Special Report: Brain Imaging Research
Volume 11, Number 5
NIDA-Supported Researchers Use Brain Imaging To Deepen Understanding
By Michael D. Meuller, NIDA NOTES Staff Writer
In addition to the neuroimaging research being conducted at Division of Intramural Research,
NIDA-supported research across the Nation also is offering a greater understanding
of addiction through the use of sophisticated neuroimaging techniques. The
studies range from identifying brain structures involved in craving to mapping
the emotional circuitry of substance abusers to imaging the neurobiological
basis of drug-induced euphoria.
"Neuroimaging allows us to see what is going on in a drug addict's
brain when he or she craves a drug or after he or she has taken it," says Dr. Joseph Frascella, chief of NIDA's Etiology and Clinical Neurobiology
Branch. "We are still in the early stages of this research, and the
techniques are being refined almost daily, but the findings are striking
and the studies get at the core of NIDA's mission-to understand and modify
the effects of drugs of abuse." (For more about how these imaging techniques
work, see The Basics of Brain Imaging)
Several NIDA-funded researchers are using positron emission tomography (PET)
to study aspects of drug abuse such as craving and the biochemical effects
of drugs on the brain. For example, Dr. Anna Rose Childress at the Addiction
Research Center at the University of Pennsylvania School of Medicine in Philadelphia and her colleagues have
used PET to image the brain's limbic system when craving occurs in cocaine
abusers. The limbic system is involved in the rewarding effects of abused
drugs and is believed to be important in learning to connect rewards to
the cues that signal them.
Dr. Childress presented her findings most recently at the 1996 Annual Meeting
of the Society for Neuroscience. The researchers prompted craving in study
participants with a videotape showing scenes of cocaine paraphernalia. Measuring
blood flow in different regions of the brain through PET, they found that
particular areas of the limbic system "light up," or are activated, among cocaine
abusers experiencing craving, an indication of increased brain activity.
"Neuroimaging allows us to see what is going
on in a drug addict's brain when he or she craves
a drug or after he or she has taken it."
"Our findings suggest that cocaine craving activates this circuitry
to an exceptionally high level," which results in craving, a very strong learned response with
powerful motivational properties, Dr. Childress says. Cues that signal cocaine
pull the drug abuser toward drug use, she says. Similar PET studies of craving
are being conducted at NIDA's Division of Intramural Research. (See NIDA Brain Imaging Research Links Cue-Induced
Craving to Structures Involved in Memory)
One goal of the imaging studies is to develop medications that block craving.
The researchers could use PET to help determine a medication's effectiveness
and how often it should be given, as well as allow researchers to search
for possible side effects.
In 1988, Dr. Nora D. Volkow, chairman of the Medical Department and director
of nuclear medicine at Brookhaven National Laboratory in Upton, New York,
became one of the first researchers to demonstrate, using PET, that cocaine
produces vascular disease in the brain. Today, she continues a wide range
of drug abuse research using PET. On the basis of her recent findings, Dr.
Volkow proposes that cocaine's powerful effects may be due in part to the
rapid rate at which the drug acts on and then leaves the brain. Other drugs
that activate the same areas are removed more slowly and do not have the
same powerful abuse potential. The drug's fast action accounts for its highly
reinforcing properties, and its fast removal promotes frequent use, she says.
Dr. Volkow and her colleagues believe that this frequent administration
of the drug activates a brain circuit that is involved in a range of behaviors
such as eating that, biologically, require repetition. Usually, this circuit
is deactivated once the behavior has achieved its goal. However, Dr. Volkow's
recent findings suggest that, in the case of cocaine, chronic use of the drug keeps the circuit "turned on," producing an almost perpetual compulsion to use the drug.
Like Dr. Childress's research, Dr. Volkow's studies have the ultimate goal
of speeding development of cocaine treatment medications. "Better understanding
of a drug's effects suggests new treatment strategies," says Dr. Volkow.
Dr. George Ricaurte, an assistant professor in the Department of Neurology
at the Johns Hopkins Medical Institutions in Baltimore, and his colleagues
are using PET to study possible long-term effects of amphetamine derivatives in the brain.
Drugs under investigation include methamphetamine; methcathinone, a methamphetamine-like
drug commonly known as "cat" that has recently appeared on the
street; and MDMA (3,4-methylenedioxymethamphetamine), known among drug users
The preliminary evidence regarding methcathinone indicates that people who
take repeated doses show lasting reductions in brain cell activity that
produces the chemical messenger dopamine. If these effects are permanent,
and there is an age-related decline in brain dopamine, methcathinone abusers
may be at increased risk of developing problems such as parkinsonism, which
is caused by a dopamine deficiency, Dr. Ricaurte says.
