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. To test the hypothesis that stimulants enhance signal to noise ratio of neuronal activity and thereby reduce cerebral activity by increasing efficiency, we measured the effects of methylphenidate on brain glucose utilization in healthy adults. We measured brain glucose metabolism (using Positron Emission Tomography and 2-deoxy-2[18F]fluoro-D-glucose) in 23 healthy adults who were tested at baseline and while performing an accuracy-controlled cognitive task (numerical calculations) given with and without methylphenidate (20 mg, oral). Sixteen subjects underwent a fourth scan with methylphenidate but without cognitive stimulation. Compared to placebo methylphenidate significantly reduced the amount of glucose utilized by the brain when performing the cognitive task but methylphenidate did not affect brain metabolism when given without cognitive stimulation. Whole brain metabolism when the cognitive task was given with placebo increased 21% whereas with methylphenidate it increased 11% (50% less). This reflected both a decrease in magnitude of activation and in the regions activated by the task. Methylphenidate's reduction of the metabolic increases in regions from the default network (implicated in mind-wandering) was associated with improvement in performance only in subjects who activated these regions when the cognitive task was given with placebo. These results corroborate prior findings that stimulant medications reduced the magnitude of regional activation to a task and in addition document a “focusing” of the activation. This effect may be beneficial when neuronal resources are diverted (i.e., mind-wandering) or impaired (i.e., attention deficit hyperactivity disorder), but it could be detrimental when brain activity is already optimally focused. This would explain why methylphenidate has beneficial effects in some individuals and contexts and detrimental effects in others.

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We measured regional brain glucose metabolism in 23 healthy subjects when they performed a mathematical task with difficulty controlled to achieve 80% accuracy. The difficulty-controlled task was performed after administration of placebo and after administration of MP (20 mg, oral), and these conditions were compared to a control condition, which consisted of viewing nature cards with not performance required (non-task condition) after being given a placebo. In addition, 16 of the subjects were tested in a fourth condition (non-task condition after being given MP) ( Figure 1 ).

The biochemical mechanisms of action of MP have been well characterized: it increases extracellular levels of dopamine and norepinephrine by blocking the respective monoamine transporters [5] . It is unclear how these actions relate to its effects in attention and performance. Since dopamine and norepinephrine decrease background firing rates of neuronal cells increasing signal-to-noise ratio [6] , [7] , we hypothesized that in humans MP's dopaminergic and noradrenergic effects by decreasing non-task related activity should reduce the amount of glucose utilized by the brain while performing a cognitive task.

Stimulant medications such as methylphenidate (MP) are used extensively in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) to decrease symptoms of inattention [1] Also, in certain conditions (e.g., sleep deprivation), MP may improve attention and performance of individuals without ADHD [2] . Indeed the past decade has seen an increase in the use of stimulant medications as cognitive enhancers that is of increasing concern both because of their side effects as well as their potential for abuse and addiction [3] , [4] .

In contrast to the differences between placebo and MP when given with the cognitive task there were no differences in brain metabolism when MP was given with the neutral non-task condition (whole brain metabolism: 35.8±5 µmol/100 g/min) when compared with the neutral non-task condition when given with placebo (36.6±6 µmol/100 g/min). The SPM analysis corroborated this and revealed no significant differences when the neutral non-task condition was given with placebo (control condition) versus when it was given with MP (data not shown).

SPM results showing the areas that had greater increases in metabolism when the cognitive task was given with placebo versus when it was given with methylphenidate (MP). Comparisons correspond to paired t-tests (p<0.005 uncorrected >100 pixels). None of the brain regions had higher metabolism for the cognitive task when given with MP than with placebo.

A. SPM results showing the areas that had increases in metabolism for the cognitive task with placebo versus the control conditions; B. SPM results showing the areas that had increases in metabolism for the cognitive task with MP versus the control conditions. Comparisons correspond to paired t tests (p<0.001 uncorrected >100 pixels). None of the brain regions had higher metabolism for the control condition (neutral non-task with placebo) than for the cognitive task conditions.

