Auditory dysfunction in schizophrenia: integrating clinical and basic features

Abstract

Schizophrenia is a complex neuropsychiatric disorder that is associated with persistent psychosocial disability in affected individuals. Although studies of schizophrenia have traditionally focused on deficits in higher-order processes such as working memory and executive function, there is an increasing realization that, in this disorder, deficits can be found throughout the cortex and are manifest even at the level of early sensory processing. These deficits are highly amenable to translational investigation and represent potential novel targets for clinical intervention. Deficits, moreover, have been linked to specific structural abnormalities in post-mortem auditory cortex tissue from individuals with schizophrenia, providing unique insights into underlying pathophysiological mechanisms.

Figure 1. Anatomy of the auditory pathway and the auditory cortex

The ascending auditory pathway in humans begins as the auditory nerve enters the brainstem, where it forms synapses in the dorsal and ventral cochlear nuclei (part a). Projections from the dorsal cochlear nucleus cross the midline and travel through the lateral lemniscus to synapse in the inferior colliculus. Neurons of the inferior colliculus project to the medial geniculate nucleus of the thalamus, which provides innervation to the auditory cortex. The auditory cortex location (in grey) in monkeys is shown in part b and in humans is shown in part c. 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. Because of this orientation, human auditory event-related potentials show a characteristic topography over the surface of the scalp, with inversion of activity between frontocentral scalp regions and mastoids (for example, see FIG. 3b). Diagrams of the regions that make up macaque (part d) and human (part e) auditory cortices are shown. The primary auditory cortex, denoted as the auditory core in monkeys, and as Brodmann’s area 41 (BA41) in humans, is indicated. In humans, BA41 is located in the posterior medial two-thirds of Heschl’s gyrus (HG). In monkeys, the auditory association cortex is subdivided into lateral belt and parabelt cortices, which together comprise BA42 in humans, in a location extending from the lateral portion of the HG onto the planum temporale (PT). The view is from above the STG, after removing the overlying cortex, revealing the superior temporal plane. Tpt, heteromodal temporoparietal region.

Figure 2. Tone matching deficits in schizophrenia

Although the majority of cognitive studies in schizophrenia use relatively complex paradigms, such as those investigating executive processing or working memory, deficits are observed even in relatively simple auditory paradigms, such as the ability to match tones following a brief delay. In this paradigm, tones are presented sequentially, and subjects must report whether the second tone is the same or different from the first or higher or lower in pitch. The difficulty of the task is defined by altering the pitch difference between the reference and test tones. a,b | Stimuli can be presented either in a no-distractor condition in which the interval between tones is silent, or in a distractor condition in which irrelevant auditory stimuli or visual stimuli are presented in the intervening period. c | In all individuals, presentation of distractor tones between the reference and test tones leads to an elevation in discrimination thresholds, which are expressed as the difference in tone frequency between stimuli (Δf). Individuals with lesions that affect the auditory cortex show elevated thresholds even in the absence of distractors, but no increased susceptibility to distraction. By contrast, individuals with lesions that affect the prefrontal cortex do not have elevated thresholds in the absence of distraction even at relatively long interstimulus intervals (for example, 5 seconds), but show increased susceptibility to distraction effects. Individuals with schizophrenia show elevated tone matching thresholds even in the absence of distraction, but are no more susceptible to distraction than controls, supporting the concept of auditory cortex-level dysfunction. d | In addition to having a normal ability to ignore auditory distractors, patients with schizophrenia show normal retention of auditory tonal information once a correction is made for the increased overall thresholds. In the experiment shown in the figure, tones pairs were presented at two difficulty levels (easy (20% Δf) and difficult (5% Δf)) with (triangles) and without (circles) a distraction condition (in which subjects had to count aloud). The subjects were asked whether the first and second tones were the same or different (chance performance (dashed line) was 50%). As expected, patients (open symbols) performed worse than controls (closed symbols) at both difficulty levels. The presence of distraction had equivalent effects in both groups only at the longest interstimulus interval. e | Crucially, when the performance of patients performing the easy discrimination task was compared with that of controls performing the hard discrimination, performance decay curves were overlapping over the 20-second interval. These findings indicate that once a correction is made for the deficit in encoding of tone difference, retention of sensory information is unimpaired in schizophrenia, which is also consistent with primary auditory cortical pathology. Error bars in parts d and e represent s.e.m. Parts d and e are Copyright © 1997 by the American Psychological Association. Modified with permission. The official citation that should be used in referencing this material is Impaired precision, but normal retention, of auditory sensory (“echoic”) memory information in schizophrenia. Javitt, Daniel C.; Strous, Rael D.; Grochowski, Sandra; Ritter, Walter; Cowan, Nelson Journal of Abnormal Psychology, Vol 106(2), May 1997, 315–324. The use of APA information does not imply endorsement by APA.

