Ruili Xie, Tessa-Jonne F. Ropp, Michael R. Kasten, and Paul B. Manis
Hearing loss generally occurs in the auditory periphery but leads to changes in the central auditory system. Noise-induced hearing loss (NIHL) and age-related hearing loss (ARHL) affect neurons in the ventral cochlear nucleus (VCN) at both the cellular and systems levels. In response to a decrease in auditory nerve activity associated with hearing loss, the large synaptic endings of the auditory nerve, the endbulbs of Held, undergo simplification of their structure and the volume of the postsynaptic bushy neurons decreases. A major functional change shared by NIHL and ARHL is the development of asynchronous transmitter release at endbulb synapses during periods of high afferent firing. Compensatory adjustements in transmitter release, including changes in release probability and quantal content, have also been reported. The excitability of the bushy cells undergoes subtle changes in the long-term, although short-term, reversible changes in excitability may also occur. These changes are not consistently observed across all models of hearing loss, suggesting that the time course of hearing loss, and potential developmental effects, may influence endbulb transmission in multiple ways. NIHL can alter the representation of the loudness of tonal stimuli by VCN neurons and is accompanied by changes in spontaneous activity in VCN neurons. However, little is known about the representation of more complex stimuli. The relationship between mechanistic changes in VCN neurons with noise-induced or age-related hearing loss, the accompanying change in sensory coding, and the reversibility of changes with the reintroduction of auditory nerve activity are areas that deserve further thoughtful exploration.
Donald M. Caspary and Daniel A. Llano
As arguably the third most common malady of industrialized populations, age-related hearing loss is associated with social isolation and depression in a subset of the population that will approach 25% by 2050. Development of behavioral or pharmacotherapeutic approaches to prevent or delay the onset of age-related hearing loss and mitigate the impact of hearing loss of speech understanding requires a better understanding of age-related changes that occur in the central auditory processor. This chapter critically reviews and discusses changes that occur in the auditory brainstem and thalamus with increased age. It briefly discusses age-related cellular changes that occur de novo within the central auditory system versus deafferentation plasticity and animal models of aging. Subsections discuss the cochlear nucleus, superior olivary complex, inferior colliculus, and the medial geniculate body with an emphasis on age-related changes in neurotransmission and how these changes could underpin the observed loss of precise temporal processing with increased age.
The Auditory Brainstem Implant: Restoration of Speech Understanding from Electric Stimulation of the Human Cochlear Nucleus
Robert V. Shannon
The auditory brainstem implant (ABI) is a surgically implanted device to electrically stimulate auditory neurons in the cochlear nucleus complex of the brainstem in humans to restore hearing sensations. The ABI is similar in function to a cochlear implant, but overall outcomes are poorer. However, recent applications of the ABI to new patient populations and improvements in surgical technique have led to significant improvements in outcomes. While the ABI provides hearing benefits to patients, the outcomes challenge our understanding of how the brain processes neural patterns of auditory information. The neural pattern of activation produced by an ABI is highly unnatural, yet some patients achieve high levels of speech understanding. Based on a meta-analysis of ABI surgeries and outcomes, a theory is proposed of a specialized sub-system of the cochlear nucleus that is critical for speech understanding.
Nell Beatty Cant
This chapter summarizes what is known about the organization of the axons that make up the white matter of the auditory brainstem. The sources of the axons in each of the major fiber bundles (the dorsal and intermediate acoustic striae, the ventral acoustic stria or trapezoid body, and the lateral lemniscus) are reviewed, and, where information is available, the organization of specific groups of axons within the fiber bundles is described. The chapter collects the extensive but scattered information about axon trajectories into one place, both to provide a summary of what is known and also to indicate important gaps in our knowledge. The emphasis is almost entirely on the routes followed by groups of axons over the relatively long distances between structures and on the organization of specific types of axons within the fiber bundles; information about the termination patterns of the axons can be obtained from the references cited and throughout the chapter. Because knowledge about axon trajectories has considerable practical value (as, for example, in designing and interpreting both anatomical and physiological studies), the most useful information is species specific. Fortunately, at least at our current level of understanding, the components and relative positions of the major fiber bundles are remarkably similar across species (undoubtedly reflecting a common mammalian developmental plan).
