Improving Neurological Health in Aging Via Neuroplasticity-Based Computerized Exercise: Protocol for a Randomized Controlled Trial.

BACKGROUND: Our current understanding of how computerized brain training drives cognitive and functional benefits remains incomplete. This paper describes the protocol for Improving Neurological Health in Aging via Neuroplasticity-based Computerized Exercise (INHANCE), a randomized controlled trial in healthy older adults designed to evaluate whether brain training improves cholinergic signaling. OBJECTIVE: INHANCE evaluates whether 2 computerized training programs alter acetylcholine binding using the vesicular acetylcholine transporter ligand [18F] fluoroethoxybenzovesamicol ([18F] FEOBV) and positron emission tomography (PET). METHODS: In this phase IIb, prospective, double-blind, parallel-arm, active-controlled randomized trial, a minimum of 92 community-dwelling healthy adults aged 65 years and older are randomly assigned to a brain training program designed using the principles of neuroplasticity (BrainHQ by Posit Science) or to an active control program of computer games designed for entertainment (eg, Solitaire). Both programs consist of 30-minute sessions, 7 times per week for 10 weeks (35 total hours), completed remotely at home using either loaned or personal devices. The primary outcome is the change in FEOBV binding in the anterior cingulate cortex, assessed at baseline and posttest. Exploratory cognitive and behavioral outcomes sensitive to acetylcholine are evaluated before, immediately after, and 3 months following the intervention to assess the maintenance of observed effects. RESULTS: The trial was funded in September 2019. The study received approval from the Western Institutional Review Board in October 2020 with Research Ethics Board of McGill University Health Centre and Health Canada approvals in June 2021. The trial is currently ongoing. The first participant was enrolled in July 2021, enrollment closed when 93 participants were randomized in December 2023, and the trial will conclude in June 2024. The study team will be unblinded to conduct analyses after the final participant exits the study. We expect to publish the results in the fourth quarter of 2024. CONCLUSIONS: There remains a critical need to identify effective and scalable nonpharmaceutical interventions to enhance cognition in older adults. This trial contributes to our understanding of brain training by providing a potential neurochemical explanation of cognitive benefit. TRIAL REGISTRATION: ClinicalTrials.gov NCT04149457; https://clinicaltrials.gov/ct2/show/NCT04149457. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/59705.

Eye movement function captured via an electronic tablet informs on cognition and disease severity in Parkinson's disease.

Studying the oculomotor system provides a unique window to assess brain health and function in various clinical populations. Although the use of detailed oculomotor parameters in clinical research has been limited due to the scalability of the required equipment, the development of novel tablet-based technologies has created opportunities for fast, easy, cost-effective, and reliable eye tracking. Oculomotor measures captured via a mobile tablet-based technology have previously been shown to reliably discriminate between Parkinson's Disease (PD) patients and healthy controls. Here we further investigate the use of oculomotor measures from tablet-based eye-tracking to inform on various cognitive abilities and disease severity in PD patients. When combined using partial least square regression, the extracted oculomotor parameters can explain up to 71% of the variance in cognitive test scores (e.g. Trail Making Test). Moreover, using a receiver operating characteristics (ROC) analysis we show that eye-tracking parameters can be used in a support vector classifier to discriminate between individuals with mild PD from those with moderate PD (based on UPDRS cut-off scores) with an accuracy of 90%. Taken together, our findings highlight the potential usefulness of mobile tablet-based technology to rapidly scale eye-tracking use and usefulness in both research and clinical settings by informing on disease stage and cognitive outcomes.

Cross-species conservation in the regulation of parvalbumin by perineuronal nets.

