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Translational Neuroscience
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Book description

Translational neuroscience is at the heart of clinical advancement in the fields of psychiatry, neurology and neurodevelopmental disorders. Written and edited by leading scientists and clinicians, this is a comprehensive and authoritative analysis of this emerging strategy for developing more effective treatments for brain disorders. Introductory chapters bring together perspectives from both academia and industry, while subsequent sections focus on disease groups, including bipolar disorder and depression, attention deficit hyperactivity disorder, substance abuse, autism, Alzheimer's disease, pain, epilepsy, Parkinson's disease and multiple sclerosis. Each section includes topical introductory and summary chapters, providing an overview and synthesis of the field. Translational Neuroscience: Applications in Psychiatry, Neurology, and Neurodevelopmental Disorders is an important text for clinicians, scientists and students in academic settings, government agencies and industry, as well as those working in the fields of public health and the behavioural sciences.

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Contents

  • Chapter 9 - Pain therapeutics
    pp 168-177
  • View abstract

    Summary

    The identification of drugs to treat major psychiatric disorders launched the fields of biological psychiatry, behavioral pharmacology, and neuropsychopharmacology. It had a profound impact not only on individuals suffering from these disorders and on the care and hospitalization of patients but also on the emergence of entirely new disciplines. The astute observations in the clinical setting that led to the first generation of psychoactive drugs created the putative framework for the potential discovery of new generations of psychotropic agents. The key challenge in the search for a new generation of improved psychoactive drugs has focused on: enhanced validation of the animal models used to characterize new chemical entities (NCEs) as bona fide models of the human disease and the use of these models to effectively translate NCEs to the human disease state. The learning curve for CNS research focuses on the unique complexity of the brain.
  • Chapter 10 - Multiple sclerosis
    pp 178-196
  • View abstract

    Summary

    Clinically, the principles of extinction learning form much of the foundation for the most effective behavioral therapies for fear-related anxiety disorders. Within the general class of anxiety disorders, posttraumatic stress disorder (PTSD) is unique in the sense that the precipitating traumatic event may provide the opportunity for acute intervention before the onset of symptoms and before memories have been consolidated. The use of propranolol to treat individuals with posttraumatic stress symptoms was initially described in a case series of physically and sexually abused children with severe symptoms of agitation. An alternative consolidation-blockade approach to the use of propranolol involves the administration of glucocorticoids to trauma-exposed patients. Finally, clinically directed interference with initial memory consolidation through the use of beta-blockers or glucocorticoids following acute trauma exposure could prevent or attenuate the formation of traumatic emotional memory and reduce risk of PTSD.
  • Chapter 11 - Parkinson's disease
    pp 197-213
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    Summary

    This chapter describes the recently identified molecular, cellular, and brain circuits thought to be responsible for the phenotypic behaviors that characterize mood disorders. It is becoming increasingly clear that the neurochemical and structurally related abnormalities are closely associated with abnormalities in cellular plasticity. The chapter presents preclinical evidence and discusses the data obtained from relevant clinical studies. It provides an overview of the recent neuroimaging findings in mood disorders, highlighting how the extant data implicate a network formed by the medial prefrontal cortex (PFC) and anatomically related areas of the striatum, thalamus, anterior temporal cortex, hippocampus, amygdala, hypothalamus, and brain stem in the pathophysiology of mood disorders. The chapter helps readers make sense of the many novel findings presented, to extract integrated themes, and draw insight from the data. It is clear that genetic factors play a major role in the etiology of mood disorders.
  • Chapter 12 - Amyotrophic lateral sclerosis
    pp 214-227
  • View abstract

