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X-ray computerized tomography (CT) allows one to explore the regional anatomy of the
brain in normal subjects and in patients suffering from neurological disease. Developed in
the early 1970's, CT is the oldest brain imaging technique.
In contrast to conventional
radiography, the CT scan distinguishes gray and white matter.
It provides images of bone,
brain tissue, and cerebrospinal fluid. Even structures within the brain can be distinguished.
Because it reveals anatomical detail, computerized tomography has greatly expanded the
clinician's capacity for diagnosis.
Nevertheless, the views of the brain produced by CT are
static, i.e., CT scans allow one to explore the structure but not the function of the brain.
To produce images of the dynamics of the living brain, other techniques must be combined
with CT.
Magnetic resonance imaging (MRI) is based on computerized tomography and has been
used to explore brain function as well as structure.
It is a powerful imaging technique that
can distinguish different body tissues because of their individual chemical composition.
MRI requires a subject to be exposed to a pulsed radio frequency signal superimposed on
a strong magnetic field gradient The pulsed field stimulates the atomic nuclei to emit
radio waves at characteristic frequencies dependent on the nuclear species and magnetic
field strength. The composite emission spectrum therefore contains spatial information.
Reorienting the magnetic field gradient allows one to image concentrations of particular
nuclear species.
III.
Passive - Invasive : This category is characterized by requiring direct access to the
brain in order to assess its activity.
Surgical procedures make up this category and very often generate useful data but involve
substantial risk and expense to the patient
IV.
Passive - Noninvasive : This category is characterized by the sensing of source
currents within the brain either through electric potentials on the scalp or extracranial
magnetic field's.
In terms of a patients perspective, this category represents the most
desirable of all the options considered.
An electroencephalogram (EEG) is record of the electrical activity of large ensembles of
neurons in the brain.
It is obtained while a subject is sleeping, sitting quietly, or during
specific sensory stimulation. The scheme is to place macroelectrodes over the top and
sides of a subjects scalp and measure the electrical potential between active electrodes.
The frequency content of the potentials recorded from the scalp of a normal human
typically vary from 1-30 Hz and are not a result of action potentials but a result of
extracellular current flow associated with summated synaptic potentials in the activated
pyramidal cells. The problem with current noninvasive tests based on EEG measurements
to assess electrical activity abnormalities appears to be with their inadequate spatial
selectivity.
While EEG is the mainstay of passive - noninvasive recording of brain electrical activity, a
relatively new passive-noninvasive technology is emerging for use in imaging the source currents
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of the brain. This technology is built around the magnetoencephalagram (MEG), i.e., a record of
the extracranial magnetic field generated by the brain source currents and has many advantages
over todays competing technologies.
In this application, the instrument used to generate images
of brain source currents is built from magnetometers based on superconducting quantum
interference device (SQUID) technology.
SQUID based magnetometers are very low noise devices that can respond to millisecond scale
activity and monitor magnetic fields one billion times weaker than the Earth's magnetic field. This
level of sensitivity and resolution is required because the magnetic fields generated by brain source
currents are typically 100 - 1000 fT in strength and extend from 0 -
1 kHz in frequency.
Clinical implementation of this technology would require a conformal array of SQUID sensors
placed in close proximity to the patients head. The array would then register brain electrical
activity during a monitoring session. By using beamforming and beamsteering techniques, familiar
to phased array antenna technology, in conjunction with an accurate patient specific brain model
one can image source current activity to within a few millimeters, depending on the size of the
sensor array. Most imaging techniques currently being used are based on an idealized dipole
source current model and a layered sphere model of the brain.
In reality, however, brain source
currents are distributed throughout regions of the brain. This beamforming and beamsteering
technique is ideally suited to mapping distributed source currents.
Unlike the competing technologies discussed above, brain source current imaging MEG
technology enables one to precisely associate brain function with underlying anatomic structure.
By understanding normal neurological phenomenology it will be possible to quantify abnormal
brain activity and the brain disorders that result Consequently, this technology will directly
impact the diagnosis of brain disorders such as stroke, epilepsy, Parkinson's disease, Alzheimer’s
disease, and head trauma.
Furthermore, the ability to quantify abnormal brain activity directly
impacts the development of new drug intervention strategies.
Currently it is impossible to
determine drug effectiveness noninvasively. Generally drug effectiveness is judged solely on the
basis of behavioral changes which are notoriously unreliable and may take days or even months to
develop. Moreover, measurements of drug concentrations in the blood stream frequently fail to
indicate the drug concentrations at the brain cells where they are active. The best measurement is
one that monitors the changes in brain activity directly, and preferably one that is passive-
noninvasive. The ability to assess drug efficacy in a timely manner will significantly reduce the
costs involved with bringing an experimental drug to market.
Presently the average cost to
achieve this is $231 million and 12 years.
One of the many promising clinical applications of the brain source current imaging technology is
in the identification of the focal point of epilepsy in persons who are candidates for surgical
removal of the epileptogenic region.
Current diagnostic procedures, namely EEG, CT, MRI, and
PET often yield inadequate information for accurately determining the location of the
epileptogenic focus within the brain. So the competing technology to diagnostic biomagnetic
imaging is an invasive diagnostic procedure involving surgical intervention using depth electrodes.
These electrodes are inserted into the brain through holes in the patient's skull and the electrical
signals are then monitored for long periods of time, 5-7 days. This procedure obviously comes at
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substantial risk and expense, $20,000-$60,000. Consequently, of the approximately 360,000
persons in the United States that are candidates for epilepsy surgery only a couple hundred a year
are actually treated.
