Regional Cerebral Glucose Metabolic Abnormality in Prader–Willi Syndrome: A ¹⁸F-FDG PET Study Under Sedation

MATERIALS AND METHODS

RESULTS

Figure 1 and Table 2 show brain regions with abnormal glucose metabolism in the PWS group versus the control group. Significant hypometabolism was observed in the right superior temporal gyrus and left cerebellar vermis. Metabolism was significantly elevated in the right orbitofrontal, bilateral middle frontal, right inferior frontal, and left superior frontal gyri. In addition, significant hypermetabolism was found in the bilateral anterior cingulate gyri, the right temporal pole, and the left uncus. Interestingly, no significant metabolic abnormality was found in the hypothalamus, the brain region believed to be most involved in energy intake and energy expenditure.

• Download figure
• Open in new tab
• Download powerpoint

FIGURE 1. 

Hypo- and hypermetabolic regions in PWS patients vs. healthy control subjects. These regions are displayed on surface rendered and transaxial images. Brain regions of abnormal glucose metabolism are displayed using height threshold of uncorrected P = 0.001 and extent threshold of 70 voxels, after removing age as a covariate of no interest. Numbers in each transaxial brain image indicate distance (mm) from the anterior commissure–posterior commissure plane.

Results of individual analysis are shown in Table 3, which confirm the group analysis findings. Hypometabolism in the superior temporal gyrus was found in 9 of the 16 patients. Most of the patients had hypermetabolism in the orbitofrontal (12/16), middle frontal (16/16), inferior frontal (6/16), superior frontal (14/16), and anterior cingulate (9/16) gyri and the uncus (10/16).

DISCUSSION

To our knowledge, the present study is the first functional brain mapping study in children with PWS. Interestingly, the metabolism of several brain areas was found to differ significantly in PWS and age- and sex-matched healthy children. PWS is known to be associated with obesity, but infantile PWS patients are rather weak and poorly nourished. The transition from a poorly nourished to an overweight state usually occurs before 6 y of age. In this study, we included PWS patients at the transitional period to see whether any brain metabolic changes were present at this period.

We attempted to interpret regional metabolic abnormalities versus abnormal eating behavior and psychobehavioral problems in PWS. We found that PWS children have reduced metabolism in the right superior temporal gyrus and left cerebellar vermis, regions that are associated with taste perception/food reward and cognitive and emotional function, respectively. The superior temporal region has been associated with liquid meal taste perception in the unpleasant state of extreme hunger (13). In addition, the superior temporal sulcus and the temporal pole have reciprocal connections with the insula (14), which, as a limbic/paralimbic area, constitutes a part of the taste pathway with the thalamus and hypothalamus, and which is involved in monitoring negative sensory input (15). It has also been suggested that the insular cortex is involved in incentive learning for food rewards (16). Moreover, cognitive and emotional problems may accompany cerebellar abnormalities or be their principal clinical presentation. Pathology in the cerebellar vermis (limbic cerebellum) and lateral hemisphere of the posterior cerebellum (involved in cognitive processing) is associated with cerebellar cognitive affective syndrome, which includes impairments in executive, visual-spatial, and linguistic abilities, with affective disturbances ranging from emotional blunting and depression to disinhibition and psychotic features (17).