"The public health question here is whether people who use methamphetamine
and related drugs are incurring brain injury similar to that observed in animals and
whether there are clinical consequences of such injury," says Dr. Ricaurte.
(For more about Dr. Ricaurte's studies, see Response to Escalating
Methamphetamine Abuse Builds on NIDA-Funded Research, and Like
Methamphetamine, 'Ecstasy' May Cause Long-Term Brain Damage.)
Other NIDA-funded researchers are using magnetic resonance (MR) imaging
and spectroscopy to observe how brain structures change as drugs are producing
their effects. MR is especially well suited for measuring changes, says
Dr. Perry Renshaw, research director of the Brain Imaging Center at McLean
Hospital in Belmont, Massachusetts, and an assistant professor at Harvard
Medical School. "We can scan patients over and over, including during
treatment, and the technique is relatively inexpensive," he says.
Dr. Renshaw and his colleagues are using phosphorus magnetic resonance spectroscopy
(31P MRS), another type of functional imaging, to measure abnormal brain
activity in drug abusers.
NIDA-funded researchers are using magnetic
resonance to observe how brain structures
change as drugs are producing their effects.
When brain cells are active, their increased metabolism generates compounds
that contain phosphorus. 31P MRS can determine which areas of the brain
are active or damaged by measuring phosphorus levels in brain tissue. Dr.
Renshaw and his colleagues are seeing that chronic drug abuse is accompanied
by abnormal brain metabolism in some areas of the brain. The brain metabolism
of drug abusers seems to improve when they stop using drugs, he says.
Dr. Hans Breiter, a psychiatrist in the Departments of Psychiatry and Radiology
at Massachusetts General Hospital, and his colleagues are using functional
magnetic resonance imaging (fMRI) to study the direct effects of cocaine
on brain function. They are observing what parts of the brain are active
when an addict is feeling high from cocaine and what parts of the brain
are active when an addict craves more cocaine after having used the drug.
"We need to understand the craving felt by the cocaine user when the
drug effects are wearing off and the user wants more cocaine, if we are
to develop effective treatment for cocaine use," says Dr. Breiter.
He and his colleagues have found that the nucleus accumbens, a structure
deep inside the brain that is important in experiencing rewards, "lights
up" during episodes of this type of craving.
Dr. Breiter and colleagues also are investigating the amygdala, another
brain structure, which other researchers have shown is activated during
cue-induced cocaine craving. "It is believed that the amygdala plays
an important role in determining what is emotionally significant in the
environment," he says.
Usually, people habituate or mentally adjust to objects in the environment
that produce an emotional response, Dr. Breiter explains. He is studying the role of the
amygdala in this process and memory-related processes when normal subjects
are shown faces with happy expressions or fearful expressions. "We
found that activation of the amygdala in response to emotional faces rapidly
decreased over time, suggesting less attention to these emotional cues,"
says Dr. Breiter. "These imaging studies are helping us understand
the basis of emotion and motivation, which may help us understand how drugs
affect the brain."
|Dr. Linda Chang of Harbor-UCLA
Medical Center combines MRI, MRS, SPECT, and perfusion MRI images using
a computer program written at the Center.|
Some NIDA-funded researchers are combining techniques to take advantage
of the strengths of each. For example, neurologist Linda Chang and her colleagues
in the Department of Neurology at the Harbor-UCLA Medical Center in Torrance,
California, are using MRI, MRS, single photon emission computed tomography
(SPECT), and perfusion MRI to study the effect of cocaine on AIDS dementia
complex, a loss of mental and physical ability caused by infection of the
brain by HIV, the virus that causes AIDS. She is also using MRI, MRS, and
SPECT to study the neurotoxicity of the drug "ecstasy." Further,
Dr. Chang and her colleagues are applying these technologies to study ethnic
and gender differences in cocaine's effects. It appears that cocaine affects
the brain chemistry of men and women differently, she says.
"Neuroimaging has rapidly become one of the
key features of research in neuroscience."
Dr. Scott E. Lukas, director of the clinical neuropsychopharmacology laboratory
at McLean Hospital and an associate professor of psychiatry at Harvard Medical
School, is using electroencephalograms (EEGs) and MRI together to produce
the equivalent of a topographic map of the brain that shows an increase
in alpha waves produced by cocaine. Alpha waves are a particular frequency
of electrical activity in the brain that indicate a relaxed state or inactivity.
