Auditory dysfunction in 22q11.2 Deletion Syndrome
2.3 Impaired auditory evoked responses in 22q11.2DS
2.2 Auditory dysfunction in 22q11.2 DS
Previous studies investigating neurobiological structural and functional changes within the auditory pathways in 22q11.2 DS have reported anatomical  and functional  abnormal connectivity between the medial geniculate nuclei (the auditory thalamus) and the auditory cortices.
In addition, neuroanatomical alterations associated with schizophrenia expression in 22q11.2 DS involve significantly thinner cortex in the left superior temporal gyrus [41, 84, 86] and progressive volumetric decreases in temporal areas predicted psychotic symptom development in 22q11.2DS youth [86, 97].
Functional auditory sensory dysfunction has been also measured in patients with 22q11.2 deletion carriers [31, 118] by many authors using evoked responses measured with non-invasive techniques, such as electroencephalogram (EEG), providing important insights into the underlying neuropathological processes of the disorders.
2.3 Impaired auditory evoked responses in 22q11.2DS
The auditory evoked response (AEP) is an electrical brain response, associated in time with an auditory input, recorded from the human scalp and extracted from the ongoing EEG after averaging the signal .
AEPs encompass components or voltage deflections (positive or negative) elicited across the auditory pathway, from the sensory organ to the brainstem, thalamus and up to the auditory cortex. Therefore, the AEPs can be divided into early, brainstem responses up to 10 ms, middle latency evoked responses between 10 and 60 ms and late latency evoked responses (N1, P2, MMN, P300, etc.) defined between 80 and 200 ms post-stimulation and cognitive responses like P300  (Figure 5).
Figure 5. Auditory Evoked Potential traveling through auditory nerve to auditory brainstem and cortical areas. Brainstem responses occurring in the first 10 ms after the stimulus presentation, middle latency responses elicited between 10 ms and 80 ms post-stimulus (P1) and late responses (N1, P2, MMN, N2, P3) elicited usually after 80 ms post-stimulus. The brain area proposed to be responsible for each component of the event relate potentials are also mentioned. Adapted from Modi & Sahin, 2017.
The evoked responses include a scalp-positive peak at about 50 ms (P50\P1), followed by a strong negative peak at about 100 ms (N100\N1) and a succession of fluctuating scalp-positive and negative peaks at about 150 ms (P200\P2), 200 ms (N200) and 300 ms (P300\P3) . The traditional approach to analyse the AEPs waveforms is to select the peaks of the components, and to measure their amplitude and latency.
AEP components have been extensively used to study the late maturation of the auditory cortex and abnormal auditory functioning in different clinical population. AEP components change with age and reach an adult like morphology around 12 years of age , co-occurring with the end of structural maturation of auditory cortex .
The literature on auditory processing in 22q11.2DS is sparse, and only a few studies have focused on understanding the components of auditory evoked potentials. The studies investigated N1, mismatch negativity, sensory gating processing, P3 and auditory state responses and provide mixed results. An overview of the findings is presented in Figure 6.
Figure 6. Summary of studies on auditory processing in 22q11.2DS presenting reduced MMN and P300 amplitude, reduced mean inter-trial phase coherence (the uniformity of phase angles across trials) of gamma oscillatory activity and unchanged P50 sensory gating response. The figure is adapted from: Rihs et al., 2013, Cantonas et al., 2019, Mannarelli et al., 2018 and Larsen et al. 2017.
Sensory gating (P50\P1)
Deficits in sensory gating, measured using the paired-click or P50 paradigm, have been reported extensively in patients with schizophrenia, and consequently were proposed as potential endophenotypes for this disorder . The P50 paradigm measures the evoked brain response elicited by two identical auditory stimuli that occur 500 ms apart and reflects the sensory filtering and gating mechanisms of attention and information processing. Typically developing individuals show a suppressed response to the 2nd stimulus relative to the 1st one that has been associated with a large network of cortical and subcortical structures involving thalamic nuclei, superior temporal, frontal and parietal brain regions [125, 126].
Deficits in sensory motor gating are inconsistent in 22q11.2 deletion carriers. Rihs et al. (2013) and Vorstman et al. (2009) report no deficit of P50 suppression [9, 127], while Zarchi et al.