Parvalbumin (PV) neurons play an integral role in regulating neural dynamics and plasticity. Therefore, understanding the factors that regulate PV expression is important for revealing modulators of brain function. While the contribution of PV neurons to neural processes has been studied in mammals, relatively little is known about PV function in non-mammalian species, and discerning similarities in the regulation of PV across species can provide insight into evolutionary conservation in the role of PV neurons. Here we investigated factors that affect the abundance of PV in PV neurons in sensory and motor circuits of songbirds and rodents. In particular, we examined the degree to which perineuronal nets (PNNs), extracellular matrices that preferentially surround PV neurons, modulate PV abundance as well as how the relationship between PV and PNN expression differs across brain areas and species and changes over development. We generally found that cortical PV neurons that are surrounded by PNNs (PV+PNN neurons) are more enriched with PV than PV neurons without PNNs (PV-PNN neurons) across both rodents and songbirds. Interestingly, the relationship between PV and PNN expression in the vocal portion of the basal ganglia of songbirds (Area X) differed from that in other areas, with PV+PNN neurons having lower PV expression compared to PV-PNN neurons. These relationships remained consistent across development in vocal motor circuits of the songbird brain. Finally, we discovered a causal contribution of PNNs to PV expression in songbirds because degradation of PNNs led to a diminution of PV expression in PV neurons. These findings in reveal a conserved relationship between PV and PNN expression in sensory and motor cortices and across songbirds and rodents and suggest that PV neurons could modulate plasticity and neural dynamics in similar ways across songbirds and rodents.

Oculomotor analysis to assess brain health: preliminary findings from a longitudinal study of multiple sclerosis using novel tablet-based eye-tracking software.

A growing body of evidence supports the link between eye movement anomalies and brain health. Indeed, the oculomotor system is composed of a diverse network of cortical and subcortical structures and circuits that are susceptible to a variety of degenerative processes. Here we show preliminary findings from the baseline measurements of an ongoing longitudinal cohort study in MS participants, designed to determine if disease and cognitive status can be estimated and tracked with high accuracy based on eye movement parameters alone. Using a novel gaze-tracking technology that can reliably and accurately track eye movements with good precision without the need for infrared cameras, using only an iPad Pro embedded camera, we show in this cross-sectional study that several eye movement parameters significantly correlated with clinical outcome measures of interest. Eye movement parameters were extracted from fixation, pro-saccade, anti-saccade, and smooth pursuit visual tasks, whereas the clinical outcome measures were the scores of several disease assessment tools and standard cognitive tests such as the Expanded Disability Status Scale (EDSS), Brief International Cognitive Assessment for MS (BICAMS), the Multiple Sclerosis Functional Composite (MSFC) and the Symbol Digit Modalities Test (SDMT). Furthermore, partial least squares regression analyses show that a small set of oculomotor parameters can explain up to 84% of the variance of the clinical outcome measures. Taken together, these findings not only replicate previously known associations between eye movement parameters and clinical scores, this time using a novel mobile-based technology, but also the notion that interrogating the oculomotor system with a novel eye-tracking technology can inform us of disease severity, as well as the cognitive status of MS participants.

A novel tablet-based software for the acquisition and analysis of gaze and eye movement parameters: a preliminary validation study in Parkinson's disease.

The idea that eye movements can reflect certain aspects of brain function and inform on the presence of neurodegeneration is not a new one. Indeed, a growing body of research has shown that several neurodegenerative disorders, such as Alzheimer's and Parkinson's Disease, present characteristic eye movement anomalies and that specific gaze and eye movement parameters correlate with disease severity. The use of detailed eye movement recordings in research and clinical settings, however, has been limited due to the expensive nature and limited scalability of the required equipment. Here we test a novel technology that can track and measure eye movement parameters using the embedded camera of a mobile tablet. We show that using this technology can replicate several well-known findings regarding oculomotor anomalies in Parkinson's disease (PD), and furthermore show that several parameters significantly correlate with disease severity as assessed with the MDS-UPDRS motor subscale. A logistic regression classifier was able to accurately distinguish PD patients from healthy controls on the basis of six eye movement parameters with a sensitivity of 0.93 and specificity of 0.86. This tablet-based tool has the potential to accelerate eye movement research via affordable and scalable eye-tracking and aid with the identification of disease status and monitoring of disease progression in clinical settings.

Pairing with Enriched Sound Exposure Restores Auditory Processing Degraded by an Antidepressant.

