Speech comprehension disorders : peripheral and central causes

Abstract

The fourth lecture in this series centered on the theme " hearing without understanding " focused on medical aspects. The theme was inspired by the words of one of the patients of Arnold Starr, a pioneer in the study of auditory neuropathy : " I can hear you, but I can't understand you ".

In 1996, Arnold Starr introduced the term auditory neuropathy in an article he first authored . In it, he reported the results of physiological and behavioral tests he had carried out on a dozen patients with hearing impairment, which he attributed to " an anomaly in the auditory portion of the cranial nerve VIII ". In these patients, the distortion products of acoustic otoemissions were preserved, as were the cochlear microphonic potentials, indicating that the CCEs had retained their ability to distort sounds and transduce them. They complained of great difficulty in understanding speech, and recordings of auditory evoked potentials showed a strong degradation of the waves, even to the point of their complete absence. And yet, surprisingly, their psychoacoustic auditory thresholds in response to pure tones were normal. In addition to this unprecedented association of responses to various tests, later refined with the identification of the diversity of cellular targets and pathogenic mechanisms involved, the term " entendre sans comprendre " ( hearing without understanding) has the merit of drawing attention to the existence of dissociations between auditory sensitivity and performance in speech sound processing modes.

The patients in this initial study had no other neurological manifestations, suggesting damage due to peripheral neuropathy, primarily affecting the auditory nerve. Today, we know that peripheral auditory neuropathies also include damage to the auditory pathways and auditory cortex, mostly suggested in the context of presbycusis, age-related sensorineural deafness. However, as far as peripheral auditory neuropathies due to genetic damage are concerned, their impact on the auditory pathways and auditory cortex has not yet been the subject of in-depth, systematic research. Auditory neuropathies therefore include rare, early-onset genetic disorders (often congenital) whose cellular targets are peripheral and whose underlying pathophysiological processes are well identified thanks to knowledge of the gene responsible and the study of corresponding animal models, but whose central impact is largely unknown. On the other hand, they include a large number of cases corresponding to late-onset disorders whose primary target is also peripheral. The latter include a large proportion of cases of presbycusis and noise-induced hearing impairment. Their underlying pathophysiological processes are much less well known ; the exploration of their central repercussions is now mainly concerned with the associations highlighted between presbycusis and cognitive decline. We then examined what is known today about auditory neuropathies, starting with peripheral neuropathies, which are still the only class of auditory sensory disorders that can be distinguished clinically from other peripheral sensory disorders. The first such neuropathy to be identified is caused by biallelic mutations in the Otof gene. This gene codes for otoferlin, a synaptic vesicle transmembrane protein with six C2 domains (four of which bind calcium), required for synaptic vesicle fusion at ribbon synapses in the cochlea's IHCs. We have discussed the work carried out in the laboratory on this protein. Over the past twenty years, this work has led to the identification of this protein as essential for sound processing in the cochlea, synaptic exocytosis in IHCs, and the demonstration of its role as a " calcium sensor " for synaptic fusion and synaptic vesicle recycling at the ribbon synapse [12 and 13]. More than a hundred mutations in the Otof gene have now been identified ; hearing impairment caused by these mutations is the most common hereditary peripheral auditory neuropathy. Two other hereditary disorders whose effects are also localized at the IHC synapse are responsible for very similar neuropathies : they are due to mutations affecting the gene coding for L-type Cav1.3, responsible for the calcium influx that triggers synaptic vesicle fusion, and others that affect the glutamate transporter of CCIs (vGlut3), which brings this neurotransmitter, the sole neurotransmitter of CCIs, into synaptic vesicles. Although there is no neurotransmitter release into the synaptic cleft between ITCs and primary auditory neurons in these disorders, the ITC synapse in otoferlin- or vGlu3-deficient mutant mice remains to some extent intact ; it is as if " frozen " in this non-functional state. This suggests that it could regain functionality if DNA encoding the defective protein is reintroduced into the cell. Recent results from Dr Saaid Safieddine's group in the laboratory and others show this to be the case and hold out the prospect of developing the first gene therapies for this form of deafness, DNFB9.

