A systematic review of altered resting-state networks in early deafness and implications for cochlear implantation outcomes.

Auditory deprivation following congenital/pre-lingual deafness (C/PD) can drastically affect brain development and its functional organisation. This systematic review intends to extend current knowledge of the impact of C/PD and deafness duration on brain resting-state networks (RSNs), review changes in RSNs and spoken language outcomes post-cochlear implant (CI) and draw conclusions for future research. The systematic literature search followed the PRISMA guideline. Two independent reviewers searched four electronic databases using combined keywords: 'auditory deprivation', 'congenital/prelingual deafness', 'resting-state functional connectivity' (RSFC), 'resting-state fMRI' and 'cochlear implant'. Seventeen studies (16 cross-sectional and one longitudinal) met the inclusion criteria. Using the Crowe Critical Appraisal Tool, the publications' quality was rated between 65.0% and 92.5% (mean: 84.10%), ≥80% in 13 out of 17 studies. A few studies were deficient in sampling and/or ethical considerations. According to the findings, early auditory deprivation results in enhanced RSFC between the auditory network and brain networks involved in non-verbal communication, and high levels of spontaneous neural activity in the auditory cortex before CI are evidence of occupied auditory cortical areas with other sensory modalities (cross-modal plasticity) and sub-optimal CI outcomes. Overall, current evidence supports the idea that moreover intramodal and cross-modal plasticity, the entire brain adaptation following auditory deprivation contributes to spoken language development and compensatory behaviours.

Tactile stimulation improves cognition, motor, and anxiety-like behaviors and attenuates the Alzheimer's disease pathology in adult APPNL-G-F/NL-G-F mice.

Alzheimer's disease (AD) is one of the largest health crises in the world. There are limited pharmaceutical interventions to treat AD, however, and most of the treatment options are not for cure or prevention, but rather to slow down the progression of the disease. The aim of this study was to examine the effect of tactile stimulation (TS) on AD-like symptoms and pathology in APPNL-G-F/NL-G-F mice, a mouse model of AD. The results show that TS reduces the AD-like symptoms on tests of cognition, motor, and anxiety-like behaviors and these improvements in behavior are associated with reduced AD pathology in APP mice. Thus, TS appears to be a promising noninvasive strategy for slowing the onset of dementia in aging animals.

Critical period regulation across multiple timescales.

Brain plasticity is dynamically regulated across the life span, peaking during windows of early life. Typically assessed in the physiological range of milliseconds (real time), these trajectories are also influenced on the longer timescales of developmental time (nurture) and evolutionary time (nature), which shape neural architectures that support plasticity. Properly sequenced critical periods of circuit refinement build up complex cognitive functions, such as language, from more primary modalities. Here, we consider recent progress in the biological basis of critical periods as a unifying rubric for understanding plasticity across multiple timescales. Notably, the maturation of parvalbumin-positive (PV) inhibitory neurons is pivotal. These fast-spiking cells generate gamma oscillations associated with critical period plasticity, are sensitive to circadian gene manipulation, emerge at different rates across brain regions, acquire perineuronal nets with age, and may be influenced by epigenetic factors over generations. These features provide further novel insight into the impact of early adversity and neurodevelopmental risk factors for mental disorders.

A Systematic Review and Meta-Analysis of Extended High-Frequency Hearing Thresholds in Tinnitus With a Normal Audiogram.