Antidepressants, while effective in treating depression and anxiety disorders, also induce deficits in sensory (particularly auditory) processing, which in turn may exacerbate psychiatric symptoms. How antidepressants cause auditory signature deficits remains largely unknown. Here, we found that fluoxetine-treated adult female rats were significantly less accurate when performing a tone-frequency discrimination task compared with age-matched control rats. Their cortical neurons also responded less selectively to sound frequencies. The degraded behavioral and cortical processing was accompanied by decreased cortical perineuronal nets, particularly those wrapped around parvalbumin-expressing inhibitory interneurons. Furthermore, fluoxetine induced critical period-like plasticity in their already mature auditory cortices; therefore, a brief rearing of these drug-treated rats under an enriched acoustic environment renormalized auditory processing degraded by fluoxetine. The altered cortical expression of perineuronal nets was also reversed as a result of enriched sound exposure. These findings suggest that the adverse effects of antidepressants on auditory processing, possibly because of a reduction in intracortical inhibition, can be substantially alleviated by simply pairing drug treatment with passive, enriched sound exposure. They have important implications for understanding the neurobiological basis of antidepressant effects on hearing and for designing novel pharmacological treatment strategies for psychiatric disorders.SIGNIFICANCE STATEMENT Clinical experience suggests that antidepressants adversely affect sensory (particularly auditory) processing, which can exacerbate patients' psychiatric symptoms. Here, we show that the antidepressant fluoxetine reduces cortical inhibition in adult rats, leading to degraded behavioral and cortical spectral processing of sound. Importantly, fluoxetine induces a critical period-like state of plasticity in the mature cortex; therefore, a brief rearing under an enriched acoustic environment is sufficient to reverse the changes in auditory processing caused by the administration of fluoxetine. These results provide a putative neurobiological basis for the effects of antidepressants on hearing and indicate that antidepressant treatment combined with enriched sensory experiences could optimize clinical outcomes.

Cross-species conservation in the regulation of parvalbumin by perineuronal nets.

Parvalbumin (PV) neurons play an integral role in regulating neural dynamics and plasticity. Therefore, understanding the factors that regulate PV expression is important for revealing modulators of brain function. While the contribution of PV neurons to neural processes has been studied in mammals, relatively little is known about PV function in non-mammalian species, and discerning similarities in the regulation of PV across species can provide insight into evolutionary conservation in the role of PV neurons. Here we investigated factors that affect the abundance of PV in PV neurons in sensory and motor circuits of songbirds and rodents. In particular, we examined the degree to which perineuronal nets (PNNs), extracellular matrices that preferentially surround PV neurons, modulate PV abundance as well as how the relationship between PV and PNN expression differs across brain areas and species and changes over development. We generally found that cortical PV neurons that are surrounded by PNNs (PV+PNN neurons) are more enriched with PV than PV neurons without PNNs (PV-PNN neurons) across both rodents and songbirds. Interestingly, the relationship between PV and PNN expression in the vocal portion of the basal ganglia of songbirds (Area X) differed from that in other areas, with PV+PNN neurons having lower PV expression compared to PV-PNN neurons. These relationships remained consistent across development in vocal motor circuits of the songbird brain. Finally, we discovered a causal contribution of PNNs to PV expression in songbirds because degradation of PNNs led to a diminution of PV expression in PV neurons. These findings reveal a conserved relationship between PV and PNN expression in sensory and motor cortices and across songbirds and rodents and suggest that PV neurons could modulate plasticity and neural dynamics in similar ways across songbirds and rodents.

Developmental Exposure to Bisphenol a Degrades Auditory Cortical Processing in Rats.

