Effects of Alcohol Dependence on the Brain

Positron Emission Tomography
by National Institute of Health

To study alcohol's effects on the structure and function of the brain in living human beings, researchers can use various imaging techniques. Positron emission tomography (PET) is a functional imaging approach used to study the metabolism and physiology of the brain. PET studies have found that both acute and chronic alcohol ingestion alter blood flow and metabolism in various brain regions, including the frontal lobes and cerebellum. Other analyses focusing on alcohol's effects on brain chemical (neurotransmitter) systems have found that both acute and chronic alcohol consumption alter the activities of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the excitatory neurotransmitters glutamate, dopamine, and serotonin. These alterations may contribute to the reinforcing and rewarding effects of alcohol as well as to symptoms of alcohol withdrawal. Imaging studies also have demonstrated that some of alcohol's adverse effects on brain function can be reversed by abstinence or alcoholism treatment interventions. In addition, imaging studies may help in the development of new medications for alcoholism treatment.

Alcohol exerts profound and harmful effects on the human nervous system. One way of determining how the brain is affected by alcohol consumption - particularly chronic excessive consumption that has led to alcohol dependence - is to look directly at the brain and its structures. Obviously, these examinations can be performed only during autopsies of deceased alcoholics. Investigations of the progression of alcohol-induced brain damage over time, its reversibility with abstinence, and the effectiveness of pharmacological and other interventions, however, require analyses in living subjects who can be studied repeatedly. Over the past few decades, various imaging techniques have been developed that allow researchers to study the structure and function of the brain both in healthy people and in people with alcoholism or other disorders. By allowing investigators to visualize alcohol's actions on the brain in living human beings, these techniques are essential tools for documenting alcohol-induced damage as well as the effects of interventions for alcoholism.

This article focuses primarily on the contributions of one imaging technique - positron emission tomography (PET) - to the analysis of alcohol-related brain damage. Following a description of PET technology, the article explores how this approach has helped elucidate alcohol's effects on the structures and functions of the brain, particularly its effects on various brain chemical (neurotransmitter) systems. Methodological considerations relevant to applying PET technology to studies of alcohol dependence also are discussed.

Pet and Other Neuroimaging Techniques

The various techniques to visually represent the nervous system that have been developed over the past few decades generally fall into two broad categories, structural and functional imaging approaches. Structural neuroimaging techniques, such as computerized tomography (CT), magnetic resonance imaging (MRI), and an MRI subtype known as diffusion tensor imaging (DTI), illustrate the anatomy of the nervous system. In alcohol research, these approaches are ideally suited for demonstrating anatomical changes that alcohol causes in the nervous system. In contrast, functional neuroimaging procedures - such as PET, functional MRI, magnetic resonance spectroscopy (MRS), and single photon emission computerized tomography - show the metabolic and physiologic processes of the nervous system in action. These imaging procedures are preferable for detecting alcohol-induced metabolic and physiologic alterations in the brain. Because each procedure has its strengths and weaknesses in the evaluation of people with alcoholism, clinicians and investigators must carefully consider the questions they want to address before deciding on the most appropriate approach.

Structural and functional neuroimaging techniques may be combined for certain research questions. For example, consecutive structural and functional neuroimaging analyses can be used to determine the exact anatomic location of alcohol's physiological and metabolic effects on the nervous system, and the results can be superimposed to obtain the most accurate estimates. An example of this procedure is the concomitant acquisition of both MRI and PET images on a person with alcoholism. The MRI and PET images then are realigned to obtain a composite image that has the benefits of the detailed structural information of MRI and the functional information from PET. (The MRI-PET procedure described here is time consuming and technically demanding and can therefore be used only in a few specialized research settings, but is not widely available for clinical purposes.)

PET makes it possible to visualize the physiology of living human beings by tracking radioactive compounds (radiotracers) that are of potential biological importance in the body. A radiotracer is produced in the laboratory by attaching a radioactive atom or molecule to a compound of interest. It then is usually injected into the patient's bloodstream, from which it can be taken up into the brain. This uptake of the radiotracer and its subsequent distribution within the brain can be measured over time to obtain information about the physiological process being studied. The amount of radiotracer administered is so small that it does not disturb the conditions in the living organism.3 (3 If a large amount of radiotracer was administered, the sudden excess of the compound under investigation could alter the rate or location of the biological processes in which that compound is involved. In general, the dose of a radiotracer for a routine PET scan is roughly 1,000 times [or three orders of magnitude] lower than the dose required to produce a pharmacological effect.) As a result, one can get direct information on the process being studied by tracking the radioactive molecule using a measuring device called a PET scanner. In addition, one can obtain quantitative information about the biological processes as they occur in the living organism by processing the data with sophisticated computer software, which also can generate three-dimensional images of the structures where the radiotracer is found.

To conduct functional brain imaging using PET, investigators need radiotracers that can cross the blood-brain barrier,4 distribute proportionally with the blood flow through the brain and remain in the brain long enough to permit PET imaging. (4 The blood-brain barrier is a physiological property of the blood vessels in the brain that prevents many substances from entering the brain, thereby protecting the brain from potentially harmful molecules.) PET tracers typically are identical or similar in structure to a naturally occurring molecule that acts specifically in the particular brain area, except that the radiotracers contain a radioactive atom. For example, the commonly used clinical radiotracer fluorodeoxyglucose is an analog of the ordinary sugar, glucose, which serves as the source of energy in active brain cells. A tracer commonly used for research purposes is a radioactive antagonist of the neurotransmitter dopamine. This tracer can interact with proteins called dopamine receptors that are located on many nerve cells and mediate dopamine's actions on the cells, but the antagonist's effect is the opposite from that of dopamine. By measuring the levels of the radioactive dopamine antagonist in various brain regions, one can estimate how many dopamine receptors are present in those regions. For example, neurons in certain brain areas (the basal ganglia) carry particularly high numbers of dopamine receptors and are therefore especially likely to be governed by dopamine's actions.

The radioactive atoms most commonly used in PET for studying the effect of alcohol on the brain are radioactive fluorine, carbon, and oxygen. Of these, 11C, and 15O have relatively short half-lives of 20 minutes and 2 minutes, respectively. This means that after those times, only half of the original radioactivity remains in the radiotracers. As a result, PET radiotracers that incorporate 11C and 15O must be produced at the same site where the PET study is conducted to avoid losing most of the radioactivity before the patient is injected with the radiotracer. Radiotracers can be produced only by machines called cyclotrons, which are extremely expensive, bulky, and require radioactive shielding. Therefore, few facilities can afford to conduct PET analyses using 11C and 15O. In contrast, 18F has a relatively long half-life of 109 minutes, which together with the possibility of rapid regional transfer of 18F, permits the performance of FDG PET scans in many facilities without cyclotrons.

About the Author

NIH is the nation's medical research agency - making important medical discoveries that improve health and save lives. The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting medical research.