Christoph Felder

Regional brain metabolic activation during craving elicited by recall of previous drug experiences

Cocaine cues elicit craving and physiological responses. The cerebral circuits involved in these are poorly understood. The purpose of this study was to assess the relation between regional brain activation and cocaine cue elicited responses. Thirteen right-handed cocaine abusers were scanned with positron emission tomography (PET) and [F-18] fluorodeoxyglucose (FDG) twice; during an interactive interview about neutral themes and during an interactive interview about cocaine themes designed to elicit cocaine craving. In parallel the behavioral (rated from 0: felt nothing to 10: felt extreme) and cardiovascular responses were recorded. During the cocaine theme interview subjects reported higher self reports for cocaine craving (+2.5+/-3.3, p < or = 0.02) and had higher heart rates (+4.7+/-7.2%, p < or = 0.001), systolic (+4+/-4%, p < or = 0.0001), and diastolic blood pressures (+2.6+/-3.8%, p < or = 0.003) than during the neutral interview. Absolute and relative metabolic values in the orbitofrontal (+16.4+/-17.1%, p < or = 0.005; +11.3+/-14.3%, p < or = 0.008) and left insular cortex (+21.6+/-19.6%, p < or = 0.002; +16.7+/-19.7%, p < or = 0.01) and relative values in cerebellum (+17.9+/-14.8%, p < or = 0.0008) were higher during the cocaine theme than during the neutral theme interview. Relative metabolic values in the right insular region (p < or = 0.0008) were significantly correlated with self reports of cocaine craving. Activation of the temporal insula, a brain region involved with autonomic control, and of the orbitofrontal cortex, a brain region involved with expectancy and reinforcing salience of stimuli, during the cocaine theme support their involvement with craving in cocaine addicted subjects.

Enhanced resting activity of the oral somatosensory cortex in obese subjects.

The cerebral mechanisms underlying excess food intake in obese subjects are poorly understood. We used PET and 2-deoxy-2[18F]fluoro-D-glucose to assess differences in regional brain metabolism between obese and lean subjects at rest. Brain metabolic images were analyzed using statistical parameter maps. We found that obese subjects have significantly higher metabolic activity in the bilateral parietal somatosensory cortex in the regions where sensation to the mouth, lips and tongue are located. The enhanced activity in somatosensory regions involved with sensory processing of food in the obese subjects could make them more sensitive to the rewarding properties of food related to palatability and could be one of the variables contributing to their excess food consumption.

Alcohol intoxication induces greater reductions in brain metabolism in male than in female subjects.

BACKGROUND The mechanisms underlying the gender differences in alcohol drinking behavior and alcohols effects are poorly understood and may reflect gender differences in brain neurochemistry. Alcohol decreases glucose metabolism in the human brain in a pattern that is consistent with its facilitation of GABAergic neurotransmission. We compared the regional changes in brain glucose metabolism during alcohol intoxication between female and male subjects. METHODS Ten female and 10 male healthy controls were scanned with positron emission tomography and 2-deoxy-2[18F]fluoro-D-glucose twice: 40 min after placebo (diet soda) or alcohol (0.75 g/kg mixed with diet soda). RESULTS Alcohol significantly and consistently decreased whole-brain metabolism. The magnitude of these changes was significantly larger in male (-25 +/- 6%) than in female (-14 +/- 11%; p < 0.005) subjects. Half of the female subjects had reductions in metabolism during intoxication that were significantly lower than those in male subjects. This blunted response in the female subjects was not due to differences in alcohol concentration in plasma, because these did not differ between the genders. In contrast, the self-reports for the perception of intoxication were significantly greater in female than in male subjects. The cognitive deterioration during alcohol intoxication, although not significant, tended to be worse in female subjects. CONCLUSIONS This study shows a markedly blunted sensitivity to the effects of acute alcohol on brain glucose metabolism in female subjects that may reflect gender differences in alcohols modulation of GABAergic neurotransmission. The greater behavioral effects of alcohol in female subjects despite the blunted metabolic responses could reflect other effects of alcohol, for which the regional metabolic signal may be hidden within the large decrements in metabolism that occur during alcohol intoxication.

Changes in brain functional homogeneity in subjects with Alzheimer's disease

Imaging studies have reported marked reductions in brain glucose metabolism in Alzheimers Disease (AD). However, less is known about disruptions in the patterns of brain metabolic activity. Here we questioned whether AD affects the patterns of homogeneity/heterogeneity in brain metabolism. PET images of 35 AD subjects were compared with those of 35 controls. A template was applied to extract a cortical rim, which was partitioned into 990 contiguous regions. Estimates of metabolic homogeneity were obtained using the coefficient of variation (CV). The CV of the entire cortex was found to be significantly larger in AD, suggesting increased heterogeneity at the whole brain level. In contrast, regional CV was significantly lower in AD in temporal and parietal cortices, which were the regions that along with the precuneus had the largest metabolic decrements, though the precuneus had increased CV. The enhanced heterogeneity for the global cortical pattern most likely reflects variability in the degree of pathology among brain regions as well as neuroanatomical disconnection. The enhanced homogeneity in parietal and temporal cortices is likely to reflect loss of regional differentiation (i.e. macrocolumnar disorganization). The enhanced CV in precuneus, despite its marked reductions in metabolism, suggests that increases in regional homogeneity in parietal and temporal cortices are not a mere reflection of the decrement in metabolism.

