Cross-modal changes in primary visual cortex induced by somatosensory manipulation

This work shows that the manipulation of the somatosensory system (in form of whisker-deprivation) cross-modally influences the spared primary visual cortex of the fully adult mice. Revealed by a two choice discrimination behavioral task (visual water task) it cloud be shown, that the deprivation of the facial whiskers for twelve days improves visual acuity and contrast sensitivity by about 40%. This effect was confirmed by determining visual system thresholds using the method of optical imaging of intrinsic signals, a minimal-invasive technique to quantify and visualize cortical activity. Moreover it cloud be shown by using this method, that the deprivation of the facial whiskers restored experience- dependent plasticity, in form of ocular dominance plasticity, which is normally absent in fully adult mice. This effect could be abolished by the treatment with a drug that prevents Long-term-potentation (LTP) which suggests an involvement of the NMDA-receptor in the observed effect. To investigate the role of cortical inhibition, conveyed by GABAergic interneurons, which is described to play an important role for experience dependent plasticity in primary visual cortex, a GABAA-receptor agonist was given. The results, determined by using the method of optical imaging of intrinsic signals, showed that the effect was not prevented by this intervention. Instead of showing effects normal for young adults the treated animals showed a form of ocular dominance plasticity which normally only found during their early live span, the so called critical period. Furthermore it could be shown that the deprivation of the facial whiskers also affects plasticity in primary visual cortex without a manipulation of the visual system, after three days of somatosensory deprivation. It is a not-long lasting effect, whose mechanisms need more investigations. In addition to the improved cortex-dependent visual capabilities in adult mouse, the optokinetic reflex was better

Evidence of Key Tinnitus-Related Brain Regions Documented by a Unique Combination of Manganese-Enhanced MRI and Acoustic Startle Reflex Testing

Animal models continue to improve our understanding of tinnitus pathogenesis and aid in development of new treatments. However, there are no diagnostic biomarkers for tinnitus-related pathophysiology for use in awake, freely moving animals. To address this disparity, two complementary methods were combined to examine reliable tinnitus models (rats repeatedly administered salicylate or exposed to a single noise event): inhibition of acoustic startle and manganese-enhanced MRI. Salicylate-induced tinnitus resulted in wide spread supernormal manganese uptake compared to noise-induced tinnitus. Neither model demonstrated significant differences in the auditory cortex. Only in the dorsal cortex of the inferior colliculus (DCIC) did both models exhibit supernormal uptake. Therefore, abnormal membrane depolarization in the DCIC appears to be important in tinnitus-mediated activity. Our results provide the foundation for future studies correlating the severity and longevity of tinnitus with hearing loss and neuronal activity in specific brain regions and tools for evaluating treatment efficacy across paradigms

Interplay between Primary Cortical Areas and Crossmodal Plasticity

Perceptual representations are built through multisensory interactions underpinned by dense anatomical and functional neural networks that interconnect primary and associative cortical areas. There is compelling evidence that primary sensory cortical areas do not work in segregation, but play a role in early processes of multisensory integration. In this chapter, we firstly review previous and recent literature showing how multimodal interactions between primary cortices may contribute to refining perceptual representations. Secondly, we discuss findings providing evidence that, following peripheral damage to a sensory system, multimodal integration may promote sensory substitution in deprived cortical areas and favor compensatory plasticity in the spared sensory cortices

The Human Auditory System

This book presents the latest findings in clinical audiology with a strong emphasis on new emerging technologies that facilitate and optimize a better assessment of the patient. The book has been edited with a strong educational perspective (all chapters include an introduction to their corresponding topic and a glossary of terms). The book contains material suitable for graduate students in audiology, ENT, hearing science and neuroscience

Cross‑Modal Reaction of Auditory and Visual Cortices After Long‑Term Bilateral Hearing Deprivation in the Rat