Nina Kraus and Trent Nicol
The encoding of speech and music in the auditory brainstem is available at the human scalp via the auditory-evoked frequency following response. The FFR, primarily reflecting activity in the inferior colliculus, may be evoked by speech or music stimulation and represents the combined activity of sensorimotor, cognitive, and reward centers in the brain. Its response properties, like the inferior colliculus itself, are influenced by long-term experience with sound. The transparency, individual-level reliability, and ability to gauge neural plasticity provide the researcher and clinician a powerful probe of auditory processing in the human brainstem. With it, we have learned a great deal about how mechanisms of decline, deprivation, and enrichment affect the processing of complex signals such as music and speech in the human brainstem.
Rie Bager Hansen and Sarah Falk
Pain is a common and feared complication for many cancer patients. Cancer pain covers numerous pain syndromes; since the treatment is complex, it is essential to assess each individual patient with cancer pain thoroughly. Cancer pain includes not only elements of inflammatory and neuropathic pain, but also, importantly, cancer-specific elements. Starting with the clinical aspects of cancer pain and the current knowledge from in vivo models, this chapter provides an overview of the neurobiology known to drive cancer-induced bone pain as it evolves through the complex interplay between primary afferents, tumor cells, and bone cells. There continue to be many uncertainties and unknown mechanisms involved in cancer pain, and an effort to discover novel therapeutic targets should be emphasized as cancer pain poses an increasing clinical and socioeconomic burden.
Changes in the Inferior Colliculus Associated with Hearing Loss: Noise-Induced Hearing Loss, Age-Related Hearing Loss, Tinnitus and Hyperacusis
Alan R. Palmer and Joel I. Berger
The inferior colliculus is an important auditory relay center that undergoes fundamental changes following hearing loss, whether noise induced (NIHL) or age related (ARHL). These changes may contribute to the induction or maintenance of phenomena such as tinnitus (phantom auditory sensations) and hyperacusis (increased sensitivity to sound). Here, we outline changes that can occur in the inferior colliculus following damage to the periphery and/or as a result of the ageing process, both immediate and long-term, and attempt to disentangle which changes relate to either tinnitus or hyperacusis, as opposed to solely hearing loss. Understanding these changes is ultimately important to reversing the underlying pathology and treating these conditions.
Uhtaek Oh and Jooyoung Jung
Pain may be induced by activation of various ion channels expressed in primary afferent neurons. These channels function as molecular sensors that detect noxious chemical, temperature, or tactile stimuli and transduce them into nociceptor electrical signals. Transient receptor potential channels are good examples because they are activated by chemicals, heat, cold, and acid in nociceptors. Anion channels were little studied in nociception because of the notion that anion channels might induce hyperpolarization of nociceptors on opening. In contrast, opening of Cl- channels in dorsal root ganglion (DRG) neurons depolarizes sensory neurons, resulting in excitation of nociceptors, thereby inducing pain. Anoctamin 1(ANO1)/TMEM16A is a Ca2+-activated Cl- channel expressed mainly in small DRG neurons, suggesting a nociception role. ANO1 is a heat sensor that detects heat over 44°C. Ano1-deficient mice elicit less nocifensive behaviors to hot temperatures. In addition, mechanical allodynia and hyperalgesia induced by inflammation or nerve injury are alleviated in Ano1-/- mice. More important, Ano1 transcripts are increased in chronic pain models. Bestrophin 1 (Best1) is another Ca2+-activated Cl- channel expressed in nociceptors. Best1 is increased in axotomized DRG neurons. The role of Best1 in nociception is not clear. GABAA receptors are in the central process of DRG neurons; GABA depolarizes the primary afferents. This depolarization consists of primary afferent depolarization essential for inhibiting nociceptive input to second-order neurons in the spinal cord, regulating pain signals to the brain. Thus, although Cl- channels in nociceptors are not as numerous as TRP channels, their role in nociception is distinct and significant.
Donata Oertel, Xiao-Jie Cao, and Alberto Recio-Spinoso
Plasticity in neuronal circuits is essential for optimizing connections as animals develop and for adapting to injuries and aging, but it can also distort the processing, as well as compromise the conveyance of ongoing sensory information. This chapter summarizes evidence from electrophysiological studies in slices and in vivo that shows how remarkably robust signaling is in principal cells of the ventral cochlear nucleus. Even in the face of short-term plasticity, these neurons signal rapidly and with temporal precision. They can relay ongoing acoustic information from the cochlea to the brain largely independently of sounds to which they were exposed previously.
