1. Temporal Processing of Sounds by Cochlear Nucleus Neurons
2. The Role of Neural Connections to the Cochlear Nucleus in Sound Coding
3. Somatosensory Innervation to the Cochlear Nucleus and its Role in Tinnitus

a. Anatomy

b. Function

c. Role of the Trigeminal Ganglion-Cochlear Nucleus Projection in Tinnitus.

1. Temporal Processing of Sounds by Cochlear Nucleus Neurons

We choose to study temporal coding in single VCN neurons for two reasons:

First is its relevance to speech perception. Speech consists of temporal sequences of spectrally complex acoustic events. Numerous psychophysical studies have shown that the temporal context of a stimulus affects the perceptual quality of individual auditory events. Detection thresholds, loudness and pitch perception can be altered depending on preceding auditory events. Distinctions between major phonetic categories such as vowels and stop-consonants are based largely on changes in the temporal structure of the signal. This includes onsets and offsets, silent intervals and the duration and order of individual segments of the signal. The little information available on neural mechanisms underlying the processing of time-varying signals indicate that neural responses can enhance spectral contrasts between successive speech segments through the processes of adaptation (in auditory nerve, Delgutte, 1986; 1995) and inhibition in more central locations (Shore, 1995; 1998). There is also evidence that central auditory neurons enhance the representation of amplitude modulation. These enhancements constitute important cues for our understanding of the encoding of voicing and pitch information which is contained in the periodic amplitude modulations of the waveform. It is becoming increasingly apparent that inhibitory mechanisms are involved in both responses to two-tone (Shore, 1995; 1998), and amplitude modulated stimuli.

Thus, the second reason for studying temporal processing is that we have the opportunity to study inhibitory mechanisms relevant to speech perception which operate over relative long time intervals.  We have chosen a forward masking paradigm as our primary method for studying temporal processing. 

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Following a masker, response rate to a subsequent probe is diminished. 

We record from single units in the cochlear nucleus using multichannel electrodes developed by the center for neural communications which enable us to record from multiple units simultaneously.  The Center for Neural Communications Technology (directed by Dr. David Anderson) provides silicon substrate neuroproble for stimulation and recording to qualified investigators.  Probes are developed by the Center and by Dr. Kensall Wise under the sponsorship of NIH Neural Prostheses Program.

2. The Role of Neural Connections to the Cochlear Nucleus in Sound Coding

a. Anatomy: As in other sensory systems, the cochlear nuclei receive efferent information from higher centers. This is demonstrated especially well in the VCN where most neurons receive extrinsic, non-cochlear synaptic endings from higher auditory and non-auditory centers. In fact, more than half of axosomatic endings on bushy cells in the VCN are non-cochlear, contradicting the commonly held view that these cells are largely relay neurons. A large proportion of their synapses have either flattened or pleomorphic vesicles, usually associated with synaptic inhibition, and contain either glycine or GABA and in some cases both. Large numbers of these putative inhibitory synapses are strategically placed on cell bodies and axon hillocks of bushy and stellate cells to affect the output of these projection. 

Sources of non-cochlear innervation arise predominantly in the superior olivary complex, inferior colliculus and contralateral cochlear nucleus (Shore et al, 1991; 1992). Other sources include the cerebral cortex, cuneate nucleus, dorsal column nuclei, interpolar and caudal spinal trigeminal nuclei (Shore et al, 1998; 2000) and vestibular nuclei. Because many of the neurons projecting out of the VCN receive descending information from their target neurons ( Shore et al, 1991; Shore et al, 1992), they may have a feedback function, presumably to enhance or attenuate incoming sensory information from the auditory nerve. We use tract tracing techniques combined with immunocytochemistry to explore the innervation to the cochlear nucleus from non-cochlear sources.

Schematic of connections from auditory brainstem nuclei to the cochlear nucleus (Shore et al., 1991).

Schematic of connections between the two cochlear nuclei (Shore et al., 1992).

b). Neuropharmacology and Lesion Studies

We use neuropharmacology to assess the effects of these various pathways on sound coding in the cochlear nucleus. Special "puffer probes" are fabricated by the center for neural communications technology (directed by Dr. David Anderson) to deliver putative neurotransmitters and their antagonists locally and remotely.

	Using the silicon drug-delivery probes, we investigate the effects of GABA, glycine and Acetylcholine agonists and antagonists on spontaneous levels and forward-masking functions of VCN neurons.
	A two dimensional probe used for puffing drugs and recording single units. Recording sites are positioned near the tips of the longest shanks. Stimulating and drug-delivery sites are positioned near the tips of the shorter shanks.

