Main characteristics of schizophrenia is a difficulty in prioritising and ranking surrounding sounds

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Our sound environment is extremely dense, which is why the brain has to adapt and implement filtering mechanisms that allow it to hold its attention on the most important elements and save energy.

When two identical sounds are repeated quickly, one of these filters – called auditory sensory gating – drastically reduces the attention that the brain directs to the second sound it hears.

In people with schizophrenia, this ability to reduce the brain’s response to identical sounds does not function properly.

The brain, it seems, is constantly assailed by a multitude of auditory stimuli, which disrupt its attentional capacity.

But the question is: Why?

Neuroscientists from the University of Geneva (UNIGE), Switzerland, have been investigating the mechanism that lies behind this auditory sensory gating, which was previously unknown.

Their results, published in the journal eNeuro, show that the filtering begins at the very beginning of the auditory stimuli processing, i. e. in the brainstem.

This finding runs counter to earlier hypotheses, which held that it was a function of the frontal cortex control, which is heavily impacted in schizophrenics.

One of the main characteristics of schizophrenia, which affects 0.5% of the population, is a difficulty in prioritising and ranking surrounding sounds, which then assail the individual. This is why schizophrenia is diagnosed using a simple test: the P50.

“The aim is to have the patient hear two identical sounds spaced 500 milliseconds apart. We then measure the brain activity in response to these two sounds using an external encephalogram,” explains Charles Quairiaux, a researcher in the Department of Basic Neurosciences in UNIGE’s Faculty of Medicine.

“If brain activity decreases drastically when listening to the second sound, everything is okay.

But if it’s almost identical, then that’s one of the best-known symptoms of schizophrenia.”

Although widely used to perform such diagnostics, the functioning of this filtering mechanism – called auditory sensory gating – is still a mystery.

Most hypotheses held that this brain property is provided by a frontal cortex control, located at the front of the brain.

“This area of control is badly affected in people suffering from schizophrenia, and it’s situated at the end of the brain’s sound processing pathway,” explains Dr Quairiaux.

The failure is situated at the base of sound processing

In order to test this hypothesis, the Geneva-based neuroscientists placed external electroencephalographic electrodes on mice, which were then subjected to the P50 test, varying the intervals between the two sounds from 125 milliseconds to 2 seconds.

The results proved to be exactly the same as those observed in humans: there was a clear decrease in brain activity when listening to the second sound.

This shows a graph from the study

Decreased brain response to the same repeated sound at an interval of half a second (left is sound 1, right is sound 2).

Illustration: the responses recorded above the auditory areas of the cortex by means of electroencephalographic electrodes. The image is credited to UNIGE.

The scientists then placed internal electrodes in the cortical and subcortical auditory regions of the brain, from the brainstem to the frontal cortex – the pathway for processing sounds.

The mice were given the P50 test a second time and, contrary to the initial hypothesis formulated by the scientists, the researchers observed that the drop in attention given to the second sound occurred already at the brainstem and not only at the cortical level, with a 60% decrease in brain activity.

“This discovery means we’re going to have to reconsider our understanding of the mechanism, because it demonstrates that the filter effect begins at the very moment when the brain perceives the sound!” points out Dr Quairiaux.

And where does this leave people suffering from schizophrenia?

“We’re currently carrying out the same study on mice with 22q11 deletion syndrome, a mutation that often leads to schizophrenia in humans, so we can see if the lack of a filter is situated in the brainstem, taking account of the new results we obtained,” continues the researcher.

And that does indeed seem to be the case!

The first tests on “schizophrenic” mice revealed the total absence of a filter for the second sound at the brain stem.

The source of one of the most common symptoms of schizophrenia is about to be discovered.


Schizophrenia is a severe psychiatric disorder that affects ~1% of the population worldwide1.

It is diagnosed primarily based on common clinical manifestations, such as agitation, paranoia, delusions and hallucinations (the ‘positive’ symptoms), and/or apathy, social withdrawal and anhedonia (the ‘negative’ symptoms).

Nevertheless, the impaired psychosocial outcome in schizophrenia is driven primarily by deficits in neurocognitive functions that are manifest across a wide range of cognitive domains.

In general, patients with this disorder show a deficit of 1–2 standard deviations in cognitive function, corresponding to a mean reduction in performance IQ to 70–85 (versus the normative value of 100)2.

The onset of schizophrenia is typically in late adolescence or early adulthood in males (age 17–21 years) and somewhat later in females, and the disorder is associated with lifelong disability thereafter1.

At present, there are no approved treatments that specifically target the neurocognitive impairments in schizophrenia.