Figure 3. Translational utility of auditory neurophysiological responses

Deficits in tone matching may also be observed using electrophysiological, event-related potential (ERP) or event-related spectral perturbation (ERSP) paradigms. a | In the auditory ‘oddball’ paradigm, a sequence of repetitive standard tones is interrupted infrequently and unexpectedly by a physically deviant oddball stimulus. Oddball stimuli may differ from standards in any of a number of physical dimensions, including pitch, duration, intensity, location or even in abstract features such as stimulus omission. In this paradigm, both standard and deviant stimuli elicit an auditory N1 potential that reflects the response of the auditory cortex to the physical properties of each stimulus in isolation. Deviant stimuli elicit an additional ERP component termed mismatch negativity (MMN) that reflects a comparison between successive stimuli, and is calculated as the difference in response to the deviant versus the standard tone (shaded region in part a). MMN for duration deviants is delayed relative to that for pitch deviants, because pitch deviance can be determined at stimulus onset, whereas duration deviance can only be determined at expected stimulus onset. This property further distinguishes MMN from N1, which is unaffected by alterations in stimulus pitch or duration. b | The MMN is distributed over the frontocentral scalp, consistent with generators that are located primarily in the supratemporal auditory cortex (FIG. 1c). The figure shows a voltage topography map of MMN-related electrical activity over the surface of the scalp, with blue representing more negative electrical activity and red more positive activity. Patients with schizophrenia show MMN amplitudes that are reduced by approximately 50% relative to controls (top panels). Dipole mapping analyses (bottom panel) show that the primary generators of the MMN are in the left and right auditory cortex. Deficits in tone matching and MMN generation are significantly interrelated, and are consistent with functional and structural impairments at the level of the primary auditory cortex. c | ERSP analysis of the MMN response. As opposed to the auditory steady-state response (ASSR) that has primary power within the gamma (30–80 Hz) frequency range, both the N1 response to the standard stimulus and the MMN (that is, the additional response to the deviant stimulus (difference between the red and blue lines)) have primary power within the theta (4–7 Hz) range. Reductions in N1 and MMN thus indicate dysfunction of neural ensembles in the auditory cortex involving GABA neuron subtypes other than the parvalbumin-expressing neurons, which are most associated with the gamma rhythm. d | Illustration of the intracranial recording approach in monkeys in which a lamina array electrode is used to sample across cortical layers. The auditory event-related potential (AEP) can be obtained from such recordings. The current source density (CSD) is calculated as the second-spatial derivative of the AEP and distinguishes regions of net inward current flow (current sinks), which represent active depolarization, from regions of net outward current flow (current sources), which represent either active hyperpolarization or passive current return. Generation of the surface MMN occurs coincidently with late activity within superficial cortical layers, suggesting that it is a product of an underlying generator. e | Schematic illustration of the MMN response. MMN reflects the increased activity within superficial cortical layers in response to deviant relative to standard stimuli. A proposed underlying mechanism for the MMN is that repetitive standard stimuli disinhibit neurons that are sensitive to different stimulus features (for example, a stimulus of one tonal frequency disinhibits neurons sensitive to other stimulus frequencies), leading to subthreshold depolarization and therefore unblocking of local NMDA receptors (NMDARs). When such neurons are subsequently stimulated, net current flow through open, unblocked NMDARs is larger than if the standard stimuli had not been previously presented. The intracortical administration of an NMDAR antagonist eliminates the differential response to deviant versus standard stimuli, supporting the role of NMDARs in the MMN. f | Schematic illustration of the intracortical auditory N1 response. The auditory N1 shows a characteristic refractoriness function, in which the amplitude of N1 decreases progressively as the interstimulus interval (ISI) is decreased from 9 to 0.3 seconds. The reduction in response amplitude reflects progressive inhibition of NMDAR-mediated current flow due to local GABAergic inhibition. Thus, infusion of an NMDAR antagonist (for example, ketamine) into the auditory cortex leads to significant inhibition of local current flow within the auditory cortex. By contrast, infusion of a type A GABA receptor (GABA_AR) antagonist, such as bicuculline, leads to significant enhancement of activity. The effects of bicuculline are reversed by administration of an NMDAR antagonist, suggesting that neurons within these layers are under tonic inhibition by local GABAergic interneurons. The top panels of part b are adapted with permission from REF. , Elsevier. Part d is adapted with permission from REF. , Elsevier.