Developmental exposure to bisphenol A (BPA), an endocrine-disrupting contaminant, impairs cognitive function in both animals and humans. However, whether BPA affects the development of primary sensory systems, which are the first to mature in the cortex, remains largely unclear. Using the rat as a model, we aimed to record the physiological and structural changes in the primary auditory cortex (A1) following lactational BPA exposure and their possible effects on behavioral outcomes. We found that BPA-exposed rats showed significant behavioral impairments when performing a sound temporal rate discrimination test. A significant alteration in spectral and temporal processing was also recorded in their A1, manifested as degraded frequency selectivity and diminished stimulus rate-following by neurons. These post-exposure effects were accompanied by changes in the density and maturity of dendritic spines in A1. Our findings demonstrated developmental impacts of BPA on auditory cortical processing and auditory-related discrimination, particularly in the temporal domain. Thus, the health implications for humans associated with early exposure to endocrine disruptors such as BPA merit more careful examination.

Degraded cortical temporal processing in the valproic acid-induced rat model of autism.

Hearing disorders, such as abnormal speech perception, are frequently reported in individuals with autism. However, the mechanisms underlying these auditory-associated signature deficits in autism remain largely unknown. In this study, we documented significant behavioral impairments in the sound temporal rate discrimination task for rats prenatally exposed to valproic acid (VPA), a well-validated animal model for studying the pathology of autism. In parallel, there was a large-scale degradation in temporal information-processing in their primary auditory cortices (A1) at both levels of spiking outputs and synaptic inputs. Substantially increased spine density of excitatory neurons and decreased numbers of parvalbumin- and somatostatin-labeled inhibitory inter-neurons were also recorded in the A1 after VPA exposure. Given the fact that cortical temporal processing of sound is associated with speech perception in humans, these results in the animal model of VPA exposure provide insight into a possible neurological mechanism underlying auditory and language-related deficits in individuals with autism.

Mapping the human auditory cortex using spectrotemporal receptive fields generated with magnetoencephalography.

We present a novel method to map the functional organization of the human auditory cortex noninvasively using magnetoencephalography (MEG). More specifically, this method estimates via reverse correlation the spectrotemporal receptive fields (STRF) in response to a temporally dense pure tone stimulus, from which important spectrotemporal characteristics of neuronal processing can be extracted and mapped back onto the cortex surface. We show that several neuronal populations can be found examining the spectrotemporal characteristics of their STRFs, and demonstrate how these can be used to generate tonotopic gradient maps. In doing so, we show that the spatial resolution of MEG is sufficient to reliably extract important information about the spatial organization of the auditory cortex, while enabling the analysis of complex temporal dynamics of auditory processing such as best temporal modulation rate and response latency given its excellent temporal resolution. Furthermore, because spectrotemporally dense auditory stimuli can be used with MEG, the time required to acquire the necessary data to generate tonotopic maps is significantly less for MEG than for other neuroimaging tools that acquire BOLD-like signals.

Plasma pTau181 predicts cortical brain atrophy in aging and Alzheimer's disease.

BACKGROUND: To investigate the association of plasma pTau181, assessed with a new immunoassay, with neurodegeneration of white matter and gray matter cross-sectionally and longitudinally, in aging and Alzheimer's disease. METHODS: Observational data was obtained from the Alzheimer's Disease Neuroimaging Initiative, in which participants underwent plasma assessment and magnetic resonance imaging. Based on their clinical diagnosis, participants were classified as cognitively unimpaired and cognitively impaired. Linear regressions and linear mixed-effect models were used to test the cross-sectional and longitudinal associations between baseline plasma pTau181 and neurodegeneration using voxel-based morphometry. RESULTS: We observed a negative correlation at baseline between plasma pTau181 and gray matter volume in cognitively unimpaired individuals. In cognitively impaired individuals, we observed a negative association between plasma pTau181 and both gray and white matter volume. In longitudinal analyses conducted in the cognitively unimpaired group, plasma pTau181 was negatively correlated with gray matter volume, starting 36 months after baseline assessments. Finally, in cognitively impaired individuals, plasma pTau181 concentrations were negatively correlated with both gray and white matter volume as early as 12 months after baseline, and neurodegeneration increased in an incremental manner until 48 months. CONCLUSIONS: Higher levels of plasma pTau181 correlate with neurodegeneration and predict further brain atrophy in aging and Alzheimer's disease. Plasma pTau181 may be useful in predicting AD-related neurodegeneration, comparable to positron emission tomography or cerebrospinal fluid assessment with high specificity for AD neurodegeneration.

