering, which is part of both the medical school and the Faculty
of Engineering on the main campus. In 2002, the new National Institute
of Biomedical Imaging and Bioengineering of the National Institutes of
Health awarded its first-ever grant to the section, $1.3 million to develop
technology to map neocortical epilepsy.
Faculty and staff at the MRRC work on their own research advancing
imaging science and also devise new ways to apply imaging technologies
to biomedical problems. “We’re developing state-of-the-art
magnetic resonance techniques,” says R. Todd Constable, Ph.D., associate
professor of diagnostic radiology and neurosurgery and director of the
fMRI group at the MRRC, “and as a function of that we’re able
to provide a state-of-the-art resource for the whole university.”
MRI is a complex technological feat, combining physics, mathematics,
computer sciences and biomedical science. The hauntingly clear MRI pictures
result from the differing radio signals given off by protons in the atoms
of tissues exposed to the intense magnetic fields. Those signals must
then be interpreted by computers and translated into graphic imagery.
The MR data require extensive manipulation, particularly in complex experiments,
to be translated into readable images. Rothman says, “Studies rarely
work straight out of the can.”
Constable and his 20-member team provide imaging support for more
than 30 faculty members directing major grant-supported investigations
utilizing fMRI within and outside the university. These include efforts
to improve the understanding of autism with Robert Schultz, Ph.D., in
the Child Study Center; studies of the role of the frontal lobe in working
memory and executive processing with neurobiologist Patricia S. Goldman-Rakic,
Ph.D.; mapping of memory processing with psychologist Marcia K. Johnson,
Ph.D.; and experiments aimed at finding better treatments for gambling
disorders with Marc N. Potenza, Ph.D. ’93, M.D. ’94, and for
schizophrenia with Bruce Wexler, M.D., FW ’77, both in the Department
of Psychiatry.
One of the most active programs utilizing MRRC resources is the
Yale Center for the Study of Learning and Attention, which has pioneered
the study of pathways the brain uses for reading. Co-director Sally E.
Shaywitz, M.D., also directs the Connecticut Longitudinal Study, which
is investigating the development of reading skills in children from ages
7 to 18, and in adults, and is the largest MRI study ever undertaken in
children. With the resources of the MRRC, Shaywitz and her husband and
research partner, Bennett A. Shaywitz, M.D., have mapped the neural systems
responsible for reading. They have also begun to explore the impact on
those neuronal pathways when educational techniques are used as interventions
to help children with dyslexia overcome their reading challenges. “We
can see how the brain is responding,” Bennett Shaywitz says of those
education interventions. “If we see effects on the brain, we’ll
know we’re on the right track.”
The Shaywitzes have begun to explore the use of MRS, a technique
for measuring metabolic rates within tissue. The technique can measure
the increased presence of a harmless biochemical tracer linked to glucose
to show where increased or decreased metabolic activity, associated with
tissue function, is occurring. The Shaywitzes will use MRS to search along
the neural pathway for reading to find where disruptions underlying learning
disorders may be taking place. “We are addressing questions at a
finer and finer level,” says Bennett Shaywitz. By using the brain
imaging technology they hope eventually to diagnose learning disorders
early enough to prevent lifelong difficulties.
Diabetes and brain energetics
Robert G. Shulman, Ph.D., founder and for many years director of research
in the MRRC and now Sterling Professor Emeritus of Molecular Biophysics
and Biochemistry, oversaw installation of the first human-sized research
magnet in Fitkin in 1986. He pioneered many of the MR techniques now used
in biomedical research around the world. His work demonstrated the validity
of MRS studies for tracing metabolism in tissue and then showed that the
technology could be used to explore the role of metabolic pathways in
humans. Many clinical advances followed those early studies.
In collaboration with professor of medicine and Howard Hughes Medical
Institute investigator Gerald I. Shulman, M.D., Ph.D. (no relation), Shulman
showed that a defect in muscle storage of glycogen was responsible for
the impairment exhibited by type 2 diabetes. That was in 1990. The following
year, Robert Shulman, Rothman and James W. Prichard, M.D., a former professor
of neurology who is now retired, were the first to demonstrate the effectiveness
of MR to follow brain functional activity, now a major application of
the technology. Shulman also directed studies that proved the feasibility
of using MR to study regional metabolic functioning in the brain.
