Biology of Brain Dysfunction

The growth of neurochemistry, molecular biology, and biochemical genetics has led to a burgeoning of new information relevant to the pathogenesis of brain dysfunction. This explosion of exciting new information is crying out for collation and meaningful synthesis. In its totality, it defies systematic summa­ tion, and, of course, no one author can cope. Thus invitations for contributions were given to various experts in areas which are under active investigation, of current neurological interest, and pregnant. Although this project is relatively comprehensive, by dint of size, other topics might have been included; the selection was solely my responsibility. I believe systematic summation a virtual impossibility-indeed, hardly worth the effort. The attempt to assemble all of the sections involved in a large treatise with mUltiple authors inevitably results in untoward delays due to the difference in the rate at which various authors work. Therefore, the following strategy has been adopted: multiple small volumes and a relatively flexible format, with publication in order of receipt and as soon as enough chapters are assembled to make publication practical and economical. In this way, the time lag between the ideas and their emergence in print is the shortest.

1 Disorders of Sphingolipid Metabolism.- I. Introduction.- II. Chemistry, Metabolism, and Distribution of Sphingolipids.- A. Chemistry.- B. Metabolism.- C. Distribution.- III. Individual Sphingolipidoses.- A. Sphingomyelinosis (Niemann-Pick Disease).- B. Glucosylceramide Lipidosis (Gaucher’s Disease).- C. Leukodystrophies.- D. Lactosylceramide Lipidosis.- E. Trihexosylceramide Lipidosis (Fabry’s Disease).- F. Gangliosidoses.- G. Miscellaneous Disorders.- IV. Summary and Concluding Remarks.- References.- 2 Disorders of the Cerebral Circulation.- I. Introduction.- II. Methods for Study of the Cerebral Circulation.- A. Cerebral Blood Flow and Cerebral Vascular Resistance.- B. Cerebral Blood Vessels.- III. Regulation of the Cerebral Circulation.- A. Regulatory Responses of Vascular Caliber and Blood Flow.- B. Vascular, Neural, and Humoral Mechanisms for the Regulation of the Cerebral Circulation.- IV. Dysfunction of Regulatory Mechanisms.- A. Effects of Ischemia.- B. Effects of Hypoxemia and Hyperoxemia.- C. Effects of Increased Intracranial Pressure.- D. Effects of Sustained Hypertension.- E. Effects of Miscellaneous Factors.- V. Intravascular Phenomena.- A. Normal Cerebral Circulation.- B. Abnormal Circulatory States.- VI. Secondary Effects of Disturbed Regulation.- A. Hyperemia and Venous Hyperoxemia.- B. Cerebral Edema.- C. “Diaschisis” and Generalized Decreases of CBF.- D. Cardiac and Systemic Effects.- VII. Conclusion.- References.- 3 Effects of Narcotic Analgesics on Brain function.- I. Introduction.- II. Physiological Effects of Narcotic Analgesics.- A. Pharmacology of Narcotics.- B. Alterations of Lower Brain Stem Functions by Narcotics.- C. Alterations of Subcortical Functions by Narcotics.- D. Alterations of Cortical Functions by Narcotics.- III. Metabolism of Narcotic Analgesics in the Nervous System.- A. Penetration and Distribution in the Nervous System.- B. Blood-Brain Barrier to Narcotics.- C. Biotransformations of Narcotics.- IV. Biochemical Responses to Narcotics.- A. General Effects.- B. Pituitary-Adrenal Effects.- C. Role of the Biogenic Amines and Acetylcholine.- D. Localization of Drug Responses.- E. Tolerance to Biochemical Responses.- V. Electroencephalography.- A. Electroencephalography in Experimental Animals.- B. Electroencephalography in Man.- VI. Theories on the Mechanism of Addiction to Narcotics.- VII. Summary and Conclusions.- References.- 4 Genetic Disorders of Brain Development: Animal Models.- I. Introduction.- II. Chromosomal Organization in Eukaryotes.- A. Structural Genes.- B. Regulatory Genes.- C. Architectural Genes.- D. Temporal Genes.- III. Development of the CNS.- A. Formation of the Neural Tube.- B. Cell Proliferation.- C. Cell Migration.- D. Differentiation of Neurons.- E. Differentiation of Oligodendrocytes: Myelination.- IV. Genetic Disorders of Brain Development.- A. Abnormal Induction of the Neural Tube.- B. Abnormal Formation of the Neural Crest.- C. Abnormal Folding of the Neural Tube.- D. Abnormal Induction of Sensory Organs.- E. Abnormal Migration and Alignment of Cortical Cells.- F. Disorders of Myelin Formation.- G. Metabolic Disorders Which May Act on Different Levels of Development.- H. Increased Death Rate of Cells.- I. Genetic Mutations Affecting Brain Metabolism.- V. Prevention of Brain Dysfunction.- References.