Further, in the framework of prediction error, MMN mechanisms can disclose how prior information can influence perceptual learning and optimize cognitive representations of the world through synaptic plasticity, presumably mediated by NMDA receptors, to help the brain better predict the environment [65].

In the field of clinical neuroscience, the feature of being elicited dependently or independently of the subject’s motivation, attention, or awareness, during sleep, or even coma, makes the MMN particularly suitable for testing many different clinical populations using many different setups. Consequently, the MMN has been found to be abnormal in a large number of neurologic and neuropsychiatric disorders [132].

The MMN response is diminished in attention deficit-hyperactivity disorders [195], autism syndrome disorder [196] and dyslexia [197]. No robust conclusion can be drawn in major depressive disorder and bipolar disorder [198]. As for schizophrenia, MMN amplitude decrease is a promising index of auditory sensory discrimination associated with cognitive and psychosocial dysfunction [199] and a promising candidate marker for predicting the responsiveness to cognitive trainings [200]. Furthermore, MMN has been recently proposed as a promising neurophysiological marker for the psychosis onset and as an informative neurophysiological tool that might reflect functional brain changes prior to the emergence of the illness [141, 161, 201].

3.5 MMN in schizophrenia

The MMN is reduced in patients with schizophrenia. This phenomenon has been robustly measured since the early 1990s [142, 143, 202] despite the heterogeneity of the disorder and the medication status (drug-naïve or under antipsychotics). The reduced MMN has a high test-retest reliability (>.80) and has been more closely associated with global functioning domains, such as better work, independent living and with better social perception than with the expression of positive and negative psychotic symptoms [199] [203].

The most reliable deficits with the largest effect size are in response to frequency (0.67; CI=

0.59, 0.75) and duration deviants (0.83; CI= 0.79, 0.88) [204]. It has been hypothesized that a reduced duration MMN (dMMN) may index a trait marker of schizophrenia, whereas a reduction in the amplitude of the frequency MMN (fMMN) may be related to lower functioning and progressive brain pathology related to the disorder [205].

The extent of the MMN deficit in schizophrenia was assessed in a meta-analysis by Umbricht and Krljes (2005). They reported robust deficits in the MMN response in adult patients with chronic schizophrenia (0.99; CI 0.79, 1.29) and increased mean effect size for the studies with


longer duration of illness (1.09) compared with the studies with shorter duration of illness (0.74) [142].

Consistent with these results, a second meta-analysis provides major insights into the nature and progression of MMN deficits in schizophrenia [143]. The authors also reported amplitude reduction in mismatch negativity response as a function of illness duration. The effect size observed in clinical high risk and first-episode schizophrenia groups was modest (.40 and .42) compared with the effect size exhibited by the chronic schizophrenia group (.81), yet significantly higher compared to healthy participants` effect size. The unaffected first-degree relatives of patients with schizophrenia exhibited also reduced MMN, however not statistically significant compared to healthy individuals. The reported effect size for this group was .26 (CI

= −.01 to .52), indicating an average, yet not a significant MMN amplitude deficit [143].

Furthermore, a meta-analysis on first episode schizophrenia reports no MMN reduction in first-episode patients to pitch-deviants (Cohen's d < 0.04), and a small-to-medium reduction to duration-deviants (Cohen's d = 0.47) [206].

Together these findings suggest that abnormal MMN might reflect the impaired functional status rather than a high genetic risk for the development of schizophrenia.

Several mechanistic explanations for reduced mismatch response in patients with schizophrenia have been proposed. First, grey matter volume loss in Heschl's gyrus and the superior temporal gyrus [207, 208], along with morphological changes of pyramidal cells in layer 3 of the auditory cortex [209] may play an important role. Patients with schizophrenia show positive correlations between gray matter volume reduction of Heschl's gyrus and MMN response [210, 211].

Second, alterations in glutamatergic neurotransmission may also play a part.

The glutamatergic model of MMN impairments in schizophrenia is based on human and animal studies showing the ability of the NMDAr antagonists, like ketamine and phencyclidine, to reduce MMN response [185, 212, 213] and further, the ability of the NMDAr agonists, like D-serine but not 5-HT2AR agonist like psilocybin to restore the MMN response [214-216].