A key goal of current schizophrenia research, therefore, has been to determine the neural mechanisms underlying these deficits to guide future interventional approaches.

Although neurocognitive studies of schizophrenia have traditionally focused on higher-order functions such as working memory and executive processing, basic sensory functions — including auditory-level function — are also impaired in this disorder and may be particularly amenable to translational, cross-species research.

In addition, these deficits contribute substantially to symptoms and overall impairments in psychosocial function.

In this Review, we first discuss the evidence for auditory sensory dysfunction in schizophrenia and its underlying mechanisms, particularly the contribution of NMDA receptor (NMDAR) dysfunction and related impairments in glutamatergic and GABAergic function.

Neurophysiological approaches, including event-related potential (ERP) and event-related spectral perturbation (ERSP) techniques, have proved particularly effective both for characterizing the clinical deficits in schizophrenia2,3 and for linking them to underlying pathogenic mechanisms4, and we thus describe them in detail.

We then discuss the mechanisms by which auditory cortical dysfunction leads to the characteristic behavioural manifestations of schizophrenia, especially the impairments in social interaction and communication skills that are tied directly to poor psychosocial function in schizophrenia.

Subsequently, we review the structural evidence for auditory cortical involvement in schizophrenia, especially from post-mortem investigations5, and highlight both the convergences and divergences between the functional and structural findings. We also consider how auditory deficits might relate to existing neurochemical theories of schizophrenia6,7 (BOX 1).

Box 1

Model psychoses and neurochemical conceptualizations of schizophrenia

The aetiological mechanisms of schizophrenia remain unclear.

Currently, there are two major neurochemical models for this disorder:

the dopaminergic and glutamatergic models.

The dopamine model is based on the fortuitous observation that the compound chlorpromazine had dramatic and unexpected effects on symptoms of schizophrenia150.

These effects were later tied to the blockade of D2-type dopamine receptors151.

In parallel, the ability of psychostimulants, such as amphetamine, to induce schizophrenia-like psychotic symptoms was found to be tied to their stimulatory effects on dopaminergic systems in the brain152.

Currently, all approved compounds for schizophrenia, including both typical and atypical antipsychotics, induce antipsychotic effects primarily by blocking neurotransmission at dopamine D2 receptors153,154.

Nevertheless, dopaminergic models are limited both by the inability of current antipsychotic agents to reverse the core negative symptoms and neurocognitive impairments associated with schizophrenia, and by the inability of psychostimulants such as amphetamine to induce such symptoms in healthy human volunteers.

Glutamatergic models are based on the observation that phencyclidine, ketamine and other ‘dissociative anaesthetics’ induce schizophrenia-like symptoms and neurocognitive deficits by blocking neurotransmission at NMDA receptors (NMDARs)6,7.

Such agents induce both negative and positive symptoms in healthy volunteers155,156 along with schizophrenia-like neurocognitive and neurophysiological deficits such as impaired generation of mismatch negativity (MMN)29,50.

Moreover, NMDAR agonists such as glycine, D-serine and N-acetylcysteine have shown beneficial effects on symptoms and neurophysiological deficits in small-scale treatment studies of schizophrenia157, including studies involving individuals at clinical high risk for this disorder158, although these findings are yet to be confirmed in larger-scale investigations157,159.

Other neurotransmitter systems may also be involved in schizophrenia.

For example, disturbances in GABAergic neurotransmission occur during the course of the disorder42 and are specifically linked to impaired generation of high-frequency (gamma band) oscillatory activity such as that observed during the auditory steady-state response42.

However, to date, GABAergic agents have not proved effective in the treatment of schizophrenia160. Cannabinoids, such as tetrohydrocannabinol (THC), also induce schizophrenia-like symptoms, in part by inducing a hypoglutamatergic state via CB1 receptors161.

Agents that target the 5-hydroxytryptamine (serotonin) receptor 2A (5-HT2A) such as psilocybin62 and dimethyltryptamine (DMT)51 also induce schizophrenia-like positive symptoms and deficits in prefrontal functioning in healthy human volunteers.

Nevertheless, these compounds do not induce negative symptoms resembling those of schizophrenia or inhibit MMN generation51,62,162, suggesting a potential role of 5-HT2A dysfunction in the positive symptoms but not the negative symptoms or neurophysiological impairments in schizophrenia.

Both genetic and environmental factors may also have key roles in the pathogenesis of schizophrenia. The concordance rate among identical twins for schizophrenia is high (~50%), suggesting that this disorder has a strong genetic component.

Nevertheless, this figure suggests that what is inherited is a susceptibility to schizophrenia rather than the disease itself.

