2000 AAAP ANNUAL MEETING SYMPOSIUM III
Neuroimaging and Substance Abuse
Neuroimaging using PET, SPECT and magnetic resonance (MR) technologies are useful tools. Findings can identify the clinical effects of alcohol, stimulants, sedatives and opioids on brain function both acutely and chronically. Dr. Renshaw discussed neuroimaging using MR technologies in substance abusers. Dr. Rubin presented positron emission tomography (PET) and single-photon emission computed tomography (SPECT) as it applies to the field of substance abuse.
Symposium Chair: Thomas R. Kosten, M.D., Yale University, VA Connecticut Health Care System, New Haven, CT.
Magnetic Resonance (MR) Imaging Studies of Substance Abuse
Perry F. Renshaw MD, PhD, McLean Hospital, Belmont, MANMR has developed over the last 62 years and we are about 16 years into the clinical magnetic resonance imaging (MRI) revolution. There have been several reasons to consider brain imaging for patients. One is that psychiatric symptomatology may derive from an underlying organic condition, e.g., tumor infarction, seizure, multiple sclerosis. In the world of substance abuse there are substance use patterns associated with different pathologies. An-other is that all functional disorders represent neuropathology at some level and, with the appropriate technology, one can detect or measure these changes.
Organic pathologies can present syndromes that might other-wise be seen as psychiatric illnesses, e.g., approximately 1/3 of those with brain tumors initially present as psychiatric syndromes. Tumors which appear with greater frequency in psychiatric populations are meningiomas and pituitary tumors. MRIs also detect undiagnosed multiple sclerosis (MS).
MRI technology includes these strengths: 1) no ionizing radiation, 2) longer scan time, 3) better detection of gray and white matter abnormalities; and these limitations: 1) not suitable for those with claustrophobia or ferrous implants, and 2) some things are not seen well, e.g., computer tomography (CT) is better for detecting changes post-trauma (fractures, acute bleeding).
Terms that are used in MRI reports are: T1-weighted, T2-weighted, or proton density weighted. This is analogous to the parameters that describe how long the shutter on a camera is open. The parameters are set at the time of scan and each type of image shows different tissue characteristics. T1-weighted shows things as you think they should be with appropriate light and dark tissue and are good for depiction of neuroanatomy. T2-weighted images don’t look like the brain, but are designed to highlight the areas of pathology. Areas that contain blood are often dark because of the effects of iron and areas that contain a tumor or edema are light because of an increased water content.
MRI contrast contains a paramagnetic nucleus (e.g., gadolinium); as opposed to CT contrast agents which contain iodine. MRI contrast is safer (1 death in 5 million doses). Contrast agents stay in the blood stream unless there is a failure of the integrity of the blood brain barrier. This could happen because of tumors or an area of active inflammation. This is called an "enhancement" (it gets lighter on T1 images after contrast).
The indications for clinical scans at Mc-Lean Hospital among 6,219 psychiatric inpatients are: 1) MS, 35 cases; 2) arachnoid cysts, 51 cases; 3) hydrocephalus, 4 cases; 4) hemorrhage, 26 cases and 5) AVM (arterial vein malfunction), 7 cases. There are published guidelines (not based on data). These include new onset of psychosis at any age, new onset of mood disorder after the age of 50, dementia of unknown etiology, focal neurological findings, acute change in mental state.
Uses of MRIs to look at the chronic effects of alcohol abuse include tissue relaxation abnormalities, ventricular enlargement, gray matter volume reduction, sulcal volume increases, white matter volume reduction (corpus callosum), cerebellar degeneration, and white matter lesions. It may be that these effects are easier to measure as we age and may be more pronounced in men. Correlations with neuro-psychological test performance are possible. If a person has a period of abstinence from alcohol, these findings will reverse, at least to a degree. Some studies have shown that there is improved brain white matter, ventricular, sulcal, and some anterior gray matter. There are also certain uncommon special conditions associated with alcohol abuse which have their own patterns of brain imaging findings such as cirrhosis and encephalopathy, Wernicke-Korsakoff Syndrome and Fetal Alcohol Syndrome.
Abnormalities with other drugs can also be shown with an MRI. Cocaine dependence shows increased incidence of white matter hyperintensities. This is thought to be neurovascular toxicity associated with cocaine ad-ministration. For the most part this is not thought to be reversible. Solvents and heroin can also lead to marked white matter abnormalities.