OBJECTIVES: Current evidence supports the growing application of extended high-frequency (EHF: 9 to 20 kHz) audiometry in hearing research, which likely results from the high vulnerability of this frequency region to damage induced by known auditory risk factors. The present systematic review and meta-analysis were performed to investigate whether adults with a normal audiogram and tinnitus show increased EHF hearing thresholds relative to control peers. DESIGN: A comprehensive search was undertaken on electronic databases consisting of PubMed, ScienceDirect, Wiley, and Google Scholar using combined keywords: "tinnitus," "extended high frequency," "normal audiogram," and "hidden hearing loss." RESULTS: From 261 articles found by searching databases, nine studies met the inclusion criteria for the meta-analysis. A significant difference was observed between tinnitus and control groups in the effect size analysis of hearing thresholds at 10, 12.5, 14, 16, and 18 kHz ( p ≤ 0.001), and the I-square heterogeneity analysis was below 50% in all studies ( p ≥ 0.131). Visual inspection by the Funnel plot and Egger's regression test ( p ≥ 0.211) also exhibited no publication bias in the meta-analyses. CONCLUSIONS: Our findings are in support of the idea that in most cases, tinnitus is associated with some degree of cochlear mechanical dysfunction, which may not be detected by conventional audiometry alone. This finding underscores the significance of EHF audiometry in clinical practice, which may help both early identification of individuals susceptible to developing tinnitus and reduce the number of new cases through preventive counseling programs.

Hearing Loss, Tinnitus, and Dizziness in COVID-19: A Systematic Review and Meta-Analysis.

OBJECTIVES: Extensive studies indicate that severe acute respiratory syndrome coronavirus (SARS-CoV-2) involves human sensory systems. A lack of discussion, however, exists given the auditory-vestibular system involvement in CoV disease 2019 (COVID-19). The present systematic review and meta-analysis were performed to determine the event rate (ER) of hearing loss, tinnitus, and dizziness caused by SARS-CoV-2. METHODS: Databases (PubMed, ScienceDirect, Wiley) and World Health Organization updates were searched using combined keywords: 'COVID-19,' 'SARS-CoV-2,' 'pandemic,' 'auditory dysfunction,' 'hearing loss,' 'tinnitus,' 'vestibular dysfunction,' 'dizziness,' 'vertigo,' and 'otologic symptoms.' RESULTS: Twelve papers met the eligibility criteria and were included in the study. These papers were single group prospective, cross-sectional, or retrospective studies on otolaryngologic, neurologic, or general clinical symptoms of COVID-19 and had used subjective assessments for data collection (case histories/medical records). The results of the meta-analysis demonstrate that the ER of hearing loss (3.1%, CIs: 0.01-0.09), tinnitus (4.5%, CIs: 0.012-0.153), and dizziness (12.2%, CIs: 0.070-0.204) is statistically significant in patients with COVID-19 (Z ≤ -4.469, p ≤ 0.001). CONCLUSIONS: COVID-19 can cause hearing loss, tinnitus, and dizziness. These findings, however, should be interpreted with caution given insufficient evidence and heterogeneity among studies. Well-designed studies and follow-up assessments on otologic symptoms of SARS-CoV-2 using standard objective tests are recommended.

Tinnitus, sound intolerance, and mental health: the role of long-term occupational noise exposure.

PURPOSE: Whereas chronic noise exposure (CNE) is a known risk factor for tinnitus, little is known about how a history of CNE impacts tinnitus characteristics and its comorbid symptoms. METHODS: Seventy-five participants with chronic tinnitus (59m/16f, 22-78 years, 48 with sensory-neural hearing loss, and 27 with a normal audiogram) including 43 individuals with (Tin-CNE group) and 32 without (Tin group) a history of long-term occupational noise exposure were studied. Tinnitus characteristics were rated by a visual analog scale, and tinnitus comorbid symptoms were scored using self-assessment questionnaires. RESULTS: The Tin-CNE group showed reduced uncomfortable loudness level (ULL), sound tolerance, and quality of life (QoL), and increased tinnitus loudness, tinnitus handicap, anxiety, depression, insomnia severity, and tinnitus annoyance scores compared to the Tin group. Higher tinnitus loudness and a lower anxiety score were observed in participants with hearing loss relative to those without. Using a stepwise regression model also showed that tinnitus-related characteristics, hyperacusis, and tinnitus comorbid symptoms enhance one another. CONCLUSIONS: The findings were in support of accumulative evidence indicating the adverse auditory and non-auditory effects of CNE, including exacerbated sound intolerance and tinnitus-related psychiatric symptoms. The results also showed that tinnitus alone can affect mental health regardless of hearing loss.

