Thesis
Reference
The underlying mechanisms of mismatch negativity response in 22q11.2 deletion syndrome
CANTONAS, Lucia-Manuela
Abstract
The 22q11.2 Deletion Syndrome (22q11.2 DS), one of the highest genetic risk for the development of schizophrenia, offers a unique opportunity to understand neurobiological and functional changes preceding the onset of the psychotic illness. In the search for biomarkers, the altered auditory function, such as reduced auditory mismatch negativity has been proposed as a reliable marker for schizophrenia. To explore the general pattern of auditory sensory processing and its underlying mechanisms, two studies were designed hypothesising schizophrenia-like functional auditory abnormalities in 22q11.2DS. Interestingly, we observe abnormal development of auditory functioning from childhood to adolescence in non-psychotic 22q11.2 deletion carriers as compared to typically developing individuals that is not associated with lower IQ or psychotic symptoms and is unrelated to structural changes measured along the auditory pathways. Therefore, our results might reveal impaired auditory emotion recognition, a key feature of social cognition, and abnormal neuromodulation of bottom-up op-down information processing.
CANTONAS, Lucia-Manuela. The underlying mechanisms of mismatch negativity response in 22q11.2 deletion syndrome. Thèse de doctorat : Univ. Genève et Lausanne, 2020, no. Neur. 287
DOI : 10.13097/archive-ouverte/unige:149673 URN : urn:nbn:ch:unige-1496731
Available at:
http://archive-ouverte.unige.ch/unige:149673
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DOCTORAT EN NEUROSCIENCES des Universités de Genève
et de Lausanne
UNIVERSITÉ DE GENÈVE FACULTÉ DE PSYCHOLOGIE ET SCIENCES DE L'ÉDUCATION
Professeur Christoph Michel, directeur de thèse Tonia Rihs, PhD, co-directrice de thèse
TITRE DE LA THÈSE
THE UNDERLYING MECHANISMS OF MISMATCH NEGATIVITY RESPONSE IN 22Q11.2 DELETION SYNDROME
THÈSE Présentée à la
Faculté des psychologie et sciences de l'éducation de l’Université de Genève
pour obtenir le grade de Docteure en Neurosciences
par
Lucia-Manuela CANTONAS
de Brasov, Romania Thèse N° 287
Genève
Editeur ou imprimeur : Université de Genève 2020
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Funding
This work has been funded by the Swiss National Science Foundation, grant number 320030_184677 and The National Centre of Competence in Research (NCCR) \Synapsy - The Synaptic Bases of Mental Diseases grant number 51NF40 – 185897 to Professor Christoph Michel.
The thesis is constructed based on main findings published in the following research articles:
1. Cantonas LM, Tomescu MI, Biria M, Jan RK, Schneider M, Eliez S, Rihs TA, Michel CM ; Abnormal development of early auditory processing in 22q11.2 Deletion Syndrome. Translation Psychiatry. 2019 Apr 16;9(1):138. doi: 10.1038/s41398-019- 0473-y.
2. Cantonas LM, Mancini V., Rihs T., Rochas V., Schneider M., Eliez M, Michel CM.;
Abnormal auditory processing and underlying structural changes in 22q11.2Deletion Syndrome; Schizophrenia Bulletin. 2020, doi:
10.1093/schbul/sbaa104
In addition, some of the methods used here are based on the following article:
3. Seeber M, Cantonas LM, Hoevels M, Sesia T, Visser-Vandewalle V, Michel CM.;
Subcortical electrophysiological activity is detectable with high-density EEG source imaging. Nature Communication 10, 753, doi:10.1038/s41467-019-08725-w (2019).
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Acknowledgements
I would like to thank Tonia Rihs and Prof. Christoph Michel for their supervision, advices, and the time dedicated in revising my work during the last years.
Special thanks to Prof. Trevor Robbins for his supervision and advices in writing the doc- mobility grant, for the great discussions we shared about various scientific topics and for the unique opportunity to be part of his team.
Many thanks to the jury members: Prof. Anne-Lise Giraud, Prof. Sophie Molholm and Prof. Stefan Kaiser for accepting to be part of my thesis committee, for revising this work and for their helpful insights.
Many thanks to all the colleagues of the FBM Lab, Miralena, Martin, Vincent, Ferran, Cristina, and Anna for all the moments we shared together, for all the advices they kindly offered.
Finally, I would like to thank Marjan Biria for a wonderful friendship.
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Abstract
Vast research has been conducted to understand the neuropathological mechanisms that underlie the core symptoms of schizophrenia. Considerable evidence suggests that schizophrenia is a neurodevelopmental disorder that follows a continuum, originating in early development and clinically manifesting in late adolescence, early adulthood [1-3]. Years before the full emergence of schizophrenia, up to 30-40% of the patients might experience subthreshold psychotic symptoms and deficits in cognition, perception, and basic sensory functions [4-6], pointing towards alteration of normal developmental trajectories.
This project focuses on a valuable neurodevelopmental model to study the functional and structural brain alterations that precede the onset of schizophrenia, namely the 22q11.2 Deletion Syndrome, and further on understanding the feasibility of auditory endophenotypes on predicting psychosis onset in schizophrenia.
The 22q11.2 Deletion Syndrome (22q11.2DS; also identified as velo-cardio-facial or DiGeorge Syndrome) is a multisystem syndrome caused by an interstitial microdeletion on the chromosome 22 and is one of the highest genetic risk factors for the development of psychosis with a percentage of 30% to 40% of the afflicted adults being diagnosed with schizophrenia spectrum disorders [7]. The 22q11.2 deletion carriers with co-morbid schizophrenia reveal characteristics similar to those manifested by patients with idiopathic schizophrenia in terms of main clinical symptoms, age of onset, prodromal symptoms and underlying morphological brain changes, and thus 22q11.2 DS has been proposed as a valuable neurodevelopmental model to study brain and behaviour changes preceding the onset of schizophrenia.
