Aging Brain and Hearing: A Mini-Review

Brain reserve is a topic of great interest to researchers in aging medicine field. Some individuals retain well-preserved cognitive function until they fulfill their lives despite significant brain pathology. One concept that explains this paradox is the reserve hypothesis, including brain reserve that assumes a virtual ability to mitigate the effects of neuropathological changes and reduce the effects on clinical symptoms flexibly and efficiently by making complete use of the cognitive and compensatory processes. One of the surrogate measures of reserve capacity is brain volume. Evidence that dementia and hearing loss are interrelated has been steadily accumulating, and age-related hearing loss is one of the most promising modifiable risk factors of dementia. Research focused on the imaging analysis of the aged brain relative to auditory function has been gradually increasing. Several morphological studies have been conducted to understand the relationship between hearing loss and brain volume. In this mini review, we provide a brief overview of the concept of brain reserve, followed by a small review of studies addressing brain morphology and hearing loss/hearing compensation, including the findings obtained from our previous study that hearing loss after middle age could affect hippocampal and primary auditory cortex atrophy.

Long-Term Enhancement of NMDA Receptor Function in Inhibitory Neurons Preferentially Modulates Potassium Channels and Cell Adhesion Molecules

Effectively enhancing the activity of inhibitory neurons has great therapeutic potentials since their reduced function/activity has significant contributions to pathology in various brain diseases. We showed previously that NMDAR positive allosteric modulator GNE-8324 and M-8324 selectively increase NMDAR activity on the inhibitory neurons and elevates their activity in vitro and in vivo. Here we examined the impact of long-term administering M-8324 on the functions and transcriptional profiling of parvalbumin-containing neurons in two representative brain regions, primary auditory cortex (Au1) and prelimbic prefrontal cortex (PrL-PFC). We found small changes in key electrophysiological parameters and RNA levels of neurotransmitter receptors, Na+ and Ca2+ channels. In contrast, large differences in cell adhesion molecules and K+ channels were found between Au1 and PrL-PFC in drug-naïve mice, and differences in cell adhesion molecules became much smaller after M-8324 treatment. There was also minor impact of M-8324 on cell cycle and apoptosis, suggesting a fine safety profile.

Different excitation-inhibition correlations between spontaneous and tone-evoked activity in primary auditory cortex neurons

Tone-evoked synaptic excitation and inhibition are highly correlated in many neurons with V-shaped tuning curves in the primary auditory cortex of pentobarbital-anesthetized rats. In contrast, there is less correlation between spontaneous excitation and inhibition in visual cortex neurons under the same anesthetic conditions. However, it was not known whether the primary auditory cortex resembles visual cortex in having spontaneous excitation and inhibition that is less correlated than tone-evoked excitation and inhibition. Here we report whole-cell voltage-clamp measurements of spontaneous excitation and inhibition in primary auditory cortex neurons of pentobarbital-anesthetized rats. The larger excursions of both spontaneous excitatory and inhibitory currents appeared to consist of distinct events, with the inhibitory event rate typically lower than the excitatory event rate. We use the ratio of the excitatory event rate to the inhibitory event rate, and the assumption that the excitatory and inhibitory synaptic currents can each be reasonably described as a filtered Poisson process, to estimate the maximum spontaneous excitatory-inhibitory correlation for each neuron. In a subset of neurons, we also measured tone-evoked excitation and inhibition. In neurons with V-shaped tuning curves, although tone-evoked excitation and inhibition were highly correlated, the spontaneous inhibitory event rate was typically sufficiently lower than the spontaneous excitatory event rate to indicate a lower excitatory-inhibitory correlation for spontaneous activity than for tone-evoked responses.