MRI technology is evolving very quickly. New methods may be available in the next 5 years. Studies are going on now with magnetic resonance spectroscopy using phosphorus and looking at a correlation between changes in brain chemistry and neuropsychological performance, and overall social well being. Hydrogen or proton magnetic resonance spectroscopy is also available. Membranes in the brain change when ethanol is administered. This raises the possibility of understanding the difference between tolerant and non-tolerant individuals. Or better yet, we may be able to understand what might be different in people who come from families with a history of alcohol dependence.
There are also studies using special techniques to highlight areas of brain GABA (clearly related to ethanol level) comparing people with and without alcohol dependence. These showed a 30% decrease in brain GABA levels in alcohol dependent subjects. This is also being shown in studies of cocaine dependence. The advantage of these measures is that if they can be tolerated by the subjects, it is acceptable to make repeated measurements.
Functional Magnetic Resonance Imaging (fMRI) has developed over the last decade for getting information that is not reflective of brain structure or chemistry, but rather has as its goal looking at how well the brain is working, or obtaining images that are sensitized to cerebral metabolism. The most common method is Blood Oxygen Level Dependent (BOLD) contrast, the phenomenon of un-coupling. A region of the brain goes from the resting state to being activated, which leads to changes in blood delivery—large changes in cerebral blood flow and more modest changes in cerebral blood volume. It is thought that alcohol is dilating the cerebral blood vessels so it becomes much more difficult to see the activation. With cocaine, the areas of activation are increased because of vessal constriction.
Of greater interest are studies of craving where some stimuli will be more salient to individuals with drug dependence than others. For example, we can compare the effects of cocaine cues on brain activation. Data from cocaine dependent subjects shows increases in signal intensity when cocaine cues are presented, relative to comparison subjects. Changes in brain areas tend to correlate well with subjective reports of craving, as well as with increases in heart rate and other peripheral data. So questions can be asked about subjective states and brain behavior. Also gender differences can be examined.
The real advantage of the use of MRI is that it is free of the use of ionizing radiation. It is also safe to use in pediatric populations. It allows us to look at the correlation with behavioral states and we can then ask questions like how does methylphenidate affect children with ADHD? While imaging techniques are relatively recent and are changing rapidly, it is reasonable to conclude that MRI holds promise for understanding many aspects of brain structure, chemistry, and function. It has been underapplied in substance abuse and that is a mistake because there is much that can be learned.
PET and SPECT Imaging Studies of Substance Abuse
Eric Rubin, MD, PhD, New York State Psychiatric Institute, New York, NY
Functional brain imaging can reveal the human neural systems contributing to psychiatric syndromes, including substance use disorders. This presentation described two functional imaging modalities derived from nuclear medicine and briefly reviewed their application to problems of substance use.
It is useful at the outset to note some neuropsychiatric principles which create the framework for such research. The symptomatology and behaviors of substance use overlap with other psychiatric disorders. Therefore it is reasonable to expect functional imaging to reveal commonalties among the neural pathways implicated as mediating symptoms in substance use and those implicated in other psychiatric syndromes. Some behaviors and thought processes of substance-dependent individuals overlap with features of obsessive-compulsive and other anxiety disorders, some perceptual symptoms related to drug use are shared with psychotic disorders and substance-related affective symptoms resemble those seen in mood disorders.
Functional imaging in humans and basic research indicate that such complex behavioral or mental symptoms reflect abnormal neural activity within specific large-scale brain pathways. The nature of such pathways in the human brain can be illustrated by schizophrenia studies. Research suggests that the prefrontal cortex may be considered a warehouse of motor programs and executive functions. Whether any particular program is enacted at any moment is influenced by contextual (environ-mental) constraints, which are processed by hippocampal function and also by affective factors, whose influence is mediated via the amygdala. Well-defined anatomical connections channel information from these areas into the nucleus accumbens where integration occurs, leading to the expression of behavior appropriate to current affective and environ-mental constraints. Dysfunction of such a regulatory pathway is likely relevant not only to schizophrenia, but also to substance abuse.
A hallmark of such pathways is that they are constructed from neurons residing in anatomically widely distributed brain regions. These neurons are linked by axon tracts ending in synapses which transfer and modulate information along the pathway using specific neurotransmitters. Dopamine is a transmitter of particular interest to substance abuse re-search, although we have come to appreciate that "the dopaminergic synapse" has many variants, all of which utilize dopamine in some fashion but may bear different dopamine-related sites (receptors, transporters) and may be co-modulated by a variety of other neurochemicals. Most drugs of abuse interfere with particular functions at the synapse.