An assessment of the functional effects of amphetamine-induced dendritic changes in the nucleus accumbens, medial prefrontal cortex, and hippocampus on different types of learning and memory function.

The present experiments investigated the effects of repeated amphetamine exposure on neural networks mediating different forms of learning and memory. Different components of these networks were assessed using various functional assays. The hypothesis was that abnormal dendritic changes in nucleus accumbens, medial prefrontal cortex, and hippocampus mediated by repeated amphetamine exposure would produce impairments on forms of learning and memory dependent on neural circuits relying on these brain systems, and have little or no effect on other forms of learning not dependent on these networks. Surprisingly, the results showed that many of the dendritic changes normally found in the nucleus accumbens, prefrontal cortex, and hippocampus following repeated amphetamine exposure were reversed back to control levels following extensive multi-domain cognitive training. Learning and memory functions associated with different neural networks also appeared normal except in one case. A neural network that includes, but is not limited to, the basolateral amygdala and nucleus accumbens was dysfunctional in rats repeatedly exposed to amphetamine despite the reversal of the majority of dendritic changes in the nucleus accumbens following cognitive training. Importantly, an increase in spine density that normally occurs in these brain regions following repeated amphetamine exposure remained following extensive cognitive training, particularly in the nucleus accumbens.

Prefrontal neuronal morphology in kindling-prone (FAST) and kindling-resistant (SLOW) rats.

The epileptogenic-prone (FAST) and epileptogenic-resistant (SLOW) rat strains have become a valuable tool for investigating neural plasticity. The strains were generated by breeding the rats that required the fewest amygdala stimulations to elicit a stage-5 convulsive seizure (FAST) and rats requiring the most stimulations (SLOW). Previous studies have shown differences in behavior and amygdala physiology in the two strains. This study examined the dendritic morphology of pyramidal neurons in the brains of adult male and female rats of the two strains. The brains were stained with the Golgi-Cox method and the length and branching from layer III pyramidal cells were measured in parietal cortex (Zilles Par1), medial frontal cortex (Zilles Cg3), and orbitofrontal cortex (Zilles AID) in these two strains of rats. We observed significantly longer dendrites in Cg3 in the FAST group but longer dendrites in the SLOW group in AID and Par1. There was also a sex difference (M > F) in Par1 in both strains. These morphological differences can provide insights into the neurobiological basis of the behavioral differences and suggest that localized changes in the amygdala do not occur independently of changes in other brain regions, and especially prefrontal cortex.

Traffic noise exposure, cognitive decline, and amyloid-beta pathology in an AD mouse model.

Concerns are growing that exposure to environmental pollutants, such as traffic noise, might cause cognitive impairments and predispose individuals toward the development of Alzheimer's disease (AD) dementia. In this study in a knock-in mouse model of AD, we investigated how chronic traffic noise exposure (CTNE) impacts cognitive performance and amyloid-beta (Aß) pathology. A group of APPNL-G-F/NL-G-F mice was exposed to CTNE (70 dBA , 8 hr/day for 1 month) and compared with nonexposed counterparts. Following CTNE, an increase in hypothalamic-pituitary-adrenal (HPA) axis responsivity was observed by corticosterone assay of the blood. One month after CTNE, the CTNE group demonstrated impairments in cognitive and motor functions, and indications of anxiety-like behavior, relative to the control animals. The noise-exposed group also showed elevated Aß aggregation, as inferred by a greater number of plaques and larger average plaque size in various regions of the brain, including regions involved in stress regulation. The results support that noise-associated dysregulation of the neuroendocrine system as a potential risk factor for developing cognitive impairment and Aß pathology, which should be further investigated in human studies.

Life-Course Contribution of Prenatal Stress in Regulating the Neural Modulation Network Underlying the Prepulse Inhibition of the Acoustic Startle Reflex in Male Alzheimer's Disease Mice.

