Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – X-ray contrast imaging agent
Reexamination Certificate
2000-04-18
2003-05-27
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
X-ray contrast imaging agent
C424S009100, C424S009200, C424S001730
Reexamination Certificate
active
06569403
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a method of evaluating the effects of external stimuli, such as pharmaceutical drugs and environmental influences like fragrances, temperature, noise, light, etc. on a subject's brain, and more particularly to a method of evaluating the effects of administering such stimuli on a subject's brain using imaging techniques with positron emission tomography (PET).
Positron emission tomography (PET) is a radiotracer based method for producing images that quantitatively represent some biochemical property of the body (or portions of the body). In relation to this work, use of PET is confined to metabolic imaging of the brain. Although other methods are often used, the aspect of PET that is relevant to this particular work involves 2-fluoro-deoxyglucose (FDG) as the tracer in studies of cerebral metabolism and oxygen-15 labeled water (0-15) as the tracer in studies of cerebral blood flow. In general, FDG is used to estimate the rate of metabolism of glucose in different parts of the brain (Sokoloff, 1985) and provides data that represent integrated metabolic activity over a 20-40 minute period. 0-15 studies determine rate of blood flow in different parts of the brain with an integration period of 40-60 seconds. Given the different temporal demands of the two kinds of tracers, metabolic studies with FDG reveal relatively long-lasting effects or conditions (such as pathologies), whereas 0-15 studies are more sensitive to rapid, transient activity (such as sensory processes or cognition).
The problem that we are interested in is to determine how certain external stimuli or treatments affect cerebral metabolism. The external stimuli or treatments are usually drugs, but other interventions would be faced with the same considerations. For example, environmental influences such as fragrances, temperature, noise, taste, vibration, light and similar stimuli clearly effect cerebral metabolism. The basic paradigm which we use to study external stimuli or treatments is conceptually very simple: 1) measure metabolism without any external stimuli or treatment; 2) apply the external stimuli or treatment; 3) measure metabolism again; and 4) determine whether the measurement at step 3 is statistically different from the measurement at step 1. In actuality, there are a number of experimental difficulties that must be dealt with before this paradigm can be applied.
First of all, it is important to realize that all images provided by PET reflect every influence on the brain at the time of a study. All perceptions, movements, thoughts, and moods, as well as vegetative functions, have correlates in brain metabolism and blood flow, and these factors, which are always present, may obscure effects due to external stimuli or treatment. Even more critically, these factors may change in unknown ways in response to the external stimuli or treatment and hence the extent of their influence on observed metabolism becomes unpredictable. It can, therefore, be difficult to determine which features of an image are due specifically to the experimental treatment and which are secondary, due to some other change that occurs because of the treatment. The objective of much of the present work has been to develop ways of processing PET images to more easily identify metabolic effects that are due to a specific external stimuli or treatment.
Some of our earliest work involved the recognition that the condition of subjects at the time of a study might vary from subject to subject or even within the same subject at different times (Levy et al., 1987). Variation in the testing condition thus could make it difficult to isolate differences introduced by an external stimuli or treatment.
Accordingly, we have developed an appropriate standard condition for testing subjects. This condition is the visual monitoring task (VMT). The VMT requires that subjects watch a screen on which is projected either a bright light or a dim light. The lights are easily distinguished from each other. One light flashes at a varying interval of 4 to 7 seconds. The two lights are equally probable. We ordinarily test subjects for 3 to 4 blocks (96 total trials each block, about 10 minutes per block) with a slight break between blocks. Subjects are instructed to press a button every time the dim light flashes and to ignore the bright flashes (a very subtle point: the natural tendency is to respond to the bright light which is more salient; by making the dim light the target a slight increase in difficulty is introduced). A computer measures reaction time (RT) to each button press (expressed as median RT per block) and whether the press was correct (a dim light), false alarm (a bright light), or missing (dim light flashed but subject did not press the button). In some situations, the VMT includes a feedback system so that subjects could see how fast their RT's to target flashes were. This produces more consistent RT's (lower variance). The VMT differs from other tasks that are occasionally used in PET studies (Buchsbaum et al., 1992; Hazlett et al., 1993) in that it is extremely simple and undemanding—subjects can do this task even if they are very young, very old, or slightly affected by a drug. At the same time, successful performance of the task precludes extraneous mental activity.
In early drug/PET work, a common procedure was to use a fairly large dose of a drug in order to produce the largest practical metabolic or blood flow “signal”. We, however, immediately recognized that this would create a problem. Some of the drugs that we were planning to study (e.g., ethanol, diazepam) would likely incapacitate subjects to the point where they would not be able to perform the VMT adequately. However, we were convinced that any dramatic change in behavior as a result of taking a drug would be impossible to interpret (as an extreme example, subjects who are sleeping after a drink of ethanol should not be compared to waking subjects—there would undoubtedly be differences, but these would not be due to the drug but the condition of the subjects). Therefore, use of the VMT as part of our drug studies necessarily limits the dose of some drugs that can be studied. Thus, we chose to sacrifice a large but confounded signal in order to get a small but clean signal.
We also recognized that some subjects became very competitive while performing the VMT, visibly trying to get the lowest possible RT. We thus recognized that the demands of the VMT affected different subjects differently and perhaps would affect them differently under various drug conditions and/or other external stimuli treatments. Therefore, (and as now used in the OMEI process) we eliminated the RT feedback. Instead, we explicitly adopted an exclusion criterion: any condition on which RT is not stable (operationally defined as deviating by more than 10% from a reference condition) must be discarded. Similarly, any subject who does not perform with at least 95% accuracy (combined hits and correct rejections) must be omitted. Because subjects are confined to a relatively narrow range of behavior, we refer to this phase of the process as a “behavioral clamp.”
The VMT provides fairly good control of subject's overt behavior and even of their inner behavior (thinking). However, it does nothing to control mood, another variable that could be different under reference versus external stimuli (e.g. drug treatment) conditions, but as with sleep in the behavioral domain, it would be incorrect to attribute metabolic changes to a drug. In order to minimize the contribution of mood to metabolic changes that we would observe, we introduced into the PET experiments a standard test procedure. We administer the Profile of Mood States—POMS (McNair et al., 1971), a brief self-administered adjective check list that has been shown to be sensitive to drug effects (de Wit et al., 1985; de Wit et al., 1986) and other external stimuli. POMS scale scores are determined before and after the placebo and before and after the administration of the st
Cooper Malcolm D.
Metz John T.
Jarvis William R. A.
McDonnell & Boehnen Hulbert & Berghoff
Miicro, Incorporated
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