The smaller task-related increase in brain consumption of glucose with MP was related to focusing of brain activity. This is shown on the statistical parametric (SPM) analysis, which revealed that the area of significant activation (p<0.001) with the cognitive task was much larger with placebo (67,985 pixels) than with MP (22,632 pixels) ( Figure 2 ). The cognitive task for both conditions (placebo and MP) increased metabolism in left frontal, left parietal, occipital, and cerebellar regions; however when given with placebo, the task additionally increased metabolism in right frontal, right parietal, anterior cingulate, and left thalamic regions ( Figure 2 ). The SPM comparison between the two cognitive task conditions corroborates these differences showing significantly greater activation in frontal, parietal, cingulate, thalamus and hippocampus when the cognitive task was given with placebo than with MP ( Figure 3 ). Independently drawn region of interest analysis revealed similar findings ( Table 2 ).

There were no differences in money made (surrogate marker of performance) when the cognitive task was done with placebo ($47.60±4) versus when it was done with MP ($48.80±3). However there was significant intersubject variability: 7 subjects made more money with MP, 4 made less money and 12 made the same amount as with placebo. Correlation analysis between the differences in money earned when performing the cognitive task with MP versus placebo and the metabolic differences in activation between these two conditions were significant in paracentral lobule (r = 0.50, p<0.02), superior (r = 0.50, p<0.02) and inferior parietal cortices (r = 0.43, p<0.05), dorsal (r = 0.45, p<0.05) and posterior CG/precuneus (r = 0.44, p<0.05). The greater the attenuation the larger the amount of money made with MP.

Correlation analysis between the differences in brain activation when the task was given with placebo versus MP showed a significant correlation with baseline metabolism (r = 0.48, p<0.05); the lower the metabolism at baseline the greater the attenuation of the activation by the task by MP. The difference in brain activation when the task was given with placebo versus MP was also significantly correlated with the activation to the task with placebo (r = 0.57, p<0.005) but not with activation to the task with MP (r = 0.02, NS) indicating that the response to MP was dependent both on metabolism at baseline and on the level of activation by the task when given without a pharmacological challenge.

PET imaging documented that 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±6 µmol/100 g/min) and the neutral non-task condition preceded by MP (35.8±5 µmol/100 g/min) than for the cognitive task with placebo (43.2±7 µmol/100 g/min) or the cognitive task preceded by MP (40.3±7 µmol/100 g/min). The increase in whole brain metabolism was significantly smaller when the cognitive task was preceded by MP, than when preceded by placebo (11±22% versus 21±26%; p<0.01). Individual analysis of the responses revealed that 16 of the 23 subjects had less activation with MP than with placebo when performing the task, 5 had greater activation with MP than with placebo and 2 did not differ (Chi-Square p<0.02) ( Table 1 ).

Discussion

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[8]. 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[9] and in prefrontal cortex when adults with ADHD performed a task of executive function[10]. 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 [18F]FDG. Glucose metabolism may offer an advantage because it is a more proximal measure of neuronal activity than CBF[11]. Moreover, regional CBF may become uncoupled from metabolism during stimulation[12], [13].

Synaptic levels of DA and NE, which are increased by MP[5], under physiological conditions act primarily as neuromodulators changing the efficacy of other transmitter signals[14], [15] as a function of ongoing neuronal activity[16]. For example, in striatum, applications of DA decrease the activity of spontaneously active neurons to a greater extent than that of glutamate-stimulated neurons[6]. This increase in glutamate-induced excitation relative to baseline is assumed to improve signal-to-noise neuronal activation[17]. Norepinephrine can also facilitate excitatory transmission by depressing the level of basal activity[18]. 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[19].

The dependency of DA and NE effects as a function of the ongoing neuronal activity[17] 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[9]. The task dependency of MP effects is consistent with clinical findings documenting that the effects of stimulant medications are context dependent[20], [21].

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[22], [23].

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[24] and activated during mind-wandering (BA 31, 29, 30)[25]. 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[26]. 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[27]. 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 [11C]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)[28]. It is also consistent with prior imaging studies showing minimal changes in regional brain glucose metabolism in ADHD subjects given MP without stimulation[29].

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.