Disorders of the Nervous System

The traditional view of central nervous system function presumed that learning is the province of the brain. From this perspective, the spinal cord functions primarily as a conduit for incoming/outgoing neural impulses, capable of organizing simple reflexes but incapable of learning. Research has challenged this view, demonstrating that neurons within the spinal cord, isolated from the brain by means of a spinal cut (transection), can encode environmental relations and that this experience can have a lasting effect on function. The exploration of this issue has been informed by work in the learning literature that establishes the behavioral criteria and work within the pain literature that has shed light on the underlying neurobiological mechanisms. Studies have shown that spinal systems can exhibit single stimulus learning (habituation and sensitization) and are sensitive to both stimulus–stimulus (Pavlovian) and response–outcome (instrumental) relations. Regular environmental relations can both bring about an alteration in the performance of a spinally mediated response and impact the capacity to learn in future situations. The latter represents a form of behavioral metaplasticity. At the neurobiological level, neurons within the central gray matter of the spinal cord induce lasting alterations by engaging the NMDA receptor and signal pathways implicated in brain-dependent learning and memory. Of particular clinical importance, uncontrollable/unpredictable pain (nociceptive) input can induce a form of neural over-excitation within the dorsal horn (central sensitization) that impairs adaptive learning. Pain input after a contusion injury can increase tissue loss and undermines long-term recovery.

Decreased ability to smell is common in older persons. Some demonstrable smell loss is present in more than 50% of those 65 to 80 years of age, with up to 10% having no smell at all (anosmia). Over the age of 80, 75% exhibit some loss with up to 20% being totally anosmic. The causes of these decrements appear multifactorial and likely include altered intranasal airflow patterns, cumulative damage to the olfactory receptor cells from viruses and other environmental insults, decrements in mucosal metabolizing enzymes, closure of the cribriform plate foramina through which olfactory receptor cells axons project to the brain, loss of selectivity of receptor cells to odorants, and altered neurotransmission, including that exacerbated in some age-related neurodegenerative diseases.

Understanding of the various types of plasticity that occur in the spinal cord, as well as understanding of spinal cord functions, has vastly improved over the past 50 years, mainly due to an increase in the number of research studies and review articles on the subject. It is now understood that the spinal cord is not merely a passive conduit of neural impulses. Instead, the spinal cord can independently execute complex functions. Numerous experimental approaches have been utilized for more targeted exploration of spinal cord functions. For example, isolating the spinal cord from supraspinal influences has been used to demonstrate that simple forms of learning can be performed by spinal neuronal networks. Moreover, reduced preparations, such as acute spinal cord slices, have been used to show that spinal neurons undergo different types of modulation, including activity-dependent synaptic modification. Most spinal cord processes, ranging from integration of incoming sensory input to execution of locomotor outputs, involve plasticity. Nociceptive processing that leads to pain and spinal learning is an example of plasticity that is well-studied in the spinal cord. At the neural level, both processes involve an interplay of cellular mediators, which include glutamate receptors, protein kinases, and growth factors. The neurotrophin brain-derived neurotrophic factor (BDNF) has also been implicated in these processes, specifically as a promoter of both pro-nociception and spinal learning mechanisms. Interestingly, the role of BDNF in mediating spinal plasticity can be altered by injury. The literature spanning approximately 5 decades is reviewed and the role of BDNF is discussed in mediating cellular plasticity underlying pain processing and learning within the spinal cord.

The majority of anxiety disorders emerge during childhood and adolescence, a developmental period characterized by dynamic changes in frontolimbic circuitry. Frontolimbic circuitry plays a key role in fear learning and has been a focus of recent efforts to understand the neurobiological correlates of anxiety disorders across development. Although less is known about the neurobiological underpinnings of anxiety disorders in youth than in adults, studies of pediatric anxiety have revealed alterations in both the structure and function of frontolimbic circuitry. The amygdala, prefrontal cortex (PFC), anterior cingulate cortex (ACC), and hippocampus contribute to fear conditioning and extinction, and interactions between these regions have been implicated in anxiety during development. Specifically, children and adolescents with anxiety disorders show altered amygdala volumes and exhibit heightened amygdala activation in response to neutral and fearful stimuli, with the magnitude of signal change in amygdala reactivity corresponding to the severity of symptomatology. Abnormalities in the PFC and ACC and their connections with the amygdala may reflect weakened top-down control or compensatory efforts to regulate heightened amygdala reactivity associated with anxiety. Taken together, alterations in frontolimbic connectivity are likely to play a central role in the etiology and maintenance of anxiety disorders. Future studies should aim to translate the emerging understanding of the neurobiological bases of pediatric anxiety disorders to optimize clinical interventions for youth.

