Early auditory processing dysfunction in schizophrenia: Mechanisms and implications

Abstract

Schizophrenia is a major mental disorder that affects approximately 1% of the population worldwide. Cognitive deficits are a key feature of the disorder and a primary cause of long-term disability. Over the past decades, significant literature has accumulated demonstrating impairments in early auditory perceptual processes in schizophrenia. In this review, we first describe early auditory dysfunction in schizophrenia from both a behavioral and neurophysiological perspective and examine their interrelationship with both higher order cognitive constructs and social cognitive processes. Then, we provide insights into underlying pathological processes, especially in relationship to glutamatergic and N-methyl-D-aspartate receptor (NMDAR) dysfunction models. Finally, we discuss the utility of early auditory measures as both treatment targets for precision intervention and as translational biomarkers for etiological investigation. Altogether, this review points out the crucial role of early auditory deficits in the pathophysiology of schizophrenia, in addition to major implications for early intervention and auditory-targeted approaches.

Keywords: Auditory; Event-related potentials; NMDA receptor; Schizophrenia; Tone-matching.

Figure 1.

Behavioral approches to early auditory assessment. A. Anatomy of the auditory cortex. The superior temporal gyrus (STG) is bordered superiorly by the lateral sulcus (LS) in monkeys and the Sylvian fissure (SF) in humans. Inferiorly, the STG is bordered by the superior temporal sulcus (STS) in both monkeys and humans. The blue dashed line shows the orientation of electrical currents generated within the auditory cortex. (adapted from Javitt and Sweet, 2015). B. Principal Component Analysis biplot showing two clusters: MCCB domains T-scores (orange) and tone-matching task (TMT), auditory emotion recognition (AER) and sarcasm percent correct (green). The two principal components captured 63.6% of the data variability. PS processing speed, AV attention/vigilence, WM working memory, VerL verbal learning, VisL visual learning, RPS reasoning/problem solving (Adapated from Donde et al., 2019b). C. Left: Line plots of mean percentage correct of tone-matching task for each level of frequency difference. Right: Density histograms of TMT percent correct responses showing unimodal distribution for the Control group only. For the SZ (schizophrenia) group, the bimodal distribution had a substantially lower BIC (Bayesian Information Criterion) than a unimodal model, and the bimodal/unimodal likelihood ratio was highly significant (χ. = 22.23, P < 0.0001) (Adapated from Donde et al., 2019b). D. Bargraph (mean +/− SD) of resting-state functional connecting z-scores between Glasser’s regions across groups. *P<0.05; **P<0.005 (Adapted from Donde et al., 2019b). E. Voxel-wise comparisons between controls and SZ-EAP- with bilateral thalamic (MGN) ROIs based on Glasser’s regions for auditory pathway. AA=Associative Auditory: A4=Brodmann area A4, A5=Brodmann area A5, STGa=anterior superior temporal gyrus, STSda=dorsoanterior superior temporal sulcus, STSdp=dorsoposterior superior temporal sulcus, STSva=ventroanterior superior temporal sulcus, STSvp=dorsoposterior superior temporal sulcus, TA2=anterosuperior temporal area. EA=Early Auditory: A1=primary auditory, LB=lateral belt, MB=medial belt, PB=parabelt, RI=retro-insula. MGN=thalamic Medial Geniculate Nuclei (Adapted from Donde et al., 2019b). F. Scatterplot of total percent correct on tone-matching performance versus rsFC-MRI between MGN and STGa, which belongs to AA. Partial r was computed across two sites (outpatient and inpatient) and two groups (Controls and SZ) (Adapted from Donde et al., 2019b).

Figure 2.

Neurophysiological approaches to early auditory assessment. A. The typical oddball sequence (A, left) utilizes two stimuli that differ in stimulus quality. One of the stimuli is designated the “redundant” and accounts for the majority of the presentations (in this case ~90%). The overabundance of redundant presentations establishes a regular pattern that is violated by “oddball” (or “deviant”) stimuli, which rarely occur (in this case ~10% of presentations) (Adapted from Ross and Hamm, 2020). B. Time-domain waveforms by group (CHR = Clinical High Risk, SZ = Schizophrenia). The peak latency window is shown in yellow (adapted from Sehatpour et al., 2020). C. Activations in response to duration changes in healthy individuals. Statistical parameter maps showing significant responses in yellow (P < 0.05 corrected) shown on an individual gray matter surface [international consortium for brain mapping single subject anatomical template; right (F) and left hemispheres (G)]. HG: Heschl’s gyrus; PFC, mid-ventrolateral prefrontal cortex; PT: planum temporale; STG, superior temporal gyrus; STS, superior temporal sulcus (Adapted from Schonwiesner et al., 2007). D. Dynamic causal model of the response to auditory deviants (frequency). The sources comprising the networks are connected with forward (dark gray), backward (gray), or lateral (light gray) connections, all of which can show condition-specific changes. This is an asymmetrical three-level hierarchical network, comprising five extrinsically interconnected cortical areas (emulating long-range connections between A1, STG, and the right IFG) and has condition-specific intrinsic connections at the level of the left and right A1 (emulating local adaptation) allowing for bothextrinsic and intrinsic connectivity changes. A1: primary auditory cortex; STG: superior temporal gyrus; IFG: inferior temporal gyrus (Adapted from Garrido et al., 2009). E. Time-Frequency plots of location MMN by group (CHR = Clinical High Risk, SZ = Schizophrenia). Box region shows alpha response interval. Inset: Scalp topographies with the alpha integration window (adapted from Sehatpour et al., 2020).