[Abstract] Visual cortex (VC) over-activation analysed by evoked responses has been demonstrated in congenital deafness and after longterm acquired hearing loss in humans. However, permanent hearing deprivation has not yet been explored in animal models. Thus, the present study aimed to examine functional and molecular changes underlying the visual and auditory cross-modal reaction. For such purpose, we analysed cortical visual evoked potentials (VEPs) and the gene expression (RT-qPCR) of a set of markers for neuronal activation (c-Fos) and activity-dependent homeostatic compensation (Arc/Arg3.1). To determine the state of excitation and inhibition, we performed RT-qPCR and quantitative immunocytochemistry for excitatory (receptor subunits GluA2/3) and inhibitory (GABAA-α1, GABAB-R2, GAD65/67 and parvalbumin-PV) markers. VC over-activation was demonstrated by a signifcant increase in VEPs wave N1 and by up-regulation of the activity-dependent early genes c-Fos and Arc/Arg3.1 (thus confrming, by RT-qPCR, our previously published immunocytochemical results). GluA2 gene and protein expression were signifcantly increased in the auditory cortex (AC), particularly in layers 2/3 pyramidal neurons, but inhibitory markers (GAD65/67 and PV-GABA interneurons) were also signifcantly upregulated in the AC, indicating a concurrent increase in inhibition. Therefore, after permanent hearing loss in the rat, the VC is not only over-activated but also potentially balanced by homeostatic regulation, while excitatory and inhibitory markers remain imbalanced in the AC, most likely resulting from changes in horizontal intermodal regulationMinisterio de Economía y Competitividad; SAF2016–78898-C2-2-RMinisterio de Economía y Competitividad; BFU2017-82375-RJunta de Castilla y León; SA070P1

MULTIMODAL ASSESSMENT OF CETACEAN CENTRAL NERVOUS AUDITORY PATHWAYS WITH EMPHASIS ON FORENSIC DIAGNOSTICS OF ACOUSTIC TRAUMA

Cetaceans encompass some of the world’s most enigmatic species, with one of their greatest adaptations to the marine environment being the ability to “see” by hearing. Their anatomy and behavior are fine-tuned to emit and respond to underwater sounds, which is why anthropogenic noise pollution is likely to affect them negatively. There are many effects of noise on living organisms, and while knowledge on their entire palette and interplay remain incomplete, evidence for insults ranging from acoustic trauma over behavioral changes, to masking and stress, is accumulating. Humans are subject to peak interest in terms of medical research on noise-induced hearing loss. As major health concerns can be expected across species, addressing this problem in free-ranging cetacean populations will lead to a more sustainable management of marine ecosystems, more effective and balanced policies, and successes in conservation. While progress has been made in behavioral monitoring, electrophysiological hearing assessments and post-mortem examination of the inner ear of cetaceans, but very little is known about the neurochemical baseline and neuropathology of their central auditory pathways. In the present work, we reviewed the known effects of sound on cetaceans in both wild and managed settings and explored the value of animal models of neurodegenerative disease. We began by evaluating a row of antibodies associated with neurodegeneration in a more readily available species, the dog, where acute neurological insult could be derived from clinical history. We then set out to systematically validate a key panel of protein biomarkers for the assessment of similar neurodegenerative processes of the cetacean central nervous system. For this, we developed protocols to adequately sample cetacean auditory nuclei, optimized the immunohistochemical workflow, and used Western blot and alignment of protein sequences between the antigen targeted by our antibodies and the dolphin proteome. A Histoscore was used to semi-quantitively categorize immunoreactivity patterns and dolphins by age and presence of pathology. First results indicated significant differences both between sick and healthy, and young and old animals. We then expanded our list of validated antibodies for use in the bottlenose dolphin and the techniques used to assess them in a multimodal, quantitative way. 7T-MRI and stereology were implemented to assess the neuronal, axonal, glial and fiber tract counts in the inferior colliculus and ventral cochlear nucleus of a healthy bottlenose dolphin, which created a baseline understanding of protein expression in these structures, and the influence of tissue processing. This will make a valuable comparison for when positive controls of acoustic trauma would become available. Furthermore, we explored the connectome and neuronal morphology of auditory nuclei and experimented with probe designs and machine learning algorithms to quantify structures of interest. Comparisons with pathological human brains revealed similarities in the configuration of extracellular matrix components to those of a healthy dolphin, in line with existing knowledge on the tolerance to hypoxia in these diving animals. This could have interesting implications in future investigation of the evolutionary development of marine mammal brains, as well as help diversify out-of-the-box approaches to researching human neurodegenerative disease, as is being done with hibernating species. The data and methodologies described herein contribute to the knowledge on neurochemical signature of the cetacean central nervous system. They are intended to facilitate understanding of auditory and non-auditory pathology and build an evidence-based backbone to future policies regarding noise and other form of anthropogenic threats to the marine environment.Cetaceans encompass some of the world’s most enigmatic species, with one of their greatest adaptations to the marine environment being the ability to “see” by hearing. Their anatomy and behavior are fine-tuned to emit and respond to underwater sounds, which is why anthropogenic noise pollution is likely to affect them negatively. There are many effects of noise on living organisms, and while knowledge on their entire palette and interplay remain incomplete, evidence for insults ranging from acoustic trauma over behavioral changes, to masking and stress, is accumulating. Humans are subject to peak interest in terms of medical research on noise-induced hearing loss. As major health concerns can be expected across species, addressing this problem in free-ranging cetacean populations will lead to a more sustainable management of marine ecosystems, more effective and balanced policies, and successes in conservation. While progress has been made in behavioral monitoring, electrophysiological hearing assessments and post-mortem examination of the inner ear of cetaceans, but very little is known about the neurochemical baseline and neuropathology of their central auditory pathways. In the present work, we reviewed the known effects of sound on cetaceans in both wild and managed settings and explored the value of animal models of neurodegenerative disease. We began by evaluating a row of antibodies associated with neurodegeneration in a more readily available species, the dog, where acute neurological insult could be derived from clinical history. We then set out to systematically validate a key panel of protein biomarkers for the assessment of similar neurodegenerative processes of the cetacean central nervous system. For this, we developed protocols to adequately sample cetacean auditory nuclei, optimized the immunohistochemical workflow, and used Western blot and alignment of protein sequences between the antigen targeted by our antibodies and the dolphin proteome. A Histoscore was used to semi-quantitively categorize immunoreactivity patterns and dolphins by age and presence of pathology. First results indicated significant differences both between sick and healthy, and young and old animals. We then expanded our list of validated antibodies for use in the bottlenose dolphin and the techniques used to assess them in a multimodal, quantitative way. 7T-MRI and stereology were implemented to assess the neuronal, axonal, glial and fiber tract counts in the inferior colliculus and ventral cochlear nucleus of a healthy bottlenose dolphin, which created a baseline understanding of protein expression in these structures, and the influence of tissue processing. This will make a valuable comparison for when positive controls of acoustic trauma would become available. Furthermore, we explored the connectome and neuronal morphology of auditory nuclei and experimented with probe designs and machine learning algorithms to quantify structures of interest. Comparisons with pathological human brains revealed similarities in the configuration of extracellular matrix components to those of a healthy dolphin, in line with existing knowledge on the tolerance to hypoxia in these diving animals. This could have interesting implications in future investigation of the evolutionary development of marine mammal brains, as well as help diversify out-of-the-box approaches to researching human neurodegenerative disease, as is being done with hibernating species. The data and methodologies described herein contribute to the knowledge on neurochemical signature of the cetacean central nervous system. They are intended to facilitate understanding of auditory and non-auditory pathology and build an evidence-based backbone to future policies regarding noise and other form of anthropogenic threats to the marine environment