For a number of other hereditary auditory neuropathies, identification of the gene involved has made it possible to elucidate the molecular and cellular mechanisms affected. These include :

neuropathy caused by overexpression of the DIAPH3 gene, which codes for a cytoskeletal regulator. Only the ICCs are affected. However, they are not affected at the level of their synapse, but at the level of their cuticular plate (located beneath their apical surface), which is severely deformed by the formation of an aberrant network of microtubules, leading to degeneration of their ciliary tuft. It remains to be seen why ECCs are not affected ;
a disorder responsible for DFNB59 deafness, caused by mutations in the gene coding for pejvakine, identified in the laboratory by Sedigheh Delmaghani. The classification of this disorder as an auditory neuropathy is due to the fact that, in some of the first patients analyzed, spontaneous acoustic otoemissions were normal and acoustic evoked potential wave latencies were increased. In close collaboration with Prof. Paul Avan of the University of Clermont-Ferrand, we have shown that mice lacking pejvakin exhibit hypervulnerability to sound, leading to abnormal variability in their auditory thresholds. A detailed study of these mutants then enabled us to show that the damage does indeed affect the IHCs and primary afferent auditory neurons (consistent with neuropathy-type damage), but that it also affects the EACs. We have shown that pejvakin is a component of peroxisomes. It conditions peroxisome proliferation induced by the oxidative stress generated by sound stimulation. The response to sound results in the production of reactive oxygen species (ROS) whose elimination by reduction depends on peroxisome proliferation. We have observed that pejvakin conditions this proliferation by intervening in an earlier step, the elimination of damaged peroxisomes by pexophagy. In the absence of pejvakin, peroxisomes damaged by ROS are not eliminated, and the formation of new peroxisomes cannot take place [14 and 15] ;
other neuropathies are caused by damage to primary auditory neurons : these include disorders involving the defective mitochondrial protein in optic atrophy, OPA1 (optic atrophy 1), which is required for mitochondrial fusion, the defective frataxin in Freidreich's disease, a mitochondrial protein involved in iron-sulfur metabolism ; they include certain abnormalities affecting the myelin sheath of auditory neurons (Charcot's disease and multiple sclerosis) ;
finally, there are other neuropathies due to metabolic impairments, such as hyperbilirubinemia, the recently reported biotinidase deficiency, and a deficiency involving an anti-apoptotic protein yet to be characterized.

In the second part of the lecture, we turned our attention to noise- and age-related auditory neuropathies. While hereditary peripheral auditory neuropathies affect few people, a considerable number of individuals worldwide suffer from noise-induced hearing loss or presbycusis. Their numbers are growing with increasing population density in urban areas and aging populations. The World Health Organization (WHO) estimates that some 1.1 billion young people between the ages of 12 and 35 are currently at risk of developing noise-induced hearing loss, due to the uncontrolled use of personal music players. As for aging people, 450 million of them, according to WHO forecasts, will suffer from presbycusis by 2050.

Finally, we turned to the effects of presbycusis on cognition, which we discussed in the light of a body of data accumulated since 2005, when we began to suspect an association between hearing loss and cognitive decline in the elderly. A meta-analysis published in 2017 [16] revealed that hearing loss is the highest modifiable risk factor for the onset of age-related dementia. Four hypotheses have been put forward to account for the associations between presbycusis and dementia :

the " cognitive overload " hypothesis, according to which hearing loss increases cognitive load, leading to cognitive decline ;
another called " sensory deprivation ", according to which any sensory deprivation (auditory or other) leads to permanent deterioration in cognitive functions ;
a hypothesis known as " information degradation ", according to which older people mobilize their cognitive resources to a greater extent to understand speech that reaches them in degraded form ;
a hypothesis that states the existence of common mechanisms at the origin of hearing loss at both peripheral and central levels.

It follows that compensating as much as possible for peripheral hearing loss (through the use of hearing aids or cochlear implants if necessary) could reduce the likelihood and/or severity of dementia. This hope is supported by the initial results of some large-scale studies, which seem to show that dementia is less frequent in elderly patients whose deafness is compensated for by a hearing aid. This explains the current recommendations of the WHO, which in a recent report details the risk factors for dementia that can be modified ; among these, hearing deficits figure prominently.

Given the loss of autonomy associated with cognitive decline, the above-mentioned hypotheses, which are not mutually exclusive, are currently the focus of research efforts in a large number of laboratories.