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The following HTML text is provided to enhance online readability. Many aspects of typography translate only awkwardly to HTML. Please use the page image as the authoritative form to ensure accuracy. The first indication that brain activity increases global CBF was reported by Roy and Sherrington over 100 years ago ( 24 ). Subsequent radioactive tracer techniques revealed increases in regional CBF (rCBF) during sensory stimulation or the performance of motor tasks ( 25 ). Recent studies that use the technique of optical imaging have demonstrated that cortical blood flow responses occur within 3 sec of sensory stimulation and are initially restricted to the 300- to 500-µm dimensions of cortical columns before spreading to involve the surrounding 3 mm to 5 mm of cortical tissue ( 26 – 28 ). The biochemical coupling of rCBF and synaptic activity is unknown and is still an area of active investigation. Studies of regional cerebral glucose utilization show that it and rCBF are normally tightly coupled and that the coupling occurs within the synaptic neuropil. The degree of coupling may vary among regions and under special experimental conditions ( 29 ), but it is reliably present in the normal mammal. Blocking the production of nitric oxide has no effect on synaptically induced rCBF responses in the rat somatosensory system ( 30 ). There is evidence that adenosine may be a critical link in this process, but it is likely that the action of several mediators may be important ( 31 ). A reduction of rCBF should occur when synaptic activity is suppressed below some resting or background level. Indeed, reductions in rCBF are observed in many PET studies of rCBF ( 32 ). However, the physiological significance of reduced rCBF is uncertain; it does not necessarily indicate the presence of inhibitory synaptic activity, because both inhibitory and excitatory synaptic activity can contribute to increases in synaptic metabolism ( 33 ). It is possible that some of the observed reductions in rCBF reflect autoregulatory mechanisms for global CBF, these reductions may not affect neuronal function; others may signal the removal of synaptic excitation (disfacilitation) by an inhibitory process located outside the area of rCBF decrease. In any event, it is not now possible to establish the valence of synaptic activity by rCBF estimation methods. PET Methodology. In most current studies, water (as H215O) or [15O]butanol is injected intravenously, or carbon dioxide (as C15O2) is inhaled and converted in the lungs to H215O. The 15O has a half-life of 122 sec. This length of time is sufficient for CBF measurements, because a bolus injection (e.g., 50 mCi) of this compound is nearly completely diffused into brain tissue on the first arterial pass ( 34 ). The count of emissions from a given volume of brain tissue is therefore a good estimate of the perfusion of that brain region during the counting period (approximately 60 sec for a typical scan). With the analytical methods that we use, we find that there are approximately 95,000 voxels in the gray matter of the average human brain. At our facility, a three-dimensional voxel is a cube 2.25 mm on each side. However, the spatial resolution of PET is limited by the smoothing introduced by image reconstruction filters and by the ability of the radiation detectors to differentiate the radiation emitted from two separate point sources. For PET, this distance, the full width at half maximum, is between 6 and 9 mm. However, the spatial accuracy in the localization of an activation focus is improved (to less than half the full width at half maximum) when subtraction images are made. Each image set is normalized to whole brain counts, and mean radioactivity concentration images are created by estimating rCBF across all subjects with stereotactic anatomical standardization techniques. Image voxel intensities are normalized to global cerebral activity with the use of a linear proportional model to remove baseline differences in global CBF between scans and subjects ( 35 ). In our facility, CBF images are aligned onto the coordinates of a standard stereotactic atlas ( 36 ), by using anatomical landmarks identified within the PET images of each individual so that the CBF differences are compared within the same brain regions ( 37 – 39 ). To determine whether a task or a stimulus has produced an increase in rCBF, the rCBF computed during a control condition is subtracted from that computed during the test condition. The resulting subtraction image, then, shows those brain regions with differences in CBF between the two conditions. A voxel-by-voxel statistical subtraction analysis (Z-score) with adjustment for multiple comparisons is performed by estimating the smoothness of subtraction images ( 40 ) following three-dimensional Gaussian filtering to enhance signal-to-noise ratio and compensate for residual anatomical variance. Typically, only those voxels with normalized CBF values larger than 60% of the global value are analyzed, because these voxels represent the gray matter of the brain. Voxels showing a significantly increased CBF compared with the average noise variance computed across all voxels (pooled variance) are identified ( 41 ). The critical level of significance is determined by using this information to adjust P = 0.05 ( 42 ). With this method, the results of interest are revealed primarily through the data analysis. However, it is also possible to perform correlations between the intensity of the rCBF responses throughout the brain and some behavioral parameter of interest, such as the perceived intensity of stimulation ( 43 ). In addition, volumes of interest (VOI) may be established within brain structures selected because of a priori hypotheses and the results of previously published PET studies. The size and shape of each VOI may be standardized across studies or determined separately according to functional criteria. We presently use a method similar to that described by Burton ( 44 ), in which voxels showing significant peak increases in CBF between comparison conditions are identified within the brain structure of interest; the voxels are progressively expanded in three dimensions to include contiguous voxels that meet the statistical criterion established by the voxel-by-voxel Z-score analysis. To determine the statistical significance of rCBF increases, a paired t statistic is computed for each VOI from the average percentage increase in CBF across all subjects. Levels of significance are established, based on the Bonferroni correction for multiple comparisons among VOI. Important Variables in the Conduct and Interpretation of PET Studies of Pain. There are now numerous studies from various facilities that have used PET during the application of experimental pain. The results are difficult to compare because they are affected by intersubject variability, type of stimulus, method of scanning, and data analysis methods. To assess the effect of some of these variables, we have conducted several investigations in normal subjects with a variety of stimulation methods. The variables we have considered thus far include gender, the physical characteristics of the stimulus, and the sources of nociceptive afferent input. Gender. The prevailing evidence suggests that although there is no reliable gender difference in pain thresholds, pain tolerance is generally higher in male than in female subjects ( 45 ). PET studies find gender differences in resting rCBF ( 46 ) or in the cerebral metabolic rate of glucose utilization ( 47 – 49 ). These findings suggest that there may be underlying gender differences in the neural mechanisms that mediate pain perception. Accordingly, we performed PET studies in normal right-handed male (n = 10) and female (n = 10) subjects (18 to 39 years old) as they discriminated differences in the intensity of innocuous and noxious heat stimuli applied to the left forearm ( 50 ). Thermal stimuli were 40°C or 50°C heat, applied with a thermode as repetitive 5-sec contacts to the left volar forearm. Both male and female subjects rated the 40°C stimuli as warm but not painful and the 50°C stimuli as painful, but females rated the 50°C stimuli as significantly more intense than did the males (P = 0.0052). Both genders showed a bilateral activation of premotor cortex during heat pain in addition to the activation of a number of contralateral structures, including the posterior insula, anterior cingulate cortex, and the cerebellar vermis ( Fig. 1 ). Overall, a nearly complete
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