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

Abstract

Background: 22q11.2 Deletion Syndrome (22q11.2DS) is the strongest known molecular risk factor for schizophrenia. Brain responses to auditory stimuli have been studied extensively in schizophrenia and described as potential biomarkers of vulnerability to psychosis. We sought to understand whether these responses might aid in differentiating individuals with 22q11.2DS as a function of psychotic symptoms, and ultimately serve as signals of risk for schizophrenia.Methods: A duration oddball paradigm and high-density electrophysiology were used to test auditory processing in 26 individuals with 22q11.2DS (13-35 years old, 17 females) with varying degrees of psychotic symptomatology and in 26 age-and sex-matched neurotypical controls (NT). Presentation rate varied across three levels, to examine the effect of increasing demands on memory and the integrity of sensory adaptation. We tested whether N1 and mismatch negativity (MMN), typically reduced in schizophrenia, related to clinical/cognitive measures, and how they were affected by presentation rate.Results: N1 adaptation effects interacted with psychotic symptomatology: Compared to an NT group, individuals with 22q11.2DS but no psychotic symptomatology presented larger adaptation effects, whereas those with psychotic symptomatology presented smaller effects. In contrast, individuals with 22q11.2DS showed increased effects of presentation rate on MMN amplitude, regardless of the presence of symptoms. While IQ and working memory were lower in the 22q11.2DS group, these measures did not correlate with the electrophysiological data.Conclusions: These findings suggest the presence of two distinct mechanisms: One intrinsic to 22q11.2DS resulting in increased N1 and MMN responses; another related to psychosis leading to a decreased N1 response.

Neurophysiological Biomarkers in Schizophrenia—P50, Mismatch Negativity, and TMS-EMG and TMS-EEG

“…An aforementioned meta-analysis showed that there was a trend for decreased MMN amplitude in relatives of patients ( 90 ), which was in agreement with another meta-analysis ( 100 ). A recently published study also demonstrated an intrinsic effect of 22q11.2 deletion syndrome, a molecular risk factor for schizophrenia, on MMN ( 54 ), suggesting a potential genetic link as well. Therefore, while a growing body of studies is supporting MMN as an endophenotype, the findings are mixed.…”

“…MMN and P50 are among the neurophysiological markers that are being considered as potential endophenotypes in this disease ( 52 – 54 ). In addition, as MMN and P50 are markers of neurological processes that are thought to be important for cognitive functioning in patients with schizophrenia, they have also garnered interest as predictive biomarkers to see if an intervention will improve cognition ( 55 – 60 ).…”

Atypical response inhibition and error processing in 22q11.2 Deletion Syndrome and schizophrenia: Towards neuromarkers of disease progression and risk

“…The mixed nature of the current 22q11.2DS sample (individuals with and without symptoms) could have impacted the ability to detect differences between those with 22q11.2DS and their age-matched neurotypical peers. A recent EEG study focused on basic auditory processing in this population suggested differences between those with and without psychotic symptomatology and argued for the presence of two opposite mechanisms in those with the deletion: one that relates to a process specific to the deletion itself and gives rise to larger amplitudes, and another, associated with psychosis that results, as in schizophrenia, in decreases in amplitude ( Francisco et al, 2020 ). And, indeed, here, whereas the 22q11.2DS− group did not differ from the neurotypical controls, but presented increased amplitudes when compared to the schizophrenia group; 22q11.2DS+ did not differ from the individuals with schizophrenia, but presented decreased amplitudes when compared to the neurotypical controls.…”

Abnormalities of synaptic mitochondria in autism spectrum disorder and related neurodevelopmental disorders

“…The DiGeorge syndrome, also known as velocardiofacial or 22q11.2 deletion syndrome (22q11.2DS), is the consequence of a hemizygous microdeletion (1.5-3 Mb) on chromosome 22, with an incidence of 1 in 4000 [117]. The syndrome often presents with different neuropsychiatric symptoms [118], including schizophrenia [119]. Additionally, individuals with 22q11.2DS manifest with attention-deficit hyperactive disorder (ADHD), ASD, anxiety, depressive, and bipolar disorders [120,121].…”