Clinical significance of MMN in 22q11.2 DS

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(10 participants in each group) and replication studies are needed to draw any solid conclusions.

Interestingly, the auditory processing pattern measured in 22q11.2 DS, namely increased N1, and reduced MMN and P300, resemble impairments seen in healthy subjects after ketamine administration (NMDAr antagonist) [151, 152], indicating that higher N1 amplitude, alongside with the decreased amplitude in MMN and P300 might reveal altered function of the glutamate N-methyl-D-aspartate receptors (NMDAr) within the cortical and\or

subcortical auditory areas.

Since the literature regarding the cortical glutamatergic function in 22q11.2 DS is scarce, the investigation of auditory evoked responses might be relevant for future studies to produce divergent markers for functional deficits in 22q11.2DS highlighting abnormal GABAergic and glutamatergic neurotransmission, as well as impaired cognitive processing.

The results from both the longitudinal and cross-sectional studies reveal the emergence of reduced MMN response only during adolescence, a period of considerable brain changes and a vulnerable window for the emergence of psychotic disorders [251-254]. In the light of these results we hypothesized that attenuated mismatch response among the 22q11.2 deletion carriers might result from progressive cortical loss and volumetric reduction in the MGN, frontal (inferior prefrontal and medial frontal gyri) and temporal cortices (superior temporal cortex, AC) [41, 255-258], impaired functional connectivity [231], and dysfunctional glutamate N-methyl-D-aspartate receptors (NMDAr) [259, 260] within these areas.

However, since decreased gray matter volumes of cortical and subcortical auditory areas were not correlated with the MMN alteration, it is thus possible that the mismatch negativity response is sensitive to subtle developmental functional and molecular changes in cortical and thalamic areas, reflecting aberrant sensory processing in 22q11.2 DS.

3.2 Clinical significance of MMN in 22q11.2 DS

The MMN was proposed as a potential neurophysiological endophenotype in schizophrenia research and as an informative neurophysiological tool that might reflect functional brain changes prior to the emergence of the illness. Finding reliable psychosis endophenotypes might be crucial since longer duration of untreated psychosis is associated with lower

functional and symptomatic outcome [261]. In addition, identifying new endophenotypes can reveal abnormal mechanisms underlying psychosis onset that might guide the development of new interventions more mechanistically informed.

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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 [224], and thus the genetic and neurobiological contributions of a biomarker must be clarified before defining it as a psychosis endophenotype.

Mismatch negativity as an endophenotype of psychosis in 22q11.2 DS

To date, the literature on MMN response in 22q11.2 DS is simply too limited to guide a clear conclusion regarding its reliability as a psychosis endophenotype.

The abnormal MMN response in 22q11.2 deletion carriers becomes evident in adolescence, while being preserved in childhood, without a clear connection to progressive structural changes within the subcortical and cortical auditory areas or to hallucinatory experiences.

Although our results show a reduction in MMN response, this finding is not a robust deficit in the 22q11.2 DS population since the literature is mainly contradictory. Moreover, MMN is reduced in young adults with and without schizophrenia (analyzed yet unpresented data) as compared to typically developing youth, and thus it cannot be used a measurable

characteristic that marks the manifestation of schizophrenia in 22q11.2 deletion carriers.

Further, even if COMT gene expression and temporal gray matter volume reduction along the auditory areas might partially explain the amplitude reduction of MMN in adolescents and young adults with 22q11.2 DS, no clear conclusion about the genetic and neurobiological contribution to the MMN deficit can be highlighted.

Consequently, our results, in line with the literature suggest that the MMN is not state independent, is not stable over time and provides no clear link between the genetic variation and the biological processes responsible for the clinical phenotype of the disorder (reduced MMN).

Nonetheless, even though MMN response may not be a psychosis endophenotype, this electrophysiological marker might be a promising index of abnormal sensory processing and add value to clinical assessments when aiming to detect abnormal function within the cortical areas responsible the MMN generation.