Although many studies on schizophrenia and 22q11.2 DS emphasize high order cognitive impairments [8], deficits manifest also at lower levels of sensory information processing [9, 10] in both visual and auditory domains.
The abnormal auditory sensory information processing measured as reduced mismatch negativity response (MMN) has been proposed as a promising index of brain pathology in schizophrenia. However, the link between the MMN response, psychosis symptoms and underlying cerebral mechanisms remain unexamined in 22q11.2DS.
To explore the general pattern of auditory sensory processing, and further to investigate in detail the underlying mechanisms of mismatch negativity response in 22q11.2 DS and its link with psychotic symptoms, two main studies were designed hypothesising schizophrenia-like functional auditory abnormalities.
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Interestingly, we observe altered auditory functioning, namely reduced MMN response alongside with increased N1 and reduced P300 responses in non-psychotic 22q11.2 deletion carriers that are not present in typically developing individuals. These results indicate a pattern of abnormal auditory processing that might be specific to 22q11.2 DS population rather than following the abnormal auditory pattern measured in patients with schizophrenia.
The mismatch response decreases in 22q11.2 DS is not linked to lower IQ or to psychotic symptom and is unrelated to the structural changes measured along the auditory pathway.
Therefore, our results might reveal impaired auditory emotion recognition, a key feature of social cognition, and abnormal neuromodulation of bottom-up\top-down information processing and impaired prediction error.
In addition, we provide evidence that the mismatch response is well developed in children with 22q11.2 DS and does not differ from typically developing children. This ability changes throughout adolescence following a particular developmental trajectory that might co-occur with an increased risk for schizophrenia, without compulsory reflecting an increased risk for the development of this psychiatric disorder. Hence, increased N1 and reduced MMN response may reveal abnormal auditory function and altered integrity of the auditory areas, rather than revealing information about the psychotic state.
Taken together our studies propose the MMN as an electrophysiological marker of abnormal sensory processing and prediction error in 22q11.2 DS that might add value to clinical assessments when aiming to detect abnormal auditory functioning within the cortical and subcortical brain areas.
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Version abrégée
De vastes recherches ont été menées pour comprendre les mécanismes neuropathologiques qui sous-tendent les principaux symptômes de la schizophrénie. Des preuves considérables suggèrent que la schizophrénie est un trouble neurodéveloppemental qui suit un continuum, prenant naissance au début du développement et se manifestant cliniquement à la fin de l'adolescence, au début de l'âge adulte [1-3].
Avant l'émergence complète de la schizophrénie, jusqu'à 30 à 40% des patients pourraient présenter des symptômes psychotiques sous-seuils et des déficits dans la cognition, la
perception et les fonctions sensorielles de base [4-6], indiquant une altération des trajectoires de développement normales.
Ce projet se concentre sur un modèle neurodéveloppemental précieux pour étudier les altérations fonctionnelles et structurelles du cerveau qui précèdent l'apparition de la
schizophrénie: le syndrome de délétion 22q11.2, et sur la compréhension des endophénotypes auditifs qui peut prédire l'apparition de la psychose.
Le syndrome de délétion 22q11.2 (22q11.2 DS; également identifié comme syndrome velo- cardio-facial ou syndrome de DiGeorge) est un syndrome multisystémique causé par une microdélétion interstitielle sur le chromosome 22 et est l'un des facteurs de risque génétique les plus élevés pour le développement de la psychose avec un pourcentage de 30% à 40% des adultes atteints de troubles du spectre de la schizophrénie [7].
Les porteurs de délétion 22q11.2 avec schizophrénie révèlent des caractéristiques similaires à celles manifestées par les patients atteints de schizophrénie idiopathique en termes de
symptômes cliniques principaux, âge d'apparition, symptômes prodromiques et modifications morphologiques sous-jacentes du cerveau, et donc 22q11.2 DS a été proposé comme un modèle neurodéveloppemental précieux pour étudier les changements du cerveau et du comportement précédant l'apparition de la schizophrénie.
Bien que de nombreuses études sur la schizophrénie et le 22q11.2 DS mettent l'accent sur les troubles cognitifs [8], les déficits se manifestent également à des niveaux inférieurs de traitement de l'information sensorielle visuel et auditif [9, 10].
Le traitement de l'information sensorielle auditive anormale mesurée comme mismatch negativity response (MMN) a été proposé comme un indice prometteur de la pathologie cérébrale dans la schizophrénie. Cependant, le lien entre la réponse MMN, les symptômes de la psychose et les mécanismes cérébraux sous-jacents restent non examinés dans 22q11.2DS.
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Pour explorer le modèle général du traitement sensoriel auditif, et pour étudier plus en détail les mécanismes sous-jacents de la mismatch negativity dans le 22q11.2 DS et son lien avec les symptômes psychotiques, deux études principales ont été conçues.
Comme supposé les résultats révèlent un fonctionnement auditif altéré : une réponse MMN réduite, ainsi qu'une augmentation des réponses N1 chez les patients avec 22q11.2 mais non psychotiques, qui ne sont pas présents chez les individus en développement typique. Ces résultats indiquent un modèle de traitement auditif anormal qui pourrait être spécifique à la population 22q11.2 DS plutôt que de suivre le modèle auditif anormal mesuré chez les patients atteints de schizophrénie.
La réponse MMN diminue en 22q11.2 DS n'est pas liée à un QI inférieur ou à un symptôme psychotique (positif ou négatif) et n'est pas liée aux changements structurels mesurés sur les voies auditives. Par conséquent, nos résultats pourraient révéler une reconnaissance des émotions auditives altérée, une caractéristique clé de la cognition sociale, et une
neuromodulation anormale du traitement de l'information ascendant / descendant, aux côtés d`une erreur de prédiction altérée.
En outre, nous fournissons des preuves que la MMN réponse est bien développée chez les enfants avec 22q11.2 DS et ne diffère pas des enfants en développement typique. Cette capacité suit une trajectoire de développement particulière qui pourrait coexister avec un risque accru de développement de la schizophrénie. Par conséquent, une augmentation de N1 et une réponse MMN réduite peuvent révéler une fonction auditive anormale et une altération de l'intégrité des zones auditives, plutôt que de révéler des informations sur l'état psychotique.
