Many previous studies have shown significant neurotrophic effects of intracochlear delivery of BDNF in preventing degeneration of cochlear spiral ganglion (SG) neurons after deafness in rodents and our laboratory has shown similar results in developing cats deafened prior to hearing onset. This study examined the morphology of the cochlear nucleus (CN) in a group of neonatally deafened cats from a previous study in which infusion of BDNF elicited a significant improvement in survival of the SG neurons. Five cats were deafened by systemic injections of neomycin sulfate (60 mg/kg, SQ, SID) starting one day after birth, and continuing for 16-18 days until auditory brainstem response (ABR) testing demonstrated profound bilateral hearing loss. The animals were implanted unilaterally at about 1 month of age using custom-designed electrodes with a drug-delivery cannula connected to an osmotic pump. BDNF (94 μg/ml; 0.25 μl/hr) was delivered for 10 weeks. The animals were euthanized and studied at 14-23 weeks of age. Consistent with the neurotrophic effects of BDNF on SG survival, the total CN volume in these animals was significantly larger on the BDNF-treated side than on the contralateral side. However, total CN volume, both ipsi- and contralateral to the implants in these deafened juvenile animals, was markedly smaller than the CN in normal adult animals, reflecting the severe effects of deafness on the central auditory system during development. Data from the individual major CN subdivisions (DCN, Dorsal Cochlear Nucleus; PVCN, Posteroventral Cochlear Nucleus; AVCN, Anteroventral Cochlear Nucleus) also were analyzed. A significant difference was observed between the BDNF-treated and control sides only in the AVCN. Measurements of the cross-sectional areas of spherical cells showed that cells were significantly larger in the AVCN ipsilateral to the implant than on the contralateral side. Further, the numerical density of spherical cells was significantly lower in the AVCN ipsilateral to the implant than on the contralateral side, consistent with the larger AVCN volume observed with BDNF treatment. Together, findings indicate significant neurotrophic effects of intracochlear BDNF infusion on the developing CN.

Both neurotrophic support and neural activity are required for normal postnatal development and survival of cochlear spiral ganglion (SG) neurons. Previous studies in neonatally deafened cats demonstrated that electrical stimulation (ES) from a cochlear implant can promote improved SG survival but does not completely prevent progressive neural degeneration. Neurotrophic agents combined with an implant may further improve neural survival. Short-term studies in rodents have shown that brain-derived neurotrophic factor (BDNF) promotes SG survival after deafness and may be additive to trophic effects of stimulation. Our recent study in neonatally deafened cats provided the first evidence of BDNF neurotrophic effects in the developing auditory system over a prolonged duration Leake et al. (J Comp Neurol 519:1526-1545, 2011). Ten weeks of intracochlear BDNF infusion starting at 4 weeks of age elicited significant improvement in SG survival and larger soma size compared to contralateral. In the present study, the same deafening and BDNF infusion procedures were combined with several months of ES from an implant. After combined BDNF + ES, a highly significant increase in SG numerical density (>50 % improvement re: contralateral) was observed, which was significantly greater than the neurotrophic effect seen with ES-only over comparable durations. Combined BDNF + ES also resulted in a higher density of myelinated radial nerve fibers within the osseous spiral lamina. However, substantial ectopic and disorganized sprouting of these fibers into the scala tympani also occurred, which may be deleterious to implant function. EABR thresholds improved (re: initial thresholds at time of implantation) on the chronically stimulated channels of the implant. Terminal electrophysiological studies recording in the inferior colliculus (IC) revealed that the basic cochleotopic organization was intact in the midbrain in all studied groups. In deafened controls or after ES-only, lower IC thresholds were correlated with more selective activation widths as expected, but no such correlation was seen after BDNF + ES due to much greater variability in both measures.

Previous cochlear implant studies using isolated electrical stimulus pulses in animal models have reported that intracochlear monopolar stimulus configurations elicit broad extents of neuronal activation within the central auditory system-much broader than the activation patterns produced by bipolar electrode pairs or acoustic tones. However, psychophysical and speech reception studies that use sustained pulse trains do not show clear performance differences for monopolar versus bipolar configurations. To test whether monopolar intracochlear stimulation can produce selective activation of the inferior colliculus, we measured activation widths along the tonotopic axis of the inferior colliculus for acoustic tones and 1,000-pulse/s electrical pulse trains in guinea pigs and cats. Electrical pulse trains were presented using an array of 6-12 stimulating electrodes distributed longitudinally on a space-filling silicone carrier positioned in the scala tympani of the cochlea. We found that for monopolar, bipolar, and acoustic stimuli, activation widths were significantly narrower for sustained responses than for the transient response to the stimulus onset. Furthermore, monopolar and bipolar stimuli elicited similar activation widths when compared at stimulus levels that produced similar peak spike rates. Surprisingly, we found that in guinea pigs, monopolar and bipolar stimuli produced narrower sustained activation than 60 dB sound pressure level acoustic tones when compared at stimulus levels that produced similar peak spike rates. Therefore, we conclude that intracochlear electrical stimulation using monopolar pulse trains can produce activation patterns that are at least as selective as bipolar or acoustic stimulation.