Neuroscience and Greek mythology.

This article highlights the major reflections of ancient Greek mythology in modern neuroscience. An analysis of ancient Greek texts and medical literature using the MeSH term mythology was performed to identify mythological references pertaining to neuroscience. The findings are discussed in relation to etymology, early conceptualization of the nervous system structure and function, incipient characterization of neuropsychiatric disease, and philosophical stance to the practice of medicine in ancient Greece. The search identified numerous observations in clinical neurology (e.g., stroke, epilepsy, cognitive and movement disorders, sleep, pain and neuromuscular medicine, neuroinfectious diseases, headache, neuroophthalmology, and neurourology), neurosurgery, and psychiatry, as well as basic neurosciences (e.g., anatomy, embryology, genetics, pathology, and pharmacology) concealed in ancient myths. Beyond mere etymological allure and imaginative reflections in science, these fables envisage philosophical concepts that still tantalize our protean medical practice today.

[Advice and treatment from the clairvoyant Croiset]. / Adviezen en behandeling van de paragnost Croiset.

Around 1960, the Dutch clairvoyant Gerard Croiset (1909-1980) was consulted by 'people with symptoms - considered to be unexplained - such as paralysis or neurological disorders'. I searched the archive of the Johan Borgman Fund Foundation for the effect of Croiset's advice and treatment in patients with these symptoms who might have had the diagnosis of conversion disorder. Contrary to my expectations, Croiset treated no patients with conversion disorder. His advice and treatment were successful in patients with poliomyelitis, epilepsy, lumbar disc prolapse and infantile encephalopathy. Four of his patients had been insufficiently stimulated by the first person who treated them to improve their remaining muscular strength through exercise; symptoms of anxiety had not been investigated sufficiently in two patients; and in one patient the treating professional had adhered too rigidly to the set treatment. Alternative healers are apparently not only successful with patients with unexplained symptoms, and their success is not always the result of a placebo effect.

A dangerous method? The German discourse on hypnotic suggestion therapy around 1900.

In the late nineteenth century, German-speaking physicians and psychiatrists intensely debated the benefits and risks of treatment by hypnotic suggestion. While practitioners of the method sought to provide convincing evidence for its therapeutic efficacy in many medical conditions, especially nervous disorders, critics pointed to dangerous side effects, including the triggering of hysterical attacks or deterioration of nervous symptoms. Other critics claimed that patients merely simulated hypnotic phenomena in order to appease their therapist. A widespread concern was the potential for abuses of hypnosis, either by giving criminal suggestions or in the form of sexual assaults on hypnotized patients. Official inquiries by the Prussian Minister for Religious, Educational and Medical Affairs in 1902 and 1906 indicated that relatively few doctors practised hypnotherapy, whereas the method was increasingly used by lay healers. Although the Ministry found no evidence for serious harm caused by hypnotic treatments, whether performed by doctors or by lay healers, many German doctors seem to have regarded hypnotic suggestion therapy as a problematic method and abstained from using it.

Neurologic approaches to hysteria, psychogenic and functional disorders from the late 19th century onwards.

The history of functional neurologic disorders in the 20th century from the point of view of the neurologist is U-shaped. A flurry of interest between the 1880s and early 1920s gave way to lack of interest, skepticism, and concern about misdiagnosis. This was mirrored by increasing professional and geographic divisions between neurology and psychiatry after the First World War. In the 1990s the advent of imaging and other technology highlighted the positive nature of a functional diagnosis. Having been closer in the early 20th century but later more separate, these disorders are now once again the subject of academic and clinical interest, although arguably still very much on the fringes of neurology and neuropsychiatry. Revisiting older material provides a rich source of ideas and data for today's clinical researcher, but also offers cautionary tales of theories and treatments that led to stagnation rather than advancement of the field. Patterns of treatment do have a habit of repeating themselves, for example, the current enthusiasm for transcranial magnetic stimulation compared to the excitement about electrotherapy in the 19th century. For these reasons, an understanding of the history of functional disorders in neurology is arguably more important than it is for other areas of neurologic practice.

A Disorder of Qi: Breathing Exercise as a Cure for Neurasthenia in Japan, 1900-1945.

Neurasthenia became a common disease and caused widespread concern in Japan at the turn of the twentieth century, whereas only a couple of decades earlier the term "nerve" had been unfamiliar, if not unknown, to many Japanese. By exploring the theories and practices of breathing exercise-one of the most popular treatments for neurasthenia at the time-this paper attempts to understand how people who practiced breathing exercises for their nervous ills perceived, conceived, and accordingly cared for their nerves. It argues that they understood "nerve" based on their existing conceptions of qi Neurasthenia was for them a disorder of qi, although the qi had assumed modern appearances as blood and nervous current. The paper hopes to contribute to the understanding of how the concept of nerves has been accepted and assimilated in East Asia. It also points out the need to understand the varied cultures of nerves not only at the level of concept and metaphor, but also at the level of perception and experience.