Figure 3.. Behavioural assessment of auditory plasticity.

A,B. Line graph of plasticity for schizophrenia and controls for the random (A) and fixed (B) conditions. C. Bar graph for final JND threshold (%f) from trials 70–80. D. Bar graph for plasticity (%f, mean trial 20–30 to 70–80). E-G. Scatter plot for just-noticeable difference (JND) thresholds versus working memory (E), auditory emotion recognition (F) or C-TOPP composite (reading) (G). Text in scatter plot shows correlations after control for group (partial r). Error bars represent standard error of the mean. ***P<0.001. {Adapted from \Kantrowitz, 2016 #97).

Figure 4 :

Neural mechanisms of early auditory processing deficits. A. Cytoarchitecture of feedforward and feedback auditory circuits. Thalamic projections from the medial geniculate nucleus (MGN) synapse onto pyramidal cells (PCs, dark blue) and interneurons (5HT3-a-R+ including Neuron-derived neurotrophic factor NDNF+ and Vasointestinal peptide VIP+, light blue; Somatostatin SST+, green; Parvalbumin PV+, red). Layer III PCs in primary auditory cortex (A1) send local intralaminar projections to other layer III PCs in this region and longer-range feedforward projections to PCs in layer III of auditory association cortex (A2). Layer V PCs in A2 in turn send excitatory feedback projections to neurons in layer I in A1. Structural alterations are indicated. {Adapted from \Parker, 2017 #123}. B. A schematic illustration of a proposed model of mismatch negativity (MMN) process related to N-methyl-D-aspartate receptor (NMDAR) function. Surface-recorded MMN activity reflects current flow through open, unblocked NMDA receptors on pyramidal neurons in the auditory cortex. In panel 1, NMDAR are normally blocked by Mg²⁺ at resting membrane potential. In panel 2, when a deviant stimulus is presented without prior standard stimuli, even though the channels open, the blockade prevents current flow. Brain responses therefore occur only through non-NMDAR glutamate receptors. In panel 3, when repetitive standard stimuli are presented, they lead to subthreshold membrane depolarization by inhibition of inhibition , leading to unblocking of the channel. In panel 4, once channels are unblocked, presentation of the deviant stimulus leads to NMDAR-mediated current flow (adapted from Javitt and Sweet, 2015). B. A schematic illustration of the MMN process in the NMDA receptor. Surface-recorded MMN activity reflects current flow through open, unblocked NMDA receptors on pyramidal neurons in the auditory cortex. 1. NMDA receptors are normally blocked by Mg²⁺ at resting membrane potential. 2. When a deviant stimulus is presented without prior standard stimuli, even though the channels open, the blockade prevents current flow. Brain responses therefore occur only through non-NMDA-type glutamate receptors. 3. When repetitive standard stimuli are presented, they depolarize the membrane, leading to unblocking of the channel. 4. Once channels are unblocked, presentation of the deviant stimulus leads to NMDA-receptor-mediated current flow (rev. in Javitt and Freedman, 2015). C. Auditory ERP curves from human studies (top) showing responses to standard and deviants and difference (MMN) curves from healthy control (HC) and schizophrenia (Sz) groups and from supragranular layer of auditory cortex (adapted from Sehatpour et al., 2020) in non-human primate (NHP) intracranial recording (bottom) showing responses pre and post ketamine administration (adapted from Lakatos et al., 2020). D. Time-frequency evoked power analyses of rodent MMN responses prior to and during treatment with vehicle alone (Control), phencyclidine (PCP, 15 mg/kg/d by minipump) or combined PCP and glycine (by diet) treatment. Open arrows show changes in α-band response showing a reduction during PCP treatment and prevention of this reduction by concurrent glycine treatment (Adapted from Lee et al., 2018a).

Figure 5:. Implications for pathophysiology and treatment.

A. Proposed model for the contribution of auditory cortex related dysfunction in the pathophysiology of schizophrenia. B. Relationships (Pearson’s r) between tone-matching, reading and functional outcome in SZ (top) (Adapted from Donde et al., 2019c). Relationships (Pearson’s r) between tone-matching, auditory emotion recognition and functional outcome in SZ (bottom). (Adapted from Javitt, 2009). C. Change in early auditory processing (tone-matching task performance) and change in cognition (MCCB composite change score) induced by cognitive remediation in schizophrenia from baseline to follow-up. MCCB: Matrics Consensus Cognitive Battery (Adapted from Medalia et al., 2019). D. Framework for sensory-targeted cognitive training impact in schizophrenia. Sensory training images are extracted from the posit science corporation programs (auditory frequency and visual gratings discrimination exercises). BDNF picture is from ‘Brain-derived neurotrophic factor’ by Microswitch and licensed under CC BY-SA 3.0 (Adapted from Donde et al., 2019d).