(2013) report reduced sensory gating in adults 22q11.2 deletion carriers relative to controls . Importantly, one study investigates the sensory gating in adults of which 14% were diagnosed with schizophrenia, while the other two studies investigate the sensory gating in children and adolescents [9, 127] with no schizophrenia diagnosis, suggesting that the deficits in sensory gating might appear later in development alongside with the development of prominent psychotic symptoms.
meta-analysis on the N100 measured using paired-click paradigms, Rosburg (2018) showed that the amplitude of this component is decreased solely in response to the first sound in patients with schizophrenia, pointing toward reduced sensory registration . Interestingly, using both paired click and oddball paradigms, two studies reported increased N100 amplitude [9, 130] in 22q11.2 deletion carriers, corresponding to increased activations in dorsal anterior cingulate and medial frontal cortex in one of the studies .
Mismatch negativity response
The auditory mismatch negativity (MMN) is a negative deflection in voltage with a latency of 150-200 ms. It is an automatic evoked response that occurs in response to a regularity violation, with or without paying attention, and indexes a prediction error signal [131-134]. The MMN response is critical for everyday function since it reflects the outcome of a surveilling process that constantly monitors the environment for potentially relevant information. It is generated in subcortical regions, such as medial geniculate nuclei, and increases in neural signal strength as it progresses towards primary and secondary auditory and spreads to additional structures such as insula, anterior cingulate cortex and inferior frontal cortex, leading to bottom-up attentional capture [135-141].
The MMN decrease in amplitude is a robust neurophysiological dysfunction in subjects with schizophrenia [142, 143], while the characteristics of MMN in 22q11.2 DS are not well understood, due to the scarce literature characterized by small sample sizes. The MMN response has been reported to decrease in amplitude by some authors , while other studies did not report significant MMN reduction in amplitude, but an altered functional connectivity from IFG to STG and enhanced N1 . Further, a reduced MMN for long stimulus onset asynchrony (>1000ms) was reported, indicating a more rapid decay of the auditory sensory memory trace in 22q11.2 DS .
Since MMN is a main topic of this thesis, it will be discussed in more detail in Chapter 3.
The P300 is a positive deflection in voltage with a latency of 300 ms. This evoked response usually encompasses two components in the waveform the P300a and P300b and is thought to
reflect cognitive processes involved in stimulus evaluation. It is elicited using an oddball task, the same as used for eliciting the MMN response, except that the participants need to actively pay attention to the deviant stimuli and to count them .
Although the P300 is a robust neurophysiological marker for schizophrenia , only one study examined this response in 22q11.2 DS. The authors report the amplitude of the P300 to be significantly decreased in participants with 22q11.2 DS as compared to typically developing for the P300b, while no change was observed for the first component P300a . These results suggest that the 22q11.2 deletion carriers show cognitive impairments and abnormal memory storage, whereas the engagement of attention towards the deviant stimuli is intact. However, replication studies are needed to draw any solid conclusions.
Auditory steady state responses
Auditory steady state responses (ASSRs) are brain responses evoked by trains of brief tones repeatedly presented at a repetition rate of 40 Hz. It is a non-invasive modality to investigate the neural gamma synchrony within the auditory system and thus the integrity of cortical inhibitory-excitatory balance in GABAergic and glutamatergic neurotransmission .
Although reduced ASSR is a reliable finding in schizophrenia and in non-affected first degree relatives [149, 150], only one study investigated this evoked response in 22q11.2 DS .
In a sample of 18 non-psychotic individuals with 22q11.2 DS, Larsen et al. (2018) measured a reduction of 24% in gamma power and a reduction of 28% in trial-to-trial phase synchronization of the ASSR, suggesting impaired gamma oscillatory activity within the auditory pathways of 22q11.2 deletion carriers .
In summary, many features of auditory processing, namely reduced MMN, P300 and ASSR, which resemble impairments seen in patients with schizophrenia are also abnormal in 22q11.2 DS. On the contrary, the increased N1 response might be a marker specific to the 22q11.2 DS population, while not observed in patients with schizophrenia.
Interestingly, the same effect was observed in healthy subjects after ketamine administration (NMDAr antagonist) [151, 152], suggesting that the increase in N1 amplitude, alongside with the decreased amplitude in MMN might point towards alterations in the cortical glutamate N-methyl-D-aspartate receptors (NMDAr). Although the literature regarding the auditory dysfunctions 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.