Injured axons fail to regenerate in the adult mammalian central nervous system, representing a major barrier for effective neural repair. Both extrinsic inhibitory environments and neuron-intrinsic mechanisms contribute to such regeneration failure. In the past decade, there has been an explosion in our understanding of neuronal injury responses and regeneration regulations. As a result, several strategies have been developed to promote axon regeneration with the potential of restoring functions after injury. This article will highlight these new developments, with an emphasis on cellular and molecular mechanisms from a neuron-centric perspective, and discuss the challenges to be addressed toward developing effective functional restoration strategies.

Spinal cord injury (SCI) disrupts the autonomic nervous system (ANS) and impairs communication with organ systems throughout the body, resulting in chronic multi-organ pathology and dysfunction. This dysautonomia contributes to the pronounced immunosuppression and gastrointestinal dysfunction seen after SCI. All of these factors likely contribute to the development of gut dysbiosis after SCI—an imbalance in the composition of the gut microbiota that can impact the development and progression of numerous pathological conditions, including SCI. The gut microbiota are the community of microbes (bacteria, viruses, fungi) that live in the GI tract and are critical for nutrient absorption, digestion, and immune system development. These microbes also communicate with the CNS through modulation of the immune system, production of neuroactive metabolites and neurotransmitters, and activation of the vagus nerve. After SCI, gut dysbiosis develops and persists for more than one year from the time of injury. In experimental models of SCI, gut dysbiosis is correlated with changes in inflammation and functional recovery. Moreover, probiotic treatment can improve locomotor recovery and immune function in the gut-associated lymphoid tissue (GALT). Since different types of bacteria produce different metabolites with unique physiological and pathological effects throughout the body, it may be possible to predict the prevalence or severity of post-injury immune dysfunction and other related comorbidities (e.g., metabolic disease, fatigue, anxiety) using microbiome sequencing data. As research identifies microbial-derived small molecules and the genes responsible for their production, it is likely that it will become feasible to manipulate these molecules to affect human biology and disease.

The hypocretins (also known as orexins) are selectively expressed in a subset of lateral hypothalamic neurons. Since the reports of their discovery in 1998, they have been intensely investigated in relation to their role in sleep/wake transitions, feeding, reward, drug abuse, and motivated behavior. This research has cemented their role as a subcortical relay optimized to tune arousal in response to various salient stimuli. This article reviews their discovery, physiological modulation, circuitry, and integrative functionality contributing to vigilance state transitions and stability. Specific emphasis is placed on humoral and neural inputs regulating hcrt neural function and new evidence for an autoimmune basis of the sleep disorder narcolepsy. Future directions for this field involve dissection of the heterogeneity of this neural population using single-cell transcriptomics, optogenetic, and chemogenetics, as well as monitoring population and single cell activity. Computational models of the hypocretin network, using the “flip-flop” or “integrator neuron” frameworks, provide a fundamental understanding of how this neural population influences brain-wide activity and behavior.

Spinal cord injury results in a wide range of behavioral changes including impaired motor and sensory function, autonomic dysfunction, spasticity, and depression. Currently, restoring lost motor function is the most actively studied and sought-after goal of spinal cord injury research. This research is rooted in the fact that although self-repair following spinal cord injury in adult mammals is very limited, there can be some recovery of motor function. This recovery is strongly dependent on the lesion size and location as well as on neural activity of denervated networks activated mainly through physical activity (i.e., rehabilitative training). Recovery of motor function is largely due to neuroplasticity, which includes adaptive changes in spared and injured neural circuitry. Neuroplasticity after spinal cord injury is extensive and includes mechanisms such as moderate axonal sprouting, the formation of new synaptic connections, network remapping, and changes to neuron cell properties. Neuroplasticity after spinal cord injury has been described at various physiological and anatomical levels of the central nervous system including the brain, brainstem, and spinal cord, both above and below injury sites. The growing number of mechanisms underlying postinjury plasticity indicate the vast complexity of injury-induced plasticity. This poses important opportunities to further enhance and harness plasticity in order to promote recovery. However, the diversity of neuroplasticity also creates challenges for research, which is frequently based on mechanistically driven approaches. The appreciation of the complexity of neuronal plasticity and the findings that recovery is based on a multitude and interlinked adaptations will be essential in developing meaningful new treatment avenues.