Layer-Specific Intracortical Amplification Shortens the Lifetime of Thalamocortical Repetition Suppression in Auditory Cortex

Neural adaptation in sensory cortex serves important sensory functions, and is altered by various neurophsychiatric diseases. Although adaptation is a widely studied phenomenon, much remains unknown about its underlying mechanisms on a cortical circuit level. Here, we investigated repetition suppression as fundamental aspect of adaptation by layer-specific current source density analyses of synaptic mass activities in primary auditory cortex of anesthetized Mongolian gerbils (Meriones unguiculatus). We disentangled different synaptic contributions to repetition suppression in different cortical layers, and separated thalamocortical from intracortical inputs by cortical silencing with GABAA-agonist muscimol. We systematically varied stimulus onset intervals and employed statistically robust model fitting based on bootstrapping to determine the full suppression kinetics of different synaptic responses in the steady state. Whereas thalamocortical input to granular and infragranular layers was governed by longer lasting repetition suppression, most likely reflecting depression of thalamocortical synapses, intracortical amplification in granular layers shortened the lifetime of suppression by re-enhancing granular responses mainly through synchronization of synaptic events. With increasing latency, the shorter lasting suppression kinetics observed in granular layers at early latencies (<100ms) passed on to deeper layers replacing the longer lasting infragranular suppression kinetics. Granular circuit dynamics can therefore actively shape neural adaptation across cortical layers.

Music-selective cortex is sensitive to structure in both pitch and time

Converging evidence suggests that neural populations within human non-primary auditory cortex respond selectively to music. These neural populations respond strongly to a wide range of music stimuli, and weakly to other natural sounds and to synthetic control stimuli matched to music in many acoustic properties, suggesting that they are driven by high-level musical features. What are these features? Here we used fMRI to test the extent to which musical structure in pitch and time contribute to music-selective neural responses. We used voxel decomposition to derive music-selective response components in each of 15 participants individually, and then measured the response of these components to synthetic music clips in which we selectively disrupted musical structure by scrambling either the note pitches and/or onset times. Both types of scrambling produced lower responses compared to when melodic or rhythmic structure was intact. This effect was much stronger in the music-selective component than in the other response components, even those with substantial spatial overlap with the music component. We further found no evidence for any cortical regions sensitive to pitch but not time structure, or vice versa. Our results suggest that the processing of melody and rhythm are intertwined within auditory cortex.

Cerebral Representation of Sound Localization Using Functional Near-Infrared Spectroscopy

Sound localization is an essential part of auditory processing. However, the cortical representation of identifying the direction of sound sources presented in the sound field using functional near-infrared spectroscopy (fNIRS) is currently unknown. Therefore, in this study, we used fNIRS to investigate the cerebral representation of different sound sources. Twenty-five normal-hearing subjects (aged 26 ± 2.7, male 11, female 14) were included and actively took part in a block design task. The test setup for sound localization was composed of a seven-speaker array spanning a horizontal arc of 180° in front of the participants. Pink noise bursts with two intensity levels (48 dB/58 dB) were randomly applied via five loudspeakers (–90°/–30°/–0°/+30°/+90°). Sound localization task performances were collected, and simultaneous signals from auditory processing cortical fields were recorded for analysis by using a support vector machine (SVM). The results showed a classification accuracy of 73.60, 75.60, and 77.40% on average at –90°/0°, 0°/+90°, and –90°/+90° with high intensity, and 70.60, 73.6, and 78.6% with low intensity. The increase of oxyhemoglobin was observed in the bilateral non-primary auditory cortex (AC) and dorsolateral prefrontal cortex (dlPFC). In conclusion, the oxyhemoglobin (oxy-Hb) response showed different neural activity patterns between the lateral and front sources in the AC and dlPFC. Our results may serve as a basic contribution for further research on the use of fNIRS in spatial auditory studies.

