Acute cochlear nucleus compression alters tuning properties of inferior colliculus neurons.

Auditory brainstem implants (ABI) have been used in neurofibromatosis type 2 (NF2) patients in an attempt to restore hearing sensation, with limited clinical success. Factors associated with poor clinical outcomes for NF2 ABI patients include larger tumour size, longer duration of hearing loss, and brainstem distortion and/or deformation caused by tumours that compress the brainstem. The present study investigated changes in tuning properties of inferior colliculus (IC) neurons following compression of the contralateral cochlear nucleus (CN). The left CN in adult rats (n = 8) was exposed and a 32-channel acute recording probe inserted along the tonotopic gradient of the right IC. In 4 animals, an ethylene vinyl acetate bead was applied to the exposed CN. Three recordings were made corresponding to T(1) = 0 min (before compression), T(2) = 45 min (during compression) and T(3) = 225 min (following bead removal/recovery). Recordings consisted of a response area protocol using pure tones of various frequencies and intensities (1-44 kHz; 10-70 dB SPL) to determine the characteristic frequency for each probe site. Compression of the CN led to sharpened tuning curves, decreased spike rate, and increased threshold and characteristic frequency in the IC. Reversal of compression enabled these variables, excluding threshold, to recover to baseline. NF2 patients may have poorer ABI performance due to damage to the physical structure of the CN, resulting in alterations to the tonotopic organisation of the auditory pathway which may complicate ABI implantation and activation.

An in vivo investigation of first spike latencies in the inferior colliculus in response to multichannel penetrating auditory brainstem implant stimulation.

The cochlear nucleus (CN) is the first auditory processing site within the brain and the target location of the auditory brainstem implant (ABI), which provides speech perception to patients who cannot benefit from a cochlear implant (CI). Although there is variance between ABI recipient speech performance outcomes, performance is typically low compared to CI recipients. Temporal aspects of neural firing such as first spike latency (FSL) are thought to code for many speech features; however, no studies have investigated FSL from CN stimulation. Consequently, ABIs currently do not incorporate CN-specific temporal information. We therefore systematically investigated inferior colliculus (IC) neuron's FSL response to frequency-specific electrical stimulation of the CN in rats. The range of FSLs from electrical stimulation of many neurons indicates that both monosynaptic and polysynaptic pathways were activated, suggesting initial activation of multiple CN neuron types. Electrical FSLs for a single neuron did not change irrespective of the CN frequency region stimulated, indicating highly segregated projections from the CN to the IC. These results present the first evidence of temporal responses to frequency-specific CN electrical stimulation. Understanding the auditory system's temporal response to electrical stimulation will help in future ABI designs and stimulation strategies.

Inferior colliculus responses to dual-site intralamina stimulation in the ventral cochlear nucleus.

A major limitation of the present auditory brainstem implant (ABI) is its inability to access the tonotopic organization of the ventral cochlear nucleus (VCN). A previous study by our group indicated that stimulation of single sites within a given VCN frequency region did not always elicit frequency-specific responses within the central nucleus of the inferior colliculus (CIC) and in some cases did not elicit a response at all. For this study, we hypothesized that sequential stimulation (with a short interpulse delay of 320 µsec) of two VCN sites in similar frequency regions would enhance responsiveness in CIC neurons. Multiunit neural recordings in response to pure tones were obtained at 58 VCN and 164 CIC sites in anesthetized rats. Among the 58 VCN sites, 39 pairs of sites with similar characteristic frequencies were chosen for electrical stimulation. Each member of a VCN pair was electrically stimulated individually, followed by sequential stimulation of the pair, while recording CIC responses. On average, CIC sites were found to respond to dual-site VCN stimulation with significantly lower thresholds, wider dynamic ranges, a greater extent of activation with increasing current levels, and a higher degree of frequency specificity compared with single-site stimulation. Although these effects were positive for the most part, in some cases dual-site stimulation resulted in increased CIC thresholds and decreased dynamic ranges, extent of activation, and frequency specificity. The results suggest that multisite stimulation within VCN isofrequency laminae using penetrating electrodes could significantly improve ABI stimulation strategies and implant performance.

Precocious terminal differentiation of premigratory limb muscle precursor cells requires positive signalling.

The timing of myogenic differentiation of hypaxial muscle precursor cells in the somite lags behind that of epaxial precursors. Two hypotheses have been proposed to explain this delay. One attributes the delay to the presence of negative-acting signals from the lateral plate mesoderm adjacent to the hypaxial muscle precursor cells located in the ventrolateral lip of the somitic dermomyotome (Pourquié et al. [1995] Proc. Natl. Acad. Sci. USA 92:3219-3223). The second attributes the delay to an absence of positive-acting inductive signals, similar to those from the axial structures that induce epaxial myotome development (Pownall et al. [1996] Development 122:1475-1488). Because both studies relied principally upon changes in the expression pattern of mRNAs specific to early muscle precursor cell markers, we revisited these experiments using two methods to assess muscle terminal differentiation. First, injection of fluorescent dyes before surgery was used to determine whether ventrolateral lip cells transform from epithelial cells to elongated myocytes. Second, an antibody to a terminal differentiation marker and a new monoclonal antibody that recognises avian and mammalian Pax3 were used for immunohistochemistry to assess the transition from precursor cell to myocyte. The results support both hypotheses and show further that placing axial structures adjacent to the somite ventrolateral lip induces an axial pattern of myocyte terminal differentiation and elongation.