Prises ensemble, nos études proposent le MMN comme un marqueur électrophysiologique du traitement sensoriel anormal et des erreurs de prédiction dans 22q11.2 DS qui pourraient ajouter de la valeur aux évaluations cliniques dans le but de détecter un fonctionnement auditif anormal.
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Table of Contents
Part 1 Introduction
Chapter 1 The 22q11.2 Deletion Syndrome ... 19
1 The 22q11.2 Deletion Syndrome ... 19
1.1 Genetics... 19
1.2 The cognitive profile ... 22
1.3 The neuropsychiatric profile ... 23
1.4 Brain abnormalities in individuals with 22q11.2 DS ... 27
1.5 The 22q11.2 DS: a model of schizophrenia ... 29
Chapter 2 Auditory dysfunction in 22q11.2 Deletion Syndrome ... 31
2.1 Human Auditory System... 31
2.2 Auditory dysfunction in 22q11.2 DS ... 34
2.3 Impaired auditory evoked potentials in 22q11.2 DS ... 34
Chapter 3 Mismatch negativity response ... 39
3.1 Mismatch negativity component of auditory evoked potentials ... 39
3.2 The mechanisms of mismatch negativity response ... 41
3.3 The generators of mismatch negativity response ... 44
3.4 The relevance of mismatch negativity ... 46
3.5 Mismatch negativity in schizophrenia ... 47
3.5.1 Mismatch negativity endophenotype for schizophrenia ... 50
3.6 Mismatch negativity in individuals with 22q11.2 DS ... 50
3.6.1 Mismatch negativity endophenotype for schizophrenia in 22q11.2 DS ... 52
Chapter 4 Neuroimaging tools to assess the mechanisms underlying mismatch negativity ... 53
4.1 Assessing event related potentials with high density EEG ... 53
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4.1.1 Assessing event related potentials ... 54
4.1.2 Analyzing event related potentials ... 54
4.2 Assessing gray matter with structural Magnetic Resonance Imaging ... 57
Chapter 5 Aims and hypotheses of the project ... 60
Chapter 6 Doc-mobility Project ... 62
Part II Results
2.1 Study 1: Abnormal development of early auditory processing in 22q11.2 Deletion Syndrome ... 662.2 Study 2: Abnormal auditory processing and underlying structural changes in 22q11.2 Deletion Syndrome ... 69
2.3 Additional results ... 73
2.3.1 Reduced mismatch negativity response: impaired repetition suppression or deviance detection? ... 73
2.3.2 COMT genotype and the mismatch negativity ... 75
Part III Discussions
3.1 Aberrant sensory auditory processing in 22q11.2 DS ... 793.2 Clinical significance of mismatch negativity in 22q11.2 DS ... 80
3.3 The underlying mechanisms of mismatch negativity in 22q11.2DS ... 84
3.4 Limitations ... 87
3.5 Further directions ... 89
3.6 Conclusions ... 89
Appendix Articles
Bibliography
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“What we observe is not nature in itself but nature exposed to our method of questioning.”
Werner Heisenberg
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The 22q11.2 deletion syndrome (22q11.2 DS), also known as velo-cardio-facial syndrome or DiGeorge Syndrome, is one of the highest genetic risks for the development of
neuropsychiatric disorders, such as attention deficits, anxiety disorders and schizophrenia spectrum disorder. It represents the most common syndrome caused by a chromosomal microdeletion and offers a unique opportunity to study biological and functional changes related to neuropsychiatric illnesses in humans.
So far, many studies focused on 22q11.2 DS as a neurodevelopmental model of schizophrenia and studied mainly cognitive, as well as neurobiological risk factors for psychosis.
A well-validated measure proposed as a potential biomarker of brain pathology related to schizophrenia is auditory mismatch negativity. This auditory function is impaired in patients with schizophrenia and in subjects who are at-risk for the development of schizophrenia and is linked to lower functioning and progressive brain pathology related to the disorder.
Although this effect has been robustly reproduced since early 1990s in schizophrenia, little is known in 22q11.2 DS. Only few studies have investigated this sensory processing signal in 22q11.2 deletion carriers and have reported contradictory results.
Therefore, our project focuses on understanding the underlying mechanisms of mismatch negativity response in 22q11.2 DS, a neurodevelopmental model of schizophrenia.
In the current thesis I investigate the functional and structural integrity of the auditory
processing mainly by means of mismatch negativity response and the volumetric values of its underlying cortical and subcortical generators.
In the first part of the introduction, I describe in detail the 22q11.2 Deletion Syndrome phenotype, highlighting the main characteristics of underlying genetics, cognitive features, and neuropsychiatric profile. I also provide a description of the structural and functional abnormalities and I highlight the main reasons why 22q11.2 deletion syndrome is a proper model to study schizophrenia.
The Introduction continues with an overview of auditory processing and a detailed
description of the auditory evoked potential and auditory functional abnormalities measured in 22q11.2 deletion carriers.
Next, I present the mismatch negativity (MMN) general characteristics, mechanism of
generation, and the underlying brain generators and I highlight the relevance of MMN and its application in cognitive and clinical neuroscience domains and the importance of MMN in schizophrenia research, as well as the feasibility of MMN of being an endophenotype of schizophrenia in 22q11.2 DS.
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Further, the neuroimaging techniques that have been used in this project are examined, namely the high-density electroencephalogram and structural magnetic resonance imaging, followed by the aims and hypothesis of the project.
The last part of the introduction contains a brief description of the project obtained as doc- mobility fellowship.
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Chapter 1
The 22q11.2 Deletion Syndrome
The 22q11.2 Deletion Syndrome is one of the highest genetic risks for the development of schizophrenia and offers a unique opportunity to understand neurobiological and neurofunctional changes preceding the onset of neuropsychiatric illnesses.
