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Cognitive deficits are a common condition in people who use crystal methamphetamine (meth).

The same is true for people infected with human immunodeficiency virus (HIV). Scientists also
speculate that children born to active meth users might suffer higher rates of cognitive and
behavioral disorders. A joint research effort by Linda Chang and Thomas Ernst at the University
of Hawai‘i’s John A. Burns School of Medicine (JABSOM) and The Queen’s Medical Center in
Honolulu has started to make crucial inroads into deciphering the root causes of these problems,
using novel adaptations of functional magnetic resonance imaging (fMRI) and magnetic
resonance spectroscopy (MRS).

Standard magnetic resonance imaging (MRI) scans only capture the structure (i.e., the shape or
size) of the brain. In contrast, fMRI goes a step further by using advanced imaging techniques to
detect brain function or brain activity in real time. MRS techniques can ascertain not just the
presence and location of certain metabolically active chemicals, but also the concentration of
these chemicals. With a grant from the White House Office for National Drug Control Policy and
other research grants from the National Institute on Drug Abuse, Chang, Ernst and a team of
physicists and neuroscientists are adding crucial capabilities to these powerful new MRI
technologies.

Despite decades of intensive research directed at decoding the inner workings of the human
brain, this most vital organ has remained an enigma. Scientists in recent decades have learned the
basic physical functions of the different parts of the brain and gained an understanding of some
of the most rudimentary biochemical mechanisms that control this complex mass of nerve cells.
But no convenient mechanism existed to study the living brain in detail. Brain chemistry changes
at death, so cadaver studies were mainly useful for physical insights. Invasive techniques, such
as electrode implantation, were both expensive and dangerous, not to mention totally
unacceptable for healthy people required as a control group for any scientific study. As non-
invasive techniques that are highly accurate and easily repeated, fMRI and MRS both offer
opportunities to examine the living brains of large groups of subjects over long periods of time,
with little impact on their well-being and at a low cost.

Scientists in the United Kingdom first applied MRS to


measure chemical compositions in living humans us ing an
MRI scanner two decades ago. Five years ago, these devices
bec ame us e ful i n diagnosing human medical conditions.
However, the capability of these devices has remained
limited. “Even though the technique is available
commercially, the software from the manufacturers does not
allow you to do many quantitative measurements. So we are
developing new methods of detecting certain important
chemicals in the brain,” says Chang.

Chang and Ernst are among the first researchers to convert


theoretical detection mechanisms of the key neurochemical
glutathione into a real-world detection and measurement
capability. They performed this work using a research-
dedicated Siemens 3 Tesla MRI device at The Queen’s Medical Center. Glutathione is believed
to play a critical role in protecting brain cells by preventing oxidative stress, a process in which
oxygenrich compounds (pro-oxidants) damage living cells. Reduced levels of the chemical in the
brain may be one of the primary causes of cognitive problems in meth users and HIV patients, as
well as a marker for brain cell death. “It may be partially responsible for causing brain damage
and dementia in HIV patients,” says Ernst.

To extract the magnetic signal for glutathione, Ernst relied


on complex physics. The magnetic detection signal for
creatine, a chemical critical to nerve cell function, overlaps
with large parts of the signal for glutathione. However,
creatine concentrations in the brain are much higher than
glutathione concentrations. In MRS scans, creatine masks
glutathione. This makes detection of the lower-
concentration biochemical difficult. Ernst and a UH
physicist on his staff, Napapon Sailasuta, used a quantum
mechanical principle called “coupling” to devise a way to
measure glutathione. Coupling describes a specific way that
hydrogen molecules bond. Hydrogen coupling is present in
glutathione, but not in creatine.

Sailasuta and Ernst wrote software that screens out magnetic


signatures not attached to the coupling phenomena. This
allowed them to accurately measure glutathione
concentrations in a living brain. Chang and Sailasuta are
planning to use this capability in their studies of the brain
chemistry of HIV/AIDS patients and meth users. To date,
the vast majority of the thousands of brain metabolites
remain below the detection threshold of even the most cutting-edge MRS systems. Regardless,
Ernst says that these limited capabilities are extremely valuable. “We may be able to measure
only 10 to 15 metabolites in the brain. But that relatively small amount yields a lot of useful
information about the status of the brain. It’s becoming one
of the most important uses of MRI,” says Ernst.

In parallel, Chang and Ernst are using fMRI to study the


effects of HIV on brain function. HIV patients are living
longer due to the efficacy of antiretroviral medications.
Chang is using fMRI to follow a group of HIV patients as
they age to determine whether aging exacerbates HIV’s
effect on brain activity. Another UH physicist, Andrew
Stenger, is developing new fMRI techniques to measure
brain function in brain regions that are typically difficult to
image with currently available methods. Together with
Chang, Stenger is planning to use these new techniques to
measure brain activity and blood flow in the brains of meth
users. The researchers hope to elucidate how the brains of
meth users are affected by drug use. This enhanced
understanding could prove important in developing new treatment approaches for these
individuals. Ernst believes that as fMRI and MRS technologies become more sensitive,
researchers will be able to track more of the real-time chemical and functional activities in the
brain. Over time, MRI could prove to be the ultimate decoding tool for the mysteries of the brain.

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