If the epileptogenic region can be surgically removed, however, the patient
may become completely free from seizures.
Brain source current imaging MEG can decrease the
need for surgical diagnostic procedures in patients with epilepsy by providing preoperative,
noninvasive localization of the epileptogenic focus in three dimensions.
It will also minimize the
collateral damage associated with the surgical removal of the epileptogenic tissue. This would
clearly reduce both the direct and indirect costs associated with epilepsy which next to stroke is
the most common neurological disease:
about 1% of the population suffers from epilepsy. There
are approximately 55 epilepsy surgery centers throughout the United States and Western Europe
that would directly benefit from this new biomagnetic imaging technology.
Although MEG machines on the market today are large and expensive, it is quite likely that future
machines will be smaller, less expensive, and readily available in a much wider market This will
permit the dynamic biomagnetic activity of electrically excitable organs (most notably the heart
and brain) to be routinely monitored quickly and noninvasively. The miniaturization of this
technology will permit rapid mass-screening of numerous medical disorders. Many disorders,
when detected in their very early stages, may be treated at a much lower cost and with much less
patient suffering than when they become acute.
In this manner, this technology may greatly
reduce medical costs by providing very early detection of disorders long before they become
clinical.
Since no physical contact is required with the patient, these machines have the capability
of screening patients rapidly for specific disorders once their capabilities are scaled-up from the
present technological level. This proposed research will result in the machine improvements
necessary to achieve this mass-screening capability. We anticipate that many private companies
would then be interested in producing such machines commercially following a cooperative
research and development activity with our laboratories.
The enormous commercial and research markets for this biomagnetic imaging technology has not
gone unnoticed by foreign governments.
In particular, Japan's Key Technology Center (JKTC)
joined with ten domestic firms Hitachi Ltd., Sumitomo Electric Industrial Company Ltd.,
Takenaka Komuten Company Ltd., Shimazu Corp., Seiko, Inc., Daikin Industries Ltd.,
Yokogawa Electric Corp, Toshiba, Shimizu, and ULVAC Corp. to establish the
"Superconducting Sensor Research Laboratory" a new laboratory that will develop SQUID
technology for basic brain research. The specific objective is to develop a 200-channel SQUID
based MEG instrument for noninvasive brain examination. The system will then be used in brain
research including source current imaging and analysis of data. This laboratory was initially
capitalized at 100 million yen, and then recapitalized at 6 billion yen over a six year period that
began in March 1990. The laboratory is funded 70% of budget by JKTC (a satellite bureau of
Japan's Ministry of International Trade and Industry, MITI) and the other 30% by the consortium
of ten companies.
The future of cognitive neuroscience hinges on our ability to study the dynamics of the living
human brain. MEG has become the "new" noninvasive imaging technique that can provide
clinically applicable information on the health of the brain, heart, and neuromuscular system.
It
shows promise of being the most important source current imaging technique to impact medical
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imaging since the advent of MRI.
It is clear that the United States must not lose the ongoing
technological battle in this area for not only economic competitiveness reasons but also national
security reasons.
III. Problem Statement
This section specifically defines many problems that can be directly addressed with the brain
source current imaging MEG system described in the proposed effort
A. Neurological problems
The improved ability to extract and pinpoint brain signals using advanced hardware and signal-
processing techniques will have numerous commercial and military applications, only a few of
which can be mentioned here. In the commercial sphere, the most significant anticipated
applications are improved clinical diagnostic tests for functional brain disorders. According to
the Health Care Financing Administration (HCFA), total annual healthcare related spending in
the United States exceeds $400 billion. More than one-third of this total, or $150 billion, is spent
on the diagnosis and care of 72 million Americans affected by neurological and mental health
disorders. The majority of these disorders are functional in nature and are poorly understood.
Despite immense expenditures, the diagnosis and care of those afflicted with these illnesses has
been inadequate because in most cases no direct noninvasive and definitive test exists to
effectively diagnose or monitor treatment. We believe MEG will provide the required test
capability, provided techniques can be developed to readily measure spontaneous and stimulated
brain electrical activity from specific places in the brain that are implicated in specific brain
disorders. This is exactly the goal of our development of the instrumentation and signal
processing techniques described in this proposal, and therefore this work has enormous
commercial potential
To appreciate the range of commercial applications for an advanced neuromagnetometer, we
have selected several significant examples:
1.
Epilepsy
The first example is the surgical cure of epilepsy, which is a grossly underutilized therapy. This
is mainly due to the high cost ($20,000 to upwards of $60,000 per patient) and invasive nature
(electrodes are surgically implanted into the brain to record the location of abnormal electrical
activity responsible for the seizures) of the presurgical evaluation. Conservative statistical
projections indicate there are at least 360,000 patients in the United States meeting the criteria
for epilepsy surgery: Their seizures cannot be controlled by drug therapy; they are severely
incapacitated by the disorder, and the brain tissue responsible for their seizures is localized and
could be removed without significant neurological or functional impairment. Yet, only a couple
of hundred epilepsy surgeries are performed annually. MEG is currently being tested as a
noninvasive
alternative to the present direct cortical recording techniques, and it shows great
promise. If we can accomplish the improvements in instrument design and signal-processing
capability that we are expecting in Phase II, MEG should be able to routinely identify the source
of single epileptic events in the brain. This will reduce the cost of presurgical evaluation by an
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