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Inflammation is a self-defensive reaction that may develop into a chronic state and become a causative factor in the pathogenesis of a broad range of disabling diseases. Similar to peripheral inflammation, brain inflammation is increasingly being viewed as a target for treating neurological diseases, not only infectious and immune-mediated disorders such as meningitis or multiple sclerosis but also stroke, trauma, and neurodegenerative diseases that were originally not considered to be inflammatory. Microglial cells, the resident macrophages of brain parenchyma, are generally viewed as major sources of pro-inflammatory and potentially neurotoxic molecules in the damaged brain, However, a direct link between activated microglia and tissue damage has not been univocally demonstrated in vivo, and recent studies have rather documented exacerbation of injury following selective microglial ablation or anti-inflammatory treatments. Recent studies have implicated inflammation in the regulation of adult neurogenesis, thus broadening the therapeutic potential of strategies aimed at controlling neuroinflammation. This chapter summarizes the main evidence supporting both detrimental and protective roles of inflammation in acute and chronic brain diseases.

This chapter examines neural cell replacement therapy for neurodegenerative diseases and spinal cord injury. While neural transplantation has the potential to regenerate the brain, results from clinical trials testing the procedure over the last twenty years have not been very promising. The goal of decelerating neural degeneration and restoring brain function is still an unrealized possibility. The chapter points out that the underlying pathophysiology of neurodegenerative diseases may limit or preclude the regenerative potential of transplanting cells into the brain. In addition, the chapter explores some of the social and psychological implications of two hypothetical scenarios: one in which regeneration of the brain does not keep pace with regeneration of the body; and one in which it does.

The phenomenon of selective neuronal vulnerability to neurological diseases or insults, such as ischemia-reperfusion, brain trauma, and ageing-associated neurodegeneration, was described in the hippocampus nearly a century ago. The hippocampus has been the focus for many of the studies designed to identify the stresses to which neurons respond differentially, as well as the molecular, cellular and physiological mechanisms that may be responsible for such differential response patterns. Although final conclusions have not yet been reached on the mechanisms for differential neuronal responses to stress and disease, genomic and proteomic analyses, in conjunction with biochemical and physiological measurements, are beginning to point to endogenous differences between vulnerable and resistant populations of neurons. Collectively, these studies have identified differential patterns of energy metabolism, generation of reactive oxygen species, handling of transient intracellular calcium elevations, and the activity of the neurotransmitter glutamate, as some of the key processes that lead to selective sensitivity to neurological stresses. The genomic and proteomic analyses have revealed that differences in gene expression related to inflammatory and immune responses and responses to oxidative stress represent endogenous processes differentially expressed in neurons selectively vulnerable to stresses. The same is true for genes involved in DNA, RNA, and protein repair. Cells that are more resistant to stresses and disease conditions express genes for energy generation, nervous system development, and synaptic transmission at higher levels than those found in vulnerable neurons. The molecular pathways identified above and described in this chapter may eventually determine the targets for future therapeutic interventions for neurodegenerative diseases.

Most dementias are associated with a widespread pattern of atrophy in the forebrain, which is most apparent as a reduction in the weight of the brain measured post-mortem. As the brain undergoes loss of cells, there is a thinning of the neocortex, and an associated flattening of the sulci on the surface of the brain and the ventricles in its depths. Dementia can come about through a number of different causes. In a series of studies in the 1950s and 1960s, Sir Martin Roth and his colleagues at the University of Newcastle undertook a systematic evaluation of the nature of the post-mortem pathology in a large series of patients dying (both with and without dementia) in a psychogeriatric hospital. These studies highlighted the fact that the cognitive disturbances of senile dementia can be associated with a number of distinct patterns of neuropathology, associated with different causes and disease processes.

