Impaired Subcortical Detection of Auditory Changes in Schizophrenia but Not in Major Depression.

The mismatch negativity is a cortical response to auditory changes and its reduction is a consistent finding in schizophrenia. Recent evidence revealed that the human brain detects auditory changes already at subcortical stages of the auditory pathway. This finding, however, raises the question where in the auditory hierarchy the schizophrenic deficit first evolves and whether the well-known cortical deficit may be a consequence of dysfunction at lower hierarchical levels. Finally, it should be resolved whether mismatch profiles differ between schizophrenia and affective disorders which exhibit auditory processing deficits as well. We used functional magnetic resonance imaging to assess auditory mismatch processing in 29 patients with schizophrenia, 27 patients with major depression, and 31 healthy control subjects. Analysis included whole-brain activation, region of interest, path and connectivity analysis. In schizophrenia, mismatch deficits emerged at all stages of the auditory pathway including the inferior colliculus, thalamus, auditory, and prefrontal cortex. In depression, deficits were observed in the prefrontal cortex only. Path analysis revealed that activation deficits propagated from subcortical to cortical nodes in a feed-forward mechanism. Finally, both patient groups exhibited reduced connectivity along this processing stream. Auditory mismatch impairments in schizophrenia already manifest at the subcortical level. Moreover, subcortical deficits contribute to the well-known cortical deficits and show specificity for schizophrenia. In contrast, depression is associated with cortical dysfunction only. Hence, schizophrenia and major depression exhibit different neural profiles of sensory processing deficits. Our findings add to a converging body of evidence for brainstem and thalamic dysfunction as a hallmark of schizophrenia.

Auditory mismatch impairments are characterized by core neural dysfunctions in schizophrenia.

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.