 

Forward masking functions change when strychnine is applied locally.

Another approach to studying the role of these connections is to eliminate them through the use of lesions. We investigate the effects of reversible lesions of the SOC on the spontaneous discharge rate, sound-evoked forward masking functions, responses to clicks and AM sound, and tuning properties of CN neurons. Major sources of CN centrifugal input in guinea pigs are the VNTB, LNTB, MNTB and DMPO and the contralateral cochlear nucleus. Thus, these nuclei are the primary targets for chemical lesions using Kainic Acid and Mellitin.

Additional studies target the function of the cochlear nucleus commissural projection (Shore et al, 1992). We stimulate the contralateral ear with sound and assess the effects on spontaneous and sound-driven responses in the ipsilateral cochlear nucleus. The goal of these studies is twofold: a) to determine the function of this pathway and b) to determine whether the ventral cochlear nucleus, by virtue of its binaural properties, plays a role in sound localization.

3. Somatosensory Innervation to the Cochlear Nucleus and its Role in Tinnitus

a. Anatomy of the Trigeminal Ganglion-Cochlear Nucleus Projection:
Our recent studies have demonstrated a new neural pathway of trigeminal ganglion projections to the auditory brainstem (Shore et. al., 2000). The projections terminate in granular and magnocellular regions of the ventral cochlear nucleus (VCN) and surrounding the lateral superior olivary complex (LSO) at the locations of olivocochlear neurons.

We have previously described a cochlear branch of trigeminal ganglion projections which modulates blood flow in the cochlea (Vass et al., 1995; 1997; 1998; 2000). 

In some animals, one fluorescent tracer was placed into the VCN and a second into the skin overlying the mandible. The cells projecting to the CN were smaller than the sensory cells innervating the skin overlying the mandible. The presence of terminal labeling on the surface of the CN - projecting cells indicates the possibility that this projection is reciprocal (see Shore et. al., 2000). 

b. Function of the Trigeminal Ganlion-Cochlear Nucleus Projection:
We are currently studying function of the brainstem portion of this projection using electrical stimulation, neuropharmacology and immunocytochemistry. Preliminary findings suggest that the projection to the VCN is excitatory (Shore et. al., 2000). The influence of the trigeminal ganglion on cochlear nucleus (CN) neurons could greatly impact processing in higher auditory centers because a high percentage of information (acoustic and somatosensory) arriving at the CN is conveyed to higher auditory centers. The project is expedited by the use of multi-channel recording and drug-delivery probes developed by the center for neural communications, enabling us to study the physiological responses of multiple CN neurons simultaneously while delivering drugs or stimulating the trigeminal ganglion. 

c. Role of the Trigeminal Ganlion-Cochlear Nucleus Projection in Tinnitus:
Injuries of the head and neck region can lead to the onset of tinnitus in patients with no hearing loss (Lockwood et al., 1998). Furthermore, two thirds of patients with tinnitus (including those with hearing loss) are able to modulate their tinnitus by activating peripheral nerves which innervate the skin or musculature of the face (Levin, 1999). These observations lead to the hypothesis that somatosensory input to auditory nuclei can play a role in the generation and/modulation of tinnitus (Lockwood et al., 1998; Levin, 1999). Adopting a "central theory of tinnitus", we propose that the CN (and perhaps other auditory nuclei) become sensitized as a result of a peripheral lesion (Møller , 1997), either in the ear, or in areas innervated by the trigeminal ganglion, such as facial skin or musculature. We have shown that the trigeminal ganglion innervates the CN and produces changes in neural firing of CN neurons. Therefore, a functional connection exists which could explain the observations that head and neck injuries can cause tinnitus and that patients can modulate their tinnitus through somatic activities. Abnormal activation of nerve fibers, as may occur in injuries of peripheral nerves, can elicit sustained activity in central neurons ( and Pinkerton, 1997). In the case of trigeminal ganglion innervation, head and neck injuries could alter the activity of those trigeminal ganglion fibers innervating the CN, resulting in a change in firing rate of CN neurons. Since patients can modulate an existing tinnitus through somatic stimulation, we will create tinnitus in guinea pigs using noise exposure that has previously been demonstrated to cause both an increase in the spontaneous rates and the perception of tinnitus (Kaltenbach and McCaslin, 1996a and b; Heffner and Kaltenbach, 1999). We will compare the population SRs with our initial studies (specific aim 1), to confirm the expected increase in SR. We will then electrically stimulate the trigeminal ganglion and examine the changes produced in the SRs of neurons in VCN and DCN.