Two Stages of Speech Envelope Tracking in Human Auditory Cortex Modulated by Speech Intelligibility

The envelope is essential for speech perception. Recent studies have shown that cortical activity can track the acoustic envelope. However, whether the tracking strength reflects the extent of speech intelligibility processing remains controversial. Here, using stereo-electroencephalogram (sEEG) technology, we directly recorded the activity in human auditory cortex while subjects listened to either natural or noise-vocoded speech. These two stimuli have approximately identical envelopes, but the noise-vocoded speech does not have speech intelligibility. We found two stages of envelope tracking in auditory cortex: an early high-γ (60-140 Hz) power stage (delay ≈ 49 ms) that preferred the noise-vocoded speech, and a late θ (4-8 Hz) phase stage (delay ≈ 178 ms) that preferred the natural speech. Furthermore, the decoding performance of high-γ power was better in primary auditory cortex than in non-primary auditory cortex, consistent with its short tracking delay. We also found distinct lateralization effects: high-γ power envelope tracking dominated left auditory cortex, while θ phase showed better decoding performance in right auditory cortex. In sum, we suggested a functional dissociation between high-γ power and θ phase: the former reflects fast and automatic processing of brief acoustic features, while the latter correlates to slow build-up processing facilitated by speech intelligibility.

A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development

Normally, dendritic size is established prior to adolescence and then remains relatively constant into adulthood due to a homeostatic balance between growth and retraction pathways. However, schizophrenia is characterized by accelerated reductions of cerebral cortex gray matter volume and onset of clinical symptoms during adolescence, with reductions in layer 3 pyramidal neuron dendritic length, complexity, and spine density identified in multiple cortical regions postmortem. Nogo receptor 1 (NGR1) activation of the GTPase RhoA is a major pathway restricting dendritic growth in the cerebral cortex. We show that the NGR1 pathway is stimulated by OMGp and requires the Rho guanine nucleotide exchange factor Kalirin-9 (KAL9). Using a genetically encoded RhoA sensor, we demonstrate that a naturally occurring missense mutation in Kalrn, KAL-PT, that was identified in a schizophrenia cohort, confers enhanced RhoA activitation in neuronal dendrites compared to wild-type KAL. In mice containing this missense mutation at the endogenous locus, there is an adolescent-onset reduction in dendritic length and complexity of layer 3 pyramidal neurons in the primary auditory cortex. Spine density per unit length of dendrite is unaffected. Early adult mice with these structural deficits exhibited impaired detection of short gap durations. These findings provide a neuropsychiatric model of disease capturing how a mild genetic vulnerability may interact with normal developmental processes such that pathology only emerges around adolescence. This interplay between genetic susceptibility and normal adolescent development, both of which possess inherent individual variability, may contribute to heterogeneity seen in phenotypes in human neuropsychiatric disease.

Neural tracking as an objective measure of auditory perception and speech intelligibility

The neural tracking framework enables the analysis of neural responses (EEG) to continuous natural speech, e.g., a story or a podcast. This allows for objective investigation of a range of auditory and linguistic processes in the brain during natural speech perception. This approach is more ecologically valid than traditional auditory evoked responses and has great potential for both research and clinical applications. In this article, we review the neural tracking framework and highlight three prominent examples of neural tracking analyses. This includes the neural tracking of the fundamental frequency of the voice (f0), the speech envelope and linguistic features. Each of these analyses provides a unique point of view into the hierarchical stages of speech processing in the human brain. f0-tracking assesses the encoding of fine temporal information in the early stages of the auditory pathway, i.e. from the auditory periphery up to early processing in the primary auditory cortex. This fundamental processing in (mostly) subcortical stages forms the foundation of speech perception in the cortex. Envelope tracking reflects bottom-up and top-down speech-related processes in the auditory cortex, and is likely necessary but not sufficient for speech intelligibility. To study neural processes more directly related to speech intelligibility, neural tracking of linguistic features can be used. This analysis focuses on the encoding of linguistic features (e.g. word or phoneme surprisal) in the brain. Together these analyses form a multi-faceted and time-effective objective assessment of the auditory and linguistic processing of an individual.