Download Introduction Intrinsic optical imaging (IOI) is an imaging modality

Introduction
Intrinsic optical imaging (IOI) is an imaging modality employed in neuroscience to detect and
isolate cortical activation and map brain function to specific areas of the cortex. IOI works by detecting
the small changes in the reflective properties of the active cortex. The main source of this signal is the
hemodynamic response. When neurons are recruited, their metabolism increases, which depletes the
local oxygen levels. When hemoglobin becomes deoxygenated, the local capillary beds expand, causing
the influx of oxygenated blood. The IOI signal is based on the balance of oxyhemoglobin to
deoxyhemoglobin. The accurate mapping of functions to particular cortical areas has many important
potential uses. One example is in neurosurgery, during excision of tumor tissue, in which the removal of
the tumor could lead to the patient’s death or severe disability if the function of the tissue is not known.
Current instruments used to map brain function include functional magnetic resonance imaging
(fMRI), which has advantages such as noninvasiveness. However, even at very high magnetic fields, the
spatial resolution of fMRIs does not equal that of optical imaging. fMRIs also have the disadvantage of
being costly and very voluminous, and cannot be performed while
neurosurgery is in progress. Electrode recordings are also used
The optical imaging system used at the onset of this project
involved a large camera with a bulky objective (Imager 3001 used
with VDAQ 2.4 data acquisition software (Optical Imaging,
Germantown, NY)) (Fig. 1). These cameras provide very good
images and can resolve extremely small changes in hemodynamic
activity. However, they are costly (approximately $100,000 for the
Fig. 1 Current method of imaging
with macaque monkey using large
camera and requiring immobilization
immobilization of the subject. The cost is mostly associated with the of subject.
camera, illumination, and software package), and require complete
expensive parts involved in the optics of this large camera. Creating a camera with smaller, simpler
optics could theoretically minimize the cost associated with parts yet provide comparable results.
The issue of immobilization also needs to be resolved. Anesthetized preparations make the
detection of higher order cortical activity essentially impossible using IOI. The macaque monkeys being
used in imaging experiments are trained to sit perfectly still while fixating on a point on a screen in front
of them. Their ability to sit still eliminates the need for anesthesia, which allows the imaging of more
areas of the visual cortex. However, much more could be revealed if the subjects did not need to be still,
and could be performing multifunctional movements. Eliminating the movement restriction could lead
to the discovery of more accurate and functional brain maps.
Problem Statement and Specifications
The goal of this project is to design a miniature charge-coupled device (CCD) chip camera
suitable for intrinsic optical imaging of cortical activation, which allows movement of the animal being
tested. By designing a miniature CCD camera that can be fixed to the skull of a subject, the number of
physical restraints could theoretically be eliminated and thus open the possibility for novel studies. The
alternatives to developing this miniature camera are continuing with the current imaging methods,
which constrain the subjects and limit the studies which can be done. This provides very good optical
imaging but restricts the possibility of new research into cortical activation during normal activity.
The most important criteria required by our advisor for the development of a camera are:

Making the camera system scalable to fit on the head of a monkey or a rat;

It must be small and lightweight (in its miniaturized size);

It must be self-contained, therefore having potential for wireless data transmission;

It must have high resolution and well depth, requiring a high performance CCD chip;

