Drug-specific laterality effects on frontal lobe activation of atomoxetine and methylphenidate in attention deficit hyperactivity disorder boys during working memory

Abstract

Background The catecholamine reuptake inhibitors methylphenidate (MPH) and atomoxetine (ATX) are the most common treatments for attention deficit hyperactivity disorder (ADHD). This study compares the neurofunctional modulation and normalization effects of acute doses of MPH and ATX within medication-naive ADHD boys during working memory (WM). Method A total of 20 medicationnaive ADHD boys underwent functional magnetic resonance imaging during a parametric WM n-back task three times, under a single clinical dose of either MPH, ATX or placebo in a randomized, doubleblind, placebo-controlled, cross-over design. To test for normalization effects, brain activations in ADHD under each drug condition were compared with that of 20 age-matched healthy control boys. Results Relative to healthy boys, ADHD boys under placebo showed impaired performance only under high WM load together with significant underactivation in the bilateral dorsolateral prefrontal cortex (DLPFC). Both drugs normalized the performance deficits relative to controls. ATX significantly enhanced right DLPFC activation relative to MPH within patients, and significantly normalized its underactivation relative to controls. MPH, by contrast, both relative to placebo and ATX, as well as relative to controls, upregulated the left inferior frontal cortex (IFC), but only during 2-back. Both drugs enhanced frontotemporo-striatal activation in ADHD relative to control boys and deactivated the default-mode network, which were negatively associated with the reduced DLPFC activation and performance deficits, suggesting compensation effects. Conclusions The study shows both shared and drug-specific effects. ATX upregulated and normalized right DLPFC underactivation, while MPH upregulated left IFC activation, suggesting drug-specific laterality effects on prefrontal regions mediating WM. Background. The catecholamine reuptake inhibitors methylphenidate (MPH) and atomoxetine (ATX) are the most common treatments for attention deficit hyperactivity disorder (ADHD). This study compares the neurofunctional modulation and normalization effects of acute doses of MPH and ATX within medication-naive ADHD boys during working memory (WM).

Functional dysconnectivity of corticostriatal circuitry and differential response to methylphenidate in youth with attention-deficit/hyperactivity disorder

“…[27][28][29] Our findings confirm and extend those of previous task-based reports and indicate that the inferior frontal cortex modulating methylphenidate response in individuals with ADHD may be a robust finding across different neuroimaging measurements. As resting-state fMRI has the advantage of being less constrained by differences among tasks, the pretreatment differences in functional connectivity observed in the present study may be a useful candidate biomarker of treatment response in patients with ADHD.…”

“…Among the patients with ADHD, good responders to methylphenidate were characterized by reduced frontostriatal functional connectivity compared with poor responders that was particularly prominent between the ventral caudate/nucleus accumbens and right orbitofrontal gyri, as expected a priori based on similar observations reported in task-based fMRI studies. [27][28][29] We demonstrated that pretreatment difference in the ventral frontostriatal functional connectivity was related to pharmacological treatment response in patients with ADHD.…”

“…24,25 On the other hand, few studies have applied restingstate fMRI to investigate the neural network correlates of treat ment response for ADHD. 26 There is some evidence that psychostimulants modulate task-related activation in inferior frontal regions, [27][28][29] suggesting a therapeutic action on ventral frontostriatal systems, although the effects of established treatments, such as methylphenidate, on circuit-level functional connectivity are as yet unclear.…”

New light on executive function and attention deficit hyperactivity disorder

“…Furthermore, although some functions may be improved on drug therapy, they do not occur through the same circuits as in normal subjects 4 . Different drugs as well as motivation and reinforcement improve executive functions, and, although sharing some final effects, in different specific ways, some directed to working memory, while others to inhibition or mental flexibility 5,6,7 . The catecholamine reuptake inhibitor methylphenidate seems to upregulate the left inferior frontal cortex and enhances fronto-temporo-striatal activation 7 .…”

“…Different drugs as well as motivation and reinforcement improve executive functions, and, although sharing some final effects, in different specific ways, some directed to working memory, while others to inhibition or mental flexibility 5,6,7 . The catecholamine reuptake inhibitor methylphenidate seems to upregulate the left inferior frontal cortex and enhances fronto-temporo-striatal activation 7 . The study by Bolfert et al highlights the effects after 3 months methylphenidate treatment on digit span backwards and arithmetic, the Taril Making Test part B and on the Stroop Color Test, executive function tests, adding new information on this matter.…”