Distribution of tracer levels of cocaine in the human brain as assessed with averaged [11C]cocaine images.

The Ability of cocaine to block the dopamine transporter (DAT) in the nucleus accumbens, as well as its non‐striatal and non‐DAT actions, appears to be crucial for its reinforcing/rewardig effects. However, we have been unable to use PET and [11C]cocaine to map small regions with greater sensitivity due in part to the low specific to non‐ specific binding ration of [11C]cocaine. In order to increase the signal to noise ratio of the individual [11]cocaine images, we averagedthe distribution volume (DV) PET images of 17 normal controls. In addition we also obtained averaged images for the dynamic set (14 time frames) and for the K1 values. The dynamic images were used to generate the average time activity curves from which we obtained the time required to half maximum clearance (T50). Twenty‐nine ROIs were identified in the Talarach‐Tournoux atlas and were then projected to the corregistered average PET image. The brain regions clustered in 3 groups according to their DV values. The highest activity (Group DV.1, 4.6–3.7) included putamen > accumbens > caudate. Intermediate DVs (Group DV.2, 3.2–2.8) included thalamus (mediodorsal and ventrolateral nucleus) > precuneus and posterior cingulate gyrus . amygdala, hippocampus, and temporal pole. Group DV.3 with low DVs (2.6–2.1) included the orbital cortex, precentral gyrus, and cerebellum. The brain regions clustered in 3 groups according to their T50 values. Regions with the faster clearance rates (15–20 minutes) included the orbital cortex, posterior cingulate, dorsomedial thalamus, precuneus, and cerebellum. Intermediate clearance rates (20–25 minutes) included caudate, putamen and accumbens regions with the slowest clearance rates (25–30 minuters) included caudate, putamen, and accumbens. In addition to the previously documented high binding of cocaine in striatum and moderate binding in thalamus in the living human brain this study also documents binding of cocaine in limbic and paralimbic brain regions. Further work is required to characterize the binding properties of cocaine in these brain areas and to elucidate their role in the reinforcing and addictive properties of cocaine. Synapse 31:290–296, 1999.

Non-MAO A binding of clorgyline in white matter in human brain

Clorgyline is an irreversible inhibitor of monoamine oxidase (MAO A) which has been labeled with carbon‐11 (C‐11) and used to measure human brain MAO A with positron emission tomography (PET). In this study we compared [11C]clorgyline and deuterium‐substituted [11C]clorgyline ([11C]clorgyline‐D2) to better understand the molecular link between [11C]clorgyline binding and MAO A. In PET studies of five normal healthy volunteers scanned with [11C]clorgyline and [11C]clorgyline‐D2 2 h apart, deuterium substitution generally produced the expected reductions in the brain uptake of [11C]clorgyline. However, the reduction was not uniform with the C‐11 binding in white matter being significantly less sensitive to deuterium substitution than other brain regions. The percentages of the total binding attributable to MAO A is largest for the thalamus and smallest for the white matter and this is clearly seen in PET images with [11C]clorgyline‐D2. Thus deuterium‐substituted [11C]clorgyline selectively reduces the MAO A binding component of clorgyline in the human brain revealing non‐MAO A binding which is most apparent in the white matter. The characterization of the non‐MAO A binding component of this widely used MAO A inhibitor merits further investigation.

Strategy for the formation of parametric images under conditions of low injected radioactivity applied to PET studies with the irreversible monoamine oxidase A tracers [11C]clorgyline and deuterium-substituted [11C]clorgyline.