Associations have been reported between schizophrenia and the genes for both the D2 receptor and NMDAR, as well as between schizophrenia and genes that affect NMDAR function more generally (for example, the gene encoding serine racemase)163. Environmental factors including autoantibodies against the NMDAR1,164 may also contribute to the risk of schizophrenia and may provide additional therapeutic targets.Go to:

Behaviour and neurophysiology

In humans, the peripheral auditory system includes the outer ear, middle ear and inner ear, which includes the cochlea.

The central auditory system begins with the auditory nerve.

Auditory information then ascends via the cochlear nucleus, superior olivary complex and inferior colliculus to the medial geniculate nucleus of the thalamus and then to the auditory cortex (FIG. 1a).

The primary auditory cortex (Brodmann’s area 41 (BA41)) is located in the posterior third of Heschl’s gyrus.

By contrast, the secondary auditory cortex (BA42), which includes the lateral belt and parabelt regions, is located in portions of Heschl’s gyrus and extends into the planum temporale, encompassing much of the superior bank of the posterior superior temporal gyrus (STG)8 (FIG. 1b–e).

Additional multisensory regions (such as the posterior auditory association cortex — area Tpt) extend to the lateral convexity of the STG, corresponding to BA22, and receive additional crossmodal input.

Auditory regions of the cortex have undergone extensive phylogenetic elaboration during primate evolution and also show ontological development, with continued maturation into even the second and third decades of life, and thus are sensitive to potential insults during the risk period for the development of schizophrenia, which probably begins in the early teenage years1,9.

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

Peripheral and brainstem auditory function

‘Hearing ability’ is typically assessed by asking subjects to detect the presence or absence of an isolated auditory stimulus.

In general, individuals with schizophrenia have intact performance on routine hearing tests or auditory brain-stem responses, indicating that peripheral and brainstem auditory processing is preserved in such individuals, at least for isolated stimuli10.

Notably, however, performance on tests of this type is preserved even following complete ablation11 or inactivation12 of the auditory cortex in animals or extensive auditory lesions in humans13,14; therefore, such tests are relatively uninformative about the existence of potential cortical-level dysfunction.

Within the brainstem, NMDARs are involved primarily in complex processes involving plasticity and integration15. Such processes have been studied in schizophrenia to only a limited degree but may also be impaired16, suggesting that dysfunction occurs even at the brainstem level.

Behavioural measures

Although the primary auditory cortex is not critical for the detection of isolated auditory stimuli, it is critical for performing a fine-grained comparison between successive auditory stimuli.

Indeed, in animals with bilateral ablations11,17 or inactivation12 of the auditory cortex, or in humans with bilateral auditory cortical infarcts14, the damage leads to a dramatic increase in the threshold for detecting physical differences — such as differences in pitch, duration or location — between successive auditory stimuli.

These impairments are observed even in the absence of distracting information (FIG. 2a,b).

By contrast, damage to other cortical regions such as the prefrontal cortex does not impair simple tone matching ability, although it does impair the ability to ignore distracting information1719 (FIG. 2b).

Individuals with schizophrenia show this ‘auditory cortical’ pattern of impairments: that is, notable elevations in tone matching thresholds even in the absence of distracting information2022, with no further increase in susceptibility to distraction when distracting information is included23,24 (FIG. 2c).

The ability to match tones following a brief delay depends on the formation of an ‘echoic’ memory trace, which typically decays over a period of 10–30 seconds in both individuals with schizophrenia and control subjects (FIG. 2d).

Moreover, when subjects are tested at their individualized tone matching thresholds (FIG. 2e), the decay in performance over time is similar between the two groups, suggesting that the patients with schizophrenia have deficits primarily in the encoding, rather than the retention, of sensory information24.

Behavioural consequences

In addition to providing strong insights into pathophysiological mechanisms underlying schizophrenia, deficits in auditory function are important because they directly contribute to symptoms and functional impairments that are associated with this disorder. As with the studies of basic auditory functions, both behavioural and neurophysiological approaches have been used to investigate the underlying neural mechanisms of these symptoms and impairments.

Auditory verbal hallucinations

Auditory verbal hallucinations (AVHs) are highly characteristic symptoms of schizophrenia and typically take the form of voices speaking either to or about an individual65.

Antipsychotic medications markedly reduce AVHs, suggesting dopaminergic involvement in these phenomena.

Nevertheless, the majority of patients with AVHs show some persistence of their hallucinations even while receiving antipsychotic medication66, indicating that other, non-dopaminergic systems may also contribute.