Network analyses in nervous system disorders involve constructing and analyzing anatomical and functional brain networks from neuroimaging data to describe and predict the clinical syndromes that result from neuropathology. A network view of neurological disease and clinical syndromes facilitates accurate quantitative characterizations and mathematical models of complex nervous system disorders with relatively simple tools drawn from the field of graph theory. Networks are predominantly constructed from in vivo data acquired using physiological and neuroimaging techniques at the macroscale of nervous system organization. Studies support the emerging view that neuropsychiatric and neurological disorders result from pathological processes that disrupt the brain’s economically wired small-world organization. The lens of network science offers theoretical insight into progressive neurodegeneration, neuropsychological dysfunction, and potential anatomical targets for interventions ranging from pharmacological agents to brain stimulation.

Bidirectional interactions between the immune system and central nervous system have been acknowledged for centuries. Over the past 100 years, pioneering studies in both animal models and humans have delineated the behavioral consequences of neuroimmune activation, including the different facets of sickness behavior. Rodent studies have uncovered multiple neural pathways and mechanisms that mediate anorexia, fever, sleep alterations, and social withdrawal following immune activation. Furthermore, work conducted in human patients receiving interferon treatment has elucidated some of the mechanisms underlying immune-induced behavioral changes such as malaise, depressive symptoms, and cognitive deficits. These findings have provided the foundation for development of treatment interventions for conditions in which dysfunction of immune-brain interactions leads to behavioral pathology. Rodent models of neuroimmune activation frequently utilize endotoxins and cytokines to directly stimulate the immune system. In the absence of pathogen-induced inflammation, a variety of environmental stressors, including psychosocial stressors, also lead to neuroimmune alterations and concurrent behavioral changes. These behavioral alterations can be assessed using a battery of behavioral paradigms while distinguishing acute sickness behavior from the type of behavioral outcome being assessed. Animal studies have also been useful in delineating the role of microglia, the neuroendocrine system, neurotransmitters, and neurotrophins in mediating the behavioral implications of altered neuroimmune activity. Furthermore, the timing and duration of neuroimmune challenge as well as the sex of the organism can impact the behavioral manifestations of altered neuroimmune activity. Finally, neuroimmune modulation through pharmacological or psychosocial approaches has potential for modulating behavior.

Nicotinic acetylcholine receptors (nAChRs) are present throughout the central nervous system and involved in a variety of physiological and behavioral functions. Nicotinic acetylcholine receptors are receptive to the presence of nicotine and acetylcholine and can be modulated through a variety of agonist and antagonist actions. These receptors are complex in their structure and function, and they are composed of multiple α and β subunits. Many affective disorders have etiological links with developmental exposure to the nAChR agonist nicotine. Given that abnormalities in nAChRs are associated with affective disorders such as depression and anxiety, pharmacological interventions targeting nAChRs may have significant therapeutic benefits.

Chronic pain lasting months or longer is very common, poorly treated, and sometimes devastating. Nociceptors are sensory neurons that usually are silent unless activated by tissue damage or inflammation. In humans their peripheral activation evokes conscious pain, and their spontaneous activity is highly correlated with spontaneous pain. Persistently hyperactive nociceptors mediate increased responses to normally painful stimuli (hyperalgesia) in chronic conditions and promote the sensitization of central pain pathways that allows low-threshold mechanoreceptors to elicit painful responses to innocuous stimuli (allodynia). Investigations of rodent models of neuropathic pain and hyperalgesic priming have revealed many alterations in nociceptors and associated cells that are implicated in the development and maintenance of chronic pain. These include chronic nociceptor hyperexcitability and spontaneous activity, sprouting, synaptic plasticity, changes in intracellular signaling, and modified responses to opioids, along with alterations in the expression and translation of thousands of genes in nociceptors and closely linked cells.

Phantom sensations are experienced by almost every person who has lost their hand in adulthood. This mysterious phenomenon spans the full range of bodily sensations, including the sense of touch, temperature, movement, and even the sense of wetness. For a majority of upper-limb amputees, these sensations will also be at times unpleasant, painful, and for some even excruciating to the point of debilitating, causing a serious clinical problem, termed phantom limb pain (PLP). Considering the sensory organs (the receptors in the skin, muscle or tendon) are physically missing, in order to understand the origins of phantom sensations and pain the potential causes must be studied at the level of the nervous system, and the brain in particular. This raises the question of what happens to a fully developed part of the brain that becomes functionally redundant (e.g. the sensorimotor hand area after arm amputation). Relatedly, what happens to the brain representation of a body part that becomes overused (e.g. the intact hand, on which most amputees heavily rely for completing daily tasks)? Classical studies in animals show that the brain territory in primary somatosensory cortex (S1) that was “freed up” due to input loss (hereafter deprivation) becomes activated by other body part representations, those neighboring the deprived cortex. If neural resources in the deprived hand area get redistributed to facilitate the representation of other body parts following amputation, how does this process relate to persistent phantom sensation arising from the amputated hand? Subsequent work in humans, mostly with noninvasive neuroimaging and brain stimulation techniques, have expanded on the initial observations of cortical remapping in two important ways. First, research with humans allows us to study the perceptual consequence of remapping, particularly with regards to phantom sensations and pain. Second, by considering the various compensatory strategies amputees adopt in order to account for their disability, including overuse of their intact hand and learning to use an artificial limb, use-dependent plasticity can also be studied in amputees, as well as its relationship to deprivation-triggered plasticity. Both of these topics are of great clinical value, as these could inform clinicians how to treat PLP, and how to facilitate rehabilitation and prosthesis usage in particular. Moreover, research in humans provides new insight into the role of remapping and persistent representation in facilitating (or hindering) the realization of emerging technologies for artificial limb devices, with special emphasis on the role of embodiment. Together, this research affords a more comprehensive outlook at the functional consequences of cortical remapping in amputees’ primary sensorimotor cortex.

