The  subunits of voltage-gated Na channels (Scnxb) regulate the gating of pore-forming ␣ subunits, as well as their trafficking and localization. In heterologous expression systems, 1, 2, and 3 subunits influence inactivation and persistent current in different ways. To test how the 4 protein regulates Na channel gating, we transfected 4 into HEK (human embryonic kidney) cells stably expressing Na V 1.1. Unlike a free peptide with a sequence from the 4 cytoplasmic domain, the full-length 4 protein did not block open channels. Instead, 4 expression favored open states by shifting activation curves negative, decreasing the slope of the inactivation curve, and increasing the percentage of noninactivating current. Consequently, persistent current tripled in amplitude. Expression of 1 or chimeric subunits including the 1 extracellular domain, however, favored inactivation. Coexpressing Na V 1.1 and 4 with 1 produced tiny persistent currents, indicating that 1 overcomes the effects of 4 in heterotrimeric channels. In contrast, 1 C121W , which contains an extracellular epilepsy-associated mutation, did not counteract the destabilization of inactivation by 4 and also required unusually large depolarizations for channel opening. In cultured hippocampal neurons transfected with 4, persistent current was slightly but significantly increased. Moreover, in 4-expressing neurons from Scn1b and Scn1b/Scn2b null mice, entry into inactivated states was slowed. These data suggest that 1 and 4 have antagonistic roles, the former favoring inactivation, and the latter favoring activation. Because increased Na channel availability may facilitate action potential firing, these results suggest a mechanism for seizure susceptibility of both mice and humans with disrupted 1 subunits.
Objectives To measure sound source localization in children who have sequential bilateral cochlear implants (BICIs); to determine if localization accuracy correlates with performance on a right-left discrimination task (i.e., spatial acuity); to determine if there is a measurable bilateral benefit on a sound source identification task (i.e., localization accuracy) by comparing performance under bilateral and unilateral listening conditions; to determine if sound source localization continues to improve with longer durations of bilateral experience. Design Two groups of children participated in this study: a group of 21 children who received BICIs in sequential procedures (5–14 years old) and a group of 7 typically-developing children with normal acoustic hearing (5 years old). Testing was conducted in a large sound-treated booth with loudspeakers positioned on a horizontal arc with a radius of 1.2 m. Children participated in two experiments that assessed spatial hearing skills. Spatial hearing acuity was assessed with a discrimination task in which listeners determined if a sound source was presented on the right or left side of center; the smallest angle at which performance on this task was reliably above chance is the minimum audible angle. Sound localization accuracy was assessed with a sound source identification task in which children identified the perceived position of the sound source from a multi-loudspeaker array (7 or 15); errors are quantified using the root-mean-square (RMS) error. Results Sound localization accuracy was highly variable among the children with BICIs, with RMS errors ranging from 19°–56°. Performance of the NH group, with RMS errors ranging from 9°–29° was significantly better. Within the BICI group, in 11/21 children RMS errors were smaller in the bilateral vs. unilateral listening condition, indicating bilateral benefit. There was a significant correlation between spatial acuity and sound localization accuracy (R2=0.68, p<0.01), suggesting that children who achieve small RMS errors tend to have the smallest MAAs. Although there was large intersubject variability, testing of 11 children in the BICI group at two sequential visits revealed a subset of children who show improvement in spatial hearing skills over time. Conclusions A subset of children who use sequential BICIs can acquire sound localization abilities, even after long intervals between activation of hearing in the first- and second-implanted ears. This suggests that children with activation of the second implant later in life may be capable of developing spatial hearing abilities. The large variability in performance among the children with BICIs suggests that maturation of sound localization abilities in children with BICIs may be dependent on various individual subject factors such as age of implantation and chronological age.
This report highlights research projects relevant to binaural and spatial hearing in adults and children. In the past decade we have made progress in understanding the impact of bilateral cochlear implants (BiCIs) on performance in adults and children. However, BiCI users typically do not perform as well as normal hearing (NH) listeners. In this paper we describe the benefits from BiCIs compared with a single CI, focusing on measures of spatial hearing and speech understanding in noise. We highlight the fact that in BiCI listening the devices in the two ears are not coordinated, thus binaural spatial cues that are available to NH listeners are not available to BiCI users. Through the use of research processors that carefully control the stimulus delivered to each electrode in each ear, we are able to preserve binaural cues and deliver them with fidelity to BiCI users. Results from those studies are discussed as well, with a focus on the effect of age at onset of deafness and plasticity of binaural sensitivity. Our work with children has expanded both in number of subjects tested and age range included. We have now tested dozens of children ranging in age from 2-14 years. Our findings suggest that spatial hearing abilities emerge with bilateral experience. While we originally focused on studying performance in free-field, where real world listening experiments are conducted, more recently we have begun to conduct studies under carefully controlled binaural stimulation conditions with children as well. We have also studied language acquisition and speech perception and production in young CI users. Finally, a running theme of this research program is the systematic investigation of the numerous factors that contribute to spatial and binaural hearing in BiCI users. By using CI simulations (with vocoders) and studying NH listeners under degraded listening conditions, we are able to tease apart limitations due to the hardware/software of the CI systems from limitations due to neural pathology.
Although cochlear implantation enables some children to attain age-appropriate speech and language development, communicative delays persist in others, and outcomes are quite variable and difficult to predict, even for children implanted early in life. To understand the neurobiological basis of this variability, we used presurgical neural morphological data obtained from MRI of individual pediatric cochlear implant (CI) candidates implanted younger than 3.5 years to predict variability of their speech-perception improvement after surgery. We first compared neuroanatomical density and spatial pattern similarity of CI candidates to that of age-matched children with normal hearing, which allowed us to detail neuroanatomical networks that were either affected or unaffected by auditory deprivation. This information enables us to build machine-learning models to predict the individual children's speech development following CI. We found that regions of the brain that were unaffected by auditory deprivation, in particular the auditory association and cognitive brain regions, produced the highest accuracy, specificity, and sensitivity in patient classification and the most precise prediction results. These findings suggest that brain areas unaffected by auditory deprivation are critical to developing closer to typical speech outcomes. Moreover, the findings suggest that determination of the type of neural reorganization caused by auditory deprivation before implantation is valuable for predicting post-CI language outcomes for young children.
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