Philosophers have hypothesized that one of the defining characteristics of being human is the production and appreciation of art. Beginning in the early 20th century, observations following isolated strokes or brain surgery supported theories that artistic behaviors were mediated by complex interactions between the frontal and parietal lobes. While these findings were instrumental in establishing the foundations of functional neuroanatomy, the association between artistic behavior and brain circuitry remained crude at best. With advances in molecular biology, improved clinical measures, and sophisticated neuroimaging techniques, the study of neurodegenerative disease has become a powerful method for investigating behavior. Already, the study of neurodegenerative disease has yielded significant insights into the process of artistic behavior. In this chapter we present an overview of visuospatial functional anatomy, how neurodegenerative disease affects artistic sensibility, and detail the paradoxical functional facilitation of artistic ability in patients diagnosed with frontotemporal dementia. Specifically, the behaviors we document developed in the setting of profound and isolated speech dysfunction, a condition known as primary progressive aphasia. Based on the specific aphasia subtype - semantic dementia versus progressive nonfluent aphasia - the quality of these patient’s artistic interest appeared to differ. Taken together, we believe that patients suffering from the language variants of frontotemporal lobar degeneration are uniquely positioned to provide the greatest insights yet into aesthetic choice and artistic creation.

Prions are infectious particles composed only of proteins. Their importance resides in the concept that information transmission between two organisms can be devoid of nucleic acid. Prions are also well-known as the etiological agents of several neurodegenerative diseases of animals and humans called transmissible spongiform encephalopathies (TSEs). Literature on prion-associated diseases, transmission mechanisms, and the related normal isoform of the protein has grown impressively in the last few years, making it very difficult to cover all aspects of prion in depth in this chapter. This chapter therefore focuses on the history, symptoms, mechanisms of transmission and diagnosis of prion diseases, and currently proposed therapies. The roles of the normal isoform of the prion in physiology are also discussed, along with neuroinvasion and pathogenicity.

While some aspects of breathlessness in neurological disease are common to various neurological diseases, some aspects are specific to particular ones. This chapter therefore addresses the pathophysiology of breathlessness in neurological diseases and considers the general management strategies for this symptom in this group of diseases. It also discusses the causes of shortness of breath in specific conditions such as Parkinson's disease, dementia, neurodegenerative diseases, and stroke. The chapter furthermore includes a discussion on the ethical considerations of palliative management and terminal sedation in patients with neurological disease or advanced disease.

One of the most hotly debated topics in the field of neurodegenerative disease is the relationship between what has recently been described as dementia with Lewy bodies (DLB) and the condition of patients with Parkinson's disease (PD) who subsequently develop dementia (PDD). Recent advances in our understanding of the pathophysiology of DLB and PDD support the proposition that both of these entities represent points on a spectrum of cortical Lewy body disease (LBD), characterized by accumulation of Lewy pathology — which includes Lewy bodies (LBs) and Lewy neurites (LNs) — within susceptible populations of both cortical and subcortical neurons. There are two widely accepted diagnostic schemes for PD, stipulating progressive parkinsonism of undetermined cause without features suggestive of an alternative diagnosis and responding to dopaminergic therapy.

How do investigators define and modulate circuits in animals that are relevant to the pathophysiology of human neurodegenerative diseases? Animal models provide a variety of advantages for translational investigations related to neurodegenerative diseases, with the best models revealing new understanding of the mechanisms of disease and stimulating new therapeutic interventions. However, animal models have also led to many missteps with investigators following false paths. This review addresses the purpose of these animals models, describes how to identify relevant circuit abnormalities, provides examples of how such models relate to human neurodegenerative diseases, warns of critical limitations of such models, and finally suggests that better tools be developed for these translational investigations.

This chapter deals with the effect of systemic inflammation on neurodegenerative disease. It demonstrates that inflammation may contribute to Alzheimer’s disease (AD) progression. This chapter shows that the interactions between systemic inflammation and the microglia might have a profound influence on the acute and chronic phases of a neurodegenerative disease. It supports the hypothesis that systemic inflammation may accelerate the rate of decline in cognition in patients with AD. It shows that environmental enrichment can have a profound effect on the developing and diseased brain.

The question of whether any non-human species displays episodic memory is controversial. Associative accounts of animal learning recognize that behaviour can change in response to single events but this does not imply that animals need or are later able to recall representations of unique events at a different time and place. The lack of language is also relevant, being the usual medium for communicating about the world, but whether it is critical for the capacity to represent and recall events is a separate matter. One reason for suspecting that certain animals possess an episodic-like memory system is that a variety of learning and memory tasks have been developed that, even though they do not meet the strict criteria required for episodic memory, have an ‘episodic-like’ character.