The prepulse inhibition (PPI) of the acoustic startle reflex (ASR), as an index of sensorimotor gating, is one of the most extensively used paradigms in the field of neuropsychiatric disorders. Few studies have examined how prenatal stress (PS) regulates the sensorimotor gating during the lifespan and how PS modifies the development of amyloid-beta (Aß) pathology in brain areas underlying the PPI formation. We followed alternations in corticosterone levels, learning and memory, and the PPI of the ASR measures in APPNL-G-F/NL-G-F offspring of dams exposed to gestational noise stress. In-depth quantifications of the Aß plaque accumulation were also performed at 6 months. The results indicated an age-dependent deterioration of sensorimotor gating, long-lasting PS-induced abnormalities in PPI magnitudes, as well as deficits in spatial memory. The PS also resulted in a higher Aß aggregation predominantly in brain areas associated with the PPI modulation network. The findings suggest the contribution of a PS-induced hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in regulating the PPI modulation substrates leading to the abnormal development of the neural protection system in response to disruptive stimuli. The long-lasting HPA axis dysregulation appears to be the major underlying mechanism in precipitating the Aß deposition, especially in brain areas contributed to the PPI modulation network.

Auditory Dysfunction in Parkinson's Disease.

PD is a progressive and complex neurological disorder with heterogeneous symptomatology. PD is characterized by classical motor features of parkinsonism and nonmotor symptoms and involves extensive regions of the nervous system, various neurotransmitters, and protein aggregates. Extensive evidence supports auditory dysfunction as an additional nonmotor feature of PD. Studies indicate a broad range of auditory impairments in PD, from the peripheral hearing system to the auditory brainstem and cortical areas. For instance, research demonstrates a higher occurrence of hearing loss in early-onset PD and evidence of abnormal auditory evoked potentials, event-related potentials, and habituation to novel stimuli. Electrophysiological data, such as auditory P3a, also is suggested as a sensitive measure of illness duration and severity. Improvement in auditory responses following dopaminergic therapies also indicates the presence of similar neurotransmitters (i.e., glutamate and dopamine) in the auditory system and basal ganglia. Nonetheless, hearing impairments in PD have received little attention in clinical practice so far. This review summarizes evidence of peripheral and central auditory impairments in PD and provides conclusions and directions for future empirical and clinical research. © 2020 International Parkinson and Movement Disorder Society.

Caffeine consumption during development alters spine density and recovery from repetitive mild traumatic brain injury in young adult rats.

Caffeine is the most commonly used psychostimulant throughout the world, with its consumption being especially prevalent among adolescents and young adults, as over 75% of this group consumes caffeine daily. Similarly, the adolescent and young adult age group exhibit the highest incidence of traumatic brain injury (TBI). Given that both caffeine consumption and mild TBI (mTBI) are more prevalent among the late adolescent/young adult age group and that changes in dendritic spine morphology during this developmental period are poorly understood, this study sought to examine the effects of caffeine consumption during late adolescence/early adulthood on recovery from repetitive mTBI (RmTBI). The study specifically focused on changes to neuronal dendritic morphology as synaptic changes likely underlie long-term behavioral outcomes. The results demonstrate that during young adulthood caffeine consumption differentially affects the RmTBI outcomes of males and females, where the effects of caffeine and RmTBI were often additive in males while being equally detrimental, but rarely additive, in females. In general, caffeine and RmTBI induced the greatest impairments in males on cognitive and motor tasks whereas in females the most significant detriments were on pain-related tasks. Both caffeine and RmTBI increased spine density in the Cg3 (medial prefrontal cortex [mPFC]), AID (orbitofrontal cortex [OFC]), and nucleus accumbens (NAc), which is proposed to reflect an impairment in the normal pruning processes. Overall, despite caffeine's neuroprotective abilities among other age groups, this study offers concerning results regarding the detrimental effects of caffeine and RmTBI, in isolation, and especially in combination, in this susceptible population.

Gestational Stress Augments Postpartum ß-Amyloid Pathology and Cognitive Decline in a Mouse Model of Alzheimer's Disease.