Critical periods of brain development.

Brain plasticity is maximal at specific time windows during early development known as critical periods (CPs), during which sensory experience is necessary to establish optimal cortical representations of the surrounding environment. After CP closure, a range of functional and structural elements prevent passive experience from eliciting significant plastic changes in the brain. The transition from a plastic to a more fixed state is advantageous as it allows for the sequential consolidation and retention of new and more complex perceptual, motor, and cognitive functions. However, the formation of stable neural representations may pose limitations on future revisions to the circuitry. If sensory experience is abnormal or absent during this time, it can have profound effects on sensory representations in adulthood, resulting in quasi-permanent adaptations that can make it nearly impossible to learn certain skills or process certain stimulus properties later on in life. This chapter begins with a brief introduction to experience-dependent plasticity throughout the lifespan (Section Introduction). Next, we define what constitutes a CP (Section What Are Critical Periods?) and review some of the key CPs in the visual and auditory systems (Section Key Critical Periods of Sensory Systems). We then discuss the mechanisms whereby cortical plasticity is regulated both locally and through neuromodulatory systems (Section How Are Critical Periods Regulated?). Finally, we highlight studies showing that CPs can be extended beyond their normal epochs, closed prematurely, or reopened during adult life by merely altering sensory inputs (Section Timing of Critical Periods: Can CP Plasticity Be Extended, Limited, or Reactivated?).

Auditory cognitive training improves prepulse inhibition in serine racemase mutant mice.

Evidence indicates that neuroplasticity-based cognitive training can improve cognition in patients with schizophrenia, but the individual response to training varies greatly between subjects. Hence, there is a need to understand the neurological underpinnings of cognitive training to reveal predictors of treatment response. D-serine is a crucial modulator of neuroplasticity, and decreased levels of D-serine may contribute to deficits in neuroplasticity in schizophrenia. Interestingly, we observed that training mice to identify auditory oddballs increased extracellular levels of D-serine in the hippocampus during training. Serine racemase (Srr) is the only source of brain D-serine; thus, it is possible that Srr may mediate the response to training. To test this hypothesis, we trained mice that have a mutated version of Srr (SrrY269*/SrrY269*) and reduced levels of D-serine in the same auditory training. SrrY269*/SrrY269* mice showed decreased performance during auditory training (defined as the capacity to discriminate an oddball during a sequence of tones). Importantly, auditory training improved prepulse inhibition (PPI) in SrrY269*/SrrY269* but not in wild-type mice. Finally, D-serine (100 mg/kg i.p.) given 30 min before training sessions to SrrY269*/SrrY269* mice improved training performance, but it did not enhance PPI. Taken together, our results show that D-serine is involved in the response to neuroplasticity-based auditory training and that PPI deficits can be improved by auditory oddball training even in the presence of neuroplasticity deficits.

Neural Modulation of the Primary Auditory Cortex by Intracortical Microstimulation with a Bio-Inspired Electronic System.

Nowadays, the majority of the progress in the development of implantable neuroprostheses has been achieved by improving the knowledge of brain functions so as to restore sensorial impairments. Intracortical microstimulation (ICMS) is a widely used technique to investigate site-specific cortical responses to electrical stimuli. Herein, we investigated the neural modulation induced in the primary auditory cortex (A1) by an acousto-electric transduction of ultrasonic signals using a bio-inspired intracortical microstimulator. The developed electronic system emulates the transduction of ultrasound signals in the cochlea, providing bio-inspired electrical stimuli. Firstly, we identified the receptive fields in the primary auditory cortex devoted to encoding ultrasonic waves at different frequencies, mapping each area with neurophysiological patterns. Subsequently, the activity elicited by bio-inspired ICMS in the previously identified areas, bypassing the sense organ, was investigated. The observed evoked response by microstimulation resulted as highly specific to the stimuli, and the spatiotemporal dynamics of neural oscillatory activity in the alpha, beta, and gamma waves were related to the stimuli preferred by the neurons at the stimulated site. The alpha waves modulated cortical excitability only during the activation of the specific tonotopic neuronal populations, inhibiting neural responses in unrelated areas. Greater neuronal activity in the posterior area of A1 was observed in the beta band, whereas a gamma rhythm was induced in the anterior A1. The results evidence that the proposed bio-inspired acousto-electric ICMS triggers high-frequency oscillations, encoding information about the stimulation sites and involving a large-scale integration in the brain.

