Both SPECT and PET images are generated to represent different signal intensities in diverse brain regions as variations in brightness or color. Because the acquired images are functional representations, their interpretation with respect to identification of specific active areas, requires a correlation with the underlying structural anatomy of the brain. There are several different approaches to overcoming the relatively poor structural resolution of these procedures. The first is to delineate a "region of interest" (ROI) around an area of predicted change on a composite PET image or on a co-registered MRI scan, allowing for comparisons of the previously defined, sometimes arbitrarily chosen, brain areas. Lately, this method has been further developed by superimposing MRI-based templates on PET scans to more reliably identify anatomical structures or regions (Meyer et al., 1999a; Resnick et al., 1993). In order to estimate specific tracer uptake, different tracer kinetic models can be applied: Either specific binding is compared to nonspecific and free radioligand in a reference region thought to be free of specific binding, which can be performed with a simplified reference tissue model (Lammertsma and Hume, 1996), or, less desirable for studies in psychiatric patients, a full arterial model measuring the arterial input function through arterial cannulation and time-consuming metabolite measurements. The parameter of interest for all models is the binding potential (BP), which is defined as the number of available binding sites (Bmax) over the dissociation constant (Kd), or affinity (Mintun et al., 1984).
Another approach aims at using a "voxel-wise" analysis of the brain. A voxel represents the smallest volume unit that can be reconstructed depending on the spatial resolution of a scanner. For a voxel-by-voxel comparison, parametric images representing the binding potential in any given voxel need to be generated. In addition, these parametric images need to be smoothed and normalized into a standardized three-dimensional coordinate system, such as one based on the Talairach brain atlas (Talairach and Tournoux, 1988) or the standard Montreal Neurologic Institute (MNI) brain space. This can be done using Statistical Parametric Mapping version 99 (Friston et al., 1995) (SPM99) and a ligand-specific template (Meyer et al., 1999a). Results can subsequently be displayed as probability maps, in which areas of significant difference or activation changes to baseline conditions (i.e., contrasts) are graphically displayed.
Since the introduction of emission-based neuroimaging techniques more than 20 years ago, a number of studies have attempted to improve our understanding of the underlying biology of mental processes in normal volunteers and humans suffering from psychiatric disorders through examining changes in cerebral metabolism and rCBF during activation paradigms as compared to a baseline condition. These activation patterns are thought to represent changes in the neuronal arousal of the corresponding brain regions, for instance, memory processing (Tulving et al., 1994). Studies of blood flow and metabolism depend on comparisons of relative changes. Studies of cerebral blood flow and metabolism have examined changes in global cerebral blood flow and hemispheric symmetry as well as in many specific cortical and subcortical regions such as the frontal lobe, temporal lobe, various limbic structures (i.e., the hippocampal formation, amygdala, and uncus), cingulate gyrus, parietal lobe, occipital lobe, basal ganglia, thalamus, and cerebellum. Although a variety of psychiatric entities have been examined in this fashion, by far the greatest body of literature has been accumulated on affective disorders and schizophrenia.
Studies of Cerebral Metabolism and Blood Flow in Depression
Because changes in rCBF and metabolism are thought to represent activation of the affected brain regions, neuroimaging enables researchers to study the involvement of specific brain regions in generating or modulating psychological phenomena such as mood and affect, drive, attention, and memory, which are the main psychological functions affected in the clinical presentation of mood disorders. For this reason, it has been the main focus of such studies to identify specific functional neuroanatomical circuits and pathological changes that may represent the biological basis of mood and related disorders. By now, a considerable body of evidence has accumulated that has led to the formulation of a neuroanatomical model of mood regulation comprising the prefrontal cortex, amygdala-hippocampus complex, thalamus, and basal ganglia as the main regions involved. In addition to the evidence provided by in vivo neuroimaging studies, these brain areas were found to have extensive interconnections in postmortem studies. It now appears that two main neuroanatomical circuits are responsible for the regulation of mood functions. The first is a limbic-thalamic-cortical circuit including the amygdala, mediodorsal nucleus of thalamus, and the medial and ventral prefrontal cortex. The second is a limbic-striatal-pallidal-thalamic-cortical circuit including the striatum, ventral pallidum, and a number of the regions also involved in the first circuit mentioned. The evidence from functional neuroimaging studies implicating the involvement of these two circuits has been summarized in several extensive reviews (e.g. Drevets, 2000; Soares and Mann, 1997).
The cingulate gyrus seems to play a central role among the findings of recent studies: Hypermetabolism in the rostral anterior cingulate cortex is predictive of good response to treatment with antidepressant drugs, while hypometabolism of the same region is predictive of malresponse (Mayberg, 1997). Another particularly interesting finding has been the demonstration of an inverse reciprocal relationship in the activation of subgenual cingulate cortex and the dorsolateral prefrontal cortex through changes from the depressed to euthymic mood state and vice versa. These two areas, both part of the above-cited functional circuits, have been shown to change dramatically in activation with changes in functional mood states. An increased activation of the first of these two regions, the subgenual cingulate cortex, has been found to represent a marker for sad or depressed mood that resolves upon remission, while increased activation of the other, the dorsolateral prefrontal cortex, has repeatedly been found to represent a marker of attentional processing (and, incidentally, metabolic normalization of this region has also been reported to be a marker of antidepressant treatment effects). These findings contribute to and support a comprehensive neurobiological model of the pathophysiology of depression, which so far has not been possible to replicate to the same extent for any other psychiatric condition. These findings may therefore also be seen as representative of the possibilities afforded by neuroimaging techniques toward advancing our understanding of the physiology and pathophysiology of mental functioning (also see Chapters 2 and 7).
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