Much about the brain remains a mystery, including how it utilizes
energy to carry out its most complex functions. Robert Shulman, Rothman,
and Fahmeed Hyder, Ph.D., an associate professor of diagnostic radiology
in the MRRC, have made a number of recent findings using MRS that have
sparked an emerging re-evaluation of the nature of brain function. These
findings were made possible by the development of MRS methods to simultaneously
image brain energy consumption and the release of glutamate and GABA,
the primary excitatory and inhibitory brain neurotransmitters, respectively.
Their studies have shown that even at rest the brain uses 80 percent of
its energy to support neuronal firing and neurotransmission, which are
the bases of brain function. Previously it was felt that there was little
neuronal activity in the resting brain.
Understanding the role of this enormous underlying activity has
implications for brain function studies of all sorts. “The baseline
is not negligible,” says Robert Shulman. Rothman adds, “Our
brains are always ‘on,’ despite the high energy cost.”
Understanding why this resting neuronal activity is necessary could help
explain the complexity of higher-order brain functions, such as learning
and memory, and potentially open up new pathways for understanding disruptions
in those functions. “These results show that the popular analogy
that the brain acts like a computer, which only accesses its processing
power when it is called on to perform a task, is not correct,” says
Rothman. “A new view of the cognition will need to account for the
data.”
Back to the OR
Novel understanding of brain metabolism made possible by Rothman, Robert
Shulman and others has radically altered neurosurgeon Spencer’s
outlook on epilepsy and its potential treatment. Epileptic seizures are
a state of electrical hyperexcitation that starts from a single site in
the brain and then spreads swiftly. Studies done at the MRRC demonstrate
what Spencer terms a paradox. The focal point triggering the seizure is
metabolically depressed relative to its surroundings. Spencer, Rothman
and Ognen A.C. Petroff, M.D., HS ’82, associate professor of neurology,
have been carrying out MRS studies to explain that paradox. MR analysis
of tissue removed from patients with epilepsy showed that it was not processing
glutamate appropriately. Instead, due to impairments in the cellular energy
supply needed to keep extracellular glutamate at a safe, low level, the
glutamate outside the cells was “backing up,” eventually setting
off an electrical fluctuation that spreads quickly into a seizure. This
and related findings may provide a key to treatment advances.
“This opened an important little door where we’ve not
had many thoughts about new therapies,” says Spencer. “If
it is an energy problem, then this is perhaps reversible.” Delivering
medication to the site of the brain malfunction could reregulate the brain’s
metabolism, much like pace-makers now do for patients with heart disease,
to prevent seizures. Utilizing new technology in the MRRC, he says, “we
can now create animal models to think about therapies. The underlying
cause of epilepsy may be reversible, but the only way to know is by imaging
before and after surgery.”
His work with the MRRC has already paved the way for better and
potentially less-invasive treatments for epilepsy patients. In association
with Spencer, the MRRC has developed new ways of bringing imaging techniques
directly into the operating room. This summer, Spencer will begin operating
on patients, utilizing computer-guided equipment developed by the Yale
team in conjunction with the firm BrainLAB. He will operate while wearing
goggles with a built-in monitor that gives him access to a virtual three-dimensional
display of MR imagery from inside patients’ brains. The images,
linked to the placement of the scalpel, will show him precisely where
the cutting blade is located beneath the surface of the brain and what
functional areas it is near. That should help reduce damage to surrounding
tissue. Already he utilizes a portable version of the BrainLAB to give
him visual information about the patient’s brain as he operates.
“It looks just like a tricorder,” he says, referring to the
medical device used in the futuristic television and movie series Star
Trek.
James S. Duncan, Ph.D., vice chair of diagnostic radiology and
director of the Image Processing and Analysis Group, is helping to develop
even more futuristic treatment methods. His group developed the software
used to integrate spatial, functional and metabolic images recorded in
MR studies into the real-time spatial coordinates of the patient’s
brain as Spencer operates. He is also attempting to develop a model that
simulates the natural deformation of the brain that takes place during
open-skull surgery. “If you are off by even less than a centimeter,
you can hit critical areas,” Duncan says. In the coming years, Spencer
will use Duncan’s models of brain deformation while he operates.
The two expect that, within the next five years, MRI and MRS testing to
identify the source of seizures and map the functional areas of the brain
in combination with Duncan’s graphic models will eliminate the need
for the costly, arduous and potentially hazardous intracranial surgery
that Taylor underwent.
Spencer credits the scientists at MRRC with changing his view of
epilepsy. “Instead of thinking of epilepsy as an electrical problem,”
he says, “I now think of it as a metabolic disease. They are much
more than MR physicists. They make you think about disease-related problems
in a different way.” YM
Marc Wortman is a contributing editor of Yale Medicine.
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