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.

Early tactile stimulation influences the development of Alzheimer's disease in gestationally stressed APP NL-G-F adult offspring NL-G-F/NL-G-F mice.

Alzheimer's disease (AD) is associated with cerebral plaques and tangles, reduced synapse number, and shrinkage in several brain areas and these morphological effects are associated with the onset of compromised cognitive, motor, and anxiety-like behaviours. The appearance of both anatomical and behavioural symptoms is worsened by stress. The focus of this study was to examine the effect of neonatal tactile stimulation on AD-like behavioural and neurological symptoms on APP NL-G-F/NL-G-F mice, a mouse model of AD, who have been gestationally stressed. Our findings indicate that neonatal tactile stimulation improves cognition, motor skills, and anxiety-like symptoms in both gestationally stressed and non-stressed adult APP mice and that these alterations are associated with reduced Aß plaque formation. Thus, tactile stimulation appears to be a promising non-invasive preventative strategy for slowing the onset of dementia in aging animals.

Tactile stimulation facilitates functional recovery and dendritic change following neonatal hemidecortication in rats.

After large neocortical lesions, such as hemidecortication, children can show significant motor and cognitive impairments. It thus is of considerable interest to identify treatments that might enhance long-term functional outcome. We have previously shown that tactile stimulation enhances recovery from perinatal focal cortical lesions in rats, so the goal of the present experiment was to explore the effectiveness of postlesion tactile stimulation in reducing functional deficits associated with neonatal hemidecortication. Rats were given hemidecortications on postnatal day 10 (P10). Half of the group was then exposed to a daily tactile stimulation treatment for 15 min, three times a day for eleven days following the surgery. All groups were then tested on a number of behavioural tasks (Morris water task, skilled reaching, forelimb placing during spontaneous vertical exploration, and a sunflower seed opening task) beginning at P 120. The brains of the male animals were prepared for Golgi-Cox staining and subsequent analysis of dendritic arborisation and spine density. There were two main findings in this experiment: 1) Tactile stimulation improved cognitive ability and some motor performance after P 10 hemidecortication; and, 2) Tactile stimulation altered cortical organization after P10 hemidecortication. Tactile stimulation may provide an important noninvasive therapy after hemispherectomy in children.

Amphetamine disrupts dopamine axon growth in adolescence by a sex-specific mechanism in mice.

Initiating drug use during adolescence increases the risk of developing addiction or other psychopathologies later in life, with long-term outcomes varying according to sex and exact timing of use. The cellular and molecular underpinnings explaining this differential sensitivity to detrimental drug effects remain unexplained. The Netrin-1/DCC guidance cue system segregates cortical and limbic dopamine pathways in adolescence. Here we show that amphetamine, by dysregulating Netrin-1/DCC signaling, triggers ectopic growth of mesolimbic dopamine axons to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to enduring cognitive deficits. In adolescent females, compensatory changes in Netrin-1 protect against the deleterious consequences of amphetamine on dopamine connectivity and cognitive outcomes. Netrin-1/DCC signaling functions as a molecular switch which can be differentially regulated by the same drug experience as function of an individual's sex and adolescent age, and lead to divergent long-term outcomes associated with vulnerable or resilient phenotypes.

Peripherally-administered amphetamine induces plasticity in medial prefrontal cortex and nucleus accumbens in rats with amygdala lesions: implications for neural models of memory modulation.

The amygdala has been implicated in a variety of functions linked to emotions. One popular view is that the amygdala modulates consolidation in other brain systems thought to be mainly involved in learning and memory processes. This series of experiments represents a further exploration into the role of the amygdala in memory modulation and consolidation. One interesting line of research has shown that drugs of abuse, like amphetamine, produce dendritic changes in select brain regions and these changes are thought to be equivalent to a usurping of normal plasticity processes. We were interested in the possibility that this modulation of plasticity processes would be dependent on interactions with the amygdala. According to the modulation view of amygdala function, amphetamine would activate modulation mechanisms in the amygdala that would alter plasticity processes in other brain regions. If the amygdala was rendered dysfunctional, these effects should not occur. Accordingly, this series of experiments evaluated the effects of extensive neurotoxic amygdala damage on amphetamine-induced dendritic changes in the nucleus accumbens and prefrontal cortex. The results showed that rats with large lesions of the amygdala showed the normal pattern of dendritic changes in these brain regions. This pattern of results suggests that the action of not all memory modulators, activated during emotional events, require the amygdala to impact memory.