Besides well-known risk factors for Alzheimer's disease (AD), stress, and in particular noise stress (NS), is a lifestyle risk factor common today. It is known that females are at a significantly greater risk of developing AD than males, and given that stress is a common adversity in females during pregnancy, we hypothesized that gestational noise exposure could exacerbate the postpartum development of the AD-like neuropathological changes during the life span. Pregnant APPNL-G-F/NL-G-F mice were randomly assigned to either the stress condition or control group. The stress group was exposed to the NS on gestational days 12-16, which resulted in a markedly higher hypothalamic-pituitary-adrenal (HPA) axis responsivity during the postpartum stage. Higher amyloid-ß (Aß) deposition and larger Aß plaque size in the olfactory area were the early onset impacts of the gestational stress (GS) seen at the age of 4 months. This pattern of increased Aß aggregation and larger plaque size were observed in various brain areas involved in both AD and stress regulation, especially in limbic structures, at the age of 6 months. The GS also produced anxiety-like behavior, deficits in learning and memory, and impaired motor coordination. The findings suggest that environmental stresses during pregnancy pose a potential risk factor in accelerating postpartum cognitive decline and AD-like neuropathological changes in the dams (mothers) later in life.

Neonatal Stress Has a Long-Lasting Sex-Dependent Effect on Anxiety-Like Behavior and Neuronal Morphology in the Prefrontal Cortex and Hippocampus.

The long-lasting effects of early stress on brain development have been well studied. Recent evidence indicates that males and females respond differently to the same stressor. We examined the chronic effects of daily maternal separation (MS) on behavior and cerebral morphology in both male and female rats. Cognitive and anxiety-like behaviors were evaluated, and neuroplastic changes in 2 subregions of the prefrontal cortex (dorsal agranular insular cortex [AID] and cingulate cortex [Cg3]) and hippocampus (CA1 and dentate gyrus) were measured in adult male and female rats. The animals were subjected to MS on postnatal day (P) 3-14 for 3 h per day. Cognitive and emotional behaviors were assessed in the object/context mismatch task, elevated plus maze, and locomotor activity test in early adulthood (P87-P95). Anatomical assessments were performed in the prefrontal cortex (i.e., cortical thickness and spine density) and hippocampus (i.e., spine density). Sex-dependent effects were observed. MS increased anxiety-related behavior only in males, whereas locomotor activity was higher in females, with no effects on cognition. MS decreased spine density in the AID and increased spine density in the CA1 area in males. Females exhibited an increase in spine density in the Cg3. Our findings confirm previous work that found that MS causes long-term behavioral and anatomical effects, and these effects were dependent on sex and the duration of MS stress.

THC alters alters morphology of neurons in medial prefrontal cortex, orbital prefrontal cortex, and nucleus accumbens and alters the ability of later experience to promote structural plasticity.

Psychoactive drugs have the ability to alter the morphology of neuronal dendrites and spines and to influence later experience-dependent structural plasticity. If rats are given repeated injections of psychomotor stimulants (amphetamine, cocaine, nicotine) prior to being placed in complex environments, the drug experience interferes with the ability of the environment to increase dendritic arborization and spine density. Repeated exposure to Delta 9-Tetrahydrocannabinol (THC) changes the morphology of dendrites in medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc). To determine if drugs other than psychomotor stimulants will also interfere with later experience-dependent structural plasticity we gave Long-Evans rats THC (0.5 mg/kg) or saline for 11 days before placing them in complex environments or standard laboratory caging for 90 days. Brains were subsequently processed for Golgi-Cox staining and analysis of dendritic morphology and spine density mPFC, orbital frontal cortex (OFC), and NAcc. THC altered both dendritic arborization and spine density in all three regions, and, like psychomotor stimulants, THC influenced the effect of later experience in complex environments to shape the structure of neurons in these three regions. We conclude that THC may therefore contribute to persistent behavioral and cognitive deficits associated with prolonged use of the drug.

Juvenile social experience and differential age-related changes in the dendritic morphologies of subareas of the prefrontal cortex in rats.

