Expansion of the clinical spectrum associated with AARS2‐related disorders

Biallelic pathogenic variants in AARS2, a gene encoding the mitochondrial alanyl‐tRNA synthetase, result in a spectrum of findings ranging from infantile cardiomyopathy to adult‐onset progressive leukoencephalopathy. In this article, we present three unrelated individuals with novel compound heterozygous pathogenic AARS2 variants underlying diverse clinical presentations. Patient 1 is a 51‐year‐old man with adult‐onset progressive cognitive, psychiatric, and motor decline and leukodystrophy. Patient 2 is a 34‐year‐old man with childhood‐onset progressive tremor followed by the development of polyneuropathy, ataxia, and mild cognitive and psychiatric decline without leukodystrophy on imaging. Patient 3 is a 57‐year‐old woman with childhood‐onset tremor and nystagmus which preceded dystonia, chorea, ataxia, depression, and cognitive decline marked by cerebellar atrophy and white matter disease. These cases expand the clinical heterogeneity of AARS2‐related disorders, given that the first and third case represent some of the oldest known survivors of this disease, the second is adult‐onset AARS2‐related neurological decline without leukodystrophy, and the third is biallelic AARS2‐related disorder involving a partial gene deletion.     

Sensitivity of auditory cortical neurons to the locations of leading and lagging sounds

We recorded unit activity in the auditory cortex (fields A1, A2, and PAF) of anesthetized cats while presenting paired clicks with variable locations and interstimulus delays (ISDs). In human listeners, such sounds elicit the precedence effect, in which localization of the lagging sound is impaired at ISDs less, similar10 ms. In the present study, neurons typically responded to the leading stimulus with a brief burst of spikes, followed by suppression lasting 100-200 ms. At an ISD of 20 ms, at which listeners report a distinct lagging sound, only 12% of units showed discrete lagging responses. Long-lasting suppression was found in all sampled cortical fields, for all leading and lagging locations, and at all sound levels. Recordings from awake cats confirmed this long-lasting suppression in the absence of anesthesia, although recovery from suppression was faster in the awake state. Despite the lack of discrete lagging responses at delays of 1-20 ms, the spike patterns of 40% of units varied systematically with ISD, suggesting that many neurons represent lagging sounds implicitly in their temporal firing patterns rather than explicitly in discrete responses. We estimated the amount of location-related information transmitted by spike patterns at delays of 1-16 ms under conditions in which we varied only the leading location or only the lagging location. Consistent with human psychophysical results, transmission of information about the leading location was high at all ISDs. Unlike listeners, however, transmission of information about the lagging location remained low, even at ISDs of 12-16 ms.     

Changes in external ear position modify the spatial tuning of auditory units in the cat's superior colliculus

This study examines the influence of external ear position on the auditory spatial tuning of single units in the superior colliculus of the anesthetized cat. Unit responses to broad-band stimuli presented in a free sound field were measured with the external ears in a forward symmetrical position or with one or the other ear turned 40 degrees to the side; the ears are referred to as contra- or ipsilateral with respect to the side of the recording site. Changes in the position of either ear modified the spatial tuning of units. The region of space from which a stimulus was most effective in activating a unit is referred to as the unit's "best area". Whenever the contralateral ear was turned to the side, best areas shifted peripherally and somewhat upward, roughly in proportion to the magnitude of the change in ear position. A turn of the ipsilateral ear to the side had more variable effects, but best areas generally shifted frontally. Best areas located between approximately 10 and 40 degrees contralateral when the ears were forward were least affected by changes in ipsilateral ear position. Changes in ear position also modified the maximum response rates of many units. Units with best areas located within approximately 20 degrees of the frontal midline when the ears were forward exhibited a pronounced decrease in responsiveness when either ear was turned. Units with more peripheral best areas tended to show no change or a slight increase in responsiveness. The influence of ear position on the directionality of the external ears was determined by mapping the cochlear microphonic response to tones or one-third-octave bands of noise before and after turning the ear. When the ears were forward, maximum interaural intensity differences (IIDs) were produced by high-frequency sound sources (greater than or equal to 20 kHz) located 20-40 degrees from the frontal midline and by lower frequency sources located further peripherally. The influence of ear position on the locations from which maximum IIDs were produced was similar to the influence of ear position on unit best areas. Changes in ipsilateral ear position had different effects on high- and low-frequency IIDs that were comparable with the effects of changes in ear position on frontally and peripherally located best areas, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)     