Hearing loss and impaired short-term memory in an Alzheimer's disease mouse model of amyloid-beta pathology.

Current evidence supports the link between hearing loss and Alzheimer's disease (AD). However, few studies report the hearing status of AD mice compared to wild-type mice. This study aimed to compare hearing thresholds and short-term memory (STM) performance of an AD (APPNL-G-F) mouse model of amyloid-beta (Aꞵ) pathology with C57BL/6 J and CBA/CaJ mice across age. The auditory brainstem response (ABR) test, using click and five tone-burst (TB) stimuli, was recorded at 2, 4, 6, 9, and 12 months. The novel object recognition (NOR) test, a measure of STM, was conducted at 6 and 12 months. While hearing thresholds were almost preserved in CBA/CaJ mice, they were not recorded at high frequencies with age in C57BL/6 J and AD mice, leading to island hearing (severe to profound hearing loss) at 9 and 12 months. AD mice showed increased hearing thresholds in TB8 and TB16 kHz at 6 and 9 months compared to C57BL/6 J mice. NOR findings were evidence of impaired STM in both C57BL/6 J and AD mice relative to CBA/CaJ mice, and a relationship was found between hearing thresholds and NOR measures in three groups. The findings were in support of the link between the degree of hearing loss and impaired STM.

Comparison of motor recovery after neonatal and adult hemidecortication.

Hemidecortication produces a wide range of cognitive and motor symptoms in both children and lab animals that are generally far greater than smaller bilateral focal lesions of cerebral cortex. Although there have been many studies of motor functions after hemidecortication, the analyses largely have been of general motor functions rather than of more skilled motor functions such as forelimb reaching. The objective of the present experiment was to analyze the sensorimotor forelimb function of rats after infant or adult hemidecortication by utilizing multiple motor analyses. Rats were given hemidecortications either on postnatal day 10 (P10) or day 90 (P90). Both groups were then tested on a number of behavioural tasks (two tests of skilled reaching, forelimb placing during spontaneous vertical exploration, and a sunflower seed opening task) beginning at P 120. In a portion of the P10 female animals, topographic movement representations were derived in the hemisphere contralateral to lesion using Intracortical Microstimulation (ICMS). The brains of the male animals were prepared for Golgi-Cox staining and subsequent analysis of dendritic arborisation and spine density. There were three main findings. 1) Both groups of hemidecorticate animals were impaired when tested on the motor tasks, but the impairments were qualitatively different in the neonatal and adult operates. For example, the P 10 hemidecorticate animals displayed simultaneous bilateral forelimb movement, or "mirror movements." 2) Hemidecortication at P90 but not P10, led to increased dendritic arborisation of Layer III pyramidal cells in the intact parietal cortex but whereas P90 animals showed a decrease in cortical thickness in the intact hemisphere, the P10 animals do not, even though there are no callosal connections. 3) P10 hemidecortication altered the details of the ICMS-delineated motor maps in a small group of female hemidecorticates that were studied. In conclusion, there was postinjury compensation for motor impairments in both P10 and P90 rats but the mechanisms were different. Furthermore, comparisons of postinjury behavioral and anatomical compensation in rats with focal cortical injuries at those ages in our previous studies showed marked differences. These results suggest that there is a fundamental difference in the way that the brain compensates from hemidecortication and focal injury in development.

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.

Patricia Goldman-Rakic: a pioneer and leader in frontal lobe research.

