LAUSR

Abstract Background: The 40 Hz auditory steady state response (ASSR) is robustly impaired in chronic schizophrenia which could reflect impaired GABAergic neurotransmission in auditory cortex. However, little is known about the presence of alterations in the 40 Hz ASSR in early and at-risk stages of psychosis. In the current study, we aimed to explore the 40 Hz ASSR impairments in individuals at ultra-high risk (UHR) of psychosis and the possible relationship of deficits in gamma-band entrainment to dysfunctional GABAergic neurotransmission through measurements of cortical GABA-levels. Methods: Fifty UHR participants recruited from the general public, NHS primary care and mental health services and 25 healthy controls were included as part of the MRC-funded Youth Mental Health Risk and Resilience (YouR)-study. MEG data were recorded while participants were passively presented with a series of 1000 Hz carrier tones amplitude modulated at 40 Hz. These data were analyzed at source-level by reconstruction in the frequency-domain using 98 nodes defined from the AAL-atlas and LCMV beamformer source-analysis algorithms. This approach was employed in order to estimate ASSR responses directly from their generating sources while suppressing sensor-level noise and activity in neighboring brain areas. Finally, GABA/Cr ratios were measured, using 1H-MRS at 3T and 2 × 2 × 2 cm voxels placed in the right visual and bilateral auditory cortices. Results: Across groups, the ASSR stimulus significantly activated 15 AAL nodes (FDR corrected), including auditory areas such as right superior temporal gyrus, right heschl’s gyrus, right medial temporal gyrus and left supramarginal gyrus. Subsequent group comparisons revealed impaired 40 Hz ASSR spectral power in secondary auditory areas in UHR participants, which was maximal at 250–750 ms post-stimulus onset in the left supramarginal gyrus. Furthermore, a significant difference was found for GABA/Cr levels in the right auditory cortex (UHR > controls). Conclusion: These results indicate that the 40 Hz ASSR is impaired in UHR participants, which could be related to aberrant GABAergic neurotransmission in auditory cortex. Accordingly, the 40 Hz ASSR could potentially constitute a biomarker for early detection and diagnosis reflecting changes in the balance between excitation and inhibition in auditory areas.