The construction of parametric positron emission tomography images of enzyme or receptor concentration obtained using irreversibly binding radiotracers presents problems not usually encountered with reversibly binding radiotracers. Difficulties are most apparent in brain regions having low blood flow and/or high enzyme or receptor concentration and are exacerbated with noisy data. This is especially true when minimal doses of radiotracer are administered. A comparison was recently reported of the irreversible monoamine oxidase A (MAO A) radiotracers [11C]clorgyline (CLG) and deuterium-substituted [11C]clorgyline (CLG-D) in the human brain using region of interest (ROI) analysis in which the authors observed an unexpected loss of image contrast with CLG-D compared with CLG. In order to more fully investigate patterns of binding of these irreversibly binding radiotracers, a strategy was devised to reduce noise in the generation of parametric images of the model term related to enzyme or receptor concentration. The generalized linear least squares (GLLS) method of Feng et al. (1995), a rapid linear method that is unbiased, was used for image-wide parameter estimation. Since GLLS can fail in the presence of large amounts of noise, local voxels were grouped within the image to increase the signal, and the GLLS method was combined with the standard nonlinear estimation methods when necessary. Voxels were grouped together depending on their proximity and whether they fell within a specified range of the time-integrated image. It was assumed that voxels meeting both criteria are functionally related. Simulations reflecting varying enzyme concentrations were performed to assess precision and accuracy of parameter estimates in the presence of varying amounts of noise. Using this approach, images were generated of the combination parameter λk3 (λ = K1/ k2, where K1 and k2 are plasma-to-tissue and tissue-to-plasma transport constants, respectively) that is related to enzyme concentration as well as images of the transport constant K1 for individual subjects. Reasonably high-quality images of both K1 and λk3 were obtained for CLG and CLG-D for individual subjects even with low injected doses averaging 6 mCi. While there were no differences in the K1 images, the λk3 images revealed the loss of contrast previously reported for CLG-D using the ROI analysis. This method should be generalizable to other tracers and should facilitate the analysis of group differences.

Intimate combination of low‐ and high‐resolution image data: I. real‐space PET and 1H2O MRI, PETAMRI

Two different types of (co‐registered) images of the same slice of tissue will generally have different spatial resolutions. The judicious pixel‐by‐pixel combination of their data can be accomplished to yield a single image exhibiting properties of both. Here, axial 18FDG PET and 1H2O MR images of the human brain are used as the low‐ and high‐resolution members of the pair. A color scale is necessary in order to provide for separate intensity parameters from the two image types. However, not all color scales can accommodate this separability. The HSV color model allows one to choose a color scale in which the intensity of the low‐resolution image type is coded as hue, while that of the high‐resolution type is coded as value, a reasonably independent parameter. Furthermore, the high‐resolution image must have high contrast and be quantitative in the same sense as the low‐resolution image almost always is. Here, relaxographic MR images (naturally segmented quantitative 1H2O spin‐density components) are used. Their essentially complete contrast serves to effect an apparent editing function when encoded as the value of the color scale. Thus, the combination of 18FDG PET images with gray‐matter (GM) relaxographic 1H2O images produces visually “GM‐edited” 18FDG PETAMR (positron emission tomography and magnetic resonance) images. These exhibit the high sensitivity to tracer amounts characteristic of PET along with the high spatial resolution of 1H2O MRI. At the same time, however, they retain the complete quantitative measures of each of their basis images. Magn Reson Med 42:345–360, 1999. Published 1999 Wiley‐Liss, Inc.

Increased activity of the temporal insula in subjects with bradycardia

Though it has been postulated that cortical brain regions participate in the regulation of heart rate, their involvement is poorly understood. Using PET and [18] FDG (to measure regional brain glucose metabolism, which serves as an index of brain function) we compared the regional brain metabolic activity between healthy subjects with bradycardia (<60 beats per minute) with those with normal heart rates in the 75-100 beats per minute range. Statistical Parametric Mapping (SPM) analyses revealed significant differences between the groups predominantly localized to the temporal insula. This finding was corroborated by a separate analysis that measured the metabolic activity for each subject in preselected regions located in the temporal insula. Subjects with bradycardia had significantly higher metabolic activity in the right (p < 0.0001) and in the left temporal insula (p < 0.015) than those with normal heart rates. Moreover, resting heart rates were negatively correlated with metabolism in the right (r = -0.77, p < 0.0001) and in the left temporal insula (r = -0.44, p < 0.05). These results corroborate the importance of the temporal insula in the regulation of resting heart rate in humans. The temporal insula is interconnected with limbic brain region and autonomic centers and suggests that this may be a mechanism by which emotional responses regulate heart rate.

Resting brain metabolic activity in a 4 tesla magnetic field.

MRI is a major tool for mapping brain function; thus it is important to assess potential effects on brain neuronal activity attributable to the requisite static magnetic field. This study used positron emission tomography (PET) and 18F‐deoxyglucose (18FDG) to measure brain glucose metabolism (a measure of brain function) in 12 subjects while their heads were in a 4 T MRI field during the 18FDG uptake period. The results were compared with those obtained when the subjects were in the earths field (PET scanner), and when they were in a simulated MRI environment in the PET instrument that imitated the restricted visual field of the MRI experiment. Whole‐brain metabolism, as well as metabolism in occipital cortex and posterior cingulate gyrus, was lower in the real (4 T) and simulated (0 T) MRI environments compared with the PET. This suggests that the metabolic differences are due mainly to the visual field differences characteristic of the MRI and PET instruments. We conclude that a static magnetic field of 4 T does not in itself affect this fairly sensitive measure of brain activity. Magn Reson Med 44:701–705, 2000.