The camera must allow for direct lighting to prevent pooling on the tissue being imaged.
The more specific design specifications desired by our advisor include resolution of 512 x 512
(minimum), to ensure sufficiently high image quality and well depth of 12 bits, to detect small signal
changes. The signal being measured is so small that chips with lower performance characteristics would
not be sufficient. The resolution and well depth are determined exclusively by the CCD chip used in the
camera. Therefore, the implementation of a high performance chip alone would yield the desired
resolution and well depth.
Another important specification is making the camera system self-contained and attachable to
the skull of the subject. This means it must be small, and not impede the movement of the animal. The
weight of the device must be less than 300 grams for larger monkeys, and even less for smaller monkeys
or rats. Part of making this system self-contained is making it wireless, while maintaining the desired
frame rate of 300 fps (frames per second). The issue with the wireless data transmission is that the
current technology does not allow for this transmission rate wirelessly. The current maximum wireless
frame rate is 10 fps, which is nowhere close to the desired 300 fps. Using a cable connection, the
maximum frame rate transmission would be 30 fps. With the current available technology, USB or
Firewire connections are the only way to get 300 fps. While Firewire could provide added flexibility, USB
being the current standard is sufficient for our application. As wireless technology develops in the next
few years, the transmission rate will reach 100 fps. It is unlikely that 300 fps will be feasible wirelessly in
the near future. The current options are limited to using USB connections, thus limiting the free
movement of the subjects, or using lower frames rates, which could be transmitted wirelessly. Lastly, to
make the camera self-contained, it must contain a way to power the CCD chip and lighting. Power can
be obtained through a USB connection. Otherwise, a battery must be incorporated or the chip will have
to be connected to DC power.
Approach
Initial investigation into miniaturized camera devices revealed several possible design examples.
The first device examined was the endoscope pill, the PillCam SB (Fig. 2). This product proved that a
small, self-contained, wireless camera can be constructed. However, the resolution and frame rate did
not meet specifications due to implementation of a CMOS (complementary metal-oxide-semiconductor)
chip rather than a CCD (charge-coupled device) chip. The next design example investigated was the
Clover black and white miniature digital security camera (Clover Electronics USA, St. Cerritos, CA) (Fig.
3), with a 1/3" Panasonic CCD chip. This camera was taken apart and its chip was utilized in a rough
optical design, despite resolution issues (which could feasibly be resolved later by simply ordering a
higher quality chip). With the Panasonic chip, we were able to implement our design ideas without the
burden of cost of a high performance chip. Our research into optics with Dr. Duco Jansen revealed that
with the implementation of a beamsplitter into our design, it would be possible to provide direct, even,
and controlled illumination (eliminating light pools) approximately parallel to the surface of the brain,
while maintaining small dimensions and high image quality. A large scale prototype was built to
investigate design feasibility. Then, following custom designing and machining of individual parts, a
smaller, more accurate prototype was assembled using the Panasonic chip. This prototype is easily
scalable to smaller dimensions; it is simply dependent upon chip and lens type (which can be ordered to
specification). All the parts can be custom made and mounted on microcontrollers for control of
translational movement (alteration of object to lens and lens to chip distances).
Literature Review and Patent Search
Constructing organized topographic maps of the primary somatosensory cortex can serve as a
basis for understanding somatosensory cortical signals. However, not as much information is known
about the topography of brain vasculature and activity in awake primates. Somatosensory studies done
at Vanderbilt have shown that cortical responses measured by IOI indicate differences in the signal
response in active regions. This evidence exemplifies the need to develop techniques for optical
imaging. In the awake animal, electrical stimuli of the finger produced an appropriate topographic
response compared to responses by an anaesthetized animal. The optical signal in the awake animal is
several times larger both in real size and signal amplitude (Chen 2005). These signals can then be imaged
by cameras. In 1996, Saturo Shiono et al. constructed the first device patented to measure brain activity
(U.S. Patent 5,566,673). Their patented design involved conducting reflected light from the brain surface
by way of an objective and focusing lens split into two beams by a beam splitter. The light beams were
passed through filters having different transmission wavelengths and received by CCD cameras (Shiono
1996). Charles Michael Fish developed and patented a method for a wireless brain wave monitoring
system. The method suggests using a polydirectional antenna to establish the wireless link (Fish 2000).
The wireless capability of this method, although it produces brain wave signals and not images can be
used to further develop the device explained in this paper.
Application of Standards
The validation and verification of the success of this device depends heavily on animal testing.
As a result, there are certain animal protocols that must be followed. The testing of this device was
conducted at Vanderbilt University. The Institutional Animal Care and Use Committee (IACUC) at
Vanderbilt Committee is a federally mandated university committee that ensures that the care and use
of animals is appropriate and humane, in accordance with animal welfare regulations. The IACUC
establishes policy and procedure on animal care and use for the institution. All testing was done with
the approval of the IACUC. Vanderbilt University is voluntarily accredited by the Association for the
Assessment of Accreditation of Laboratory Animal Care, International (AAALAC). By volunteering to be
accredited by this non-profit organization, the University shows that it meets the minimum standards
required by law, and is also going the extra step to achieve excellence in animal care and use.
The International Organization for Standardization has standards for medical equipment and
healthcare technology. This device meets the standards set by ISO 13485:2003 for medical devices as
well as the requirements for regulatory purposes.
Potential Applications/Markets
This device has the potential to serve in many markets. The images taken by this device can be
used to construct optical maps of cortical function. With this information on primates, neurologists will
be able to construct vasculature maps of the human brain (Roe 2006). The device is not restricted to just
one area of the brain however. Researchers who are studying epileptic centers of the brain can also use
this device. Many universities and hospitals conduct research on treating the epileptic center. Imaging
companies can also use this device to expand their product range. There is a great need for cameras of
this size and this capacity in companies such as McKesson, Toshiba Medical Systems, and GE Healthcare.
A goal of neurological surgery is the complete removal of abnormal or pathological tissue without
affecting the normal areas. Neurosurgeons can use this device to locate boundaries of the tumor tissue
so that they are able to successfully map adjacent, normal areas of the tumor committed to important
functions such as language, motor, and sensory areas (Honchman 2000).