STUDIES ON THE MECHANISMS OF ACTION OF METHYLPHENIDATE AS COGNITIVE ENHANCER IN HEALTHY CONTROLS ? ? The use of stimulants (methylphenidate and amphetamine) as cognitive enhancers by the general public is increasing and is controversial. It is still unclear how they work or why they improve performance in some individuals but impair it in others. In this study we tested the hypothesis that stimulants enhance signal to noise ratio of neuronal activity and thereby increase neuronal efficiency. Methods: We measured the effects of methylphenidate (MP) on brain glucose metabolism using PET and FDG in 23 healthy adults. We predicted that by decreasing noise MP would reduce the glucose needed to perform the task. Brain metabolism was measured four times: when subjects performed a mathematical task after administration of placebo and after administration of MP (20 mg po), and when subjects were exposed to a control condition (viewing nature cards with not performance) after being given a placebo and after being given MP. Results: The cognitive task significantly increased whole brain metabolism when compared with the control condition both when given with placebo and with MP. Whole brain metabolism differed significantly for the conditions (p < 0.0005) and was lower for the control (36.6 b6 mol/100g/min) and the neutral non-task condition preceded by MP (35.8 b5 mol/100g/min) than for the cognitive task with placebo (43.2 b7 mol/100g/min) or the cognitive task preceded by MP (40.3 b7 mol/100g/min). The increase in whole brain metabolism was significantly smaller when the cognitive task was preceded by MP, than when preceded by placebo (11 b22 % versus 21 b26 %; p < 0.01). In contrast, when MP was given with the neutral non-task condition whole brain metabolism did not differ from the control condition (< -2% change). The smaller task-related increase in brain consumption of glucose when it was done with MP was related to focusing of brain activity. This was shown on the statistical parametric (SPM) analysis, which revealed that the area of significant activation (p < 0.001) with the cognitive task was larger with placebo (67,985 pixels) than with MP (22,632 pixels). Conclusion: Inasmuch as the brain required about 50% less increase in glucose for the same level of performance, this provides evidence that MP may increase the brains efficiency to a single task in healthy controls. While beneficial when neuronal resources are diverted by distracting stimuli this could be detrimental when brain resources are already optimally focused.? ? ? STUDIES ON THE INVOLVEMENT OF DOPAMINE AND PREFRONTAL REGIONS IN OBESITY? ? The role of dopamine (DA) in inhibitory control is being increasingly recognized and its disruption may contribute to behavioral disorders of discontrol such as obesity. However, the mechanism by which impaired dopamine neurotransmission interferes with inhibitory control is poorly understood. We had previously documented a reduction in dopamine D2 receptors in morbidly obese subjects. To assess if the reductions in D2 receptors were associated with activity in brain regions implicated in inhibitory control (cingulate gyrus, dorsolateral prefrontal and orbitofrontal cortex). Methods: PET was used with 11Craclopride to assess D2 receptors, with 11Cd-threo methylphenidate to assess dopamine transporters (DAT) and with 18FFDG to assess regional brain glucose metabolism in ten morbidly obese subjects (BMI > 40 kg/m2). Correlation analysis were done too assess the relationship between brain glucose metabolism and D2 receptor and DAT availability. Results: D2 receptor availability was associated with metabolism in dorsolateral prefrontal (p < 0.003), medial orbitofrontal (p < 0.01) and anterior cingulate gyrus (p < 0.01). In addition D2 receptors were associated with metabolism in somatosensory cortices (p < 0.01). The correlations with DAT and regional metabolism were not significant, which suggests that the association of synaptic dopamine markers with prefrontal metabolism was not general but specific to D2 receptors. Conclusion: This study shows a significant association between D2 receptors in striatum and the activity in dorsolateral prefrontal cortex, medial orbitofrontal and cingulate gyrus, which are brain regions implicated in inhibitory control and in compulsive behaviors, which suggests that this may be one of the mechanisms by which low D2 receptors in obesity could lead to poor behavioral control and overeating. In addition we also document a significant association between D2 receptors availability and metabolism in somatosensory cortex, which process palatability and that may modulate the incentive salience of food. ? ? ? STUDIES ON THE EFFECTS OF SLEEP DEPRIVATION ON BRAIN DOAPMINE ACTIVITY AND COGNITIVE FUNCTION? ? Sleep deprivation (SD) is associated with disruption in cognitive performance and changes in mood and energy. The mechanisms through which sleep deprivation deteriorates human performance are poorly understood but medications that increase dopamine (DA) revert some of the changes. Here we assess the effects of SD on brain DA neurotransmission in healthy controls and its relationship to brain function during a cognitive task. Methods: We measured changes in DA using PET and 11Craclopride (D2/D3 receptor radioligand that is sensitive to competition with endogenous DA) during rested wakefulness (RW) and after 24 hours of SD in 15 healthy controls. We also measured DA transporters (DAT) using PET and 11Ccocaine as a DAT radioligand. We measured DAT since they are the main synaptic mechanism that regulates extracellular concentration of DA and are also the pharmacological targets of stimulant medications used to promote wakefulness. To quantify D2/D3 receptor availability as well as DA transporter availability we quantified Bmax/Kd (distribution volume ratio in striatum to that in cerebellum V 1). We also measured cognitive performance using visual attention and working memory tasks and assessed self-reports of sleepiness and tiredness. Results: SD did not change the specific binding of 11Ccocaine in striatum (Bmax/Kd measures in caudate, putamen and thalamus), which indicated that it did not change DAT availability. In contrast, SD significantly decreased the specific binding of 11Craclopride (Bmax/Kd measures in caudate, putamen and thalamus) when compared with RW. The differences in ventral striatum were not significant. The correlation between changes in D2 receptor availability (measure of DA changes) with SD and the behavioral reports were significant for a positive correlation with fatigue (Caudate: r = 0.83, p 0.0001) and with desire for sleep (Caudate: r = 0.72, p < 0.003). The correlation between DA changes and performance in the visual attention was significant in putamen (r = 0.79, p < 0.001), thalamus (r = 0.80, p < 0.001) and caudate (r = 0.56, p < 0.05) and for working memory in putamen (r = 0.71, p < 0.004), and thalamus (r = 0.57, p < 0.03). Conclusion: Here we show that one night of SD increases DA in striatum and thalamus. Inasmuch as DA enhancing drugs help to maintain wakefulness we postulate that the DA increases serve to maintain arousal as the drive to sleep increases but one that is insufficient to counteract behavioral and cognitive impairment.
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