Response properties of the inferior colliculus following unilateral noise induced hearing loss : the effects of cholinergic enhancement and auditory training

Tinnitus is a common and potentially debilitating condition that is often associated with hearing loss. Noise induced hearing loss is a frequently utilised animal model, in studies investigating the underlying mechanisms of tinnitus. In the central auditory system, the inferior colliculus (IC) is an obligatory nucleus for the ascending processing of auditory signals. It has been comprehensively investigated in animal models of unilateral noise induced hearing loss (UNIHL). Previous studies have mostly investigated the dominant, contralateral pathway with little attention being paid to the ipsilateral path. In normal hearing animals, contralaterally driven IC neurons are primarily excitatory while ipsilaterally driven IC neurons are primarily inhibitory. However, there are also ipsilaterally driven IC neurons that are excitatory. Literature that have investigated the response properties of these neurons, and their consequential response properties within an animal model of UNHIL is very limited. The first study presented in this thesis investigated the consequences of UNIHL of both dominant contralaterally excitatory and non-dominant ipsilaterally excitatory neurons of the IC. The findings in this thesis may have implications for the development of therapies for tinnitus. By using a human equivalent dose of an approved drug, paired with a well-known neuro-rehabilitation intervention, together these interventions can significantly affect the consequential response properties of IC neurons that are observed following acoustic trauma. In a condition where currently there are no reliable cures, further development of these findings may provide insights that could lead to the generation of novel therapeutic approaches