Mapping alpha waves during cocaine use shows what the brain looks like when
the drug abuser feels cocaine-induced euphoria, Dr. Lukas says.
These EEG measurements are used to produce the coordinates that pinpoint
where these alpha waves are coming from in the brain. Next, Dr. Lukas images
the patient's brain with MRI, which shows brain structures, and matches
this image with the coordinates. The research-ers are finding that a source
of cocaine-induced euphoria is the thalamus, a major relay center for sensory
information that both receives and sends out messages.
This investigation of alpha wave activity suggests a potential clinical
value for medications that could produce alpha waves at lower levels for
longer periods of time. "Presumably, these medications would be less
likely to be abused because they produce less euphoria," says Dr. Lukas.
"Neuroimaging has rapidly become one of the key features of research
in neuroscience," says NIDA's Dr. Frascella. These studies allow scientists
to really understand the brain processes that are altered by drugs, he believes.
NIDA expects many important findings and treatment applications to emerge
from these and other NIDA-funded imaging studies, he says.
Dr. Scott Lukas and his colleagues at McLean Hospital and Harvard Medical
School combined electroencephalograms and MRI to create this topographic
brain map. The image at the right shows the increase in alpha wave activity
during cocaine-induced euphoria.
Breiter, H., et al. Response and habituation of the human amygdala during
visual processing of facial expression. Neuron 17:875-887, 1996.
Breiter, H., et al. Activation of human brain reward circuitry by cocaine
observed using fMRI. Proceedings of the Society for Neuroscience 3:1933,
Chang, L. In vivo magnetic resonance spectroscopy in HIV and HIV-related
brain diseases. Reviews in the Neurosciences 6(4):365-378, 1995.
Chang, L.; Ernst, T.; and Strickland, T. Neurochemical abnormalities and
gender effects in abstinent asymptomatic cocaine users. Proceedings of the International
Society for Magnetic Resonance in Medicine 2:992, 1996.
Childress, A.R.; Mozley, P.D.; Fitzgerald, J.; Reivich, M.; Jaggi, J.; and
O'Brien, C.P. Regional brain blood flow during cue-induced cocaine craving.
Society for Neuroscience Abstracts 20:666.2, 1994.
Childress, A.R.; Mozley, P.D.; Fitzgerald, J.; Reivich, M.; Jaggi, J.; and
O'Brien, C.P. Limbic activation during cue-induced cocaine craving. Society
for Neuroscience Abstracts 21:767.1, 1995.
Childress, A.R.; McElgin, W.; Mozley, D.; Reivich, M.; and O'Brien, C.P.
Brain correlates of cue-induced cocaine and opiate craving. Society for
Neuroscience Abstracts 22:365.5, 1996.
Christensen, J.D.; Kaufman, M.J.; Levin, J.M.; Mendelson, J.H.; Holman,
B.L.; Cohen, B.M.; and Renshaw, P.F. Detection of abnormal cerebral metabolism
in polydrug abusers during early withdrawal using 31P MR spectroscopy. Magnetic
Resonance in Medicine 35:658-663, 1996.
Grob C.; Poland, R.; Chang, L.; and Ernst, T. Psychobiologic effects of
3,4-methylenedioxymethamphetamine (MDMA) in humans; methodological considerations
and preliminary observations. Behavioral Brain Research 73:103-107, 1996.
Lukas, S.E. Advanced electrophysiological imaging techniques for studying
drug effects. In: London, E.D., ed. Imaging Drug Action in the Brain. Boca
Raton, FL: CRC Press, Inc., pp. 389-404, 1993.
Ricaurte, G.; Wong, D.; Szabo, Z.; Yokoi, F.; Scheffel, U.; Mathews, W.;
Ravert, H.; and Dannals, R. Reductions in brain dopamine and serotonin transporters
detected in humans previously exposed to repeated high doses of methcathinone
using PET. Society for Neuroscience Abstracts 22:1915, 1996.
Sparago, M.; Wlos, J.; Yuan, J.; Hatzidimitriou, G.; Tolliver, J.; Dal Cason,
T.A.; Katz, J.; and Ricaurte, G. Neurotoxic and pharmacologic studies on
enantiomers of the N-methylated analog of cathinone (methcathinone): A new
drug of abuse. Journal of Pharmacology and Experimental Therapeutics 279(2):1043-1052,1996.
Volkow, N.D.; Ding, Y.-S.; Fowler, J.S.; and Wang, G.J. Cocaine addiction:
Hypothesis derived from imaging studies with PET. Journal of Addictive Diseases
From NIDA NOTES, November/December, 1996
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