Methylphenidate decreased the amount of glucose needed by the brain to perform a cognitive task

Abstract

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.

Figure 1. Schematic diagram of experimental procedure.

Placebo (PL) or methylphenidate (MP) was given 60 minutes prior to initiation of Cognitive or Neutral tasks, which lasted 45 minutes. [¹⁸F]FDG was injected 15 minutes after task initiation (75 minutes after MP or PL) and scans were started 35 minutes after injection.

Figure 2. Brain activation with the task after placebo (PL) and after methylphenidate (MP).

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.

Figure 3. Differences in task activation between placebo (PL) and methylphenidate (MP).

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.