Deficits in Pre-attentive Processing of Spatial Location and Negative Symptoms in Subjects at Clinical High Risk for Schizophrenia

Abstract

Deficits in mismatch negativity (MMN) generation are among the best-established biomarkers for cognitive dysfunction in schizophrenia and predict conversion to schizophrenia (Sz) among individuals at symptomatic clinical high risk (CHR). Impairments in MMN index dysfunction at both subcortical and cortical components of the early auditory system. To date, the large majority of studies have been conducted using deviants that differ from preceding standards in either tonal frequency (pitch) or duration. By contrast, MMN to sound location deviation has been studied to only a limited degree in Sz and has not previously been examined in CHR populations. Here, we evaluated location MMN across Sz and CHR using an optimized, multi-deviant pattern that included a location-deviant, as defined using interaural time delay (ITD) stimuli along with pitch, duration, frequency modulation (FM) and intensity deviants in a sample of 42 Sz, 33 CHR and 28 healthy control (HC) subjects. In addition, we obtained resting state functional connectivity (rsfMRI) on CHR subjects. Sz showed impaired MMN performance across all deviant types, along with strong correlation between MMN deficits and impaired neurocognitive function. In this sample of largely non-converting CHR subjects, no deficits were observed in either pitch or duration MMN. By contrast, CHR subjects showed significant impairments in location MMN generation particularly over right hemisphere and significant correlation between impaired location MMN and negative symptoms including deterioration of role function. In addition, significant correlations were observed between location MMN and rsfMRI involving brainstem circuits. In general, location detection using ITD stimuli depends upon precise processing within midbrain regions and provides a rapid and robust reorientation of attention. Present findings reinforce the utility of MMN as a pre-attentive index of auditory cognitive dysfunction in Sz and suggest that location MMN may index brain circuits distinct from those indexed by other deviant types.

Mismatch negativity as an index of target engagement for excitation/inhibition-based treatment development: a double-blind, placebo-controlled, randomized, single-dose cross-over study of the serotonin type-3 receptor antagonist CVN058

“…Our secondary analysis suggests that a multivariate approach across deviant types may increase sensitivity to treatment effects and thus increase statistical power. In addition, location MMN has been studied less extensively in schizophrenia than other MMN types, although it has been found to be consistently reduced both in schizophrenia [75,76] and a clinical high risk group [81]. The finding of its significant sensitivity to CVN058 argues for location MMN's greater inclusion in multivariate paradigms.…”

“…The primary outcome measure was amplitude of MMN elicited by duration deviants, with other deviants (pitch, intensity, frequency modulation, location) and EEG measures (P50 inhibition, ASSR, and P300) exploratory using previously described methods [70,80,81]. EEG collection began ~1.5 h post dose, during the expected peak serum levels.…”

“…As previously [81], for MMN, auditory stimuli consisted of a sequence of tones presented in random order with a stimulus onset asynchrony (SOA) of 500 ms. Standard stimuli (45% sequential probability) were harmonic tones composed of three superimposed sinusoids (500, 1000 and 1500 Hz) 100 ms in duration with 5 ms rise/fall time presented at ~85 dB.…”

“…Seven runs of 5 mins each (600 stimuli/run) were presented as the subjects listened to the tones while watching a silent movie as a distractor. Full details on data analysis can be found in [81].…”

Impaired interaural correlation processing in people with schizophrenia

“…Matthews et al (2013) have found that schizophrenic patients exhibit both the impaired binaurally temporal processing ability in an interaural time difference (ITD) discrimination task and the reduced ability to use binaural temporal cues to extract signals from noise in a masking level difference paradigm (Matthews et al, 2013). Using interaural time delay to define the location deviants, schizophrenic patients and individuals at symptomatic clinical high risk show significant location-MMN deficits, and the MMN deficits are correlated with impaired higher-order neurocognitive functions (Sehatpour et al, 2021). Although, binaural temporal processing affected by schizophrenia has been shown by a certain number of studies, interaural correlation discrimination, however, has not been studied in people with schizophrenia.…”