Abstract
BackgroundRobust impairments in the power and phase of 40 Hz auditory steady state responses (ASSR) have been reported in chronic schizophrenia patients. This could reflect changes in the balance between inhibitory GABAergic and excitatory glutamatergic neurotransmission in auditory cortex. However, the direct link between the ASSR and alterations in these neurotransmitter systems has not been systematically explored. Furthermore, it remains unclear whether 40 Hz ASSR impairments are present in early and at-risk stages of psychosis. The current study aims to explore the 40 Hz ASSR in first-episode of psychosis patients and individuals at clinical high risk (CHR) of psychosis, and the possible relationship of deficits in gamma-band entrainment to a dysfunctional excitation inhibition balance, as reflected by alterations in cortical GABA and glutamate.MethodsData from 80 CHR, 11 FEP and 40 age-matched healthy control participants were collected as part of the MRC-funded Youth Mental Health Risk and Resilience study. MEG data were recorded on a 4D Neuroimaging Magnes 3600 Whole Head 248 Channel system, while participants were passively presented with a series of 1000 Hz carrier tones amplitude modulated at 40 Hz. Data were analysed at sensor and source-level in the frequency-domain for spectral power and intertrial phase-coherence (ITPC). For source-reconstruction, an eLoreta source-analysis algorithms was employed. Auditory regions of interest (ROIs) were defined using 98 nodes defined from the AAL-atlas. Levels of right auditory GABA and Glx (glutamate + glutamine) were measured using 1H-MRS at 3T and 2*2*2 cm voxels and were estimated relative to water. GABA levels were further corrected for grey and white matter and cerebrospinal fluid levels within the voxel. Finally, 40 Hz ASSR power in right auditory cortex was explored in relation to neurotransmitter levels in the same region.ResultsAcross groups, the ASSR stimulus activated temporal regions, including bilateral heschl’s gyrus and superior temporal cortex. A significant effect of hemisphere was found, reflecting higher 40 Hz ASSR power in the right hemisphere across groups. CHR and FEP participants showed attenuated 40 Hz ASSR power and ITPC compared to healthy control participants in right temporal regions, but an increase in spectral power in the left hemisphere. A moderate positive correlation was found between right auditory GABA and 40 Hz ASSR power in the right superior temporal gyrus in CHR, but not in controls.DiscussionThese results provide a link between MRS measures of GABA and 40 Hz ASSR power impairments in CHR individuals. Furthermore, these preliminary findings indicate that slight alterations in the 40 Hz ASSR are present in FEP patients and may arise already in the CHR stage, prior to the onset of psychosis.
Highlights
The function, cytoarchitecture and connectivity of the insula cortex are diverse
The current study aims to explore the 40 Hz auditory steady state responses (ASSR) in first-episode of psychosis patients and individuals at clinical high risk (CHR) of psychosis, and the possible relationship of deficits in gamma-band entrainment to a dysfunctional excitation inhibition balance, as reflected by alterations in cortical GABA and glutamate
CHR and FEP participants showed attenuated 40 Hz ASSR power and intertrial phasecoherence (ITPC) compared to healthy control participants in right temporal regions, but an increase in spectral power in the left hemisphere
Summary
We find strong correlations of EEG with both PEs in both samples: lower-level PEs show effects early on (Study1: 133ms post-stimulus, Study2: 177ms), higher-level PEs later (Study1: 240ms, Study2: 450ms). The temporal order of these signatures mimics the hierarchical relationship of the PEs, as proposed by our computational model, where lower level beliefs need to be updated before learning can ensue on higher levels. Ketamine significantly reduced the representation of the higher-level PE in Study. (Study has not been unblinded.) Discussion: These studies present first evidence for hierarchical PEs during MMN and demonstrate that single-trial analyses guided by a computational model can distinguish different types (levels) of PEs, which are differentially linked to neuromodulators of demonstrated relevance for schizophrenia. Our analysis approach provides better mechanistic interpretability of pharmacological MMN studies, which will hopefully support the development of computational assays for diagnosis and treatment predictions in schizophrenia. Ye Tian*,1, Chad Bousman, Chenxing Liu, Christos Pantelis, Andrew Zalesky3 1The University of Melbourne; 2University of Calgary; 3The University of Melbourne, Melbourne Neuropsychiatry Centre
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