Dexamphetamine selectively increases 40 Hz auditory steady state response power to target and nontarget stimuli in healthy humans

Abstract

Background: An emerging endophenotype of schizophrenia is the reduction of both power and phase locking of the 40 Hz auditory steady state response (ASSR), and there have been a number of reports linking increased γ activity with positive psychotic symptoms. Schizophrenia and, more specifically, positive psychotic symptoms have been closely linked to increased dopamine (DA) neurophysiology. Therefore, we gave dexamphetamine to healthy participants to determine the effect that increased DA transmission would have on the ASSR.

Methods: We administered 0.45 mg/kg of dexamphetamine orally in a double-blind placebo-controlled crossover study. Stimuli were 20 Hz and 40 Hz click trains presented in an auditory oddball-type stimulus format (probability of stimulus presentation: 0.2 for targets, 0.8 for nontargets).

Results: We included 44 healthy volunteers (18 women) in the study. Dexamphetamine significantly increased the 40 Hz power for both target and nontarget ASSR stimuli. Dexamphetamine did not significantly affect the 40 Hz phase-locking factor (PLF) or the 20 Hz power and PLF. Whereas there were significant effects of selective attention on power and PLF for 20 and 40 Hz ASSR, there were no significant interactions between dexamphetamine and selective attention.

Limitations: Dexamphetamine releases both noradrenaline and DA with equal potency. Further research with selective dopaminergic and noradrenergic agents will better characterize the effects of monoamines on γ activity.

Conclusion: The results demonstrate a frequency-specific effect of dexamphetamine on the ASSR. This finding is consistent with previous research that has found an association between increased γ and positive symptoms of psychosis. However, this result also raises the possibility that previous 40 Hz ASSR findings in people with schizophrenia may be confounded by effects of antipsychotic medication. Possible neural mechanisms by which dexamphetamine specifically increases 40 Hz power are also discussed. AUSTRALIAN AND NEW ZEALAND CLINICAL TRIALS REGISTRY NUMBER: ACTRN12608000610336.

Fig. 1

Topographic maps of power (top) and phase-locking factor (PLF; bottom) during the 40 Hz target stimuli when participants were under placebo (left) and dexamphetamine (right). Both power and PLF values were averaged over the period between 100 and 500 ms poststimulus onset.

Fig. 2

The effects of dexamphetamine on 40 Hz power over time at electrode FCz. Both standard and rare stimuli are pooled in the analysis as there was no drug × stimulus type interaction. Displayed are the means and standard error of the mean. Dexamphetamine significantly increased 40 Hz power for both stimulation frequencies for all time bins except for the last 50–600 ms time bin. Holm-corrected p values: *p < 0.05, **p < 0.01; n = 44.