This chapter provides an overview of the 22q11.2 Deletion Syndrome phenotype, highlighting the main characteristics of underlying genetics, cognitive features, and neuropsychiatric profile. It continues with a detailed description of the structural and functional abnormalities and ends with the main reasons why 22q11.2 deletion syndrome is a proper model to study psychotic disorders, such as schizophrenia.
1. 22q11.2 Deletion Syndrome (DS)
The 22q11.2 Deletion Syndrome received over time several names according to its clinical aspects or genetic abnormalities: Shprintzen Syndrome, Sedlackova Syndrome, DiGeorge syndrome, and Velo-cardio-facial Syndrome [11]. Due to overlapping clinical phenotypic features with other chromosomal deletions, like 10p13–14 [12] , as well as with single-gene disorders, like T-box1mutations [13], multiple aetiologies for this syndrome were proposed.
In the early 1990s using fluorescence in situ hybridization (FISH), the 22q11.2 microdeletion was identified as the most common cause of DiGeorge or Shprintzen syndrome [14, 15], and therefore, the disorders previously mentioned under different names although sharing the same genetic cause, are currently referred to as 22q11.2 deletion syndrome (22q11.2 DS).
1.1 Genetics
The 22q11.2 Deletion Syndrome (DS) is a multisystem syndrome caused by microdeletions of 0.7 to 3 million base pairs on the long arm (q) of chromosome 22, region 1, band 1, sub- band 2 (22q11.2) detectable by fluorescence in situ hybridization (FISH) and affects 1 in 4000 live births [16, 17].
The majority of 22q11.2 DS cases are caused by de novo mutations (90%), with less than 10%
of the cases being inherited from an afflicted parent [18].
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The most common microdeletions are 3 Mb (90%) and 1.5 Mb (5.2%) involving the deletion of 35 to 60 known genes, many being critical for normal brain development [19, 20]. Early studies suggested no effects of the deletion size on the phenotype severity [21]. However, more recent investigations reveal new insights regarding brain cortical phenotypic differences between patients with 1.5 Mb or 3.0 Mb deletion sizes, such as cortical thickness and cortical surface area [22].
Figure 1.
Representation of the 22-chromosome showing the short and long arms and the 11.2 band depicted by a red cross. The most typical deletion of 3Mb (A-D), and 1.5Mb (A-B) and the most commonly studied genes and their role in
neuromodulation or synaptic plasticity are indicated. Adapted from Karayiorgou et al., 2010 [23].
To date, only few deleted genes, including TBX1, COMT, PRODH or DGCR8 have received more attention due to their involvement in neuromodulation, synaptic transmission, and cortical development (Figure 1).
The TBX1 is a transcription factor that plays a crucial role in the formation of tissue
and organs, therefore, the loss of TBX1 has been particularly linked with the somatic phenotype of the deletion carriers, such as cardiac, thymic or craniofacial malformations [24]. The TBX1, in relationship with diminished dosage of other genes [20], has been also involved in the regulation of cortical development and maturation affecting both the glutamatergic and GABAergic neurons [25].
The PRODH gene encodes for a mitochondrial enzyme (proline dehydrogenase-oxidase) that ensures the metabolization of L-proline, a key neuromodulator of glutamate synaptic transmission [26]. The glutamate, the main excitatory neurotransmitter and GABA, the main
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inhibitory neurotransmitter, are crucially involved in learning and memory. Thus, individuals with 22q11.2 DS who express cognitive impairments might as well express excitatory/inhibitory balance abnormalities within the cortical and subcortical areas [27, 28].
The integrity of the glutamatergic system can be assessed directly using proton magnetic resonance spectroscopy (1H-MRS) and indirectly using cortical gamma and mismatch negativity responses measured with high-density electroencephalogram (EEG). Two studies claimed to measure glutamate in children [29] and adults [30] with 22q11.2 DS and found no glutamate alterations within the prefrontal areas, whereas few studies using EEG reported both reduced [31] or unchanged [32] mismatch response, and abnormal cortical gamma responses [33].
The COMT gene encodes the instructions for making the Catechol-O-Methyltransferase enzyme involved in catecholamines metabolism, including dopamine. It is mostly expressed in the prefrontal cortex [34], and alongside with PRODH gene is considered a candidate for several psychiatric symptoms, including the psychopathological phenotype associated with the 22q11.2 microdeletion [35].
Individuals with 22q11.2 DS can only have either too high or too low dopamine levels, depending on the polymorphism of the COMT gene they carry, valine allele (VAL/-) or methionine allele (MET/-) respectively.
In 2000 Goldman-Rakic and colleagues [36] proposed a model explaining the relationship between dopamine levels and cognitive function suggesting an optimal level of dopamine for an optimal cognitive functioning. Therefore, depending on the polymorphism of the COMT gene, individuals with 22q11.2 DS might express prefrontal dopaminergic alterations and thus cognitive difficulties and increased proneness for psychosis [37]. In addition, the expression of COMT(MET/-) in 22q11.2 deletion carriers has been involved in sensory processing dysfunction [31, 38].
The haploinsufficiency of DGCR8 genes was also of interest for researchers due to its involvement in the abnormal development of the cortical architecture in animal models of 22q11.2DS. Schofield et al., (2011) [39] and Stark et al., (2008) [40] demonstrated altered morphology and electrical properties of the pyramidal neurons in the medial prefrontal cortex and altered short-term plasticity in Dgcr8+/- mice.
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1.2 The cognitive profile of individuals with 22q11.2 DS
The 22q11.2 DS is associated with widespread thinner cortical gray matter and altered white matter microstructural organization in major cortico-cortical and thalamo-cortical tracts [41, 42] that might predispose 22q11.2 deletion carriers to a wide range of cognitive impairments across the lifespan. The infants tend to struggle more with motor delays and language impairments, while children and adolescents suffer from learning deficits, executive function and multitasking impairments [43, 44]. Most individuals have higher scores in the verbal than the nonverbal domains, scores that seem to decay with age [45]. More severe cognitive decline was measured in patients with 22q11.2 DS and a psychotic disorder, and lower baseline verbal IQ was associated with stronger psychotic symptoms at follow-up evaluations, suggesting that IQ decline may be predictive of psychosis in this syndrome [46, 47].