Thus the synapse is a pivotal site for abused substances to alter the function of large-scale pathways. Drugs may acutely dampen or amplify synaptic signaling. Direct drug toxicity may alter the number or distribution of synapses and hence the strength of linkage between neurons in a pathway. Toxicity can interact with the stage of development of the organism, such that the brain of an adolescent may react differently than that of an adult to a neural insult presented by a sub-stance of abuse. Less well understood, but likely also representing synaptic changes, is the process of associative learning related to substance use whereby the experience of drug reinforcement changes the salience of stimuli in drug-related environments. Subsequent exposure to such contexts can evoke additional modulation of particular brain. This view of the brain thus ascribes behaviors to regulated activity within specific neural pathways. Current research clearly indicates that we need to think in terms of such complex functional net-works and the synapses which define them, rather than focusing our attention on single regions of the brain, when we consider neural mechanisms of drug-related behavior.
PET and SPECT principles: As the names indicate, positron emission tomography (PET) and single photon emission computed tomography (SPECT) both employ an emitter. The emitter is a molecule tagged with a radio-isotope, administered intravenously or by in-halation. Based on the molecule’s biological activity, it distributes within the living brain according to local levels of neural activity or local neurochemistry (see below). PET and SPECT both also use a detector, a sophisticated camera which can identify at a distance how the emitter has distributed in the brain.
While sharing many features, PET and SPECT differ in that SPECT emitters produce single photons, while PET tracers emit a positron, the latter initiating atomic events which make PET a higher resolution modality. In this presentation, the focus is therefore primarily be on PET. Unstable atoms such as fluoride-18 and carbon-11, linked to biomolecules, are positron emitters commonly used in PET. The emitter-labeled tracer distributes in the brain according to its molecular properties, and positrons, which are emitted combine with electrons in the local tissue environment leading to annihilation of both particles. The aftermath of each such annihilation is the emission of paired gamma rays at 180 degrees from each other in a "coincidence line". These rays are of high enough energy to penetrate outward from the subject’s tissues and to be detected by a camera outside the head. The camera contains detectors arranged in pairs. Many detector pairs are arrayed in a ring a-round the head, and there may be dozens of such rings in modern cameras, all working simultaneously, ultimately scanning the entire brain for the location of the positron emitter. This geometry, plus high-powered computation, yields a series of slices imaging the distribution of the tracer in the brain. The reconstructed images are typically displayed on a gray-scale, but are often overlaid with a gaudy color scale for ease of qualitative reading.
Applications: Two major arenas for PET and SPECT imaging are mapping neuronal activity and mapping neurochemistry. The "metabolic" approach to mapping neuronal activity involves use of a glucose analog, 18-F-deoxyglucose, which becomes trapped in synapses as a function of their level of activity, and so distributes positron emissions as a reflection of the brain’s regional glucose metabolism. Only PET is used for such metabolic mapping. A different means of mapping neuronal activity depends on measures of regional cerebral blood flow (rCBF): more blood flows to regions that are more active via autoregulation of the brain’s vasculature. Both PET and SPECT can be used for mapping rCBF, with PET yielding spatial resolution superior to that currently available with SPECT. Whether one selects metabolic or blood flow mapping depends on the question at hand. rCBF methods offer better temporal resolution and so are generally better for studying responses to laboratory challenges, such as the acute effects of drug administration. For examination of a steady state, such as what the brain looks like several weeks into drug abstinence, the glucose metabolism method is often preferable.
Neurochemical mapping involves radioligands tailored to bind to specific neurochemical sites in the brain. PET and SPECT are both used for such studies, which address issues such as the kinetics and distribution of drug entry to the brain, sites of drug binding, or the degree of receptor occupancy under different conditions (e.g., during drug challenge or medication treatment). Neurochemical mapping offers an opportunity to deter-mine the effect of abused drugs on specific transmitter systems, with an eye to medication development or better under-standing the molecular pathology of drug abuse. Limitations in neurochemical mapping include the difficulty of detecting target molecules in regions where they may be functional but present in densities below the camera’s sensitivity. There are also constraints due to ligand affinity on the use of repeated measures to follow dynamic neurochemical events (e.g., the acute response to drug administration).
