Cortical Neuroplasticity in Hearing Loss

Overview and Methodology for Studying Neuroplasticity in Pediatric Hearing Loss

Pediatric hearing loss is a very prevalent chronic condition in children, affecting 1 to 3 per 1000 children in the United States. Pediatric hearing loss may be congenital or acquired. Among children, genetic forms of hearing loss account for more than 50% of cases, whereas in utero infections, meningitis, hyperbilirubinemia, ototoxic drug exposure, trauma, and other conditions contribute to the remainder of nongenetic cases. Untreated hearing loss during development may have long-lasting effects. For example, pediatric hearing loss has been linked to receptive and expressive delays in oral language acquisition, delays in educational achievement, behavioral and psychosocial problems, negative impacts on quality of life, and a weighty economic burden from a societal and socio-economic standpoint.

Many forms of audiological intervention exist for the treatment of pediatric hearing loss. Hearing aids and CIs are two of the most common forms of intervention. CIs are used to treat deafness while hearing aids are small electronic devices considered a treatment option for lesser degrees of hearing loss. Hearing aids consist of a microphone, amplifier, and receiver. Hearing aids amplify and convert acoustic sound from the environment into digital signals sent to the ear via the air conduction pathway, providing enhanced audibility. A CI is a biomedical device consisting of an internally implanted receiver/stimulator coupled to an external processor. The CI bypasses the deficient or damaged portions of the inner ear and provides direct electrical stimulation of the auditory nerve, thus restoring hearing in more severe cases of more sensorineural hearing loss. These clinical interventions have provided researchers with a natural framework in which they can study the effects of auditory deprivation on the brain, and the ability for these interventions to restore or reverse deprivation-induced changes in neuroplasticity.

Many neuroimaging methods are used to study neuroplasticity in hearing loss in humans: functional magnetic resonance imaging (fMRI), functional near-infrared spectroscopy (fNIRs), positron emission tomography (PET), magnetoencephalography (MEG), and EEG, and each method has significant value. In this chapter, we focus primarily on the utilization of EEG for several reasons. First, EEG is not susceptible to the same types of acoustic artifact during auditory experiments as other neuroimaging techniques, and is very compatible with clinical populations with CI. Second, EEG provides essential millisecond-level temporal resolution superior to other neuroimaging methods, providing detailed timing information about neural processing along the auditory pathway. And finally, EEG is noninvasive, inexpensive, and is relatively easy to apply, making it feasible on both pediatric and adult populations in a clinical setting. In addition to EEG recordings in humans, we will discuss evidence from other neuroimaging methods (e.g., fMRI, PET) and near-field EEG recordings in animal models, which provide us with more detailed spatial resolution about sensory processing in specific brain regions.

Typical Development of the Central Auditory Pathways

While the field of otology is primarily concerned with diagnosis and treatment of disorders of the auditory system, it is useful to first understand neuroplasticity of the central auditory system under the conditions of typical development. During normal development, the central auditory pathways are formed via a series of intricate, sequenced, and time-dependent processes. Both intrinsic neuroplasticity and extrinsic neuroplasticity play a role in typical development of the central auditory pathways. Intrinsic neuroplasticity refers to strictly regulated genetic, molecular, and cellular processes that occur early in development. These intrinsic processes help regulate neurogenesis (the creation of new neurons), migration, differentiation, and synaptogenesis (the creation of new synapses) in the developing auditory cortex. For instance, synaptogenesis within auditory cortex begins in the fetal brain by the 27th week of gestation. Rapid myelination of axons in the auditory cortex peaks within the first 3 months of life, then continues at a slower rate into childhood. By 1 year after birth, all 6 layers of the auditory cortex can be reliably differentiated.