Figure 4. Contributions of auditory sensory dysfunction to higher-order cognitive impairments

Schematic illustration of pathways from auditory sensory cortex dysfunction to impaired psychosocial function in schizophrenia. The ability to detect changes in auditory tone or rhythm is crucial for the detection of alterations in tone of voice (prosody), which communicates information about emotion (for example, whether someone is happy or sad) and/or attitude (for example, sincerity versus sarcasm), which in turn contributes to understanding of another person’s mental state (‘theory of mind’). Auditory tonal ability is also critical for functions such as ‘sounding words out’ (that is, phonological processing) during reading. As a result of reduced auditory feature discrimination, individuals with schizophrenia show impairments in processes such as auditory emotion recognition^, and phonological processing that lead to social cognitive and reading impairments, respectively. Mismatch negativity (MMN) is an additional auditory cortical process that is critical for everyday function. MMN reflects the outcome of a screening process, located in the auditory cortex that constantly monitors the environment for potentially relevant alterations in the pattern of background auditory stimulation, even when such events occur outside the focus on conscious attention. In healthy volunteers, generation of MMN within the auditory cortex is linked to subsequent activation of structures such as the insula and the anterior cingulate cortex that are part of the salience network, and to deactivation of visual regions, leading to bottom-up attentional capture. In schizophrenia, these processes are impaired, leading to reduced sensitivity to ongoing environmental (auditory) events^,. Deficits in MMN are highly interrelated to impaired functional outcome in schizophrenia, including impairments in reading and educational achievement^,. As opposed to behavioural measures that may be difficult to translate across species, MMN provides an objective neurophysiological measure that can be implemented in primates and/or rodents to investigate underlying neural mechanisms.

Figure 5. Impaired delta entrainment during auditory processing in schizophrenia

In addition to showing reduced responses to individual auditory stimuli, individuals with schizophrenia also fail to take advantage of the regularity of stimulation rate across stimulus presentation. In most cognitive paradigms, stimuli are presented at regular presentation rates of about 0.25–2 seconds, corresponding to frequencies in the delta range (0.5–4 Hz). The regularity of this rate allows the brain to predict when the next stimulus will be presented in order to optimize use of processing resources. a | In healthy controls, the average delta activity across trials increases as the task condition goes from passive auditory stimulation to easy auditory discrimination to difficult discrimination. This change in average response across trials corresponds to a progressive increase in the degree to which individual responses are phase-locked to the stimulus presentation rate. Thus, under passive listening conditions, delta activity is randomly distributed relative to the stimulation rate so that activity averages towards zero across trials. As task difficulty increases, the degree of inter-trial coherence (ITC) increases, leading to reduced cancellation across trials and thus greater average surface activity while performing the task. Individual trial responses are shown schematically in different shades, with the mean response in the darkest shade. b | In schizophrenia, no increase in average delta activity is observed across trials, suggesting that stimuli do not effectively reset the phase of the ongoing delta activity even in the difficult task condition. Schematics are based on data from REF. .