Synaptic Plasticity in A Visual Cortical Region Induced by Early-Deafness

When organisms learn and adapt to their environment or lose a sensory modality, neurons in the brain undergo a cellular process called ‘plasticity.’ This thesis explores the loss of a non- visual system (early deafness) and how it can affect visual plasticity. To examine this question, Golgi-stained cortical neurons were studied from the visual region PLLS from early-deaf cats and their hearing controls. Dendritic spine density and dendritic spine diameter are well-known indicators of synaptic plasticity and these neuronal features were measured using light microscopic techniques and Neurolucida. Within the visual PLLS, the mean spine density for the deaf cats was 1.171 ± 0.295 spines/micron, while for hearing cats it was 0.984 ± 0.227 spines/micron, which was a statistically significant increase (p\u3c0.0001). The mean spine diameter for the deaf cats was 0.478 ± 0.119 microns, while for hearing cats it was 0.527 ± 0.211 microns, which is a statistically significant decrease (p\u3c0.0001). These changes in dendritic spine properties indicate that the neurons in the PLLS underwent synaptic plasticity. These findings are significant because they show that visual regions of cortex can be affected by non- visual conditions or treatments such as early deafness

Neural and behavioral plasticity in olfactory sensory deprivation

The human brain has a remarkable ability to reorganize as a consequence of altered demands. This ability is particularly noticeable when studying the neural effects of complete sensory deprivation. Both structural and functional cerebral reorganization have repeatedly been demonstrated in individuals with sensory deprivation, most evident in cortical regions associated with the processing of the absent sensory modality. Furthermore, sensory deprivation has been linked to altered abilities in remaining sensory modalities, often of a compensatory character. Although anosmia, complete olfactory sensory deprivation, is our most common sensory deprivation, estimated to affect around 5 % of the population, the effects of anosmia on brain and behavior are still poorly understood. The overall aim of this thesis was to investigate how the human brain and behavior are affected by anosmia, with a focus on individuals with congenital (lifelong) sensory deprivation. Specifically, Study I and Study IV assessed potential behavioral and neural multisensory compensatory abilities whereas Study II and Study III assessed potential reorganization beyond the processing of specific stimuli; the latter by determining morphological and resting-state functional connectivity alterations. Integration of information from different sensory modalities leads to a more accurate perception of the world around us, given that our senses provide complementary information. Although an improved ability to extract multisensory information would be of particular relevance to individuals deprived of one sensory modality, multisensory integration has been sparsely studied in relation to sensory deprivation. In Study I, multisensory integration of audio-visual stimuli was assessed in individuals with anosmia using two different experimental tasks. First, individuals with anosmia were better than matched controls in detecting multisensory temporal asynchronies in a simultaneity judgement task. Second, individuals with congenital, but not acquired, anosmia demonstrated indications of an enhanced ability to utilize multisensory information in an object identification task with degraded stimuli. Based on these results, the neural correlates of audio-visual processing and integration were assessed in individuals with congenital anosmia in Study IV. Relative to matched normosmic individuals, individuals with congenital anosmia demonstrated increased activity in established multisensory regions when integrating degraded audio-visual stimuli; however, no compensatory cross-modal processing in olfactory regions was demonstrated. Together, Study I and IV suggest that complete olfactory sensory deprivation is linked to enhanced audio-visual integration performance that might be facilitated by increased processing in multisensory regions. In Study II, whole-brain gray matter morphology was assessed in individuals with congenital anosmia. Both increases and decreases in the orbitofrontal cortex, a region associated with olfaction and sometimes referred to as secondary olfactory cortex, were observed in individuals with congenital anosmia in relation to matched controls. However, in contrast to our expectations, no sensory deprivation-dependent effects were demonstrated in piriform cortex, a region commonly referred to as primary olfactory cortex. Furthermore, Study III revealed an absence of differences in resting-state functional connectivity between individuals withcongenital anosmia and normosmic individuals within the primary olfactory cortex (including piriform cortex) as well as between core olfactory processing regions. In conclusion, the studies presented within this thesis suggest the existence of a potential multisensory compensatory mechanism in individuals with anosmia, but demonstrate a striking lack of morphological and functional alterations in piriform (primary olfactory) cortex. These results demonstrate that complete olfactory deprivation is associated with a distinct neural and behavioral reorganization in some regions but also a clear lack of effects in other regions; the latter underline the clear differences between our senses and suggest that extrapolating from individual senses should be done cautiously

Update On Hearing Loss

Update on Hearing Loss encompasses both the theoretical background on the different forms of hearing loss and a detailed knowledge on state-of-the-art treatment for hearing loss, written for clinicians by specialists and researchers. Realizing the complexity of hearing loss has highlighted the importance of interdisciplinary research. Therefore, all the authors contributing to this book were chosen from many different specialties of medicine, including surgery, psychology, and neuroscience, and came from diverse areas of expertise, such as neurology, otolaryngology, psychiatry, and clinical and experimental audiology