In particular, AVHs have been associated with volume loss67,68 and functional hyperactivity69,70 of the auditory cortex, suggesting that local pathology within these regions may contribute as well.

Several mechanistic explanations for AVHs have been proposed.

First, impaired thalamocortical input to the auditory cortex by itself may have an important role, as AVHs are observed during sensory deprivation71.

Second, increased synchrony between productive and receptive speech regions, along with reduced suppression of auditory regions during speaking versus listening, may also play a part72.

Third, AVHs are also associated with reduced MMN amplitudes73 and impaired predictive coding in the auditory cortex74, suggesting the involvement of additional local mechanisms.

Finally, AVHs may also reflect a failure to correctly localize thoughts in space75, leading to the perception that they originate outside, rather than inside, the head.

Although dopamine agonists and NMDAR antagonists produce only mild AVHs during acute challenge76, both lead to apparent hallucinatory-like activity during chronic administration in monkeys (for example, attending to or threatening non-existent objects in space)7780, suggesting that adaptive changes induced during a persistent hypo-NMDAR–hyper-dopaminergic state may be crucial for their manifestation.

Although AVHs cannot be attributed solely to dysfunction in the auditory cortex, auditory-based treatments may contribute to their clinical management.

Thus, inhibitory brain stimulation methods such as low-frequency transcranial magnetic stimulation (TMS)81 or cathodal transcranial direct current stimulation82 applied over the auditory cortex are reported to reduce the frequency and the severity of AVHs.

The magnitude of these effects has been variable across studies. Nevertheless, a recent meta-analysis reported a 2.9-fold higher response rate to active than to sham TMS83, with some studies also showing alterations in underlying physiological disturbances such as functional (fMRI) hyperactivity within the superior temporal sulcus84,85.

The use of physiological approaches to select appropriate candidates86 and target interventions87 may lead to further enhancement of therapeutic efficacy for neuromodulatory, brain stimulation-based approaches such as TMS.

Social and role function

In addition to symptoms, auditory deficits strongly contribute to the overall psychosocial dysfunction in schizophrenia10.

One key process that is affected by impaired sensory capabilities is the ability to interpret the prosody of verbal communications.

In Western languages, tonal transitions do not contribute strongly to the perception of individual speech sounds (phonemes) but do convey non-verbal information such as emotion or attitude.

For example, happiness is typically accompanied by an increase in both the base pitch and degree of pitch variation in speech, whereas sadness is conveyed by reductions in base pitch and pitch variability88,89.

Other types of non-verbal information, such as attitudinal prosody (‘sarcasm’) are also conveyed by subtle shifts in the pitch90,91.

In schizophrenia, deficits in tone matching strongly correlate with deficits in prosodic processing, including both emotional22 and attitudinal91 prosody.

These deficits, in turn, lead to impairments in more global aspects of function, such as social and role function (FIG. 4).

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Figure 4
Contributions of auditory sensory dysfunction to higher-order cognitive impairmentsSchematic 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 recognition22,90 and phonological processing93 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) events10,94. Deficits in MMN are highly interrelated to impaired functional outcome in schizophrenia, including impairments in reading93 and educational achievement32,167. 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.

In tonal languages such as Mandarin Chinese, tonal information contributes specifically to word meaning. For example, the phoneme ‘ya’ said with one type of inflection (ya1) means ‘tooth’, whereas with another inflection (ya4) means ‘duck’.

Consistent with other auditory findings, Mandarin-speaking individuals with schizophrenia show notable deficits in the ability both to identify and to discriminate words that are phonemically identical but tonally distinct (for example, ya1 versus ya4).

As with deficits in prosodic processing and reading in Western languages, deficits in word discrimination in Mandarin-speaking individuals with schizophrenia markedly correlate both with underlying deficits in tone matching ability and with global measures of psychosocial function such as work status92.

Fluent reading ability also depends on the ability to perceive and manipulate speech sounds (phonological processing).

Consistent with other auditory findings, deficits in phonological processing have recently been demonstrated in schizophrenia and lead to a severe degeneration in mechanical reading ability relative to the premorbid state93. As expected, deficits in reading were associated with impairments in both basic auditory function on the one hand and overall psychosocial disability on the other93.


Source:
University of Geneva
Media Contacts:
Charles Quairiaux – University of Geneva
Image Source:
The image is credited to UNIGE.

Original Research: Closed access
“Large-Scale Networks for Auditory Sensory Gating in the awake mouses”. Abbas Khani, Florian Lanz, Gerard Loquet, Karl Schaller, Christoph Michel and Charles Quairiaux.
eNeuro doi:10.1523/ENEURO.0207-19.2019

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