Auditory mismatch responses are differentially sensitive to changes in muscarinic acetylcholine versus dopamine receptor function

Abstract

The auditory mismatch negativity (MMN) has been proposed as a biomarker of NMDA receptor (NMDAR) dysfunction in schizophrenia. Such dysfunction may be caused by aberrant interactions of different neuromodulators with NMDARs, which could explain clinical heterogeneity among patients. In two studies (N=81 each), we used a double-blind placebo-controlled between-subject design to systematically test whether auditory mismatch responses under varying levels of environmental stability are sensitive to diminishing and enhancing cholinergic vs. dopaminergic function. We found a significant drug x mismatch interaction: while the muscarinic acetylcholine receptor antagonist biperiden delayed and topographically shifted mismatch responses, particularly during high stability, this effect could not be detected for amisulpride, a dopamine D2/D3 receptor antagonist. Neither galantamine nor levodopa, which elevate acetylcholine and dopamine levels, respectively, exerted significant effects on MMN. This differential MMN sensitivity to muscarinic versus dopaminergic receptor function may prove useful for developing tests that predict individual treatment responses in schizophrenia.

EEG mismatch responses in a multimodal roving stimulus paradigm provide evidence for probabilistic inference across audition, somatosensation, and vision

“…Although unnoticed by participants, given that the statistical regularities changed across experimental runs, the generative model continuously required updating. As such, our results might be reflective of a volatile sensory environment and relate to previous findings which indicate that later MMRs, such as the P3, reflect belief updates about the volatility of the underlying (hidden) statistics governing sensory observations (e.g., Weber et al, 2020 ; Weber et al, 2022 ). We leave it for future research to design experiments which are better suited to evaluate these speculations more specifically and more thoroughly.…”

Circadian rhythms in auditory hallucinations and psychosis

“…In the auditory domain, the much-studied auditory mismatch negativity response (MMN) is as a marker for sensory evidence accumulation. Compelling evidence has been collected suggesting a reductiwon of MMN in psychosis, 54 and that it responds to pharmacological NMDA-receptoraffine interventions (see e.g., 55 ). Also, the strikingly high confidence with which hallucination-prone individuals hold ambiguous auditory percepts is commensurate with the Bayesian Perception framework, 56 in that overly strong prior expectations can come to dominate a relatively weakened representation of sensory evidence.…”

Markers of muscarinic deficit for individualized treatment in schizophrenia

“…However, a reduction in MMN through an antimuscarinic drug (scopolamine as compared to glycopyrrolate, a peripheral anticholinergic without effects in the CNS) has also been demonstrated in healthy individuals ( 44 ). Importantly, it was shown in a recent preregistered trial that only biperiden, a muscarinic acetylcholine receptor antagonist, but not amisulpride, a dopamine D2/D3 receptor antagonist, galantamine, an acetylcholinesterase inhibitor increasing acetylcholine levels, nor levodopa, a dopamine precursor increasing dopamine levels, changed mismatch negativity in healthy individuals ( 45 , 46 ). Taken together, these findings suggest that muscarinic deficits entail reduced mismatch negativity, possibly through dysfunctional modulation of NMDA-dependent neurotransmission ( 4 , 47 ).…”