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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.

3.6 MMN in 22q11.2 Deletion Syndrome

The characteristics of MMN in 22q11.2 DS are not well understood, as the literature to date is scant and characterized by small sample sizes. Only four studies were found to investigate mismatch negativity response in 22q11.2 DS [31, 32, 38, 130].

The first study published more than a decade ago by Baker et al., 2005 provided evidence that MMN amplitude in response to duration deviant is decreased in adolescents with 22q11.2 DS as compared to typically developing group. Furthermore, they demonstrated that the presence of COMT(108/158)Met allele was linked with increased MMN amplitude reduction and lower neuropsychological performance [31].

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Zarchi et al. (2013) also investigated the associations between mismatch negativity impairments and dopaminergic and glutamatergic networks in the adults with 22q11.2 DS [38]

and in line with Baker et al. (2005) they reported that the presence of COMT Met allele and the PRODH Pro-Arg haplotype were linked with smaller MMN amplitude. In addition, smaller MMN amplitude predicted increased severity of executive functions and schizophrenia-like negative symptoms in 22q11.2 DS.

On the contrary, Larsen et al. (2018) reported no altered MMN amplitude in adolescents with 22q11.2DS; however, they observed an altered functional connectivity from inferior frontal gyrus to superior temporal gyrus [130]. These results, even though did not survive multiple comparison correction, might be informative and complementary by adding the connectivity information highlighting the imperious need for further investigation.

More recently, Francisco et al. (2020) reported no significant MMN amplitude reduction in 22q11.2 deletion carriers as compared to typically developing individuals but found a significant group x stimulus onset asynchrony interaction (SOA; for this study they used three SOA: 450ms, 900ms and 1800 ms). They reported larger MMN amplitude in response to longer than shorter SOAs (450ms vs. 900ms and 1800ms) in the 22q11.2DS group as compared to the control group. Further, they observed no MMN amplitude correlations with age, IQ or working memory performance [32].

Several mechanistic explanations for reduced mismatch response in patients with 22q11.2 DS can be proposed.

First, individuals with 22q11.2 DS show brain structural abnormalities in frontal and temporal regions [83] that have been involved in the MMN response elicitation, such as insula, superior temporal gyri, and anterior cingulate cortex [41]. In addition, aberrant brain connectivity has also been reported in humans [230, 231] and animal models of 22q11.2 DS [232]. Ottet et al.

(2013) describe reduced left fronto-temporal connections and increased right fronto-frontal connections in patients with 22q11.2 DS as compared with typically developing participants [231], while in animal models, Chun et al. (2017) found disruptions in the activity of thalamo-cortical glutamatergic projections from the medial geniculate nuclei to the auditory cortex, that became evident only after 3 months of age in a mouse model of 22q11.2 DS (corresponding to early adulthood in humans) [232].

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

Two studies demonstrated a link between COMT and PROHD haploinsufficiency and reduced MMN amplitude suggesting a symbiotic association between the dopaminergic and glutamatergic systems that may have an impact on MMN response in this clinical population.

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Further, only one neurochemical imaging study using proton magnetic resonance spectroscopy (1H-MRS) investigated the glutamatergic alteration in 22q11.2 deletion carriers [30]. Da Silva Alves et al. (2011) measured higher glutamate and myo-inositol concentrations in the hippocampus of patients with 22q11.2DS and schizophrenia as compared to those without co-morbid schizophrenia, while no concentration changes in glutamate levels were measured in dorsal-lateral-prefrontal cortex.

Consequently, the structural and neurochemical changes measured in the cortical auditory, as well as in subcortical associated regions indicate a potential link between the auditory dysfunction and brain structural abnormalities reported consistently in 22q11.2 deletion carriers. However, no clear pattern of MMN dysfunction and no clear link between MMN and brain abnormalities can be drawn from these results in patients with 22q11.2 DS.

3.6.1 MMN endophenotype for schizophrenia in 22q11.2 DS

Whereas the MMN decrease in amplitude is a robust neurophysiological dysfunction and a promising endophenotype in subjects with schizophrenia, in 22q11.2 deletion carriers this deficit is not well understood.

An endophenotype is a quantitative marker that links the genotype to the clinical phenotype of a disorder. To be an endophenotype of schizophrenia in 22q11.2 DS, the MMN should be stable over time, state-independent (present when the illness is inactive) and heritable, therefore present in unafflicted relatives [224]. Additionally, the genetic and neurobiological contributions to the MMN must be clarified before defining it as a potential endophenotype in 22q11.2 DS.

To date, no results are to be found about the reliability and heritability of MMN in 22q11.2 DS, and the genetic and neurobiological contributions of this response need further investigation on large samples.

Consequently, although the MMN can be a strong endophenotype candidate for schizophrenia, in 22q11.2 DS MMN needs to be intensively investigated before any assertion can be made.

In summary, the mismatch negativity response is a well-studied component of the auditory evoked potential measured as a negative deflection in voltage with a latency of 150-200 ms that occurs in response to a regularity violation and indexes a prediction error signal generated by a complex network. The MMN decrease in amplitude is a robust neurophysiological dysfunction in subjects with schizophrenia and has been proposed as a potential endophenotype for this disorder. However, the characteristics of MMN in 22q11.2DS are not well understood, due to the scarce literature.

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Chapter 4

Neuroimaging tools to assess