J.A. Kaltenbach and D.A. Godfrey
Tinnitus most commonly begins with alterations of input from the ear resulting from cochlear trauma or overstimulation of the ear. Because the cochlear nucleus is the first processing center in the brain receiving cochlear input, it is the first brainstem station to adjust to this modified input from the cochlea. Research published over the last 30 years demonstrates changes in neural circuitry and activity in the cochlear nucleus that are associated with and may be the origin of the signals that give rise to tinnitus percepts at the cortical level. This chapter summarizes what is known about these disturbances and their relationships to tinnitus. It also summarizes the mechanisms that trigger tinnitus-related disturbances and the anatomical, chemical, neurophysiological, and biophysical defects that underlie them. It concludes by highlighting some major controversies that research findings have generated and discussing the clinical implications the findings have for the future treatment of tinnitus.
Roy E. Ritzmann and Sasha N. Zill
This article discusses legged locomotion in insects. It describes the basic patterns of coordinated movement both within each leg and among the various legs. The nervous system controls these actions through groups of joint pattern generators coupled through interneurons and interjoint reflexes in a range of insect species. These local control systems within the thoracic ganglia rely on leg proprioceptors that monitor joint movement and cuticular strain interacting with central pattern generation interneurons. The local control systems can change quantitatively and qualitatively as needed to generate turns or more forceful movements. In dealing with substantial obstacles or changes in navigational movements, more profound changes are required. These rely on sensory information processed in the brain that projects to the multimodal sensorimotor neuropils collectively referred to as the central complex. The central complex affects descending commands that alter local control circuits to accomplish appropriate redirected movements.
Brett R. Schofield and Nichole L. Beebe
Descending auditory pathways originate from multiple levels of the auditory system and use a variety of neurotransmitters, including glutamate, GABA, glycine, acetylcholine, and dopamine. Targets of descending projections include cells that project to higher or lower centers, setting up circuit loops and chains that provide top-down modulation of many ascending and descending circuits in the auditory system. Descending pathways from the auditory cortex can evoke plasticity in subcortical centers. Such plasticity relies, at least in part, on brainstem cholinergic systems that are closely tied to descending cortical projections. Finally, the ventral nucleus of the trapezoid body, a component of the superior olivary complex, is a major target of descending projections from the cortex and midbrain. Through its complement of different neurotransmitter phenotypes, and its wide array of projections, the ventral nucleus of the trapezoid body is positioned to serve as a hub in the descending auditory system.
Manuel S. Malmierca, Guillermo V. Carbajal, and Carles Escera
In the past, there was a rather corticocentric conception of the processing of relationships between sounds that used to mostly relegate the midbrain function to a mere relay. However, increasing neurophysiological evidence demonstrates that the midbrain is, in fact, playing a crucial role in encoding some sorts of regularities present in the flow of acoustic stimulation, adapting the neuronal response for processing efficiency. Midbrain neurons are capable of responding more rapidly and strongly when a new stimulus is not matching to a previously encoded regularity; a phenomenon referred to as deviance detection. This chapter discusses deviance detection evidence in the midbrain, mainly describing the characteristics and mechanisms of stimulus-specific adaptation (SSA), and closing with an interpretation from the standpoint of the predictive coding theory.
Nanna Brix Finnerup and Nadine Attal
The present chapter presents an update of the current classification, diagnosis, assessment, mechanisms, and treatment of neuropathic pain. Neuropathic pain, which is defined as pain associated with a lesion or disease of the somatosensory nervous system, may be caused by a variety of conditions, such as diabetic neuropathy, herpes zoster, surgical trauma, spinal cord injury, and stroke. The diagnostic criteria for neuropathic pain are a history of a nervous system disease or lesion and pain distribution and sensory signs in a neuroanatomically plausible distribution. The treatment of neuropathic pain is often multidisciplinary and involves specific drugs. Recent progress in the diagnosis, assessment, and understanding of its mechanisms offers the perspective of a more rational therapeutic management, which should result in better therapeutic outcome.
Hanns Ulrich Zeilhofer and Robert Ganley
The spinal dorsal horn and its equivalent structure in the brainstem constitute the first sites of synaptic integration in the pain pathway. A huge body of literature exists on alterations in spinal nociceptive signal processing that contribute to the generation of exaggerated pain states and hence to what is generally known as “central sensitization.” Such mechanisms include changes in synaptic efficacy or neuronal excitability, which can be evoked by intense nociceptive stimulation or by inflammatory or neuropathic insults. Some of these changes cause alterations in the functional organization of dorsal horn sensory circuits, leading to abnormal pathological pain sensations. This chapter reviews the present state of this knowledge. It does not cover the contributions of astrocytes and microglia in detail as their functions are the subject of a separate chapter.
