Human Auditory System

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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 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.