Previous studies have also shown visuospatial cognitive impairments, altered executive functions and social cognitive deficits.
In a two‐center study, Weinberger et al. (2016) [48] investigated the executive and social cognition in patients with 22q11.2 DS, with and without psychotic symptoms, compared to typically developing controls. They observed that the 22q11.2 DS subjects performed poorly in all cognitive domains compared to controls, with the participants with 22q11.2 DS and psychotic symptoms expressing more severe deficits in global cognitive performance, executive function, episodic memory, and social cognition.
Furthermore, executive functions develop progressively in typically developing individuals, emerging in early childhood and improving into adulthood, a pattern that is not followed by individuals with 22q11.2 DS [44]. Interestingly, the impairments in executive function abilities such as inhibition, working memory, cognitive flexibility, consistently observed in the 22q11.2 DS population [44, 49, 50] are linked with abnormal brain maturation within the prefrontal areas [27].
Social cognitive deficits are also observed in this population (for a review [51]). The social cognition underlies various mental operations, including emotion processing (face and emotion recognition) and theory of mind (TOM), that guide social interactions and integration [52] and help individuals to develop and nurture healthy social relationships. As revealed by studies using eye-tracking technique, useful for measuring eye positions and eye movement, the face recognition abilities are impaired in individuals with 22q11.2 DS, presumably due to fewer eye fixations and lower time spent on the main facial features (eyes, nose, mouth) [53, 54].
Alongside with impaired face recognition abilities, reduced theory of mind competences are
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also observed in patients with 22q11.2 DS, exacerbating their cognitive incapacity to represent others mental states by reading facial traits and respond accurately to social cues [55].
Although many studies of 22q11.2 DS describe impairments in higher-order cognitive processes, such as working memory and executive function [56, 57], there is evidence that, in this disorder, deficits manifest also at early stages of sensory processing during both visual and auditory tasks [9, 10]. Since the auditory sensory processing is a main topic of this thesis, a summary of auditory deficits observed in both 22q11.2 DS and schizophrenia will be presented in detail in Chapter 3.
1.3 The neuropsychiatric profile of individuals with 22q11.2 DS
The individuals with 22q11.2 DS express abnormal cognitive and social functioning, as well as neuroanatomical alterations, being one of the highest genetic risk factors for the development of neuropsychiatric disorders [19, 23, 28].
The 22q11.2 deletion carriers present disruptions across multiple symptom domains, and therefore the accurate characterization of the neuropsychiatric profile requires multi- dimensional assessment that contains various aspects of cognitive and emotional processing impairments. Notably, in a recent review of 15 studies and 1402 participants, Schneider and colleagues (2014), described the most common psychiatric conditions observed in this population and their prevalence across age [7]. The most prevalent paediatric neuropsychiatric disorders are attention deficits (37%), autism spectrum (12%), mood and anxiety disorders (38%). They observed that attention deficit disorder (ADHD) and oppositional defiant disorder (ODD) are overrepresented in males and are diagnosed more frequently during childhood, while autism spectrum disorder seems to be highly expressed both during late childhood and adolescence.
On the contrary, schizophrenia spectrum disorder was expressed mostly during adulthood being present in 25% of the emerging adults (18 to 25 years old), and 41% of the adults [7].
Furthermore, neuropsychiatric diagnoses, such as anxiety and ADHD, may serve as premorbid signs for later development of schizophrenia spectrum disorder [58, 59]. A summary is provided in Figure 2.
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Figure 2. The neuropsychiatric phenotypes in 22q11.2 deletion syndrome and the estimated comorbidity rates across disorders. The most common psychiatric conditions observed in this population and their prevalence across ages, including attention-deficit/hyperactivity disorder (ADHD), anxiety disorders, psychosis, schizophrenia, and autism spectrum disorder (ASD). Adapted from R.K. Jonas et al. 2014.
ADHD
The attention deficits characterize most of the individuals with 22q11.2 DS (37%).
Although, ADHD is the most common psychiatric disorder, the clinical presentation in 22q11.2 DS differ from the one measured in idiopathic ADHD. The 22q11.2 DS deletion carriers exhibit higher rates of ADHD inattentive subtype associated with higher rate of generalized anxiety disorder, and fewer hyperactive-impulsive symptoms compared to the clinical group [60].
Niarchou et al. (2018) examined longitudinally a large cohort of 22q11.2 deletion carriers to clarify the potential role of ADHD inattention symptoms in psychosis development in 22q11.2 DS. The authors observed a positive association between inattention symptoms and positive, negative and disorganized symptoms [59].
However, a recent longitudinal study [61] found a reduced persistence of ADHD symptoms from childhood to adolescence in 22q11.2 DS ( only 15%) predicted by increased rates of familial ADHD and history of childhood depression, suggesting that additional factors, like family history and psychiatric co-morbidities, may also play a role in the psychosis proneness alongside with inattention symptoms.
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Anxiety and depression
Anxiety disorders are often reported to be highly prevalent, both in schizophrenia (10 to 15 %) [62] and in individuals with 22q11.2 deletion syndrome (38%) [7], although the rates highly vary across studies. Symptoms of anxiety or depression are more frequently observed in the pediatric population with 22q11.2 DS and together with the COMT genotype are significant early childhood predictors for the later development of psychotic symptoms [46]. This may imply that genetic factors may predispose 22q11.2 deletion carriers to express a wide range of psychiatric phenotypes defined by anxiety or attention deficits early in development that may change into psychotic symptomatology during adolescence and youth.