    Summary

    Recent advances in research on schizophrenia have significantly changed the manner in which translational research is being conducted in this field. Although there is a lack of gross morphological change observed in the brains of schizophrenic patients, there is substantial evidence that this disorder is one of impaired synaptic connectivity, which has been observed in numerous humans postmortem as well as in functional and structural brain imaging studies. This chapter outlines the major neuropathological and behavioral abnormalities associated with schizophrenia. It discusses the risk genes most implicated in the pathophysiology of schizophrenia and outlines their roles in regulating aspects of neuroplasticity thought to be perturbed in this disease. The chapter describes the pharmacological and genetic animal models that are being used in translational research. It highlights novel therapeutic targets currently being investigated for treating schizophrenia.
  • Chapter 13 - Epilepsy
    pp 228-252
  • View abstract

    Summary

    The fundamental basis of addiction is learning which is mediated by neuroplasticity. Treatment of addiction usually begins with detoxification. The signs and symptoms of withdrawal are usually opposite to the changes produced by the acute effects of the drug, appearing as a kind of rebound. The first treatment to use cross-tolerance as a maintenance strategy was discovered in heroin addiction by Vincent Dole and colleagues in the early 1960s. Researchers have been working for decades to learn the mechanism of action of important medications such as opioids. Another approach to the treatment of opioid addiction developed in preclinical laboratories involves the use of partial opioid agonists. The next advance in the treatment of tobacco dependence was the serendipitous discovery that the antidepressant bupropion reduced craving for cigarettes and improved abstinence rates. The clinical effects are analogous to the effects of buprenorphine in opioid addicts.
  • Chapter 14 - Section summary and perspectives: Translational medicine in neurology
    pp 253-260
  • View abstract

    Summary

    The fact that risk genes for schizophrenia are salient for brain development or that fetal brain insults mimic the cortical and behavioral pathology of schizophrenia has led to a certain degree of pessimism that these deficits could be ameliorated in the mature brain. Animal models of disorders like schizophrenia that are manifest primarily by cognitive symptoms such as disorganized thinking and hallucinations are based on rather tenuous behavioral inferences such as hyperactivity and stereotypic behavior and are equivalent to psychosis because it is reduced by antipsychotic drugs. Although it has long been known that schizophrenia is associated with loss of cortical volume and increased size of the lateral ventricles, the pathology of the mood disorders was thought to be primarily functional. Biogenic amine neurotransmitters were the major focus of translational research, given their role in mediating the therapeutic effects of antipsychotic and antidepressant medications.
  • Chapter 15 - Historical perspectives on the use of therapeutic agents to treat neurodevelopmental disorders
    pp 261-272
  • View abstract

    Summary

    Currently available treatments for neurodegenerative diseases are exclusively palliative. In Alzheimer's disease (AD) they are focused on the cholinergic deficit and alterations in glutamate function related to neurotoxicity. Finding drugs that can attenuate or reverse neurodegenerative disease progression is challenging in the absence of a complete understanding of the underlying causes. Biomarkers represent any measure that can be used to indicate the presence of a disease state. Biomarkers are critical both for making an accurate diagnosis of each of the neurodegenerative diseases and for assessing their status and response to treatment. They are crucial for clinical trials from their initial design, to patient recruitment, to establishing objective end points. Neurodegenerative disease-associated genes continue to be identified at an ever-increasing rate using genome-wide association studies (GWAS) in cohorts of affected individuals. A large number of candidate genes and loci identified for neurodegenerative diseases, for example, in excess of 120 for AD.
  • Chapter 16 - Autism spectrum disorders
    pp 273-302
  • View abstract

    Summary

    This chapter describes the syndromes of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Many elderly persons exhibit MCI, characterized by memory complaints and mild abnormalities of performance on formal tests, associated with intact general cognition and preserved activities of daily living. The clinical manifestations of AD arise from abnormalities involving brain regions and neural circuits composed of populations of neurons that are essential for memory, learning, and cognitive performance. Early information about the involvement of neurotransmitter-specific circuits damaged by the disease led to the design of early therapies for AD. The genetics of AD are complex, often influencing phenotype in an age-dependent manner. Late onset cases of AD without clear familial association reflect the influences of a variety of risk factors. The chapter emphasizes the need for safe and effective mechanism-based therapies for AD. New treatments will probably require combinatorial approaches.
  • Chapter 17 - Attention deficit hyperactivity disorder
    pp 303-320
  • View abstract

