**4.1 Neuroanatomy and physiology**

Cochlear function including the sensitivity and frequency tuning of the peripheral auditory system is influenced by incoming acoustic stimuli but also higher cochlear function. The olivocochlear pathway is a neural pathway which innervates cochlear outer hair cells (OHC), linking the superior olivary complex to the cochlea. Further insights into this pathway may improve our ability to screen for various forms of hearing loss such as ANSD.

The olivocochlear neural pathway is comprised of efferent neurons that travel from the superior olivary complex in the brainstem to cochlear hair cells. First described in 1946, Rasmussen (Rasmussen, 1946) traced the neural fibres from the floor of the fourth ventricle, along the inferior and superior vestibular nerves, then into the cochlear nerve in the bundle of Oort (the vestibulocochlear anastomosis). Later he confirmed passage of the pathway into the cochlea and named it the olivocochlear bundle (Rasmussen, 1953). This neural pathway, the olivocochlear efferent pathway, is now thought to play an important role in the olivocochlear reflex. There appear to be two forms of olivocochlear efferent fibres, medial olivocochlear (MOC) and lateral olivocochlear (LOC) efferents. The majority are the thin, unmyelinated fibres of the LOC system arising from the lateral superior olive and travel via the vestibular nerve to the cochlea where they innervate the auditory nerve supplying the inner hair cells (Kimura & Wersäll, 1962; Warr, 1975). While the LOC system received contributions from both sides of the brainstem, the majority of fibres innervate the ipsilateral cochlea (Guinan Jr, 2006). Thick, myelinated neurons of the MOC pathway originate in the medial part of the superior olivary complex. A portion of fibres cross the midline to the contralateral cochlea while others project to the ipsilateral cochlea both via the vestibular nerves (Guinan Jr, 2006). Within the cochlea the MOC fibres innervate the outer hair cells; this is referred to as the medial olivocochlear system (MOCS). The MOCS is innervated by ascending and descending neural pathways. Descending innervations arises from the inferior colliculus and auditory cortex (Mulders & Robertson, 2000a; Mulders & Robertson, 2000b).

Ascending innervation arises predominantly from the contralateral cochlea, by way of interneurons which cross the brainstem from cochlear nucleus to the olivary complex (Brown, Venecia, & Guinan, 2003; Morest, 1973; Ye, Machado, & Kim, 2000). The majority of MOCS fibres cross back over the midline to innervate the cochlea from which innervation is received (Azeredo et al., 1999; M. Liberman & Brown, 1986). A smaller proportion of MOCS fibers do not travel back across the brainstem and therefore innervate the cochlea on the same side. As they are stimulated by signals from the contralateral ear they provide a mechanism by which stimulation of one ear can influence the detection of acoustic signals by the other ear (Azeredo et al., 1999; Warren III & Liberman, 1989a).

Contralateral Suppression of Otoacoustic Emissions:

**5. New technology** 

Working Towards a Simple Objective Frequency Specific Test for Hearing Screening 33

Descending neural pathways also contribute to the MOCS. This has been shown in humans by increased MOCS activity when attention is focused on acoustic signals (Maison, Micheyl, & Collet, 2001). Animal studies have shown that electrical stimulation of the inferior colliculus increases MOCS activity (Mulders & Robertson, 2000a; Scates, Woods, & Azeredo, 1999). Axonal transport studies also suggest that MOCS neurons are innervated directly by neurons arising in the auditory cortex (Mulders & Robertson, 2000b). Though giving insight into olivocochlear activity electrophysiological studies have many limitations (Collet et al., 1990). Sectioning experiments, especially at the level of the floor of 4th ventricle, are imprecise and are not fully selective for efferents (though their effectiveness has been carefully demonstrated (M. C. Liberman, 1989; Warren III & Liberman, 1989b)). Electrical stimuli provide global stimulation, and in the floor of the 4th ventricle may simulate both crossed and uncrossed medial efferents that loop close to the midline (however, the LOCS is probably less easily stimulated this way as its fibers are unmyelinated). The main disadvantage with electrical stimulation is that it does not necessarily reflect normal cochlear input/output activity. Stimulation is often at supraphysiological levels, and provides unnatural synchronization and frequency of stimulation. Results can be confounded by stimulation artifact. Also neither sectioning nor electrical stimulation can be applied to humans, which limits extrapolation of findings from the animal models. The opportunity to study the MOCS non-invasively in animal models and humans was

facilitated by the discovery of otoacoustic emissions (OAEs) (Kemp, 1978a).

**5.1 Frequency specificity in the Medial Olivocochlear System (MOCS)** 

The function of the LOCS is not well understood. Some groups have proposed a role in providing "binaural balance" for sound localization has been proposed (Darrow, Maison, &

It is now well established that the sensitivity and frequency tuning of the peripheral auditory system is influenced by the cochlear efferent neural pathways (Guinan Jr, 2006). Activation of the MOCS by acoustic stimulation of the contralateral ear has been shown to suppress sensitivity of the cochlea, for example by reduction in cochlear nerve action potential amplitude (Fex, 1962). It is considered that this effect is mediated by suppression of the cochlear amplifier effect of OHC activity (Siegel & Kim, 1982). It is likely that relatively specific stimulus conditions are required for efferents to play a role in hearing (M. C. Liberman, 1988), but despite intensive investigation, the nature of this role remains unclear. Further assessment of how the MOCS is activated by different stimuli should improve understanding of this issue (Maison, Micheyl, Andéol, Gallégo, & Collet, 2000). Tonotopicity of the MOCS has been clearly demonstrated in recordings from single olivocochlear fibers in the cat and guinea pig (Brown, 1989; Cody & Johnstone, 1982; M. Liberman & Brown, 1986). In these studies, efferent neural tuning curves were derived by measuring firing rate in response to contralateral tones of different frequency, and were found to have a shape and sharpness similar to cochlear afferent tuning curves. In addition, horseradish peroxidase injection was used to reveal the projection of some fibers, and in all cases they terminated on OHCs at a cochlear position where afferent

Liberman, 2006; Guinan Jr, 2006). Studies to confirm this hypothesis are still needed.