Nevertheless, patients carrying the 22q11.2 deletion often express a mixed symptomatology from different disorders. Even with a clear diagnosis of depression, they often express comorbidities, such as anxiety or ADHD and thus, classifications into distinct categories defined as “anxiety”, “psychosis”’ or “depression” are unrealistic and to a large extent unhelpful for the development of future interventions [63].
Schizophrenia spectrum disorder and psychosis
Schizophrenia spectrum disorders are also highly prevalent in patients with 22q11.2 DS affecting approximately 10% of the adolescents, 25% of the emerging adults (18 to 25 years old), and 41% of the adults [7].
Figure3. The prevalence of schizophrenia spectrum disorders across ages in 22q11.2 deletion carriers. Adapted from Schneider et al., 2014 [7].
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Some studies suggest that up to 80% of the deletion carriers experience subthreshold positive and negative psychotic symptoms, with the positive symptoms being experienced by 30 to 60%
of adolescents, while the negative symptoms being present in 60 to 80% of adolescents and young adults with 22q11.2DS [7, 58]. Nevertheless, a recent multisite study part of the International 22q11.2 Deletion Syndrome Brain Behavior Consortium (IBBC) using the largest cohort (760 participants aged 6–55 years) investigated the development of subthreshold psychotic symptoms by age groups, and their association with cognitive deficits. The authors reported that 32.8% of participants met criteria for positive subthreshold psychotic symptoms, 21.7% of participants met criteria for negative subthreshold psychotic symptoms and 25.6%
met criteria for both positive and negative/disorganized subthreshold psychotic symptoms.
Further, the most prevalent subthreshold symptoms were the negative (poor ideational richness, avolition, and low occupational functioning) and disorganized (trouble with focus and attention) subthreshold symptoms [64].
There are evidence that positive and negative symptoms may underlie distinct physiological abnormalities.
The most characteristic positive symptoms are hallucinations or false perceptions, and delusions or persistent irrational beliefs. In schizophrenia, one common mechanism proposed to explain the positive symptoms involves the prediction error signal. This signal reflects processes like perception and inference, and thus abnormal mechanisms of prediction error may cause both false perceptions and irrational beliefs [65].
In 22q11.2 the prediction error mechanisms have not yet been investigated, and thus positive symptoms are explained mostly by neuroanatomical deficits, such as abnormal maturation of auditory thalamocortical connectivity [66] and hippocampal volume decrease during late adolescence [67].
The most characteristic negative symptoms are divided in two main domains: avolution/apathy and diminished expression of emotion and speech (alogia) [68]. In schizophrenia, the first domain has been proposed to underlie impairments in various dimensions of motivation [69], while the second domain has been proposed to underlie impairments in emotion perception (for blunted affect) [70] and reduced cognitive resources (for alogia) [71].
In 22q11.2 DS, the negative symptoms are also divided in two domains as shown by Schneider et al. (2012). Applying a factor analysis, the authors revealed two main domains related to negative symptomatology: the lack of motivation and impoverished emotional expression [72].
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Importantly, the negative symptoms in 22q11.2 DS might impact negatively daily-life functioning through reduced motivation towards goal-directed activities [72, 73] and verbal initiation impairment [74].
Predictors of transition to psychotic disorders and ages of onset in 22q11.2 deletion carriers have been reported to be similar with those from idiopathic psychosis populations [75, 76].
Additionally, impairments in various cognitive domains, as well as neuroanatomical abnormalities measured in 22q11.2 DS, are comparable with those measured in non-deleted clinical risk populations[77].
The 22q11.2 deletion carriers experience also a broad range of sensory processing impairments, like reduced mismatch response, a marker of prediction error, similar to those measured in schizophrenia which develop years before the full emergence of the disorder [4-6].
Consequently, the 22q11.2 DS provides the researchers the opportunity to investigate the neurobiological and functional changes preceding the onset of the schizophrenia and further, to identify markers that might guide early diagnosis and intervention in the near future.
1.4 Brain abnormalities of individuals with 22q11.2 DS Structural
Magnetic resonance imaging studies report overall brain volume alterations, including decreased gray and white matter, in 22q11.2 DS since the beginning of 2000 [78, 79] . An early pattern of regionally specific cortical thinning was observed in frontal, parietal and occipital regions [80, 81]. Since these first investigations were conducted, the number of studies has increased markedly over the last 20 years, permitting more precise estimates of effects and more cortical and subcortical regions to be examined.
A first meta-analysis on 22 studies with data acquired on 1.5-T MRI scanner report global brain volume reduction of both gray and white matter with a rostro-caudal gradient, meaning smaller posterior regions as compared to the anterior regions [82].
More recently, Rogdaki et al. 2020, in a meta-analysis on 988 individuals with 22q11.2 DS and 873 typically developing individuals, replicated these findings. They reported overall gray and white matter decreases in 22q11.2 DS compared with controls, specifically in the frontal, temporal and parietal lobes, cerebellum and hippocampus[83].
Additionally, Sun et al. (2018) in a large multicenter study on 474 subjects with 22q11.2 DS (age = 18.2 ± 8.6; 47% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 46% female) focused on the cortical volumetric subcomponents, the surface
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area and the cortical thickness. They reported thicker cortex in insula, and thinner cortex in parahippocampal and superior temporal gyri, and left caudal anterior cingulate cortex and reductions in the surface area in the medial occipital and anterior cingulate cortex, superior parietal cortex and rostral middle frontal gyrus in 22q11.2 deletion carriers relative to typically developing. The authors also compared 22q11.2 deletion carriers with co-morbid psychosis with matched individuals with 22q11.2 DS without psychosis and observed that individuals with 22q11.2 DS and psychosis showed thinner cortex in the left superior temporal gyrus and lateral occipital cortex, and in the right medial superior frontal, cingulate, and supramarginal gyri, while no significant differences in surface area (SA) were found between the two groups [22].
These results are in line with studies reporting volumetric decreases in frontal and superior temporal gyri in adults with 22q11.2 DS and schizophrenia relative to 22q11.2 DS adults without schizophrenia [79, 84, 85], and further with longitudinal studies reporting progressive volumetric decreases in superior temporal gyri that predicted later psychotic symptoms in 22q11.2 DS youth [86].