Modifying the Adult Rat Tonotopic Map with Sound Exposure Produces Frequency Discrimination Deficits That Are Recovered with Training.

Frequency discrimination learning is often accompanied by an expansion of the functional region corresponding to the target frequency within the auditory cortex. Although the perceptual significance of this plastic functional reorganization remains debated, greater cortical representation is generally thought to improve perception for a stimulus. Recently, the ability to expand functional representations through passive sound experience has been demonstrated in adult rats, suggesting that it may be possible to design passive sound exposures to enhance specific perceptual abilities in adulthood. To test this hypothesis, we exposed adult female Long-Evans rats to 2 weeks of moderate-intensity broadband white noise followed by 1 week of 7 kHz tone pips, a paradigm that results in the functional over-representation of 7 kHz within the adult tonotopic map. We then tested the ability of exposed rats to identify 7 kHz among distractor tones on an adaptive tone discrimination task. Contrary to our expectations, we found that map expansion impaired frequency discrimination and delayed perceptual learning. Rats exposed to noise followed by 15 kHz tone pips were not impaired at the same task. Exposed rats also exhibited changes in auditory cortical responses consistent with reduced discriminability of the exposure tone. Encouragingly, these deficits were completely recovered with training. Our results provide strong evidence that map expansion alone does not imply improved perception. Rather, plastic changes in frequency representation induced by bottom-up processes can worsen perceptual faculties, but because of the very nature of plasticity these changes are inherently reversible.SIGNIFICANCE STATEMENT The potent ability of our acoustic environment to shape cortical sensory representations throughout life has led to a growing interest in harnessing both passive sound experience and operant perceptual learning to enhance mature cortical function. We use sound exposure to induce targeted expansions in the adult rat tonotopic map and find that these bottom-up changes unexpectedly impair performance on an adaptive tone discrimination task. Encouragingly, however, we also show that training promotes the recovery of electrophysiological measures of reduced neural discriminability following sound exposure. These results provide support for future neuroplasticity-based treatments that take into account both the sensory statistics of our external environment and perceptual training strategies to improve learning and memory in the adult auditory system.

Reactivation of critical period plasticity in adult auditory cortex through chemogenetic silencing of parvalbumin-positive interneurons.

Sensory experience during early developmental critical periods (CPs) has profound and long-lasting effects on cortical sensory processing perduring well into adulthood. Although recent evidence has shown that reducing cortical inhibition during adulthood reinstates CP plasticity, the precise cellular mechanisms are not well understood. Here, we show that chemogenetic inactivation of parvalbumin-positive (PV+) interneurons is sufficient to reinstate CP plasticity in the adult auditory cortex. Bidirectional manipulation of PV+ cell activity affected neuronal spectral and sound intensity selectivity and, in the case of PV+ interneuron inactivation, was mirrored by anatomical changes in PV and associated perineuronal net expression. These findings underscore the importance of sustained PV-mediated inhibitory neurotransmission throughout life and highlight the potential of chemogenetic approaches for harnessing cortical plasticity with the ultimate goal of aiding recovery from brain injury or disease.

Evidence of Hyperacusis in Adult Rats Following Non-traumatic Sound Exposure.

