Handbook of clinical neurology最新文献

Sleep and circadian rhythms are regulated by dynamic physiologic processes that operate across multiple spatial and temporal scales. These include, but are not limited to, genetic oscillators, clearance of waste products from the brain, dynamic interplay among brain regions, and propagation of local dynamics across the cortex. The combination of these processes, modulated by environmental cues, such as light-dark cycles and work schedules, represents a complex multiscale system that regulates sleep-wake cycles and brain dynamics. Physiology-based mathematical models have successfully explained the mechanisms underpinning dynamics at specific scales and are a useful tool to investigate interactions across multiple scales. They can help answer questions such as how do electroencephalographic (EEG) features relate to subthalamic neuron activity? Or how are local cortical dynamics regulated by the homeostatic and circadian mechanisms? In this chapter, we review two types of models that are well-positioned to consider such interactions. Part I of the chapter focuses on the subthalamic sleep regulatory networks and a model of arousal dynamics capable of predicting sleep, circadian rhythms, and cognitive outputs. Part II presents a model of corticothalamic circuits, capable of predicting spatial and temporal EEG features. We then discuss existing approaches and unsolved challenges in developing unified multiscale models.

Neuroglia in the CNS, represented by astroglia, oligodendroglia, and microglia, are responsible for the homeostatic support and protection of the nervous tissue. Neuroglia are intimately involved in the pathogenesis of all neurologic diseases, and neuroglial changes to a large extent define the progression of these diseases and their neurologic outcome. In contrast to neurons, neuroglia are capable of mounting an evolutionary conserved response to pathology known as reactive gliosis. Reactive gliosis is initially protective and allostatic, and it is aimed at preserving the nervous tissue function and integrity. However, in many diseases, neuroglial cells undergo atrophy and functional asthenia, contributing to nervous tissue damage.

This chapter introduces and discusses maternal immune activation (MIA) as a contributing factor in increasing the risk of neurodevelopmental disorders, particularly in relation to its interactions with neuroglia. Here we first provide an overview of the neuroglia-astroglia, oligodendroglia, microglia, and radial glial cells-and their important role during early brain development and in adulthood. We then present and discuss MIA, followed by a critical overview of inflammatory molecules and temporal stages associated to maternal inflammation during pregnancy. We provide an overview of animal and human models used to mimic and study MIA. Furthermore, we review the possible interaction between MIA and neuroglia, focusing on the current advances in both modeling and therapeutics. Additionally, we discuss and provide preliminary and interesting insights into the most recent pandemic, COVID-19, and how the infection may be associated to MIA and increased risk for neurodevelopmental disorders. Finally, we provide a critical overview of challenges and future opportunities to study how MIA may contribute to higher risk of developing neurodevelopmental disorders.

Anxiety disorders are some of the most prevalent in the world and are extraordinarily debilitating to many individuals, costing millions in disability. One of the most disabling is posttraumatic stress disorder (Snijders et al., 2020). Understanding the pathophysiology of these illnesses further and the cell types involved will allow better targeting of treatments. Glial cells, encompassing microglia, astrocytes, and oligodendrocytes, play critical roles in the pathophysiology of PTSD and other anxiety illnesses. Each of these cell types interacts with aspects of neuro-epigenetics, neuroimmune, and neuronal signaling and may contribute to the pathophysiology of anxiety illnesses. This chapter covers the literature on the role of glial cells in the neurobiology and pathology of anxiety disorders, more specifically PTSD. PTSD is one of the most debilitating anxiety disorders and one of the most complicated from a neurobiologic perspective. This chapter also features a discussion surrounding the current state of treatment and some of the hypothesized mechanisms for novel treatments including tetrahydrocannabidiol and 3,4-methylenedioxymethamphetamine. Finally, thoughts on the future directions for precision treatment and pharmacologic development with a focus on neuroglia are undertaken.