Finally, Sun et al. (2018) also observed an effect of the deletion size on the cortical surface area (SA), but not on the cortical thickness. The 22q11.2DS cases with 3 Mb (A-D) deletion size as compared to those cases with 1.5Mb (A-B) deletion size revealed highly significant, global reductions in cortical SA, most prominently in the anterior medial and lateral cortical regions [22].
Cortical surface area is genetically distinct from cortical thickness [87] reflecting the density of the cortical columns, while cortical thickness reflects the neuronal density within the columns [88]. Therefore, in the future these two measures of cortical volume might help disentangle abnormal developmental processes occurring during corticogenesis in distinct brain regions in this syndrome.
Functional
Functional neuroimaging studies offer insights into how the aforementioned structural changes in 22q11.2DS manifest as functional alterations. These studies use a variety of paradigms to characterize the abnormal functional organization of large-scale networks during rest and active engagement in cognitive or sensory tasks.
Both spontaneous and task driven activity in the brain have been extensively studied with functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). Using event-related functional magnetic resonance imaging (fMRI) researchers measured wide range
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of functional abnormalities, such as reduced activity in fusiform area, anterior cingulate cortex, and superior prefrontal cortices during social cognition and emotion processing tasks and lower activation in dorsolateral prefrontal cortex, anterior cingulate, and precuneus during working memory tasks [89]. On the other hand, evoked brain activity measured with EEG revealed additional abnormal processing in the auditory and visual sensory domains during auditory steady state responses, mismatch negativity and P300 components, offering important insights into the underlying neuropathological mechanisms of the disorder during the early stages of cognitive processing [90].
In addition, resting-state functional brain imaging, has revealed functional brain connectivity alterations within the fronto-parietal, anterior cingulate and self-referential network, both using EEG and fMRI techniques [91, 92].
1.5 The 22q11.2 DS as a model of schizophrenia
The 22q11.2 deletion carriers with co-morbid schizophrenia reveal characteristics similar to those manifested by patients with idiopathic schizophrenia in terms of main clinical symptoms, age of onset, prodromal symptoms and underlying morphological brain changes [22, 47, 77, 93] , and thus 22q11.2 DS has been proposed as a valuable neurodevelopmental model to study brain and behaviour changes preceding the onset of schizophrenia [7, 94, 95].
The 22q11.2 DS might be an informative model to bring more light into schizophrenia research in two general ways.
Firstly, it supports the neurodevelopmental approach to psychosis. The neurodevelopment hypothesis of schizophrenia attempts to understand the interaction between aberrant genes, early cortical abnormal development and deviant synaptic development and pruning [96]. Both human and mice studies have suggested that the deleted genes within the 22q11.2 or 16qA13 locus respectively play a crucial role in the neuronal migration and cortical circuit formation and further play a role in the development of cognitive impairments [23].
For example, the 22q11.2 DS model can clarify the relationship between the cognitive impairments and the abnormalities in dopaminergic and glutamatergic systems by understanding the interactions between the two susceptibility genes: COMT and PRODH. The animal model expressing PRODH deficiencies showes abnormal glutamatergic transmission and additional enhanced dopaminergic signaling in frontal cortex altering working memory performance [35].
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Furthermore, the 22q11.2 DS offers a unique opportunity to identify early brain changes related to schizophrenia and to detect behavioural symptoms at their early stage. Neuroanatomic alterations associated with schizophrenia expression in 22q11.2 DS involve significantly thinner cortex in the left superior temporal gyrus, lateral occipital cortex, and superior medial frontal lobe [41, 84, 86]. In addition, progressive volumetric decreases in temporal areas predicted psychotic symptom development in 22q11.2 DS youth [86, 97].
Secondly, schizophrenia presents a highly heterogeneous clinical phenotype and genetic profile that complicates the understanding of this disorder and the treatment development. To address this issue, some authors propose the “endophenotype” approach [98]. This approach suggests the endophenotypes as measurable traits closely linked to the aetiology of the illness falling within the genotype to phenotype pathway and being the link between the genetic variation and the biological processes responsible for the clinical phenotype of the disorder [94]. The 22q11.2 DS might be a useful model for the endophenotype strategy. With an emphasis on neurocognitive and neurophysiological measures, the 22q11.2 DS provides a model to map the link between neurobiology of specific brain dysfunction, and the genes causing the phenotype.
In summary the 22q11.2 DS is a multisystem disorder with a highly variable clinical phenotype.
The individuals caring this microdeletion express cognitive deficits, develop structural and functional brain abnormalities alongside with a spectrum of neuropsychiatric symptoms.
Further, it involves the deletion of many genes among which only a small number is well studied and linked with the clinical profile. Therefore, the 22q11.2DS offers a unique opportunity to understand neurobiological and neurofunctional changes associated with the specific neuropsychiatric symptoms.
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Chapter 2
Auditory dysfunction in 22q11.2 Deletion Syndrome
The brain is permanently receiving auditory sensory inputs that are used to model and understand the environment. However, to represent the incoming stimuli accurately, the brain is relying on prior information by actively forming predictions from contextual regularities [65]. The active sensory predictions might be crucial to enhance the processing of behaviorally relevant information, and thus studying dysfunctional auditory sensory prediction in 22q11.2 deletion carriers might shed light on how patients with schizophrenia, develop impairments in communication and social interaction. In addition, the abnormal auditory sensory processing might underlie structural changes within the auditory cortical areas, such as reduced cortical thickness in the superior temporal gyrus that might predispose 22q11.2 deletion carriers to develop psychosis [86].
This chapter provides an overview of auditory processing within the human auditory system.
It continues with a detailed description of the auditory evoked potential and auditory functional abnormalities, such as sensory gating deficits, mismatch negativity and auditory steady state response impairments.
