Auditory mismatch impairments are characterized by core neural dysfunctions in schizophrenia

Abstract

Major theories on the neural basis of schizophrenic core symptoms highlight aberrant salience network activity (insula and anterior cingulate cortex), prefrontal hypoactivation, sensory processing deficits as well as an impaired connectivity between temporal and prefrontal cortices. The mismatch negativity is a potential biomarker of schizophrenia and its reduction might be a consequence of each of these mechanisms. In contrast to the previous electroencephalographic studies, functional magnetic resonance imaging may disentangle the involved brain networks at high spatial resolution and determine contributions from localized brain responses and functional connectivity to the schizophrenic impairments. Twenty-four patients and 24 matched control subjects underwent functional magnetic resonance imaging during an optimized auditory mismatch task. Haemodynamic responses and functional connectivity were compared between groups. These data sets further entered a diagnostic classification analysis to assess impairments on the individual patient level. In the control group, mismatch responses were detected in the auditory cortex, prefrontal cortex and the salience network (insula and anterior cingulate cortex). Furthermore, mismatch processing was associated with a deactivation of the visual system and the dorsal attention network indicating a shift of resources from the visual to the auditory domain. The patients exhibited reduced activation in all of the respective systems (right auditory cortex, prefrontal cortex, and the salience network) as well as reduced deactivation of the visual system and the dorsal attention network. Group differences were most prominent in the anterior cingulate cortex and adjacent prefrontal areas. The latter regions also exhibited a reduced functional connectivity with the auditory cortex in the patients. In the classification analysis, haemodynamic responses yielded a maximal accuracy of 83% based on four features; functional connectivity data performed similarly or worse for up to about 10 features. However, connectivity data yielded a better performance when including more than 10 features yielding up to 90% accuracy. Among others, the most discriminating features represented functional connections between the auditory cortex and the anterior cingulate cortex as well as adjacent prefrontal areas. Auditory mismatch impairments incorporate major neural dysfunctions in schizophrenia. Our data suggest synergistic effects of sensory processing deficits, aberrant salience attribution, prefrontal hypoactivation as well as a disrupted connectivity between temporal and prefrontal cortices. These deficits are associated with subsequent disturbances in modality-specific resource allocation. Capturing different schizophrenic core dysfunctions, functional magnetic resonance imaging during this optimized mismatch paradigm reveals processing impairments on the individual patient level, rendering it a potential biomarker of schizophrenia.

Keywords: classification; functional magnetic resonance imaging; mismatch negativity; multivariate pattern analysis; schizophrenia.

Reduced mismatch negativity is a well-established phenomenon in schizophrenia, but its underlying mechanisms are unclear. Using fMRI, Gaebler et al. reveal that auditory mismatch stimuli trigger multiple neural dysfunctions associated with schizophrenia. The fMRI response enables diagnostic separation of patients and controls with high accuracy, suggesting biomarker potential.

Figure 1

Schematic illustration of the optimized mismatch paradigm applied in this study. In a block design (8 min), presentation of standard events (tone with complex partials, 100 ms duration, stimulus onset asynchrony = 500 ms) served as baseline (S; 30 s duration each block). During mismatch blocks (M; 30 s), every second event varied in one randomly chosen feature, i.e. either in duration, location, frequency, amplitude or an introduced gap.

Figure 2

Hemodynamic response to mismatch blocks. Activation clusters of healthy controls (n = 24; first row), schizophrenia patients (n = 24; second row) and healthy controls > schizophrenia patients (third row) for the contrast mismatch > standard (baseline) condition. Both groups exhibited prominent auditory activations, which differed at the right auditory cortex. Prefrontal and salience network responses were only observed in the control group yielding a significant group difference. The deactivation in the visual system was significantly stronger in the controls. For each contrast, the threshold was set to P < 0.05 and a corrected cluster size threshold based on a Monte-Carlo simulation was applied. z-coordinates refer to the Talairach system.

Figure 3

Information increase for many functional connectivity features. Classification accuracy depending on the number of selected features from GLM effect estimates (blue line) and functional connectivity measures (green line). Already based on few features from the region of interest activation (GLM analysis), accuracy was ∼80%; this rate is similar to other MMN studies (e.g. Thönnessen et al., 2008). For connectivity features, higher numbers of features led to still higher classification accuracy (up to 90%), suggesting distributed contribution of network dysfunction to schizophrenia.