Imaging Techniques for Studying Neuronal Activity

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The technique of functional magnetic resonance imaging (fMRI) using either relative cerebral blood volume (rCBV), blood oxygenation level dependent (BOLD) or Trbased cerebral blood flow (CBF) techniques has led to a revolution in brain mapping [1 -3]. This is largely due to the fact that the advent of a noninvasive tool with reasonable contrast to noise, spatial, and temporal resolution, allows for studies to be conducted more easily than the prior positron emission tomography (PET) studies of brain activation. Both fMRI and PET studies of brain activation are based upon the coupling between neuronal activity, metabolism, and hemodynamics (see also Chapter 11, Section 2). The possibility that fMRI may help understand the organization and flow of information in the brain has led to an explosion in the number of centers dedicated to performing the technique. In addition to the interest in fMRI by the neuroscience community, a number of clinical conditions has the potential to benefit from the development of fMRI techniques, such as perfusion studies of stroke, presurgical planning for conservation of eloquent cortex during brain surgery, and investigation of motor systems in movement disorders. Most fMRI studies have used task activation, such as photic stimulation or finger movements, or a cognitive challenge to induce neuronal activity. However, it is also possible to elicit neuronal activity using pharmacologic ligands. This approach has the potential to generate maps of the metabolic consequences of receptor stimulation of relevance to a large number of cerebral disorders. Studies of receptor binding can be performed in vivo using PET imaging, or post mortem with autoradiography. These techniques allow one to use direct agonists or antagonists to map out the receptor binding parameters or the density of these sites in the brain. Such studies are of diagnostic value for the examination of dopamine receptor depletion in Parkinson's disease (PD) and have great potential for study of conditions such as drug abuse and schizophrenia.

Autoradiographic and PET studies have also examined metabolic changes (both blood flow and glucose utilization) after neurotransmitter stimulation using, for example, amphetamine [4]. While PET is the gold standard tool for measurement of regional changes in glucose utilization in vivo, the same cannot be said for PET studies of metabolic activation using CBF. A number of studies used PET to assess changes in CBF after drug stimulation. These studies suffer from the fact that, with PET, CBF is usually only measured once after administration of the drug whereas with MRI one can obtain the entire hemodynamic time course with temporal resolution on the order of 1 sec. The technique of fMRI is well suited to study these metabolic changes [5]. Several reports using MRI to study the acute effects of amphetamine [5-7], cocaine or cocaine analogs [5,8-10], apomorphine or L-dopa [11-13], nicotine [14], heroin [15], and serotonin ligands [16] have appeared. Nonetheless, there is a number of issues that render interpretation of the signal changes induced more difficult than in conventional task-related fMRI. Since drugs are used as the stimuli of interest, and because drugs can have effects very different from functional activation tasks, we have coined the term pharmacologic MRI (phMRI) to describe these experiments [5].

Unlike in conventional task-related fMRI studies where the time courses of the stimuli can be controlled at will, in phMRI the time course is determined by the pharmacodynamic profile of the drug administered to induce the signal changes. Since most drugs can be anticipated to have long time courses compared with task-related stimuli (tens of minutes or more compared with seconds for conventional fMRI), data collection and analysis schemes become important for accurate determination of metabolically induced signal changes after pharmacologic stimulus. A number of approaches to this problem will be discussed in Section 10.2.

There are generally two flavors of what might be considered pharmacologic MRI. The first is what has been discussed in the papers referenced above. This paradigm is most often run in the form of a drug challenge study in which MR signal changes are monitored after the acute administration of the drug of interest. Clearly, there are many permutations on this basic model, such as antagonism of the effects of one drug with another, or examining perhaps the acute effects of one drug upon the chronic effects of another (useful perhaps for studying cocaine addiction). The second flavor of what might be considered phMRI is the observation of the modulatory effects of a pharmaceutical upon a conventional task-related fMRI study, such as the effects of dopaminergic and glutamatergic drugs upon cognitive tasks [17,18]. Since this chapter is primarily concerned with animal studies such approaches will not be discussed further; however, the review by Honey and Bullmore provides an excellent summary of the work to date in humans [17] (see also Chapter 11, Section 11.3 and Section 11.4). The effects of such a drug administration during a cognitive task however, must be kept in mind when interpreting the hemodynamic changes — as the drug itself may have modulatory effects upon the hemodynamics. With this as a general background we proceed to compare the possibilities of studying neuroreceptors using MRI techniques with the more traditional techniques, such as PET and autoradiography.

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