2.1 Human Auditory System
The human auditory system is the sensory system responsible for processing the auditory inputs. It is divided into two main subsystems, the peripheral auditory system, comprising the outer, middle and inner ears and the central auditory system, from the cochlear nucleus up to the auditory cortex [99].
Audition begins in the inner ear. The hair cells in the Organ of Corti convert the sound waves to electrical signals, a process that is called mechanical-to-electrical transduction. At the tips of the hair cells are cilia. The bend of cilia causes an increased influx of K+ which depolarizes the cell, and further opens the voltage dependent Ca2+ channels. This determines the release of neurotransmitters at the end of the hair cells, which elicits an action potential in the VIIIth cranial nerve. These electrical signals travel from the cochlea to the cochlear nuclei. Some of
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these neurons project to contralateral and ipsilateral superior olivary nuclei. From these nuclei, the signal is projected up to the inferior colliculi (IC) in the midbrain through the lateral lemniscus and further through the brachium of the inferior colliculus, the signal reaches the medial geniculate nuclei (MGN) in the thalamus [99]. The medial geniculate nuclei provide predominant input into auditory cortex and have at least two thalamocortical projection systems. The core or lemniscal pathway originates largely in the ventral nucleus of the MGN (MGNv) and transmits stimulus-specific information into the layer 4 of auditory cortex. This pathway is characterized by strong frequency tuning and tonotopic organization. The nonlemniscal pathway originates largely in dorsal and medial nuclei of the MGN (MGNd/m) and targets supra- and infragranular layers (L2\L3, L1) of the auditory cortex. It has broad frequency tuning and widely projects to auditory and nonauditory brain regions, indicating that it may be involved in higher-order perceptual processes [100-102]. Additionally, the pulvinar nucleus of the thalamus is implicated in higher-level neurocognitive processing which also includes the auditory domain [103]. Subsequently, the descending (corticofugal) auditory pathways modulate the neural responses to adjust and improve auditory processing [104].
The auditory cortex (AC) is an important area within the posterior superior temporal gyrus, predominantly involved in the processing of acoustic stimuli and language. The AC is morphologically subdivided into six layers, each with different anatomical connectivity and functionality [105].
The supragranular layer 1 receives inputs from several thalamic nuclei, such as MGN and higher-order thalamic nuclei, and differentially targets inhibitory and excitatory neurons across other cortical layers [106]. It contains mainly inhibitory neurons which are involved in the processing of auditory salient signals [107] via inhibitory and disinhibitory modulation of cortical output pyramidal neurons [108].
The supragranular layers L2 and L3 are not a homogeneous layer, instead they show diverse underlying cell morphology and functional microcircuits [109, 110]. The L2 contains small- medium size pyramidal and non-pyramidal neurons that project locally to adjacent layers and regions (L1-L3), whereas the L3 contains neurons with complex dendritic arborization that projects to ipsilateral and contralateral cortical areas [109].
The neurons from layer 5 and layer 6 have different intrinsic physiological and morphological features and have been involved in auditory subcortical modulation of the thalamus and inferior colliculi [111].
The laminar-specific connections have been intensively applied to generate computationally informed models of columnar microcircuitry in frameworks such as predictive coding, a
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feasible neurobiological candidate for understanding how the brain actively models its sensory inputs [112].
The auditory cortex (AC) has a number of subdivisions. A broad distinction can be made between the primary area, the core, and the associational area, the belt and parabelt. The primary area encompass the posterior medial side of Heschl`s gyrus, while the secondary area is located on the lateral side of Heschl`s gyrus on the planum temporale [99, 113].
The main function of the auditory cortex is to identify the auditory inputs and their location in space and to transform them into a perceptual representation [113].
Some authors suggest that the primary auditory cortex is asymmetrically developed with a greater involvement of right AC in certain aspects of frequency discrimination or pitch processing, comparing to left auditory cortical areas that are more active in processing temporal cues [114]. Other authors propose that auditory information is processed in parallel hierarchical pathways, and the cortical auditory areas are divided into areas processing spatial cues (the dorsal pathway) versus areas involved in processing non-spatial cues (the ventral pathway) [115]. The evoked auditory activity is initiated in the thalamo-recipient layers (L4) and travels rapidly across superficial layers [116].
Figure.4 A diagram which illustrates the main human auditory pathways and projections of cranial nerve VIII, from spiral ganglion up to auditory cortex. The inner hair cell deflection triggers an action potential in the primary auditory neurons of the spiral ganglion which further projects to cochlear nuclei. Contra and ipsilateral projections from the dorsal cochlear nucleus reach the superior olivary nuclei and travel through the lateral lemniscus to synapse in the inferior colliculus in the midbrain.
Neurons of the inferior colliculus extend to the medial geniculate nucleus within the thalamus, which further innervate the primary auditory cortex. The primary auditory cortex conserves the tonotopy of the basilar membrane of the cochlea. The anterior auditory cortex, sensitive to low frequencies, corresponds to apex of the cochlea, while the more posterior auditory cortex, sensitive to high frequencies, corresponds to the base of the cochlea. Adapted from Elgoyhen et al., 2015.
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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 [117] and functional [66] 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 [119].
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 [120] (Figure 5).
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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 scalp-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) [121]. 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 [122], co-occurring with the end of structural maturation of auditory cortex [123].
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.
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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 [124]. 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 [38]. Importantly, one study investigates the sensory gating in adults[38] 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.
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The N100 component is a prominent negative deflection occurring around 100 ms post- stimulation at the vertex, and has been proposed to reflect the onset of an acoustic change detection underlying a complex network of brain generators [128]. In a systematic 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 [129]. 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 [9].
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 [31], while other studies did not report significant MMN reduction in amplitude, but an altered functional connectivity from IFG to STG and enhanced N1 [130]. 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 [144].
Since MMN is a main topic of this thesis, it will be discussed in more detail in Chapter 3.
P300
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
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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 [145].
Although the P300 is a robust neurophysiological marker for schizophrenia [146], 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 [147]. 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 [148].
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 [33].
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 [23].
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.