Additionally, Umbricht et al. (2002) reported that a weaker MMN response before the ketamine administration was predictive of more severe positive symptoms under ketamine in healthy participants [217]. Interestingly, a significant negative correlation was also measured between MMN amplitude and plasma levels of dopamine metabolites, and not of serotonin metabolites, suggesting an association between the dopaminergic and glutamatergic systems and a potential impact of long term therapeutic blockade of dopamine receptors on MMN in patients with schizophrenia [218].


Recently, Rowland et al. (2016) highlight a presumptive role of MMN in working memory impairments in patients with schizophrenia. The authors investigated the role of glutamate and GABA measured in medial prefrontal cortices in MMN elicitation and verbal working memory using both the EEG and magnetic resonance spectroscopy methods. The results indicate that a reduced MMN amplitude was linked to lower GABA and glutamate levels and to poor verbal working memory in patients with schizophrenia [219].

These results go in line with histological studies that report hypofunction of NMDA receptors in this clinical population [220].

Consequently, these structural changes measured at the auditory macro- and microcircuit levels highlight the convergence between the functional and structural findings in patients with schizophrenia. However, it remains unclear whether patients with schizophrenia exhibit deficits in SSA, or deviance detection that leads to prediction errors.

According to the prediction error paradigm proposed by Garrido (2009) the role of MMN is to signal potentially relevant changes in the environment that do no match sensory memory-based predictions. Consequently, for accurate prediction errors both the encoding of regularities and the error estimations encoding must be accurate.

Javitt et al. (1997) reported two decades ago that patients with schizophrenia show decreased delayed tone matching performance that normalize when the patients are tested at their individualized thresholds [221]. Abnormal pitch discrimination of non-verbal tones has been recently confirmed by a meta-analysis reporting large abnormal tone-matching ability in patients as compared with controls [222]. In addition, using a roving standard oddball paradigm, with trains of 3, 8, or 33 standards before one deviant, McCleery et al. (2019) reported a significant memory trace effect in both patients with schizophrenia and healthy controls, with stronger negative MMN amplitude when the deviants were delivered after 33 versus 3 or 8 standards [223].

These results indicate that MMN deficits in patients with schizophrenia might reflect a problem in prediction error estimation due to inaccurate representation of standards and impaired discrimination ability, rather than reduced memory trace formation for the standard.


3.5.1 MMN endophenotype in schizophrenia

An endophenotype is a measurable quantitative feature closely linked to the etiology of the illness that should fall within the genotype to phenotype pathway of the illness being the link between the genetic variation and the biological processes responsible for the clinical phenotype of the disorder. It is stable over time, state-independent (present whether the illness is not active) and heritable, therefore present in unafflicted relatives [224].

The auditory mismatch negativity response is reduced in patients with schizophrenia and in subjects who are at-risk for the development of schizophrenia. A meta-analysis reports a modest effect size in clinical high risk and first-episode schizophrenia groups (.40 and .42) compared with the effect size exhibited by the chronic schizophrenia group (.81), while the unaffected first-degree relatives of patients with schizophrenia exhibited reduced (.26), yet non-significant MMN amplitude compared to healthy individuals [143]. The heritability of the MMN has been estimated to be .68 for mean amplitude [225] and the test-retest reliability to be >.80 [226, 227]. Further, it has been reported to be stable over time in patients with chronic schizophrenia despite the antipsychotic use or modest fluctuations in clinical symptoms [124].

The temporal gray matter volume reduction [210] [211] along with alterations in glutamatergic neurotransmission within the auditory areas [185] have been proposed to underlie the reduced auditory MMN observed in patients with schizophrenia.

Neuregulin-1 is one of susceptibility genes for schizophrenia involved in glutamatergic and GABAergic signalling [228]. The haploinsufficiency of Nrg1(+/-) mice exhibited reduced MMN, demonstrating a potential role of these gene in MMN expression [229]. However, the genetic and neurobiological contributions to MMN need further investigation in patients with schizophrenia.

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