Our understanding of the organization of the frontal cortex can be traced back to the experimental studies in the late 1800s by Fritsch and Hitzig on the frontal cortex of dogs and the frontal cortex of monkeys by Ferrier. These studies and many other studies that followed focused on motor functions, but halfway through the 20th century, very little was understood about the role of the frontal lobe in the control of other functions, and it was generally thought that the frontal lobe did not play a significant role in cognition. One result was that studies of cortical functions in cognition were carried out largely on parietal and temporal cortical regions with surprisingly little interest in the frontal lobe. The first systematic studies of the effects of prefrontal lesions on non-human primates began around 1950, especially by Rosvold and Mishkin in the Laboratory of Psychology at the National Institute of Mental Health (NIMH) in the United States. With her background in development, Pat Goldman joined this laboratory in 1965 and began an examination of the effects of prefrontal lobectomy on behavior in infant rhesus monkeys, both during development and later as the animals grew into adulthood. Her developmental studies were groundbreaking as they demonstrated that the effects of early prefrontal lesions varied with precise age (including prenatal), precise lesion location, behaviors measured, and age at assessment. She also began in parallel extensive studies of the role of the prefrontal cortex for a range of functions (especially working memory) in adult monkeys, which led to an examination of factors that influenced functional outcomes after injury or disease. This research was critical in helping to identify the significant role of the prefrontal cortex in cognition in both normal brains and neurological diseases such as schizophrenia. Her pioneering study demonstrating the role of the prefrontal cortex in cognition led to a remarkable increase in the number of researchers studying prefrontal functions in both non-human primates and rodents. This review will chronicle the key findings in her 35+ years studying the prefrontal cortex and illustrate the course she set for generations to follow.

Complex housing partially mitigates low dose radiation-induced changes in brain and behavior in rats.

PURPOSE: In recent years, much effort has been focused on developing new strategies for the prevention and mitigation of adverse radiation effects on healthy tissues and organs, including the brain. The brain is very sensitive to radiation effects, albeit as it is highly plastic. Hence, deleterious radiation effects may be potentially reversible. Because radiation exposure affects dendritic space, reduces the brain's ability to produce new neurons, and alters behavior, mitigation efforts should focus on restoring these parameters. To that effect, environmental enrichment through complex housing (CH) and exercise may provide a plausible avenue for exploration of protection from brain irradiation. CH is a much broader concept than exercise alone, and constitutes exposure of animals to positive physical and social stimulation that is superior to their routine housing and care conditions. We hypothesized that CHs may lessen harmful neuroanatomical and behavioural effects of low dose radiation exposure. METHODS: We analyzed and compared cerebral morphology in animals exposed to low dose head, bystander (liver), and scatter irradiation on rats housed in either the environmental enrichment condos or standard housing. RESULTS: Enriched condo conditions ameliorated radiation-induced neuroanatomical changes. Moreover, irradiated animals that were kept in enriched CH condos displayed fewer radiation-induced behavioural deficits than those housed in standard conditions. CONCLUSIONS: Animal model-based environmental enrichment strategies, such as CH, are excellent surrogate models for occupational and exercise therapy in humans, and consequently have significant translational possibility. Our study may thus serve as a roadmap for the development of new, easy, safe and cost-effective methods to prevent and mitigate low-dose radiation effects on the brain.

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.

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.

Sensitive Periods for Recovery from Early Brain Injury.

The developing brain is remarkably plastic as it changes in response to a wide range of experiences including sensory and motor experience, psychoactive drugs, peer relationships, parent-infant interactions, gonadal hormones, intestinal flora, diet, and injury. There are sensitive periods for many of these experiences, including cerebral injury. Comparisons across mammalian species (humans, monkeys, cats, rats, mice) show a sensitive period for good outcomes from cerebral injury around the time of intense synaptogenesis. This period is postnatal in humans, cats, and rats, but prenatal in monkeys, reflecting the differences in neuronal development at birth across species. In addition, there appears to be a sensitive period prenatally during the time of maximum cortical neurogenesis and possibly during adolescence as well, although these periods are not as well studied as the period related to synaptogenesis and to date only examined in rats. Here we review the evidence for sensitive periods related to brain injury across species and propose mechanisms that may underlie the plasticity during these periods.

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.

Knowledge gaps for functional outcomes after multilobar resective and disconnective pediatric epilepsy surgery: Conference Proceedings of the Patient-Centered Stakeholder Meeting 2019.