- 5 Experimental Allergic Encephalomyelitis.- I. Introduction.- II. Historical Background.- A. Clinical “Accidents” Related to Injections of CNS Tissue.- B. Induction of EAE in Laboratory Animals.- III. Identification of Specific Encephalitogenic Components of CNS Tissue.- A. Early Studies.- B. Bioassay.- C. Isolation of the Encephalitogen and Its Characterization as Myelin Basic Protein.- D. Structural Studies.- E. Species Relationships.- IV. Pathogenesis of EAE.- A. Delayed Hypersensitivity.- B. Role of Serum Antibody.- V. Possible Relationship of EAE to Human Demyelinative Disorders.- Acknowledgments.- References.- 6 Disorders of Fatty Acids.- I. Introduction.- II. Fatty Acids in Normal Brain and Nerve.- A. Distribution and Composition of Fatty Acids in Brain and Nerve.- B. Origin of Brain Fatty Acids.- III. Phytanic Acid Storage Disease (Refsum’s Disease).- A. Clinical and Biochemical Abnormalities.- B. Pathophysiology of Phytanic Acid Storage Disease.- IV. Disorders with Storage of Ceroid.- V. Other Storage Disorders.- VI. Demyelination of Known Etiology.- VII. Multiple Sclerosis.- A. Abnormalities in Fatty Acids in Multiple Sclerosis.- B. Relation of the Analytical Findings to the Clinical Syndrome.- VIII. Other Human Disorders.- IX. Animal Disorders.- X. Criteria for Establishing Primary Disorders of Cerebral Fatty Acid Metabolism.- References.- 7 Bilirubin Encephalopathy.- I. Introduction and Historical Perspective.- II. Chemistry and Metabolism of Bilirubin with Special Note of Variations Seen in the Newborn Period.- III. Protein Binding of Bilirubin.- A. Influence of Molar Ratios and pH on Binding of Bilirubin and Albumin.- B. Other Factors Which Affect Binding of Bilirubin by Albumin.- IV. Problems Hampering Research.- V. Pathological Lesion of Bilirubin Encephalopathy.- A. Gross Observations.- B. Observations with Light Microscopy.- C. Observations with Electron Microscopy.- VI. Extraneural Pathological Lesions Induced by Bilirubin.- VII. Metabolic Lesions Induced by Bilirubin.- A. Effects of Bilirubin on Tissue Respiration.- B. Effects of Bilirubin on Lipids.- C. Effects of Bilirubin on Cell Membrane Systems.- D. Other Metabolic Reactions.- VIII. Why Is Brain Damage the Main Pathological Phenomenon Induced by Bilirubin?.- References.- 8 The Action of Thyroid Hormones and Their Influence on Brain Development and function.- I. Introduction.- A. Chemical Nature of Thyroid Hormones.- B. General Biological and Biochemical Effects of Thyroid Hormones.- II. General Role of Thyroid Hormones in the Structural and Functional Maturation of the Nervous System.- A. Morphology.- B. Electrical Activity.- C. Behavior and Learning in Experimental Animals.- D. Maturation of Brain Function in Man.- E. Conclusions Regarding the Role of Thyroid Hormones in the Functional Development of the Nervous System.- III. Biochemical and Metabolic Effects of Thyroid Hormones in Nervous Tissues.- A. Energy Exchange.- B. Lipid Synthesis.- C. Miscellaneous Enzymes.- D. Nucleic Acid and Protein Synthesis.- References.- 9 Biology of the Striatum.- I. Introduction.- II. Role of the Striatum in Motility.- A. “Filter” Mechanism in Tone Control.- B. “Set” Function of the Striatum.- C. Definition of Akinesia.- D. “Trigger” Function of the Striatum.- E. The “Drive” Mechanism.- III. Role of the Striatum in Mental Function.- IV. Role of the Striatum in Autonomic Functions.- A. Neuronal Regulation of Dopamine Metabolism.- B. Hormonal Regulation of Dopamine Metabolism.- V. Conclusions.- References.- 10 Pathophysiology of Central Nervous System Regulation of Anterior Pituitary function.- I. Introduction.- A. Experimental Approaches Utilized.- B. Principles of Neuroendocrine Regulation.- II. Concept of Endocrine Regulation Via Releasing Hormones of Neural Origin.- A. Anatomical Factors.- B. Chemical Nature of Hypothalamic Releasing Hormones.- C. Mode of Secretion of Hypothalamic Releasing Hormones.- D. Mode of Action of Hypothalamic Releasing Hormones.- E. Neurotransmitters Involved in the Release of Hypophysiotropic Releasing Hormones.- F. Feedback Regulation of Pituitary Hormone Secretion.- III. Factors Involved in the Periodic Release of Pituitary Hormones.- A. Introduction.- B. Specific Examples of Periodic Hormone Release.- IV. Effect of Neonatal Hormonal Milieu on Neuroendocrine Control Mechanisms.- A. Concept of a Critical Period.- B. Gonadal Steroids.- C. Adrenal Steroids.- D. Thyroid Hormone.- V. Clinical Correlates.- A. Testing for Neuroendocrine (Hypothalamic) Dysfunction.- B. Endocrine Disorders in CNS Disease.- C. Clinical Use of Releasing Hormones.- References.- of Volume 1.- Articles Planned for Future Volumes.