Edward C. Emery and Patrik Ernfors
Primary sensory neurons of the dorsal root ganglion (DRG) respond and relay sensations that are felt, such as those for touch, pain, temperature, itch, and more. The ability to discriminate between the various types of stimuli is reflected by the existence of specialized DRG neurons tuned to respond to specific stimuli. Because of this, a comprehensive classification of DRG neurons is critical for determining exactly how somatosensation works and for providing insights into cell types involved during chronic pain. Here, we review the recent advances in unbiased classification of molecular types of DRG neurons in the perspective of known functions as well as predicted functions based on gene expression profiles. The data show that sensory neurons are organized in a basal structure of three cold-sensitive neuron types, five mechano-heat sensitive nociceptor types, four A-Low threshold mechanoreceptor types, five itch-mechano-heat–sensitive nociceptor types and a single C–low-threshold mechanoreceptor type with a strong relation between molecular neuron types and functional types. As a general feature, each neuron type displays a unique and predicable response profile; at the same time, most neuron types convey multiple modalities and intensities. Therefore, sensation is likely determined by the summation of ensembles of active primary afferent types. The new classification scheme will be instructive in determining the exact cellular and molecular mechanisms underlying somatosensation, facilitating the development of rational strategies to identify causes for chronic pain.
Leonard K. Kaczmarek
All neurons express a subset of over seventy genes encoding potassium channel subunits. These channels have been studied in auditory neurons, particularly in the medial nucleus of the trapezoid body. The amplitude and kinetics of various channels in these neurons can be modified by the auditory environment. It has been suggested that such modulation is an adaptation of neuronal firing patterns to specific patterns of auditory inputs. Alternatively, such modulation may allow a group of neurons, all expressing the same set of channels, to represent a variety of responses to the same pattern of incoming stimuli. Such diversity would ensure that a small number of genetically identical neurons could capture and encode many aspects of complex sound, including rapid changes in timing and amplitude. This review covers the modulation of ion channels in the medial nucleus of the trapezoid body and how it may maximize the extraction of auditory information.
Giedre Milinkeviciute and Karina S. Cramer
The auditory brainstem carries out sound localization functions that require an extraordinary degree of precision. While many of the specializations needed for these functions reside in auditory neurons, additional adaptations are made possible by the functions of glial cells. Astrocytes, once thought to have mainly a supporting role in nervous system function, are now known to participate in synaptic function. In the auditory brainstem, they contribute to development of specialized synapses and to mature synaptic function. Oligodendrocytes play critical roles in regulating timing in sound localization circuitry. Microglia enter the central nervous system early in development, and also have important functions in the auditory system’s response to injury. This chapter highlights the unique functions of these non-neuronal cells in the auditory system.
Felix Viana and Thomas Voets
Noxious cold and noxious heat have detrimental effects on key biological macromolecules and thus on the integrity of cells, tissues, and organisms. Thanks to the action of a subset of somatosensory neurons, mammals can swiftly detect noxiously cold or hot objects or environments. These temperature-sensitive nociceptor neurons become activated when the temperature at their free endings in the skin or mucosae reaches noxious levels, provoking acute pain and rapid avoidance reflexes. Whereas acute temperature-induced pain is essential to prevent or limit burn injury, pathological conditions such as inflammation or tissue injury can deregulate the thermal sensitivity of the somatosensory system, resulting in painful dysesthesias such as heat and cold hypersensitivity. In recent years, important advances have been made in our understanding of the cellular and molecular mechanisms that underlie the detection of painful heat or cold. These research efforts not only provided key insights into an evolutionary conserved biological alarm system, but also revealed new avenues for the development of novel therapies to treat various forms of persistent pain.
James J. Cox, Ingo Kurth, and C. Geoffrey Woods
Inherited pain disorders are typically rare in the general population. However, in the postgenomic era, single-gene mutations for numerous human Mendelian pain disorders have been described owing to advances in sequencing technology and improvements in pain phenotyping. This chapter describes the history, phenotype, gene mutations, and molecular/cellular pathology of painless and painful inherited monogenic disorders. The study of these disorders has led to the identification of key genes that are needed for the normal development or function of nociceptive neurons. Genes that are covered include ATL1, ATL3, DNMT1, DST, ELP1, FLVCR1, KIF1A, NGF, NTRK1, PRDM12, RETREG1, SCN9A, SCN10A, SCN11A, SPTLC1, SPTLC2, TRPA1, WNK1, and ZFHX2. The study of some Mendelian disorders of pain sensing has the potential to lead to new classes of analgesic drugs.