Central auditory maturation and behavioral outcomes after cochlear implantation in prelingual auditory neuropathy spectrum disorder related to OTOF variants (DFNB9): Lessons from pilot study

Abstract

The cortical auditory evoked potential (CAEP)-based P1 component acts as a biomarker for cochlear implantation (CI) outcomes in children with auditory neuropathy spectrum disorder (ANSD). To date, early intervention primarily before the age of two years and six months of CI usage is necessary and sufficient to achieve age-appropriate cortical maturation and good prognosis. However, varying degrees of neural dyssynchrony, resulting from the etiological heterogeneity of ANSD, may preclude uniform application of this hypothesis to ensure auditory cortical maturation. Thus, a focused evaluation of those carrying OTOF variants, which may be the salient molecular etiology of prelingual ANSD, would circumvent the issue of heterogeneity. Here, we sought to provide a much better understanding of the brain perspectives (i.e., P1 maturation) in OTOF-associated ANSD subjects and set the stage for an optimal strategy to enhance language development. We conducted a preliminary study comprising 10 subjects diagnosed with OTOF-related ANSD who underwent CI by a single surgeon and subsequently underwent measurements of the P1 component. We observed that DFNB9 subjects who received CI after 2 years of age exhibited "absent" or "anomalous" P1 components that correspond to delayed language development. However, timely implantation, as early as 12 months of age per se, might be insufficient to achieve age-appropriate cortical maturation of DFNB9 in cases with six to seven months of device use. This suggests the importance of sustained rehabilitation in DFNB9 than in other etiologies. Indeed, an additional follow-up study showed that a reduction in P1 latency was linked to an improvement in auditory performance. Collectively, our results suggest that central auditory maturation and successful outcome of CI in DFNB9 may have more demanding requirements, that is, earlier implantation and more sustained rehabilitation. We believe that the current study opens a new path toward genome-based neuroimaging in the field of hearing research.

Fig 1. Individual cortical auditory-evoked potential in groups 1, 2, and 3.

Each patient in all groups showed typical P1 with varying latencies, except the last two patients in group 3, who displayed anomalous (absent) P1 morphology.

Fig 2. P1 latency as a function of age for 10 patients fit with CI.

Circles indicate latencies in the patients within the normal P1 range after sufficient use with early (pink circles) or late (green squares with no border line) implantation. Hexagons indicate latencies in patients with delayed P1 response who had insufficient use of CI in spite of early stimulation. Green squares with black borderline indicate latencies in the patients with late implantation and insufficient use resulting in abnormal/absent P1 response. The upper and lower solid lines indicate the 95% confidence intervals for the 190 normal-hearing data (Sharma et al. 2002a).

Fig 3. Longitudinal observation of the P1 latency in subjects 5 and 6.

(A) A decrease of 23 msec in subject 5 and a decrease of 38 msec in subject 6 during the follow-up test. (B) The trajectories of P1 latency superimposed on the line of best-fit with the 95% confidence interval for the 190 normal-hearing listeners (Sharma et al. 2002a). The empty symbols indicate the first test, and the filled symbols indicate the second test.

Fig 4. Correlation analyses of the auditory performance and P1 latency.

(A, B) The Z-scores were found to be inversely correlated with preoperative CAP (r = -0.758, P = 0.02) and SIR (r = -0.840, P = 0.005). (C) A better Z-score as reflected by shorter P1 latency did not correlate with a higher postoperative IT-MAIS score, although a very weak tendency was observed (r = -0.536, P = 0.17). (D) The Z-scores were found to be inversely correlated with the follow-up duration between CI and CAEP testing, observed only in subjects included in groups 1 and 2 (r = -0.944, P = 0.005). The grey dotted color indicates the 95% confidence interval.