For children with medication-resistant epilepsy who undergo multilobar or hemispheric surgery, the goal of achieving seizure freedom is met with a variety of potential functional consequences, both favorable and unfavorable. However, there is a paucity of literature that comprehensively addresses the cognitive, medical, behavioral, orthopedic, and sensory outcomes across the lifespan following large epilepsy surgeries in childhood, leaving all stakeholders underinformed with regard to counseling and expectations. Through collaboration between clinicians, researchers, and patient/caregiver stakeholders, the "Functional Impacts of Large Resective or Disconnective Pediatric Epilepsy Surgery: Identifying Gaps and Setting PCOR Priorities" meeting was convened on July 18, 2019, to identify gaps in knowledge and inform various patient-centered research initiatives. Clinicians and researchers with content expertise presented the best available data in each functional domain which is summarized here. As a result of the meeting, the top three consensus priorities included research focused on postoperative: (1) hydrocephalus; (2) mental health issues; and (3) literacy and other educational outcomes. The proceedings of this meeting mark the first time research on functional outcomes after resective and disconnective pediatric epilepsy surgery has been codified and shared among multidisciplinary stakeholders. This joint initiative promotes continued collaboration in the field and ensures that advancements align with actual patient and family needs and experiences. Collaboration around common objectives will lead to better informed counseling around postoperative expectations and management for children undergoing epilepsy surgery.

Bilingual experience and intrinsic functional connectivity in adults, aging, and Alzheimer's disease.

The past decade marked the beginning of the use of resting-state functional connectivity (RSFC) imaging in bilingualism studies. This paper intends to review the latest evidence of changes in RSFC in language and cognitive control networks in bilinguals during adulthood, aging, and early Alzheimer's disease, which can add to our understanding of brain functional reshaping in the context of second language (L2) acquisition. Because of high variability in bilingual experience, recent studies mostly focus on the role of the main aspects of bilingual experience (age of acquisition (AoA), language proficiency, and language usage) on intrinsic functional connectivity (FC). Existing evidence accounts for stronger FC in simultaneous rather than sequential bilinguals in language and control networks, and the modulation of the AoA impact by language proficiency and usage. Studies on older bilingual adults show stronger FC in language and frontoparietal networks and preserved FC in posterior brain regions, which can protect the brain against cognitive decline and neurodegenerative processes. Altered RSFC in language and control networks subsequent to L2 training programs also is associated with improved global cognition in older adults. This review ends with a brief discussion of potential confounding factors in bilingualism research and conclusions and suggestions for future research.

Age-related hearing loss and cognitive decline: MRI and cellular evidence.

Extensive evidence supports the association between age-related hearing loss (ARHL) and cognitive decline. It is, however, unknown whether a causal relationship exists between these two, or whether they both result from shared mechanisms. This paper intends to study this relationship through a comprehensive review of MRI findings as well as evidence of cellular alterations. Our review of structural MRI studies demonstrates that ARHL is independently linked to accelerated atrophy of total and regional brain volumes and reduced white matter integrity. Resting-state and task-based fMRI studies on ARHL also show changes in spontaneous neural activity and brain functional connectivity; and alterations in brain areas supporting auditory, language, cognitive, and affective processing independent of age, respectively. Although MRI findings support a causal relationship between ARHL and cognitive decline, the contribution of potential shared mechanisms should also be considered. In this regard, the review of cellular evidence indicates their role as possible common mechanisms underlying both age-related changes in hearing and cognition. Considering existing evidence, no single hypothesis can explain the link between ARHL and cognitive decline, and the contribution of both causal (i.e., the sensory hypothesis) and shared (i.e., the common cause hypothesis) mechanisms is expected.

Prenatal stress dysregulates resting-state functional connectivity and sensory motifs.

Prenatal stress (PS) can impact fetal brain structure and function and contribute to higher vulnerability to neurodevelopmental and neuropsychiatric disorders. To understand how PS alters evoked and spontaneous neocortical activity and intrinsic brain functional connectivity, mesoscale voltage imaging was performed in adult C57BL/6NJ mice that had been exposed to auditory stress on gestational days 12-16, the age at which neocortex is developing. PS mice had a four-fold higher basal corticosterone level and reduced amplitude of cortical sensory-evoked responses to visual, auditory, whisker, forelimb, and hindlimb stimuli. Relative to control animals, PS led to a general reduction of resting-state functional connectivity, as well as reduced inter-modular connectivity, enhanced intra-modular connectivity, and altered frequency of auditory and forelimb spontaneous sensory motifs. These resting-state changes resulted in a cortical connectivity pattern featuring disjoint but tight modules and a decline in network efficiency. The findings demonstrate that cortical connectivity is sensitive to PS and exposed offspring may be at risk for adult stress-related neuropsychiatric disorders.

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.