#### **4.2 Physiology of the olivocochlear pathway**

Despite decades of investigation since the discovery of the olivocochlear pathway, understanding of its purpose remains somewhat speculative (Rasmussen, 1946). Proposed roles include protection against noise-induced hearing loss, enhancement of discrimination of sound in noise, or a role predominantly during development of the auditory pathway (Micheyl, Khalfa, Perrot, & Collet, 1997; Rajan & Johnstone, 1988; Walsh, McGee, McFadden, & Liberman, 1998).

There are a few studies of inter-cochlear interaction in humans which are consistent with MOCS functioning to reduce sensitivity of the cochlea to auditory stimuli. For example, contralateral pure tone stimulation causes a reduction of compound action potentials (Folsom & Owsley, 1987). Contralateral narrow band noise causes a 'negativation' of the summating potential response to ipsilateral tone bursts (i.e. the negative amplitude of summating potential increases) (Innitzer & Ehrenberger, 1977). There are indications that cortical function (e.g. visual or auditory attention tasks) influences olivocochlear activity via descending neural pathways (Froehlich, Collet, & Morgon, 1993; Maison, Durrant, Gallineau, Micheyl, & Collet, 2001).

Much more information on olivocochlear function has come from electrophysiological studies in animal models. Various investigations have supported the conclusion that MOCS activity turns down the gain of the cochlear amplifier (Siegel & Kim, 1982). The cochlear amplifier is an active process within the cochlea in which motor activity of OHCs increases sensitivity of the cochlea, by amplification of the basilar membrane motion induced by acoustic energy. With electrical stimulation of the olivocochlear bundle (OCB) in the floor of 4th ventricle, the amplitude of the compound action potential of the auditory nerve induced by auditory stimuli is reduced (Galambos, 1956; Nieder & Nieder, 1970; Wiederhold & Peake, 1966). In this way, the threshold of the auditory nerve can be increased by as much as 25dB an effect referred to as the 'level shift' (Galambos, 1956). By using focal simulation near the cell bodies of olivocochlear fibers, it has been shown that MOCS mediates this effect (i.e., via action on OHCs), rather than LOCS (Gifford & Guinan Jr, 1987). Electrical stimulation of the OCB increases the cochlear microphonic and causes a decrease in the electrical impedance of scala media of the guinea pig (Mountain, Daniel Geisler, & Hubbard, 1980). These changes are considered to be due to hyperpolarization of outer hair cells (Art, Fettiplace, & Fuchs, 1984; Mountain et al., 1980). Thus electrical stimulation of MOCS suppresses OHC activity so dampening basilar membrane motion and reducing cochlear amplification. This has an indirect effect on IHC activity, as demonstrated by the level shift.

Contralateral acoustic stimulation (CAS) has been found to elicit similar effects to electrical stimulation of the MOCS. This was first reported by Fex, who found that CAS increased the cochlear microphonic (Fex, 1962). Recording from the round window in cats, Liberman showed that the compound action potential generated by ipsilateral tone pips was suppressed by contralateral noise or tones. Sectioning of the olivocochlear bundle in the floor of 4th ventricle or in the inferior vestibular nerve abolished this contralateral suppression effect (M. C. Liberman, 1989; Warren III & Liberman, 1989b). Such studies clearly show that the MOCS is stimulated by ascending signals from the auditory pathway.

Descending neural pathways also contribute to the MOCS. This has been shown in humans by increased MOCS activity when attention is focused on acoustic signals (Maison, Micheyl, & Collet, 2001). Animal studies have shown that electrical stimulation of the inferior colliculus increases MOCS activity (Mulders & Robertson, 2000a; Scates, Woods, & Azeredo, 1999). Axonal transport studies also suggest that MOCS neurons are innervated directly by neurons arising in the auditory cortex (Mulders & Robertson, 2000b). Though giving insight into olivocochlear activity electrophysiological studies have many limitations (Collet et al., 1990). Sectioning experiments, especially at the level of the floor of 4th ventricle, are imprecise and are not fully selective for efferents (though their effectiveness has been carefully demonstrated (M. C. Liberman, 1989; Warren III & Liberman, 1989b)). Electrical stimuli provide global stimulation, and in the floor of the 4th ventricle may simulate both crossed and uncrossed medial efferents that loop close to the midline (however, the LOCS is probably less easily stimulated this way as its fibers are unmyelinated). The main disadvantage with electrical stimulation is that it does not necessarily reflect normal cochlear input/output activity. Stimulation is often at supraphysiological levels, and provides unnatural synchronization and frequency of stimulation. Results can be confounded by stimulation artifact. Also neither sectioning nor electrical stimulation can be applied to humans, which limits extrapolation of findings from the animal models. The opportunity to study the MOCS non-invasively in animal models and humans was facilitated by the discovery of otoacoustic emissions (OAEs) (Kemp, 1978a).

The function of the LOCS is not well understood. Some groups have proposed a role in providing "binaural balance" for sound localization has been proposed (Darrow, Maison, & Liberman, 2006; Guinan Jr, 2006). Studies to confirm this hypothesis are still needed.
