Imaging Techniques: Visualizing The Living Brain

Images of the human BRAIN constructed using sophisticated computer systems have proven valuable for studying the effects of abused drugs. Nuclear medicine techniques, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), allow noninvasive studies of brain function in human volunteers by the administration of small amounts of radioisotopes. These procedures allow visualization and quantification of biochemical processes in the living brain. Functional MRI (magnetic resonance imaging) is a recently developed technique that makes it possible to construct functional brain images without radiation.

PET scanning uses radioisotopes that decay by emitting positrons (positively charged particles), which collide with electrons (negatively charged particles that surround atomic nuclei). In each collision, both the electron and positron are annihilated and energy is released in the form of two photons (quanta of light) that move in opposite directions. The detectors of a PET scanner surround the tissue being studied and register the arrival of photons. The associated computer system can calculate the location of each collision and reconstruct an image of the concentration of radioactivity in different parts of the tissue.

The most common applications of PET scanning involve functional measurements of cerebral (brain) metabolism or cerebral blood flow. PET is also used to map and quantify specific RECEPTORS for drugs and NEUROTRANSMITTERS in the brain. Cerebral glucose consumption (metabolism) and cerebral blood flow both reflect the activity of brain cells. Under normal circumstances, the cerebral metabolism and blood flow are tightly coupled. The most active brain cells require the most glucose, a sugar that is the primary energy source of the adult brain. Brain regions that contain the active cells also require high rates of blood flow for the delivery of nutrients and oxygen. In some conditions, however—including those caused by some drugs—cerebral metabolism and blood flow rates may be dissociated.

Rates of consumption of glucose in the whole brain or in specific brain regions have been measured using fluorodeoxyglucose (FDG) labeled with the positron-emitting isotope fluorine-18 (18F). Cerebral blood flow has been measured using oxygen-15 (15O), either inhaled in C15O2 or injected in 15O-labeled water.

In SPECT, radionuclides that emit single photons are used, including iodine-123 (123I) and technetium-99m (99mTc), and the photons are measured using a rotating gamma camera. The isotopes used in SPECT have longer half-lives (thirteen hours for 123I and six hours for 99m Tc than those used in PET (110 minutes for18F and 1015O). Therefore, whereas PET generally requires an on-site cyclotron to produce radio-isotopes, SPECT radioactive tracers can be made elsewhere and brought in for use. Although SPECT produces useful images, it does not provide either the quantitative precision or the spatial resolution of PET. Currently available PET scanners can resolve differences in the radioactivity of objects only 4 to 5 millimeters (mm) apart, while the resolution of new SPECT scanners is for 6 to 8 mm.

Before the advent of PET and SPECT, blood flow was measured using xenon-133, given by brief inhalation or intracarotid artery injection. Xenon-133 has a gamma emission with a half-life of 5.27 days, and the radioactivity is monitored outside the skull by an array of detectors that each record a beam of particles from a specific location. Unlike PET, the xenon-133 methods do not provide tomographic information—they do not produce images of "slices" of the brain. Therefore, activity in deep brain structures cannot be measured this way.

Recent advances in magnetic resonance imaging (MRI) technology have permitted functional measurement of cerebral blood volume, which is closely related to cerebral blood flow. Functional MRI assessments are based upon the difference between the paramagnetic properties of oxygenated and unoxygenated hemoglobin. Activation of a brain area causes increased blood flow to the region. Oxygen carried to the activated region is delivered in excess of that which is required by the increased activity. Therefore, it accumulates, as does oxyhemoglobin. Functional MRI produces brain images of very spatial and temporal resolution.

Since researchers are interested in the activity of specific brain structures, data are obtained by functional imaging techniques often adjusted (normalized) to remove the effects of differences between individuals in whole brain activity measurements considered irrelevant to the question under study. Normalized data may be expressed numerically as the quotient of the activity in a minutes for region of interest divided by the activity in the whole brain or in the slice containing the region. Such data are not always easy to interpret, since changes in the denominator can obscure the direction and magnitude of change in a region.

ACUTE EFFECTS OF DRUGS

Alcohol.

Acute administration of ALCOHOL (ethanol)—a depressant—reduces cerebral glucose utilization, as we learned from measurements taken by the FDG technique. Modest decreases of 15 percent or less are seen in the whole brain in response to a dose of 1 gram/kilogram (g/kg) of ethanol (about 2 oz. of 100 proof whiskey for a 150-lb. person). Slightly more dramatic reductions in metabolism have been noted in the brain's cortex, particularly in the frontal and the occipital regions.

In contrast, acute ethanol administration does not reduce cerebral blood flow. Therefore, ethanol appears to dissociate cerebral blood flow from glucose metabolism. Studies with xenon-133 have indicated that ethanol (0.75 g/kg) increases cerebral blood flow by about 20 percent overall. Furthermore, normalized data obtained by PET scanning, using15O-labeled water, indicate regional effects of ethanol on cerebral blood flow. The largest changes were noted in the cerebellum (decrease), the prefrontal cortex (increase), and the temporal cortex (increase).

Stimulants.

Studies with STIMULANTS have indicated that drugs of this class—including COCAINE and AMPHETAMINE—like the DEPRESSANT alcohol, reduce cerebral glucose utilization. Oral AMPHETAMINE at a dose of 0.5 milligrams/kilogram (mg/kg) decreases cerebral glucose metabolism by an average of about 6 percent of values in the unperturbed state, with no variation in the effect of the drug in different brain regions. A euphorigenic intravenous dose of cocaine (40 mg iv) also reduces cerebral glucose metabolism globally, averaging about a 14 percent decrease overall. The largest reductions occur in the left temporal pole and in the left lateral occipital gyrus.