In the present study, significant hypermetabolism was found in the right orbitofrontal, bilateral middle frontal, right inferior frontal, left superior frontal, and bilateral anterior cingulate gyri, right temporal pole, and left uncus in PWS children. The pre- and middle frontal and anterior cingulate regions are related to food intake in humans, and the frontal lobe is involved in cognitive functions related to eating; moreover, a feeding-suppression mechanism has been suggested to be located in the frontal lobe (18). Supporting this, frontal regions have been postulated to exert suppressing effects on other cerebral regions, such as the hypothalamus, which respond to food-related stimuli (19). The orbitofrontal cortex is a main cerebral area related to motivation and reward and is especially sensitive to food and monetary reward (20). Studies in nonhuman primates have shown that the orbitofrontal cortex is a cerebral region where responses to visual representations of food are modulated by an animal's hunger status (21). In humans, there was increased activation to visual food stimuli in the medial frontal/orbitofrontal cortex, amygdala, and insula in the premeal condition, which resolved after ingestion of a small meal (22,23). Frontal regions have also been shown to be associated with hunger and satiation in healthy humans—that is, hunger with increased blood flow in the posterior orbitofrontal cortex and satiety with increased blood flow in the ventromedial and dorsolateral prefrontal cortices (24). In obsessive–compulsive disorder, PET studies have identified hypermetabolism in the orbitofrontal cortex, caudate nucleus, and anterior cingulate cortex (25–27). In addition, a volumetric study found that patients with obsessive–compulsive disorder have more total gray matter in the anterior cingulate gyrus (28) Orbitofrontal and anterior cingulate hypermetabolism, which is the most consistent finding in obsessive–compulsive disorder, and which was observed in our PWS patients, may constitute a neural correlate of obsessive–compulsive symptoms in PWS (29–31). Studies in monkeys have revealed a role for the temporal pole in a variety of functions, including taste and olfaction. The uncus is a bulbar allocortical protrusion located in the anterior–inferior medial part of the temporal lobe and receives a projection from the lateral striae of the olfactory tract. Gustatory and olfactory hallucination or auras have long been thought to originate from lesions in this area (32,33). In summary, our results indicate that PWS children have decreased glucose metabolism in the right superior temporal gyrus and left cerebellar vermis, which are associated with taste perception/food reward or cognitive and emotional function, respectively, and increased metabolism in the right orbitofrontal, bilateral middle frontal, right inferior frontal, left superior frontal, and bilateral anterior cingulate gyri, right temporal pole, and left uncus, regions involved in cognitive functions related to eating or obsessive–compulsive behavior.

Recent functional brain imaging studies demonstrated abnormal brain responses after food intake in adults with PWS (34). This study found that the satiety response in the orbitofrontal cortex is insensitive to food intake in PWS adults. Shapira et al. reported a delay in activation after glucose administration in the hypothalamus and other brain regions associated with satiety, such as insula, ventromedial prefrontal cortex, and nucleus accumbens in adults with PWS (35). Interestingly, we found no significant metabolic abnormality in the hypothalamus, which has a major role in the control of food intake. However, neurotracing studies have shown that the hypothalamus receives input from several other regions of the brain (e.g., the amygdala, hippocampal complex, insula, and several polymodal association areas of the prefrontal cortex) that are likely to modulate its activity (36,37). Therefore, the hypothalamus is likely to be only one of several brain centers involved in the regulation of eating behavior, all of which integrate central and peripheral signals before, in turn, transmitting impulses to sets of as yet-unidentified efferent sites. In this context, metabolic abnormalities in the prefrontal and limbic/paralimbic areas, as revealed in the present study, may represent a neural correlate of abnormal food intake in PWS.

This study has some limitations. First, a major limitation of this study is that study subjects were sedated with chloral hydrate before PET. Sedatives are known to lower cerebral glucose metabolism. Although the exact effects of chloral hydrate on cerebral glucose metabolism of pediatric patients are not known, animal studies have reported a 180% elevation of cortical extracellular glucose levels (38) and suppression of the phosphorylation process by hexokinase (39) during chloral hydrate anesthesia. During a state of generalized suppressed ¹⁸F-FDG uptake, the differences between children with PWS and children without PWS while awake are likely underestimated. Furthermore, there are differential patterns of suppression of ¹⁸F-FDG uptake in different cortical and subcortical structures induced by sedatives or during sleep. Although we found distinct cerebral metabolic features in PWS patients at a similar level of sedation with control subjects during the PET procedure, the extrapolation from the sedated state to the awake state indeed needs to be further proven. Second, the ages of PWS children in our investigation overlap the period from failure to thrive to compulsive overeating. Therefore, further analysis should be done to look at potential differences in brain metabolism during these stages of disease progression. Third, for SPM analysis, we spatially normalized PET images of child brains into the MNI template that is based on adult brains. It might be better to spatially normalize the images into the group template or an age-matched template to obtain more precise statistical results. However, our SPM analysis using an adult template yielded consistent metabolic findings across the patients. Suspicious artifacts, which were observed on the edge or outside the brain profile, could be easily differentiated by visual inspection. In addition, using a standard template (e.g., MNI template) allows more direct comparisons between data from different populations or conditions.

CONCLUSION

Our voxelwise analysis of ¹⁸F-FDG PET images of PWS children revealed metabolic abnormalities in brain regions that are directly or indirectly related with food intake and obsessive–compulsive behavior. Thus, this study describes, in part, the neural substrate underlying abnormal eating behavior and psychobehavioral problems (such as obsessions and compulsions) in PWS.