Abnormal development of early auditory processing in 22q11.2 Deletion Syndrome

Abstract

The 22q11.2 Deletion Syndrome (22q11.2 DS) is one of the highest genetic risk factors for the development of schizophrenia spectrum disorders. In schizophrenia, reduced amplitude of the frequency mismatch negativity (fMMN) has been proposed as a promising neurophysiological marker for progressive brain pathology. In this longitudinal study in 22q11.2 DS, we investigate the progression of fMMN between childhood and adolescence, a vulnerable period for brain maturation. We measured evoked potentials to auditory oddball stimuli in the same sample of 16 patients with 22q11.2 DS and 14 age-matched controls in childhood and adolescence. In addition, we cross-sectionally compared an increased sample of 51 participants with 22q11.2 DS and 50 controls divided into two groups (8–14 and 14–20 years). The reported results are obtained using the fMMN difference waveforms. In the longitudinal design, the 22q11.2 deletion carriers exhibit a significant reduction in amplitude and a change in topographic patterns of the mismatch negativity response from childhood to adolescence. The same effect, reduced mismatch amplitude in adolescence, while preserved during childhood, is observed in the cross-sectional study. These results point towards functional changes within the brain network responsible for the fMMN. In addition, the adolescents with 22q11.2 DS displayed a significant increase in amplitude over central electrodes during the auditory N1 component. No such differences, reduced mismatch response nor increased N1, were observed in the typically developing group. These findings suggest different developmental trajectories of early auditory sensory processing in 22q11.2 DS and functional changes that emerge during the critical period of increased risk for schizophrenia spectrum disorders.

Assessing auditory processing endophenotypes associated with Schizophrenia in individuals with 22q11.2 Deletion Syndrome

“…Increased auditory evoked potentials have been described in a 22q11.2DS mouse model: Loudness dependent amplitudes were enlarged in mice with the deletion (89). Likewise, two human studies looking at auditory processing in 22q11.2DS showed enhanced responses (76,90).…”

“…While larger N1s have been associated with elevated activity in the anterior cingulate and dorsomedial frontal cortex (76) and alterations in the cortical glutamate N-methyl-D-aspartate (NMDA) receptors (90)(91)(92), the nature of the neural mechanisms underlying adaptation are not fully understood. Decreases in amplitude with faster presentation rates may be observed due to temporal limitations intrinsic to the mechanisms underlying N1 generation, i.e., faster presentations of auditory stimuli do not allow for full recovery of such mechanisms and a decline in N1 amplitude is observed (43).…”

“…Previous studies on MMN in 22q11.2DS have yielded somewhat inconsistent evidence (for a review, see (95)): Whereas some studies have found reduced pitch, duration and frequency MMNs (90,96), others failed to show differences between individuals with 22q11.2DS and their neurotypical peers (75,97). Such inconsistencies in MMN differences may reflect the phenotypic heterogeneity that is characteristic of 22q11.2DS, as well as, possibly, methodological and stimulus related differences (e.g., (96) only report differences in frontal channels; (90) tested children and adolescents between the age of 8 and 20 years old). Adding to the range of findings, we observed that at the fast stimulation rate, which is similar to the rate often used in MMN studies (see, for instance, Cantonas et al, 2019), the response was intact and appeared typical.…”

Assessing auditory processing endophenotypes associated with Schizophrenia in individuals with 22q11.2 deletion syndrome

“…Increased auditory evoked potentials have been described in a 22q11.2DS mouse model: Loudness dependent amplitudes were enlarged in mice with the deletion 87 . Likewise, two human studies looking at auditory processing in 22q11.2DS showed enhanced responses 74,88 . While larger N1s have been associated with elevated activity in the anterior cingulate and dorsomedial frontal cortex 74 and alterations in the cortical glutamate N-methyl-D-aspartate (NMDA) receptors [88][89][90] , the nature of the neural mechanisms underlying adaptation are not fully understood.…”

“…Likewise, two human studies looking at auditory processing in 22q11.2DS showed enhanced responses 74,88 . While larger N1s have been associated with elevated activity in the anterior cingulate and dorsomedial frontal cortex 74 and alterations in the cortical glutamate N-methyl-D-aspartate (NMDA) receptors [88][89][90] , the nature of the neural mechanisms underlying adaptation are not fully understood. Decreases in amplitude with faster presentation rates may be observed due to temporal limitations intrinsic to the mechanisms underlying N1 generation, i.e., faster presentations of auditory stimuli do not allow for full recovery of such mechanisms and a decline in N1 amplitude is observed 41 .…”