Benzodiazepines.

The effects of diazepam (Valium), a benzodiazepine anxiolytic, on cerebral metabolism and blood flow have also been studied, and results indicate that both of these parameters of brain function are reduced. Glucose metabolism is reduced by taking doses as low as 0.07 milligrams/kilogram orally (about 5 mg, the dose that might be given for anxiety), and the effect does not show regional specificity. Small reductions in cerebral blood flow, as measured with xenon-133, are also seen in response to intravenous diazepam (0.1 mg/kg). The reductions average about 6 percent overall, with the largest reduction seen in the right frontal cortex.

Opioids.

The acute effects of HEROIN on cerebral metabolism or blood flow have not been reported, but a euphorigenic intramuscular dose of MORPHINE (30 mg) reduces cerebral metabolism globally, averaging about a 10 percent decrease overall. The largest reduction is found in the left superior frontal gyrus.

Marijuana.

The active ingredient in MARIJUANA, delta-9-TETRAHYDROCANNABINOL (THC), produces variable effects on global cerebral glucose consumption but increases normalized metabolism in the cerebellum, as is consistent with the localization of cannabinoid receptors to this region. The metabolic effect is correlated with self-reported intoxication and with the plasma concentration of THC.

Effects of Abused Drugs.

Taken together, these results indicate that all drugs of abuse that have consistent effects on cerebral metabolism produce decreases, but the magnitude of the decrease varies. This discrepancy is due, at least in part, to differences in dose and route of administration. The regional distribution of drug effects also varies, but the regional differences in percent change are not large in any of these studies. It seems that drugs of abuse—whether classified as depressants (alcohol), stimulants (cocaine), tranquilizers (benzodiazepines), or ANALGESICS (OPIOIDS)—reduce cerebral glucose metabolism globally.

Effects of abused drugs on global cerebral blood flow are less consistent, with decreases by the tranquilizer diazepam but increases by the depressant alcohol. Differences in regional effects of drugs on cerebral blood flow are minimal or absent, and the effects are generally global. Drugs of abuse may influence cerebral blood flow by direct effects on the cerebral blood vessels. Such direct vascular effects do not reflect changes in blood flow to meet the energy demand of the brain—in contrast, measurements of glucose metabolic rates are less sensitive to vascular responses that are seen as alterations in cerebral blood flow. In this respect, glucose metabolism can be a better measure of brain function than cerebral blood flow.

CHRONIC EFFECTS OF ABUSED DRUGS

Long-term drinking (chronic ethanol abuse) has toxic effects on the brain, and imaging techniques have added to the understanding of these effects. Brain glucose metabolism is decreased in recovering alcoholics (abstinent at least seven days), even if they do not show brain damage severe enough to be diagnosed as organic brain syndrome. The largest differences from controls were found in frontal lobe structures. Cerebral blood flow, measured using xenon-133, is also decreased in chronic alcoholics, with the largest differences in frontal and temporal lobe structures. To some extent, the changes are reversible with abstinence. Low cerebral blood flow is related to heavy drinking history, with the lowest flow rates in patients with brain damage (organic brain syndrome) due to alcohol.

Chronic use of cocaine has also been associated with persistent effects on functional markers in the brain. Whether measured by PET or SECT, cerebral blood flow in recovering cocaine addicts (abstinent four to fourteen days) shows focal abnormalities and lower flow rates than controls, particularly in frontal cortex. The etiology of abnormalities in cerebral blood flow in those with histories of cocaine abuse is not clear. In some cases, focal decrements may be related to the use of alcohol or other drugs of abuse or to the dysphoria related to the withdrawal of cocaine. Heroin addicts showed perfusion abnormalities as measured by SPECT during withdrawal (one week of abstinence), but cerebral blood flow had improved by three weeks of abstinence.

Taken together, studies using imaging techniques suggest that chronic use of alcohol and cocaine may damage certain structures in the frontal lobe of the brain. The frontal lobe is thought to be involved in decision making, planning, and other executive functions necessary for self-control. Thus chronic abuse of these drugs may injure the very brain structures that are required for a person to terminate drug use.

Current imaging techniques offer the promise of delineating the anatomical substrates of the acute and chronic effects of drugs of abuse. Such information may contribute to a further understanding of the causes and the consequences of substance abuse and, ultimately, may lead to more effective prevention and treatment strategies.

(SEE ALSO: Brain Structures and Drugs; Complications; Reward Pathways and Drugs)

BIBLIOGRAPHY

ANDREASEN, N. C. (1989). Brain imaging: Applications in psychiatry. Washington, DC: American Psychiatric Press.

BELLIVEAU, J. W., ET AL. (1991). Functional mapping of the human visual cortex by magnetic resonance imaging. Science, 254, 716-719.

HOLLOWAY, M. (1991). Rx for addiction. Scientific American, March, 94-103.

LONDON, E. D. (1984). Metabolism of the brain: A measure of cellular function in aging. In J. E. Johnson, Jr. (Ed.), Aging and cell function. New York: Plenum.

LONDON, E. D., ET AL. (1990). Cocaine-induced reduction of glucose utilization in human brain. Archives of General Psychiatry, 47, 567-574.

MORGAN, M. J., & LONDON, E. D. (in press). The use of positron emission tomography to study the acute effects of addictive drugs on cerebral metabolism.

ROLAND, P. E. (1993). Brain activation. New York: Wiley-Liss.

ROSE, J. S., ET AL. (1995). Cerebral perfusion in early and late opiate withdrawal: A technetium-99m-HMPAO SPECT study. Unpublished manuscript.

JUNE M. STAPLETON

EDYTHE D. LONDON

REVISED BY MARY CARVLIN