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Pattern classification of working memory networks reveals differential effects of methylphenidate, atomoxetine, and placebo in healthy volunteers.

ABSTRACT: Stimulant and non-stimulant drugs can reduce symptoms of attention deficit/hyperactivity disorder (ADHD). The stimulant drug methylphenidate (MPH) and the non-stimulant drug atomoxetine (ATX) are both widely used for ADHD treatment, but their differential effects on human brain function remain unclear. We combined event-related fMRI with multivariate pattern recognition to characterize the effects of MPH and ATX in healthy volunteers performing a rewarded working memory (WM) task. The effects of MPH and ATX on WM were strongly dependent on their behavioral context. During non-rewarded trials, only MPH could be discriminated from placebo (PLC), with MPH producing a similar activation pattern to reward. During rewarded trials both drugs produced the opposite effect to reward, that is, attenuating WM networks and enhancing task-related deactivations (TRDs) in regions consistent with the default mode network (DMN). The drugs could be directly discriminated during the delay component of rewarded trials: MPH produced greater activity in WM networks and ATX produced greater activity in the DMN. Our data provide evidence that: (1) MPH and ATX have prominent effects during rewarded WM in task-activated and -deactivated networks; (2) during the delay component of rewarded trials, MPH and ATX have opposing effects on activated and deactivated networks: MPH enhances TRDs more than ATX, whereas ATX attenuates WM networks more than MPH; and (3) MPH mimics reward during encoding. Thus, interactions between drug effects and motivational state are crucial in defining the effects of MPH and ATX.

SUBMITTER: Marquand AF

PROVIDER: S-EPMC3079849 | biostudies-other | 2011 May

REPOSITORIES: biostudies-other

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Pattern classification of working memory networks reveals differential effects of methylphenidate, atomoxetine, and placebo in healthy volunteers.

Marquand Andre F AF De Simoni Sara S O'Daly Owen G OG Williams Steven C R SC Mourão-Miranda Janaina J Mehta Mitul A MA

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20110223 6

Stimulant and non-stimulant drugs can reduce symptoms of attention deficit/hyperactivity disorder (ADHD). The stimulant drug methylphenidate (MPH) and the non-stimulant drug atomoxetine (ATX) are both widely used for ADHD treatment, but their differential effects on human brain function remain unclear. We combined event-related fMRI with multivariate pattern recognition to characterize the effects of MPH and ATX in healthy volunteers performing a rewarded working memory (WM) task. The effects of ...[more]

PMID: 21346736

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Project description:Working memory performance can be influenced by motivational factors, which may be associated with specific brain activities, including suppression of alpha oscillations. We investigated whether providing individuals online feedback about their ongoing oscillations (EEG-neurofeedback) can improve working memory under high and low reward expectancies. We combined working memory training with neurofeedback to enhance alpha suppression in a monetary-rewarded delayed match-to-sample task for visual objects. Along with alpha, we considered the neighbouring theta and beta bands. In a double-blind experiment, individuals were trained over 5 days to suppress alpha power by receiving real-time neurofeedback or control neurofeedback (placebo) in reward and no-reward trials. We investigated (i) whether neurofeedback enhances alpha suppression, (ii) whether monetary reward enhances alpha suppression and working memory, and (iii) whether any performance benefits of neurofeedback-training would transfer to unrelated cognitive tasks. With the same experimental design, we conducted two studies with differing instructions given at the maintenance, yielding together 300 EEG recording sessions. In Study I, participants were engaged in a mental calculation task during maintenance. In Study II, they were instructed to visually rehearse the sample image. Results from Study I demonstrated a significant training and reward-anticipation effect on working memory accuracy and reaction times over 5 days. Neurofeedback and reward anticipation showed effects on theta suppression but not on alpha suppression. Moreover, a cognitive training effect was observed on beta suppression. Thus, neurofeedback-training of alpha was unrelated to working memory performance. Study II replicated the training and reward-anticipation effect on working memory but without any effects of neurofeedback-training on oscillations or working memory. Neither study showed transfer effects of either working memory or neurofeedback-training. A linear mixed-effect model analysis of neurofeedback-independent training-related improvement of working memory combining both studies showed that improved working memory performance was related to oscillatory changes over training days in the encoding and maintenance phases. Improvements in accuracy were related to increasing beta amplitude in reward trials over right parietal electrodes. Improvements in reaction times were related to increases in right parietal theta amplitude during encoding and increased right parietal and decreased left parietal beta amplitudes during maintenance. Thus, while our study provided no evidence that neurofeedback targeting alpha improved the efficacy of working memory training or evidence for transfer, it showed a relationship between training-related changes in parietal beta oscillations during encoding and improvements in accuracy. Right parietal beta oscillations could be an intervention target for improving working memory accuracy.

Project description:Ulotaront, a trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A receptor agonist without antagonist activity at dopamine D2 or the serotonin 5-HT2A receptors, has demonstrated efficacy in the treatment of schizophrenia. Here we report the phase 1 translational studies that profiled the effect of ulotaront on brain responses to reward, working memory, and resting state connectivity (RSC) in individuals with low or high schizotypy (LS or HS). Participants were randomized to placebo (n = 32), ulotaront (50 mg; n = 30), or the D2 receptor antagonist amisulpride (400 mg; n = 34) 2 h prior to functional magnetic resonance imaging (fMRI) of blood oxygen level-dependent (BOLD) responses to task performance. Ulotaront increased subjective drowsiness, but reaction times were impaired by less than 10% and did not correlate with BOLD responses. In the Monetary Incentive Delay task (reward processing), ulotaront significantly modulated striatal responses to incentive cues, induced medial orbitofrontal responses, and prevented insula activation seen in HS subjects. In the N-Back working memory task, ulotaront modulated BOLD signals in brain regions associated with cognitive impairment in schizophrenia. Ulotaront did not show antidepressant-like biases in an emotion processing task. HS had significantly reduced connectivity in default, salience, and executive networks compared to LS participants and both drugs reduced this difference. Although performance impairment may have weakened or contributed to the fMRI findings, the profile of ulotaront on BOLD activations elicited by reward, memory, and resting state is compatible with an indirect modulation of dopaminergic function as indicated by preclinical studies. This phase 1 study supported the subsequent clinical proof of concept trial in people with schizophrenia.Clinical trial registration: Registry# and URL: ClinicalTrials.gov NCT01972711, https://clinicaltrials.gov/ct2/show/NCT01972711.

Dataset Information

Pattern classification of working memory networks reveals differential effects of methylphenidate, atomoxetine, and placebo in healthy volunteers.

Publications

Pattern classification of working memory networks reveals differential effects of methylphenidate, atomoxetine, and placebo in healthy volunteers.

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