Human spinal cord injury (SCI) results in long-lasting disabilities due to the failure of damaged neurons to regenerate. The barriers to axon regeneration in mammalian central nervous system (CNS) are so great, and the anatomy so complex that incremental changes in regeneration brought about by pharmacological or molecular manipulations can be difficult to demonstrate. By contrast, lampreys recover functionally after a complete spinal cord transection (TX), based on regeneration of severed axons, even though lampreys share the basic organization of the mammalian CNS, including many of the same molecular barriers to regeneration. And because the regeneration is incomplete, it can be studied by manipulations designed to either inhibit or enhance it. In the face of reduced descending input, recovery of swimming and other locomotor functions must be accompanied by compensatory remodeling throughout the CNS, as would be required for functional recovery in mammals. For such studies, lampreys have significant advantages. They have several large, identified reticulospinal (RS) neurons, whose regenerative abilities have been individually quantified. Other large neurons and axons are visible in the spinal cord and can be impaled with microelectrodes under direct microscopic vision. The central pattern generator for locomotion is exceptionally well-defined, and is subject to significant neuromodulation. Finally, the lamprey genome has been sequenced, so that molecular homologs of human genes can be identified and cloned. Because of these advantages, the lamprey spinal cord has been a fertile source of information about the biology of axon regeneration in the vertebrate CNS, and has the potential to serve as a test bed for the investigation of novel therapeutic approaches to SCI and other CNS injuries.

Neuroimmunology is the study of the interaction between the immune system and nervous system during development, homeostasis, and disease states. Descriptions of neuroinflammatory diseases dates back centuries. However, in depth scientific investigation in the field began in the late 19th century and continues into the 21st century. Contrary to prior dogma in the field of neuroimmunology, there is immense reciprocal crosstalk between the brain and the immune system throughout development, homeostasis, and disease states. Proper neuroimmune functioning is necessary for optimal health, as the neuroimmune system regulates vital processes including neuronal signaling, synapse pruning, and clearance of debris and pathogens within the central nervous system. Perturbations in optimal neuroimmune functioning can have detrimental consequences for the host and underlie a myriad of physical, cognitive, and behavioral abnormalities. As such, the field of neuroimmunology is still relatively young and dynamic and represents an area of active research and discovery.

Spinal cord injury (SCI) is a life-altering event for which there is no treatment. Depending on injury location and severity, the breadth of the effects can go far past simple mobility. Primary mechanical trauma triggers a variety of secondary cellular events that exacerbate tissue loss as well as facilitate endogenous repair. A large focus of SCI research is on understanding the pathophysiological mechanisms through which these secondary responses contribute to morbidities associated with SCI. Neuroinflammation, a common response to central nervous system (CNS) insult, is central to the secondary injury cascade. In the context of SCI, the inflammatory response plays a contradictory role in recovery; immune cells release both pro- and anti-inflammatory cytokines at the injury site and clear debris while also causing damage to spared tissue. The major innate and adaptive immune cells that respond to SCI are neutrophils, astrocytes, microglia/macrophages, B cells, and T cells. For each cell type, the timing of the cellular response (in both human and rodent models of SCI), the potential role each cell type plays in the pathophysiology of injury, and the therapeutic implications of targeting each cell type for SCI recovery are discussed.