Figure 6. Auditory cortical circuitry: neurophysiological and histological findings in schizophrenia

Illustration showing the convergence between neurophysiological (event-related potential (ERP) and event-related spectral perturbation (ERSP)) and post-mortem findings in schizophrenia. In the auditory cortex, as in other brain regions, GABAergic interneurons can be subdivided by markers such as parvalbumin (PV), cholecystokinin (CCK), somatostatin (SST) and calretinin (CR). Inputs to the cortex arise predominantly from the medial geniculate nucleus (MGN) and form synapses on glutamatergic pyramidal (principal) neurons in layer 4 and lower layer 3. These inputs also synapse onto PV-expressing basket cells (PV_b), which originate local feedback and play a critical part in the generation of local gamma rhythms. Histological findings show that density and expression levels of vesicular glutamate transporter (VGluT) are relatively intact in schizophrenia in terminals of both MGN thalamocortical afferents (VGluT2) and corticocortical glutamatergic synapses (VGluT1), suggesting that the input to the cortex is also relatively intact. However, synaptophysin expression is reduced in deep layer 3, potentially increasing the susceptibility of these inputs to synaptic depression and thereby altering neurophysiological activation patterns. Dendritic spine density is reduced on pyramidal neurons in deep layer 3 of the auditory cortex, potentially owing to impaired NMDA receptor (NMDAR) function and impaired spine maintenance. Expression of glutamate decarboxylase 65 (GAD65) in terminals of GABA neurons is also reduced in deep layer 3, although whether this affects all or some the GAD65-expressing GABA neuron subtypes is not known. Only PV-expressing chandelier cells (PV_ch) do not express GAD65. The putative generator layers for specific neurophysiological components are shown in boxed text. In particular, generators for auditory P1, mismatch negativity (MMN) and auditory steady-state response (ASSR) are localized primarily to supragranular layers, whereas generators for auditory N1 are localized primarily to infragranular layers. In general, electroencephalographic activity recorded from the scalp reflects current flow through glutamatergic and voltage-sensitive ion channels within the dendritic arbors of pyramidal neurons. Dendritic arbors contribute disproportionately to electroencephalographic activity both because of their greater extent relative to axonal arbors and because the low impedance of dendritic (versus axonal) membranes gives rise to large currents that can be detected even at a distance. In addition, the asymmetrical structure of pyramidal neurons (versus interneurons) gives rise to an ‘open-field’ generator configuration that allows neural activity to propagate outside the local ensemble and thus to be detectable with far-field or scalp electrodes. In schizophrenia, the extent of neuronal arbors may be reduced in part due to a reduced number of spines, leading to less membrane surface area and thus to a smaller amplitude ERP. Furthermore, functional impairments of thalamocortical input, possibly due to reduced synaptophysin levels may lead to both reduced amplitude of response to individual stimuli and decreased synchronization across successive trials. Downregulation of PV and GAD65, particularly within PV_b may lead to impaired regulation of high-frequency gamma (30–80 Hz) activity, whereas impaired interaction between SST and pyramidal neurons may be responsible for impaired theta (4–7 Hz) frequency activity, as reflected in impaired auditory N1 and MMN generation. NMDARs are primarily located on pyramidal cell dendrites and GABAergic interneurons, and may thus lead to glutamatergic and GABAergic dysfunction.