Cochlear implant electrode configuration effects on activation threshold and tonotopic selectivity

The multichannel design of contemporary cochlear implants (CIs) is predicated on the assumption that each channel activates a relatively restricted and independent sector of the deaf auditory nerve array, just as a sound within a restricted frequency band activates a restricted region of the normal cochlea The independence of CI channels, however, is limited; and the factors that determine their independence, the relative overlap of the activity patterns that they evoke, are poorly understood. In this study, we evaluate the spread of activity evoked by cochlear implant channels by monitoring activity at 16 sites along the tonotopic axis of the guinea pig inferior colliculus (IC). "Spatial tuning curves" (STCs) measured in this way serve as an estimate of activation spread within the cochlea and the ascending auditory pathways. We contrast natural stimulation using acoustic tones with two kinds of electrical stimulation either (1) a loose fitting banded array consisting of a cylindrical silicone elastomer carrier with a linear series of ring contacts; or (2) a space-filling array consisting of a tapered silicone elastomer carrier that is designed to fit snugly into the guinea pig scala tympani with a linear series of ball contacts positioned along it Spatial tuning curves evoked by individual acoustic tones, and by activation of each contact of each array as a monopole, bipole or tripole were recorded. Several channel configurations and a wide range of electrode separations were tested for each array, and their thresholds and selectivity were estimated. The results indicate that the tapered space-filling arrays evoked more restricted activity patterns at lower thresholds than did the banded arrays. Monopolar stimulation (one intracochlear contact activated with an extracochlear return) using either array evoked broad activation patterns that involved the entire recording array at current levels <6dBSL, but at relatively low thresholds. Bi- and tri-polar configurations of both array types evoked more restricted activity patterns, but their thresholds were higher than those of monopolar configurations. Bipolar and tripolar configurations with closely spaced contacts evoked activity patterns that were comparable to those evoked by pure tones. As the spacing of bipolar electrodes was increased (separations >1mm), the activity patterns became broader and evoked patterns with two distinct threshold minima, one associated with each contact.     

Intraneural stimulation for auditory prosthesis: modiolar trunk and intracranial stimulation sites

We have demonstrated recently in an animal model that stimulation with a penetrating auditory nerve electrode array is a feasible means of activating the ascending auditory pathway for auditory prosthesis. Compared to a conventional intrascalar cochlear implant, intraneural stimulation provides access to fibers serving a broader frequency range, activation of more tonotopically restricted fiber populations, lower thresholds, and reduced interference between simultaneously stimulated channels. The spread of excitation by a single intraneural electrode is broader than that by an acoustic tone but narrower than that by a cochlear-implant electrode. In the present study, we compare in an animal model two sites of intraneural stimulation: the modiolar trunk of the nerve accessed using a transcochlear approach and the intracranial portion of the nerve accessed using a posterior fossa approach. The two stimulation sites offer very similar thresholds, spread of activation, and dynamic ranges. The intracranial site differed in that there was greater between-animal variation in tonotopic patterns. We discuss the implications of these results for possible improvements in hearing prosthesis for human subjects.     

Temporal Pitch Sensitivity in an Animal Model: Psychophysics and Scalp Recordings

Journal of the Association for Research in Otolaryngology - Cochlear implant (CI) users show limited sensitivity to the temporal pitch conveyed by electric stimulation, contributing to impaired...