Study design: Factors to consider in designing or evaluating functional imaging studies include: 1) Choice of imaging approach: This issue evolves from the physics of the camera and isotope used, encompasses spatial and temporal resolution requirements for a given study and includes the realities of cost, isotope stability and camera availability. SPECT devices are more widely available and less expensive than PET cameras. 2) Subject comfort and tolerance: Immobilization in a scanner can make a patient anxious, jittery or irritable. Unless attended to, the brain responses accompanying such emotions may contaminate the functional imaging data. 3) There is great value to entering an imaging study with an a priori hypothesis. The analysis of imaging data is plagued by multiple comparisons and power problems (thousands of pixels, dozens of definable brain regions and often small numbers of subjects in a study), which can be eased by a focused hypothesis. 4) As in any clinical research study, subject age, gender and health are variables to specify. Handedness makes a difference to brain organization and should be controlled in brain imaging studies. In terms of substance abuse, one should note the mix and severity of sub-stances used in the sample studied, medical or psychiatric comorbidity, in- or out-patient status, whether abstinence has been adequately monitored, and the composition of control groups.
Image analysis: Qualitative interpretation of PET and SPECT images—recognizing characteristic patterns of tracer distribution—has a role in clinical diagnostic work. How-ever, most imaging procedures can also be utilized quantitatively, and this approach is of value for discerning functional differences among brain regions which may escape a less formal visual analysis. Computer-assisted procedures allow metabolic rate, rCBF or neurochemical labeling to be quantified region by region. Alternatively, current statistical methods allow entire images obtained under different conditions to be compared with one another, subtracting out commonalties to look at the significant differences in brain function across conditions. Quantitative PET studies have demonstrated that some manipulations (including administration of many medications and drugs of abuse) cause not only regional effects, but also can exert global effects (a uniform shift across all brain regions in either metabolism or blood flow). Setting the statistical threshold for detection of such regional or global effects is a crucial decision in any functional imaging study. The gold standard for detecting regional and global changes across conditions is to use absolute data quantification, which may require more invasive and technically demanding procedures. As an alternative, relative quantification can be used, with the most popular approach consisting of dividing all regional values by the global value.
For metabolic or CBF studies, after identifying brain regions activated or deactivated in response to an intervention or in a particular clinical condition, one wants to find out how these regions are linked into functional path-ways. There are now statistical procedures which can allow inferences about a hierarchy of function among activated regions.
Imaging studies in substance use disorders: The burgeoning application of PET and SPECT imaging to substance abuse and dependence will be only briefly and selectively described here, merely to convey the scope of current research. PET and SPECT studies of brain metabolism and rCBF have indicated the human brain pathways likely involved in mediating the acute euphoriant effects of cocaine. Other PET and SPECT studies in the last few years have focused on identifying the brain substrate mediating cocaine craving, a key trigger for relapse during abstinence. As a result, the orbitofrontal cortex and related limbic regions are now under scrutiny as potential sites for pharmacologic manipulation in treating cocaine dependence. Neurochemical imaging studies have demonstrated that the degree to which the dopamine transporter in the striatum is occupied after cocaine administration is proportional to the reported high. Moving beyond dopamine, sophisticated study designs and a growing array of transmitter-specific radioligands are be-ginning to reveal the brain substrates involved in interactions among multiple transmitter systems in substance use.
PET and SPECT are also being applied to understand the brain correlates of drug-related neuropsychological deficits, the individual propensity for addiction or relapse, and psychiatric comorbidity secondary to substance use. Taken together, findings derived from functional brain imaging have greatly widened our view of the brain systems involved in substance abuse and dependence. No longer are we focused simply on the dopaminergic projection from the ventral tegmental area to the nucleus accumbens, but we now recognize the involvement of the thalamus, orbital frontal cortex, the amygdala and a host of related brain regions. We also have a growing appreciation of how these areas dynamically influence one another’s activity, and so may mediate the mental states and observable behaviors of substance abuse and dependence. In summary, PET and SPECT are powerful tools for investigating the neurobiology of substance use disorders. These imaging approaches can identify behaviorally relevant brain pathways, and can reveal the neurotransmitter mechanisms involved in the nor-mal and abnormal function of such circuits. Combined with thoughtful study design and the formulation of hypotheses to guide image acquisition and analysis, PET and SPECT will provide a more complete picture of what goes awry in the brains of our substance-using patients. Ultimately, such knowledge can be expected to give us pathophysiological leads to improving therapy.
2000 AAAP Annual Meeting Proceedings Copyright 2001 AAAP