This study documents that when MP was given with a cognitive task it markedly attenuated the brain metabolic increases induced by the task and reduced the regions activated by it. The reduction in activation with MP included the parietal cortex, cingulate gyrus and thalamus, which are regions involved in the orienting, executive, and alerting attentional networks respectively
. Thus, we interpret our findings to indicate that compared to placebo MP reduced (focused) the use of attentional resources in the human brain that are necessary to achieve similar levels of performance on a task.
These findings are consistent with those of prior imaging studies showing reductions with MP in the increases in cerebral blood flow (CBF) in dorsolateral prefrontal and posterior parietal cortices when healthy controls performed a working memory task
and in prefrontal cortex when adults with ADHD performed a task of executive function
. However, the MP-related attenuation of CBF increases by the task in these studies was much more restricted (focused to discrete brain regions) than the large and extensive attenuation in whole brain metabolism we report using [18
F]FDG. Glucose metabolism may offer an advantage because it is a more proximal measure of neuronal activity than CBF
. Moreover, regional CBF may become uncoupled from metabolism during stimulation
Synaptic levels of DA and NE, which are increased by MP
, under physiological conditions act primarily as neuromodulators changing the efficacy of other transmitter signals
as a function of ongoing neuronal activity
. For example, in striatum, applications of DA decrease the activity of spontaneously active neurons to a greater extent than that of glutamate-stimulated neurons
. This increase in glutamate-induced excitation relative to baseline is assumed to improve signal-to-noise neuronal activation
. Norepinephrine can also facilitate excitatory transmission by depressing the level of basal activity
. The greater decreases in spontaneous neuronal firing (basal activity) than in task relevant neuronal responses from MP's dopaminergic and noradrenergic effects could therefore explain the reduction in the metabolic increases (as well as CBF decreases) induced by the cognitive task. In addition the global effects in metabolism that we observed with MP while performing the task may reflect downstream effects of increasing signal to noise in regions processing the task into regions whose background activity covary with that of regions activated by the task
The dependency of DA and NE effects as a function of the ongoing neuronal activity
could explain the differential response to MP we observed across the neutral and cognitive task conditions (i.e., no effect when given with a neutral non-task but attenuation of increases in metabolic activation when given with a cognitive task). Similar results were reported for MP effects on CBF; decreases in task related activation but no changes with the control condition
. The task dependency of MP effects is consistent with clinical findings documenting that the effects of stimulant medications are context dependent
It is worth noting that while most individuals showed lower metabolic activation during the cognitive task with MP than with placebo (16 of 23), five subjects showed greater activation with MP than with placebo and 2 subjects did not change. Because only 5 subjects showed an enhancement with MP we did not have sufficient power to assess if there were differences in baseline brain metabolism or in brain activation to the task between the group of subjects in whom MP decreased versus those in whom it enhanced activation. However, the correlation analysis revealed that the difference in activation between MP and placebo during the cognitive task was correlated both with baseline brain metabolism (control condition) and with the brain activation to the task when preceded by placebo. That is, subjects in whom MP produced the largest attenuation in activation to the task were the ones that had lower brain metabolism at baseline but also had the largest brain metabolic increases when the cognitive task was given with placebo. Subjects with minimal activation to the task were the ones in whom MP produced the least change and were also the ones that did not improve performance with MP (assessed by monetary earnings). This is consistent with the notion that those individuals who already have “optimal focusing” of brain resources would show no benefit from MP. The dependency of MP effects to the magnitude of activation to the task (when given with placebo) is also consistent with idea that the effects of MP in a given subjects are rate dependent; that is determined by their baseline level of performance
The correlation analysis between the difference in money between the cognitive task with MP versus with placebo and the differences in metabolic activation between these two conditions was significant in the paracentral lobule (BA 5), dorsal and posterior CG/precuneus (BA 23, 29, 30, 7) and in parietal cortex (BA 39, 40, 7); subjects in whom MP induced the largest attenuation were the ones that made more money with MP than with placebo. The dorsal and posterior CG, the paracentral lobule and the inferior parietal cortices are regions that form part of the default network, which is deactivated when performing a task
and activated during mind-wandering (BA 31, 29, 30)
. Thus one could speculate that the ability of MP to decrease the activation in the default network and to decrease mind-wandering is one of the mechanisms that accounts for its beneficial effects in subjects in whom it improves performance. However, in individuals in whom the default network is already optimally deactivated during the task, MP may deteriorate performance as was the case for the 4 subjects in our study who made less money with MP than with placebo.
Though it was once assumed that the beneficial effects of stimulant medications (including MP) on individuals with ADHD were paradoxical, studies have demonstrated that the direction of response is the same in healthy individuals without ADHD
. This confusion may reflect in part the fact that the responses to stimulant medications are dependent on the initial level of performance; typically performance is improved only when cognitive processing is below optimal, resulting in a non-monotonic (U-shaped) function
. Our findings suggest a neural mechanism for this: we postulate that when neuronal resources are widely distributed across brain regions, the action of MP to focus (reduce) regional activation would improve performance on a specific task, whereas the MP-related restriction of regional brain activation when already optimally deployed could impair performance.
The oral dose of MP used in this study (20 mg) is within the range used therapeutically for the treatment of ADHD in adults. The lack of an effect on brain metabolism with the neutral non-task suggests that this dose of MP without a concomitant cognitive activation does not affect brain activity. This is consistent with our prior findings showing that 20 mg of oral MP did not significantly increase DA in the striatum (assessed with PET and [11
C]raclopride) when given with a neutral non-task whereas it increased it when MP was administered concomitantly with a cognitive task (same numerical calculations task used for the current study)
. It is also consistent with prior imaging studies showing minimal changes in regional brain glucose metabolism in ADHD subjects given MP without stimulation
Limitations for this study include the fact that the assessment of brain glucose metabolism with PET and FDG reflects the average activity of the brain over a 30 minute period, which does not allow an assessment of the dynamic changes that may occur during that time period. Our experimental design did not allow us to evaluate the relationship between the inter-subject variability in the brain metabolic responses to MP during the task and an individual's level of performance. In our design, the difficulty of the task was adjusted so that each subject would achieve a constant level of performance (about 80% accuracy), and the adjustments varied across individuals since they depended on each individual's level of ability on the mathematical task as well as his/her ability for the different mathematical operations. Also in this study the amount of money made during the task (a possible indicator of a subject's overall performance) was constrained by the adjustment procedures. In future studies, different designs with more precise measures of performance could be used to evaluate the extent to which the differences between subjects and within subjects in response to MP relate to difference in their performance capacity and how this information can be used to predict response to stimulant medications.
This study shows that compared to placebo, an oral dose of MP reduced the brain metabolic increases associated with performance of a cognitive task. Inasmuch as the brain required about 50% less increase in glucose to perform the task at the same level of performance, this provides evidence that one of the mechanisms of action of MP is to focus activation and make the brain more efficient.
Our study of the effects of MP on brain function in healthy adults may contribute to theoretical basis for how and when stimulant drugs may (or may not) enhance attention and performance. To the extent that neuronal resources are non-optimally distributed, reduced task-induced regional activation could result in improved performance. Non-optimal distribution of attentional resources may occur in some individuals (ie., those with ADHD) or in healthy individuals after sleep deprivation. However, if neuronal resources are already optimally deployed, further focusing of neuronal activity could result in stimulant-related deterioration of performance.