Manipulations that enhance neuroplasticity may inadvertently create opportunities for maladaptation. We have previously used passive exposures to non-traumatic white noise to open windows of plasticity in the adult rat auditory cortex and induce frequency-specific functional reorganizations of the tonotopic map. However, similar reorganizations in the central auditory pathway are thought to contribute to the generation of hearing disorders such as tinnitus and hyperacusis. Here, we investigate whether noise-induced reorganizations are accompanied by electrophysiological or behavioral evidence of tinnitus or hyperacusis in adult Long-Evans rats. We used a 2-week passive exposure to moderate-intensity (70 dB SPL) broadband white noise to reopen a critical period for spectral tuning such that a second 1-week exposure to 7 kHz tone pips produced an expansion of the 7 kHz frequency region in the primary auditory cortex (A1). We demonstrate for the first time that this expansion also takes place in the ventral auditory field (VAF). Sound exposure also led to spontaneous and sound-evoked hyperactivity in the anterior auditory field (AAF). Rats were assessed for behavioral evidence of tinnitus or hyperacusis using gap and tone prepulse inhibition of the acoustic startle response. We found that sound exposure did not affect gap-prepulse inhibition. However, sound exposure led to an improvement in prepulse inhibition when the prepulse was a 7 kHz tone, showing that exposed rats had enhanced sensorimotor gating for the exposure frequency. Together, our electrophysiological and behavioral results provide evidence of hyperacusis but not tinnitus in sound-exposed animals. Our findings demonstrate that periods of prolonged noise exposure may open windows of plasticity that can also be understood as windows of vulnerability, potentially increasing the likelihood for maladaptive plasticity to take place.

Reversible external auditory canal ligation (REACL): A novel surgical technique to induce transient and reversible hearing loss in developing rats.

BACKGROUND: Cases of sensory loss provide an excellent model to study the plastic nature of cortical sensory systems. Models of reversible sensory loss are particularly useful for establishing the timeline of various critical periods for cortical plasticity. However, there currently is an absence of adequate methods to produce reversible hearing loss in neonatal and developing rodents. NEW METHOD: We propose a novel and reversible adaptation of an existing surgical technique-external auditory canal ligation (EACL)-that produces a reliable and moderate hearing loss. RESULTS: Auditory brainstem responses (ABRs) were used to measure both the magnitude of the hearing loss induced by EACL and the auditory thresholds following hearing restoration. The EACL and reopening procedures, as assessed by visual inspection, had success rates of 81% and 78%, respectively. The average hearing thresholds, as assessed with ABRs, increased by nearly 40 decibels across all tested frequencies. Hearing thresholds returned to normal levels following the reopening procedure. COMPARISON WITH EXISTING METHODS: Our procedure yields similar benefits to other methods, such as producing a reliable and moderate hearing loss that is entirely reversible. Furthermore, to our knowledge, it is the first that can be performed in neonatal rodents, thus allowing researchers the opportunity to assess the effects of sensory loss on behavior and cortical neurophysiology during developmental critical periods. CONCLUSION: Our modified technique of reversible external auditory canal ligation offers an easy, and reliable method to induce a transient state of hearing loss that mimics naturally occurring congenital conductive hearing loss.

The Prolonged Masking of Temporal Acoustic Inputs with Noise Drives Plasticity in the Adult Rat Auditory Cortex.

The prolonged masking of auditory inputs with white noise has been shown to reopen the critical period for spectral tuning in the adult rat auditory cortex. Here, we argue that the masking of salient temporal inputs in particular is responsible for changes in neuronal activity that lead to this experience-dependent plasticity. We tested this hypothesis by passively exposing adult rats to 2 weeks of amplitude-modulated (AM) white noise with different modulation depths from 0% (no modulation) to 100% (strong modulation). All exposed rats displayed evidence of cortical plasticity as measured by receptive field bandwidths, tonotopic gradients, and synchronization during spontaneous activity. However, this plasticity was fundamentally different in nature for rats exposed to unmodulated noise, as a second passive exposure to pure tones elicited tonotopic reorganization in rats exposed to 0% AM noise only. Detection of c-FOS expression in excitatory and inhibitory cells through post-mortem immunohistochemistry also revealed different patterns of cellular activation depending on modulation depth. Together, these results indicate that the absence of temporal modulation promotes noise-induced plasticity in the adult auditory cortex and suggest an important and continuous role for temporally salient inputs in the maintenance of mature auditory circuits.