Rett syndrome, a genetic disorder caused by mutations in the X-linked Mecp2 gene, is characterized by typical early development followed by rapid developmental regression between 6 and 18 months of age. Affected individuals exhibit seizures, cognitive impairments, motor deficits, and difficulties in speech-language processing. Post-regression rodent models of Rett syndrome have been observed to follow similar regression, presenting sensory processing difficulties during auditory discrimination tasks, as well as degraded auditory cortical responses. However, little is known about the auditory processing prior to the onset of regression symptoms. This study documents primary auditory cortex responses to sounds in pre-regression heterozygous Mecp2 rats compared to age-matched wild-type controls. Pre-regression Mecp2 rats exhibited weaker and delayed cortical responses to speech sounds, alterations in the temporal processing of rapidly presented sounds, and an overrepresentation of high-frequency tones in conjunction with a reduction in the cortical representation of low-frequency tones. Despite these impairments, pre-regression Mecp2 rats demonstrated intact neural classifier performance for consonant discrimination, which is consistent with the high accuracy these pre-regression Mecp2 rats exhibit for a behavioral consonant discrimination task. These findings reveal that cortical deficits in Mecp2 rats emerge before behavioral regression. Insights derived from this study expand upon the current understanding of the progression of sensory processing deficits in Rett syndrome and other neurodevelopmental disorders and lay the groundwork for the development of therapeutics for this population.

IntroductionPrenatal exposure to valproic acid (VPA) is a common environmental cause of autism spectrum disorder (ASD) and often leads to expressive and receptive language impairments. Similar communication difficulties among individuals with ASD are often linked to abnormal subcortical and cortical sound processing. Rodents prenatally exposed to VPA exhibit degraded cortical responses to speech and an impaired ability to behaviorally discriminate speech sounds.MethodsWe sought to determine whether sound processing could be restored with paired vagus nerve stimulation (VNS). In a first experiment, we evaluated whether sound-paired VNS would alter in vivo extracellular multi-unit responses to tones, noise burst trains, and speech sounds from the anterior auditory field. We next sought to evaluate whether improvements to neural sound processing led to improvements in sound discrimination ability. In a second experiment, rats underwent go/no-go sound discrimination testing where VNS was paired with successful trials.ResultsWe found that VPA-exposed rats had degraded spectral, temporal, and speech sound processing compared to saline-exposed control rats. VPA-exposed rats which received sound-paired VNS exhibited a partial or full restoration of processing across sound types. However, across several sound discrimination tasks, we did not observe changes in behavioral performance in response to prenatal exposure to VPA or VNS.DiscussionOur study is the first to show that speech-paired VNS leads to a generalized improvement in cortical sound processing across sound types, rescuing neural processing among VPA-exposed rats. These results provide a framework for future studies to develop VNS-based interventions for communication disorders.

Receptive language deficits and aberrant auditory processing are often observed in individuals with autism spectrum disorders (ASD). Symptoms associated with ASD are observed in rodents prenatally exposed to valproic acid (VPA), including deficits in speech sound discrimination ability. These perceptual difficulties are accompanied by changes in neural activity patterns. In both cortical and subcortical levels of the auditory pathway, VPA-exposed rats have impaired responses to speech sounds. Developing a method to improve these neural deficits throughout the auditory pathway is necessary. The purpose of this study was to investigate the ability of vagus nerve stimulation (VNS) paired with sounds to restore degraded inferior colliculus (IC) responses in VPA-exposed rats. VNS paired with the speech sound "dad" was presented to a group of VPA-exposed rats 300 times per day for 20 days. Another group of VPA-exposed rats were presented with VNS paired with multiple tone frequencies for 20 days. The IC responses were recorded from 19 saline-exposed control rats and 18 VPA-exposed with no VNS, 8 VNS-speech paired VPA-exposed, and 7 VNS-tone paired VPA-exposed female and male rats. Pairing VNS with tones increased the IC response strength to speech sounds by 44% compared to VPA-exposed rats alone. Contrarily, VNS-speech pairing significantly decreased the IC response to speech compared with VPA-exposed rats by 5%. The present research indicates that pairing VNS with tones improved sound processing in rats exposed to VPA and suggests that auditory processing can be improved through targeted plasticity.NEW & NOTEWORTHY Pairing vagus nerve stimulation (VNS) with sounds has improved auditory processing in the auditory cortex of normal-hearing rats and autism models of rats. This study tests the ability of VNS-sound pairing to restore auditory processing in the inferior colliculus (IC) of valproic acid (VPA)-exposed rats. Pairing VNS with tones significantly reversed the degraded sound processing in the IC in VPA-exposed rats. The findings provide evidence that auditory processing in autism rat models can be improved through VNS.