    Summary

    The specific classification of pain states can help guide therapeutic approaches, and often clinical pain states are complex and involve multiple mechanisms. The choice of drug treatment for acute pain is typically a function of the severity of the pain. The treatment of inflammatory pain typically focuses on reducing the inflammation. Unlike inflammatory pain, the current approved treatments for neuropathic pain focus on treating the symptoms and not necessarily the underlying causes. To better understand the role of translational medicine in the development of pain treatments, it is useful to have a general understanding of the drug discovery process for pain drugs with particular emphasis on the use of animal models that currently play a major role in identifying candidate molecules for clinical trials. In pain research the most commonly used neuroimaging techniques are functional magnetic resonance imaging (fMRI) and positron emission tomography (PET).
  • Chapter 18 - Epigenetic mechanisms in central nervous system disorders
    pp 321-333
  • View abstract

    Summary

    Translational medicine is beginning to be successfully applied in multiple sclerosis (MS). This chapter reviews how advances in our understanding of MS and our ability to measure MS are contributing to the application of translational medicine in this disorder. It presents a historical perspective on the evolution of disease-modifying treatments, and then proceeds to provide a discussion on molecular pathophysiology. Next, the factors that contribute to the efficiency of translational medicine are explained. Lastly, the future of disease-modifying therapies is discussed. Interferon beta (IFNβ) was the first effective disease-modifying therapy to become available for MS. The factors that improve the efficiency of translational medicine in MS include: the identification of drug targets within well-validated biological pathways; and the use of pharmacodynamic markers, especially in early proof-of-concept and dose-ranging clinical trials. The continuing accumulation of knowledge and understanding of MS can help to accelerate the developing novel therapies for MS.
  • Chapter 19 - Section summary and perspectives: Neurodevelopmental disorders and regulation of epigenetic changes
    pp 334-338
  • View abstract

    Summary

    Parkinson's disease (PD) is the second most common neurodegenerative disease in the USA. Although PD is traditionally recognized by its motor symptoms, refinement of our clinical and pathological tools has led to increasing recognition that PD also causes significant nonmotor deficits. Three main treatment strategies are currently used to provide motor symptom relief in patients with early PD. These strategies include using dopamine agonists as monotherapy, long lasting dopamine therapy, and nondopaminergic agents. The mortality rate of PD is about three times higher than the mortality rate in the normal age-matched population before the introduction of l-dopa treatment. To accelerate the development of novel PD therapies, it is essential to identify reliable biomarkers for PD. Lastly, equipped with new understanding of the molecular basis of PD, efforts are now targeted toward overcoming the major obstacles to developing an effective neuroprotective therapy for PD, including accurate animal models of PD.
  • Chapter 20 - Promises and challenges of translational research in neuropsychiatry
    pp 339-358
  • View abstract

    Summary

    Amyotrophic lateral sclerosis (ALS) is the most common form of adult motor neuron disease. A brief overview of some of the more important genes identified in familial ALS is provided. To date, riluzole is the only drug that has demonstrated efficacy in patients with ALS. One of the most challenging aspects in translating candidate therapeutic agents for ALS to clinical use is the appropriate clinical trial design. ALS-relevant compounds has recently increased, and the potential for interfering RNA (RNAi) and antisense technologies to target a specific but well-characterized (mutant superoxide dismutase 1) protein responsible for many cases of familial ALS may offer proof of the principle that ALS can be effectively treated if the upstream causative etiologies are identified. Finally, recent advances in stem cell research, including the development of induced pluripotent stem cells, offer the potential for autologous cell transplantation as well as drug discovery.

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