Juvenile social interactions have been shown to influence the dendritic complexity of neurons in the prefrontal cortex (PFC). In particular, social play induces pruning of the cells in the medial prefrontal cortex (mPFC), whereas interacting with multiple partners, whether those interactions involve play or not, increases the complexity of cells in the orbital frontal cortex (OFC). Previous studies suggest that these changes differ in their stability during adulthood. In the present study, rats were reared in groups of either four (quads) or two (pairs) and the brains of the rats from each rearing condition were then harvested at 60 days (i.e., shortly after sexual maturity) and 100 days (i.e., fully adult). The rats housed with multiple partners had more complex neurons of the OFC at 60 days and this complexity declined to a comparable level to that of pair housed rats by 100 days. In contrast, the play-induced changes of the mPFC remained similar at both ages. These findings suggest that the changes in the PFC induced by different social experiences in the juvenile period differ in how long they are maintained in adulthood. Differences in the functions regulated by the OFC and the mPFC are considered with regard to these differences in the stability of juvenile-induced neural changes.

Ancestral Exposure to Stress Generates New Behavioral Traits and a Functional Hemispheric Dominance Shift.

In a continuously stressful environment, the effects of recurrent prenatal stress (PS) accumulate across generations and generate new behavioral traits in the absence of genetic variation. Here, we investigated if PS or multigenerational PS across 4 generations differentially affect behavioral traits, laterality, and hemispheric dominance in male and female rats. Using skilled reaching and skilled walking tasks, 3 findings support the formation of new behavioral traits and shifted laterality by multigenerational stress. First, while PS in the F1 generation did not alter paw preference, multigenerational stress in the F4 generation shifted paw preference to favor left-handedness only in males. Second, multigenerational stress impaired skilled reaching and skilled walking movement abilities in males, while improving these abilities in females beyond the levels of controls. Third, the shift toward left-handedness in multigenerationally stressed males was accompanied by increased dendritic complexity and greater spine density in the right parietal cortex. Thus, cumulative multigenerational stress generates sexually dimorphic left-handedness and dominance shift toward the right hemisphere in males. These findings explain the origins of apparently heritable behavioral traits and handedness in the absence of DNA sequence variations while proposing epigenetic mechanisms.

Principles of plasticity in the developing brain.

The developing brain is especially sensitive to a wide range of experiences, showing a remarkable capacity for plastic changes that influence behavioural outcomes throughout the lifetime. We review the principles that regulate this plasticity in development and consider the factors that modulate the developing brain. These include early sensory, motor, and language experience, early stress, caregiver interactions, peer interactions, psychoactive drugs, diet, microbiome, and the immune system. Emphasis is given to changes in behaviour, epigenetics, and neuronal morphology. WHAT THIS PAPER ADDS: A discussion of the surprising range of factors influencing brain development Life experiences interact resulting in a phenomenon called metaplasticity.

The mane effect in the horse (Equus ferus caballus): Right mane dominance enhanced in mares but not associated with left and right manoeuvres in a reining competition.

A human physical asymmetry is the near 90% clockwise occipitoparietal scalp hair-whorl direction in Europeans, an incidence that approximates the left lateralization of speech and right-handedness. Hair-whorl direction is also asymmetric in horses, Equus ferus caballus and placement is proposed to be related to temperament and lateralized skill in equitation manoeuvres. We describe a hair-whorl asymmetry in the horse, mane direction. Of 526, 3-year-old American Quarter horses, 69% of horses had mane directed to the right and 31% had mane directed to the left. The bias was larger in females, with 74% of females vs. 65% of males having mane directed to the right. Mane direction was unrelated to coat colour. The behavioural significance of mane asymmetry was investigated using judges' scores from a reining competition requiring symmetrical maneuvers of spin, circle and roll-back to either the left or to the right. There was no relation between mane asymmetry and overall reining performance and no relation between mane direction and scores for left or right manoeuvres. The results are discussed in relation to the significance of morphological asymmetries, neural function and the influence of planar cell polarity genes, such as Frizzled, that influence epidermal hair cell patterning.