Therefore, it is relevant to explore some hypotheses about its clinical significance.

Mismatch negativity and psychotic symptoms

Given the high presence of subthreshold positive and negative symptoms in 22q11.2 deletion carriers [64] we investigated the link between these symptoms and the amplitude of MMN.

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Firstly, in the longitudinal study we did not find significant correlations between the

prodromal symptoms, positive or negative, and the mismatch response attenuation and we did not observe a significant change in the intensity of symptoms from childhood to adolescence, even though we observe a decrease in the amplitude of MMN. Secondly, the presence of moderate and severe auditory hallucinations revealed no effect on the MMN amplitude.

These results go in line with a meta-analysis showing no consistent relationships between MMN size and the severity of psychotic symptoms [262].

However, the 22q11.2 deletion carriers with hallucinations express reduced volume of lhMGN and bilateral STG compared to 22q11.2DS without hallucinationsand control participants, in line with prior investigations indicating abnormal developmental trajectories of MGN volume and immature pattern of connectivity with secondary auditory cortices in 22q11.2 DS [66]. Interestingly, MGN was shown to be hyperconnected to auditory cortical regions at rest, with a negative correlation between the connectivity and its volume (the higher the connectivity, the lower MGN volume) in 22q11.2 deletion carriers experiencing auditory hallucinations, suggesting that psychotic deletion carriers exhibit hyperactivity of the brain regions underlying auditory processing at rest and abnormally activate the same network during an auditory task [66]. In addition, the structural changes, such as left-sided volume reduction of the STG in 22q11.2DSH⁺ group might be related to hallucinatory experiences as previously reported in both 22q11.2DS youth [86, 97], as well as

schizophrenia [263]. These results are relevant and indicate that impaired MMN response in 22q11.2 DS might underly auditory functional abnormalities, without a compulsory link with the severe structural changes.

Mismatch negativity and IQ

A second line of investigation is the link between the cognitive decline, reported to be predictive of psychosis in this syndrome [46, 47] and MMN. Our results, confirmed by other recent study (2020) [32] show no link between the IQ and MMN response.

Consequently, our results are in line with previous studies and reveal that MMN is not related with psychotic symptoms or cognitive dysfunction in individuals with 22q11.2DS, and rather might reflect associated functional disability [199].

Mismatch negativity and functional disabilities

A schematic illustration of associated functional disabilities that might be indirectly linked with abnormal auditory processing in patients with schizophrenia is proposed by Javitt and

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Sweet (2015). The authors hypothesise that inability to correctly process the changes in pitch or rhythm can lead to alterations in prosody detection, which further can lead to abnormal auditory emotion recognition and impaired 'theory of mind' (the ability to understand others beliefs or perspectives) [264].

Figure 11. Schematic illustration of auditory sensory dysfunctions that might impact normal higher order cognitive processing. Adapted from Javitt and Sweet [264].

In line, based on prior results reporting musical auditory processing impairments [265] in 22q11.2 deletion carriers we can speculate that reduced MMN in response to frequency deviant sounds might reveal abnormal auditory tonal ability which can be responsible for impaired auditory emotion recognition and phonological processing deficits, that might further impact the everyday social cognitive function of these individuals.

Further, the MMN response reflects the outcome of a surveilling process that constantly monitors the environment for potentially relevant information [154]. In typically developing individuals the generation of MMN response is linked to subsequent activation of salience network structures such as the insula and the anterior cingulate cortex [141]. On the contrary, the 22q11.2 deletion carriers, show deficient function of the salience resting state networks [92] and increased activations in dorsal anterior cingulate and medial frontal cortex during a sensory gating auditory task [9], suggesting abnormal function of the salience related brain areas in deletion carriers as compared to healthy controls.

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Consequently, in this view reduced MMN amplitude in response to frequency deviant sounds might indirectly suggest abnormal monitoring of the environment and social cognition

deficits, including abnormal auditory emotion recognition which is crucial for social interactions and integration [52].