Multiple lines of evidence indicate that mood disorders, such as major depressive and bipolar disorder, are associated with abnormalities in neuroglial cells. This chapter discusses the existing literature investigating the potential role of astrocytes, oligodendrocytes, and microglia in mood pathology. We will describe evidence from in vivo imaging, postmortem, animal models based on (stress) paradigms that mimic depressive-like behavior, and biomarker studies in blood and cerebrospinal fluid in patients with mood disorders. The effect of medication used in the treatment of mood disorders, such as antidepressants and lithium, on glial function is discussed. Lastly, we highlight the most relevant findings about potential deficiencies in glia-glia crosstalk in mood disorders. Overall, decreased astrocyte and oligodendrocyte density and expression and microglial changes in homeostatic functions have frequently been put forward in MDD pathology. Studies of BD report similar findings to some extent; however, the evidence is less well established. Together, these findings are suggestive of reduced glial cell function leading to potential white matter abnormalities, glutamate dysregulation, disrupted neuronal functioning, and neurotransmission. However, more research is required to better understand the exact mechanisms underlying glial cell contributions to mood disorder development.

Microglia, the resident innate immune cells of the central nervous system (CNS), play an important role in neuroimmune signaling, neuroprotection, and neuroinflammation. In the healthy CNS, microglia adopt a surveillant and antiinflammatory phenotype characterized by a ramified scanning morphology that maintains CNS homeostasis. In response to acquired insults, such as traumatic brain injury (TBI) or spinal cord injury (SCI), microglia undergo a dramatic morphologic and functional switch to that of a reactive state. This microglial switch is initially protective and supports the return of the injured tissue to a physiologic homeostatic state. However, there is now a significant body of evidence that both TBI and SCI can result in a chronic state of microglial activation, which contributes to neurodegeneration and impairments in long-term neurologic outcomes in humans and animal models. In this review, we discuss the complex role of microglia in the pathophysiology of TBI and SCI, and recent advancements in knowledge of microglial phenotypic states in the injured CNS. Furthermore, we highlight novel therapeutic strategies targeting chronic microglial responses in experimental models and discuss how they may ultimately be translated to the clinic for human brain and SCI.

In Parkinson disease (PD), cholinergic dysfunction develops in the early stages of the neurodegenerative process and progresses over time. Basal forebrain cholinergic system dysfunction is historically linked to cognitive decline in the dementia spectrum, and its pathophysiologic role in PD-related cognitive impairment has now been well established. However, cholinergic system dysfunction is also linked to several other manifestations of PD, such as gait difficulties, REM sleep behavior disorder (RBD), neuropsychiatric manifestations such as depression and visual hallucinations, and olfactory dysfunction. Furthermore, disruption of the striatal intrinsic cholinergic system, which modulates dopamine release, has been linked to cardinal motor manifestations and dyskinesia. Manifestations of cognitive decline, gait problems, falls, and RBD tend to cluster in a subset of people with PD, so that a "cholinergic phenotype" has been proposed. In this chapter, the involvement of the cholinergic system and its clinical correlates in PD will be discussed.

Acute coma in the intensive care unit and persistent disorders of consciousness (DoC) in neuro-rehabilitation are frequent in patients with hypoxic-ischemic encephalopathy after cardiac arrest (CA), traumatic brain injury, intracranial hemorrhage, or ischemic stroke. Reliable prognostication of long-term neurologic outcomes cannot be made by clinical examination alone in the early phase for many patients, and thus, additional investigations are necessary. Evoked potentials provide inexpensive, real-time, high temporal resolution, bedside, quantifiable information on different sensory pathways into the brain including local and global cortical processing. Short-latency somatosensory evoked potentials can reliably predict poor neurologic long-term outcome in the early phase after CA and are recommended by guidelines as one investigation within an early multimodal assessment. Middle-latency and event-related or cognitive evoked potentials provide information on the integrity of more advanced cortical processing, some closely related to consciousness. This information can help to identify those comatose patients with a good prognosis in the acute phase and help to better understand their precise clinical state and the chances of further recovery in patients with persistent DoC in neuro-rehabilitation. Further studies are necessary to improve the applicability of research findings in the clinical sphere.