Intense noise exposure is a leading cause of hearing loss, which results in degraded speech sound discrimination ability, particularly in noisy environments. The development of an animal model of speech discrimination deficits due to noise induced hearing loss (NIHL) would enable testing of potential therapies to improve speech sound processing. Rats can accurately detect and discriminate human speech sounds in the presence of quiet and background noise. Further, it is known that profound hearing loss results in functional deafness in rats. In this study, we generated rats with a range of impairments which model the large range of hearing impairments observed in patients with NIHL. One month after noise exposure, we stratified rats into three distinct deficit groups based on their auditory brainstem response (ABR) thresholds. These groups exhibited markedly different behavioral outcomes across a range of tasks. Rats with moderate hearing loss (30 dB shifts in ABR threshold) were not impaired in speech sound detection or discrimination. Rats with severe hearing loss (55 dB shifts) were impaired at discriminating speech sounds in the presence of background noise. Rats with profound hearing loss (70 dB shifts) were unable to detect and discriminate speech sounds above chance level performance. Across groups, ABR threshold accurately predicted behavioral performance on all tasks. This model of long-term impaired speech discrimination in noise, demonstrated by the severe group, mimics the most common clinical presentation of NIHL and represents a useful tool for developing and improving interventions to target restoration of hearing.

Hearing loss is a very common and often debilitating neurological disorder, estimated to affect over 5% of the population. A major source of disability related to hearing loss stems from deficits in speech processing. Assistive devices, such as hearing aids, can yield modest improvements in speech perception, but these devices often provide inadequate utility in complex, challenging environments. We have developed a new approach to drive robust, specific plasticity that substantially enhances recovery after neurological damage. This strategy uses brief bursts of vagus nerve stimulation (VNS) paired with sound presentation. Like humans, rats are significantly impaired in their ability to accurately discriminate speech sounds following intense noise exposure. Additionally, noise trauma results in substantial maladaptive plasticity in multiple auditory structures. In these experiments, we test the hypothesis that VNS paired with sound therapy, 300 times per day for 20 days, will reverse maladaptive plasticity and restore auditory processing. Following the last day of VNS-sound pairing, the reversal of maladaptive plasticity is tested through behavioral discrimination ability, auditory brainstem responses (ABR), and auditory cortex responses. The successful development of adjuvant therapies to restore speech processing has real potential to yield tangible benefits for millions suffering from hearing loss.

While the N170 to printed words in alphabetic scripts is consistently left-lateralized, the available evidence on logographic scripts is much less consistent. Here, we examined the extent to which use of single-character (e.g., 121) versus compound-character (e.g., 2 1) words in a logographic script could account for differences in the laterality of early neural responses in fluent readers. Participants included both fluent Kanji readers (n = 17) as well as naive Kanji readers (n = 19), in order to separate out differences due to low-level physical differences between stimuli. While fluent Kanji readers showed a larger amplitude N170 overall relative to naive readers, this expertise effect was bilateral, rather than left-lateralized as is common with alphabetic scripts. Trend-level differences in laterality were observed at the earlier P1 response, which has not been extensively examined in previous studies of logographic script reading, with naive readers only tending to show right-lateralization across both single-and compound-character Kanji words. Both participant groups differentiated single and compound Kanji words, but contrary to predictions these effects were bilateral and evident during different stages of processing in each group. Among naive readers, compound Kanji elicited a larger amplitude P1, suggesting influence on early perceptual processing, whereas among fluent readers, these differences were not apparent until the later N170. Taken together, findings from the present study indicate that lowlevel visual characteristics and perceptual expertise interact during the specialization of neural circuits for print, with implications for theories of lateralization of neural circuits for print.