The modulatory influence of sex hormones on acute pain, chronic pain disorders, and pain management has been reported for over seven decades. The effect of hormones on pain is clearly evidenced by the multitude of chronic pain disorders that are more common in women, such as headache and migraine, temporomandibular joint disorder, irritable bowel syndrome, chronic pelvic pain, fibromyalgia, rheumatoid arthritis, and osteoarthritis. Several of these pain disorders also fluctuate in pain intensity over the menstrual cycle, including headache and migraine and temporomandibular joint disorder. The sex steroid hormones (estrogen, progesterone, and testosterone) as well as some peptide hormones (prolactin, oxytocin, and vasopressin) have been linked to pain by both clinical and preclinical research. Progesterone and testosterone are widely accepted as having protective effects against pain, while the literature on estrogen reports both exacerbation and attenuation of pain. Prolactin is reported to trigger pain, while oxytocin and vasopressin have analgesic properties in both sexes. Only in the last two decades have neuroscientists begun to unravel the complex anatomical and molecular mechanisms underlying the direct effects of sex hormones and mechanisms have been reported in both the central and peripheral nervous systems. Mechanisms include directly or indirectly targeting receptors and ion channels on sensory neurons, activating pain excitatory or pain inhibitory centers in the brain, and reducing inflammatory mediators. Despite recent progress, there remains significant controversy and challenges in the field and the seemingly pleiotropic role estrogen plays on pain remains ambiguous. Current knowledge of the effects of sex hormones on pain has led to the burgeoning of gender-based medicine, and gaining further insight will lead to much needed improvement in pain management in women.

Spinal cord injury (SCI) affects well over a million people in the United States alone, and its personal and societal costs are huge. This article provides a current overview of the organization of somatosensory and motor pathways, in the context of hand/paw function in nonhuman primate and rodent models of SCI. Despite decades of basic research and clinical trials, therapeutic options remain limited. This is largely due to the fact that (i) spinal cord structure and function is very complex and still poorly understood, (ii) there are many species differences which can make translation from the rodent to primate difficult, and (iii) we are still some way from determining the detailed multilevel pathway responses affecting recovery. There has also been little focus, until recently, on the sensory pathways involved in SCI and recovery, which are so critical to hand function and the recovery process. The potential for recovery in any individual depends on many factors, including the location and size of the injury, the extent of sparing of fiber tracts, and the post-injury inflammatory response. There is also a progression of change over the first weeks and months that must be taken into account when assessing recovery. There are currently no good biomarkers of recovery, and while axon terminal sprouting is frequently used in the experimental setting as an indicator of circuit remodeling and “recovery,” the correlation between sprouting and functional recovery deserves scrutiny.

Spinal cord injury is characterized by a complex set of events, which include the disruption of connectivity between the brain and the periphery with little or no spontaneous regeneration, resulting in motor, sensory and autonomic deficits. Transplantation of neural stem cells has the potential to provide the cellular components for repair of spinal cord injury (SCI), including oligodendrocytes, astrocytes, and neurons. The ability to generate graft-derived neurons can be used to restore connectivity by formation of functional relays. The critical requirements for building a relay are to achieve long-term survival of graft-derived neurons and promote axon growth into and out of the transplant. Recent studies have demonstrated that mixed populations of glial and neuronal progenitors provide a permissive microenvironment for survival and differentiation of early-stage neurons, but inclusion of growth factors with the transplant or cues for directional axon growth outside the transplant may also be needed. Other important considerations include the timing of the transplantation and the selection of a population of neurons that maximizes the effective transmission of signals. In some experiments, the essential neuronal relay formation has been developed in both sensory and motor systems related to locomotion, respiration, and autonomic functions. Despite impressive advances, the poor regenerative capacity of adult CNS combined with the inhibitory environment of the injury remain a challenge for achieving functional connectivity via supraspinal tracts, but it is possible that recruitment of local propriospinal neurons may facilitate the formation of relays. Furthermore, it is clear that the new connections will not be identical to the original innervation, and therefore there needs to be a mechanism for translating the resulting connectivity into useful function. A promising strategy is to mimic the process of neural development by exploiting the remarkable plasticity associated with activity and exercise to prune and strengthen synaptic connections. In the meantime, the sources of neural cells for transplantation are rapidly expanding beyond the use of fetal CNS tissue and now include pluripotent ES and iPS cells as well as cells obtained by direct reprogramming. These new options can provide considerable advantages with respect to preparation of cell stocks and the use of autologous grafting, but they present challenges of complex differentiation protocols and risks of tumor formation. It is important to note that although neural stem cell transplantation into the injured spinal cord is primarily designed to provide preclinical data for the potential treatment of patients with SCI, it can also be used to develop analogous protocols for repair of neuronal circuits in other regions of the CNS damaged by injury or neurodegeneration. The advantages of the spinal cord system include well-defined structures and a large array of quantitative functional tests. Therefore, studying the formation of a functional relay will address the fundamental aspects of neuronal cell replacement without the additional complexities associated with brain circuits.