Creativity is not a phenomenon that arises from the brain in isolation; it has an experiential, sociopolitical, and cultural context. Nonetheless, studies of the brain illuminate mechanistic aspects of human creativity with a clarity sufficient clearly to allow some predictions of the potential for creativity and have suggested ways in which it can be enhanced. This chapter briefly reviews associations between creativity and disease, focusing on rare case studies of people with neurodegenerative disease affecting the frontal lobe and executive processing. These suggest that impaired frontal activity can enhance more creative behaviors under some conditions, a hypothesis confirmed by direct testing with transient, noninvasive electrical interference with frontal lobe functions in healthy volunteers. The use of some drugs also has been associated with increased creativity. Improved performance on tests of creative cognition by people with Parkinson’s disease after treatment with L-dopa has highlighted roles for dopamine and norepinephrine in modulating cognitive flexibility. However, most of the recent advances in understanding brain mechanisms of creativity from functional brain imaging studies have highlighted that creativity is not localizable to one or a few brain regions, but instead engages coordinated activities across major systems in the brain, including the default mode network and executive control, salience, or attentional networks. With information on genotype and patterns of brain activity, neuroscientists may be able to classify people for their potential creativity.

This chapter describes the effects of deep brain stimulation on speech in Parkinson's disease (PD). The process involves the implantation of two electrodes either in the ventro-intermediate nucleus (Vim) of the thalamus, or the globus pallidus internum (Gpi) or the subthalamic nucleus (STN), depending on the symptomatology. Speech outcome is variable following DBS in the STN with improvement noted in some acoustic measures and oro-motor non-speech tasks, but deterioration of speech intelligibility in the majority of patients. Factors affecting speech response following STN-DBS are partly surgical, i.e., current spread and contact location. There is the need for further research into ways speech is affected by deep brain stimulation in order to maximize the benefits of the treatment.

The MMN amplitude is decreased and/or peak latency prolonged in a large number of different neurological disorders, such as neurodegenerative diseases, brain lesions, cochlear lesions, chronic pain, or tinnitus. This is to a great extent due to a decreased brain plasticity affecting the formation of memory traces for different sensory stimuli essential for different cognitive operations of the brain. Furthermore, MMN can serve as a measure of recovery or neural reorganization in different neurological disorders. For example, the recovery from aphasic symptoms after stroke was associated with the enhancement of MMN. MMN has also been useful in determining neural plastic changes of the auditory system associated with cochlear implantation.

This concluding chapter compares the work of Alain Prochiantz and Fred Gage—both of which presented the idea that some basic embryogenetic processes might continue in adult brains. While Prochiantz began to wonder whether homeoproteins could be plastic forces, Gage sought to invent a language that would allow thinking of the adult brain in terms of its embryogenesis. The background to Gage's conceptual innovation was very different from Prochiantz's. Gage had made a name for himself since the 1970s by grafting fetal brain tissue to mature brains to fight neurodegenerative diseases (mostly Parkinson's). He was interested in reintroducing, through cutting and pasting fetal tissue, the possibility of embryogenetic growth in diseased brains.

This chapter focuses on data from three speech disorders to illustrate articulatory changes that arise when the larynx is the nominal target of treatment. In each case, articulatory acoustic or kinematic data were collected to determine whether clinical efforts directed at phonation would have measurable effects on articulator movement. The finding of treatment effects spreading beyond the target of the larynx has important implications for our understanding of disordered speech motor control as well as for intervention strategies in these populations. Lip kinematics in seven speakers with spasmodic dysphonia were recorded before and after Botox injection of the vocal folds. Bilabial coordination indexes were more aberrant when spasm severity was greatest, moving towards control speaker values after voice treatment. Pre/post treatment recordings from 111 women with muscle tension dysphonia were analyzed for evidence of articulatory changes. Although treatment focused on the larynx, increases in vowel space and diphthong formant transitions suggest that increased articulatory dynamics accompanied the voice improvements. Lip kinematic data from ten speakers with Parkinson's disease (PD) revealed increased amplitudes and velocities, along with more consistent trajectories over multiple repetitions for loud speech. Acoustic recordings from a speaker with PD were analyzed for F2 diphthong transitions, which revealed evidence of increased articulatory excursions following intensive voice treatment, even though no therapy exercises involved articulation. The data from these speakers reveal altered vocal tract behavior when the larynx is the primary target of therapy.