Extrinsic neuroplasticity refers to experience-driven forces (e.g., auditory input), which take place during development and across the human lifespan. Over the first 4 to 12 years of life, auditory stimulation guides the process of synaptic pruning, or refinement, of the central auditory pathways. During this developmental period, the age-old maxim in neuroscience, “neurons that fire together wire together,” holds true. That is, synapses or neuronal connections receiving repetitious and consistent auditory input are strengthened, while unstimulated or underutilized connections are eliminated. Repetitious and consistent auditory stimulation also leads to the long-term potentiation (LTP) and long-term depression (LDP) (strengthening or weakening, respectively) of existing synapses, processes which are known to play a vital role in learning and memory. In the developing auditory cortex, feed-forward connections (e.g., thalamo-cortical connections)—which are thought to be largely intrinsically regulated—develop first. Later on, feed-back cortical connections (e.g., cortico-thalamic connections)—which are thought to be more extrinsically regulated—start developing. In this sense, while a structural and rudimentary neuronal framework is already in place by birth, the central auditory pathways are continually refined through repetitious and consistent auditory experience during infancy and childhood.

Biomarkers of Central Auditory Development in Children

The term biomarker is defined by the National Institutes of Health as a “characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.” The P1 CAEP biomarker is an EEG event-related potential (ERP) recorded in response to an auditory stimulus. The P1 CAEP biomarker reflects maturation in synaptic efficiency along the central auditory pathways at the level of the primary auditory cortex (A1) and the thalamus ( Fig. 132.1A4 ). The P1 CAEP response is the dominant response in infants and young children (see Fig. 132.1A1 ), occurring at a latency of approximately 300 ms. As children age, the P1 latency decreases dramatically at first and then gradually (coinciding with the aforementioned intrinsically-regulated and extrinsically-regulated developmental changes over the first few years of life), until eventually reaching adult-like latency between 12 and 16 years of age.

Our laboratory has established normative data for P1 CAEP latency in typically developing, normal hearing children, from infancy through adolescence, providing a basis by which we can examine the effects of auditory disorders such as deafness and hearing loss. Fig. 132.1A5 depicts P1 CAEP latencies in individual normal hearing children as a function of age. The top and bottom black lines in Fig. 132.1A5 represent the 5% and 95% confidence intervals for normal P1 CAEP latency, where P1 latency values falling outside of the top black line indicate significant delays in maturation of the central auditory pathways with 95% confidence. Because P1 CAEP latency varies with age, it can be used as a clinical biomarker of the maturation of the auditory cortex. That is, by comparing P1 latencies in clinical populations with hearing loss to these normative values, we can determine whether the central auditory pathways are maturing at an age-appropriate rate, or whether there are statistically significant delays in typical maturation of these pathways. In many previous studies, we have utilized the P1 CAEP biomarker to evaluate the efficacy of intervention with hearing aids, to establish candidacy for CI, and to monitor development of the central auditory pathways.

The morphology of the CAEP response can also be used as an objective indicator of the maturational status of the central auditory pathways. While the P1 response is the predominant waveform component in the CAEP response in infants (see Fig. 132.1A1 ), as a child ages, extrinsic input to the auditory system drives higher-level development of the central auditory pathways and eventually the emergence of two later waveforms, the N1 and P2 components, can be observed (see Fig. 132.1A2 and 132.1A3 ). The N1 and P2 components are negative-going and positive-going peaks in the CAEP waveform following the P1 response in time. While the P1 response reflects cortical processing at the primary auditory cortex (A1) and thalamus, the N1 and P2 components reflect higher-level auditory cortical processing at the level of secondary auditory cortex (A2), cortico-cortical processing between areas of the auditory cortex, and feedback (cortico-thalamic) processing between A2, A1, and the thalamus (see Fig. 132.1A4 ).

Our laboratory and other laboratories have systematically examined the emergence of the N1 CAEP response under typical development. For example, in a study by Campbell, Cardon, and Sharma (2015), we evaluated the occurrence of the N1 CAEP response in typically developing, normal hearing children at various ages. Results from this study indicate that the N1 CAEP response was present in approximately 57% and 71% in normal hearing children between ages 3 to 6 years and ages 6 to 9 years, respectively. In children 9 to 12 and 12 to 15 years of age, 100% of these children exhibited present N1 CAEP responses. Thus, the morphology of the CAEP response (e.g., presence or absence of the N1 CAEP component) can be used to assess whether higher-level auditory cortical maturation is occurring at a normal rate in clinical populations with hearing loss.