Santiago Ramón y Cajal e Ivan Petrovich Pavlov: ¿existe complementariedad entre sus teorías? / Santiago Ramon y Cajal and Ivan Petrovich Pavlov: does complementarity exist between their theories?

Introducción. Pocos autores han comparado la vida y obra de Cajal y Pavlov, y, cuando lo hacen, se refieren generalmente a su coincidencia en el XIV Congreso Internacional de Medicina que tuvo lugar en Madrid en 1903. Objetivo. Presentar los modelos teóricos de ambos autores para estudiar la posible complementariedad entre sus teorías. Desarrollo. Se presentan las principales características de la teoría neuronal de Cajal, la teoría reticular que le antecedió, los principales resultados de las investigaciones de Cajal y las aportaciones que brindó al concepto de plasticidad. En cuanto a la teoría de los reflejos condicionales de Pavlov, se describen sus principales postulados, las leyes pavlovianas y la tipología del sistema nervioso según Pavlov. Conclusiones. Los niveles de organización en los que trabajan Cajal y Pavlov se pueden entender como complementarios si tenemos en cuenta la propuesta de Henry Wallon o las de marcos epistemológicos como la epistemología estratégica, donde el avance de la ciencia se logra desde estrategias diferentes, pero complementarias, que ayudan a construir modelos teóricos más fuertes (AU)

Introduction. Few authors have compared the life and work of Cajal and Pavlov and they refer normally to their coincidence at the XIV Medicine International Congress of Madrid in 1903. Aims. To describe the theoretical models of both authors and to explain the possible complementarities between the works of Cajal and Pavlov. Development. We describe the principal bases of the ‘neuron theory’ of Cajal, compared to the ‘reticulated theory’, the principal results of Cajal’s investigations and the contributions he made to the concept of plasticity. We describe the ‘Pavlov’s conditional reflections theory’, its principal postulates, pavlovians laws and the typology of the nervous system according to Pavlov. Conclusions. The works of Cajal and Pavlov can be understood as complementary under Wallon’s proposal and in the frame of the ‘strategic epistemology’, where the advance of the science is achieved from different but complementary strategies that help each other to construct stronger theoretical models (AU)

Neurological implications and neuropsychological considerations on folk music and dance.

Neurological and neuropsychological aspects of folk music and traditional dance have been poorly investigated by historical and scientific literature. Some of these performances could be indeed the manifestation of latent pathological conditions or the expression of liberation rituals. This chapter aimed at analyzing the relationships between traditional dance, folk music, and neurological and psychiatric disorders. Since ancient times, dance has been used in the individual or collective as treatment of some diseases, including epilepsy and movement disorders (dyskinesia, chorea, etc.). Dionysia in Ancient Greece, St. Vitus dance in the Middle Age, tarantism and other traditional dances of southern Italy and of non-Western countries might be credited as curative rituals of these neurological and psychiatric conditions. During the nineteenth century, dance was also used for the treatment of psychiatric patients; the relationship between dance and insanity could also be reflected in classical ballets and music of that period. Nowadays, neuropsychiatric manifestations could also be evidenced in modern dances (mass fainting at rock concerts, flash mobs); some ballroom dances are commonly used for the rehabilitation of patients suffering from neurodegenerative and psychiatric conditions. Interdisciplinary research on these subjects (ethnomusicology and cultural anthropology, clinical neurology and dynamic psychology, neuroradiology and neurophysiology, and socioneurology and neuromusicology) should be increased.

The body electric: a long view of electrical therapy for functional neurological disorders.

The use of electricity in medical treatment has always been technology-driven, rather than aetiology-driven; as new techniques have appeared, clinicians have quickly looked to try them in the treatment of all sorts of conditions where existing treatment options are limited. Functional disorders--as identified anachronistically in our analysis--have been key contenders for emerging electrical treatments: with Leyden jars, with galvanic and electromagnetic machines, and more recently with TMS and TENS. Parallels can be drawn with the history of electrical treatments for migraine and headache (Koehler and Boes, 2010). Regardless of the mode of delivery of electricity, stimulating a limb to produce movement has repeatedly been found to aid and assist recovery in functional motor disorders. This may also be true of non-electrical methods: we have found benefits using both therapeutic sedation and explanatory demonstration of a positive Hoover's sign as therapeutic methods of demonstrating normal movement in functionally weak limbs (Stone et al., 2014). Each surge in enthusiasm for new electrical treatments has been followed by questions about the nature of the disorder and validity of the treatment response. Physicians have tended to attribute therapeutic success initially to powerful biological or even metaphysical effects, but with time and experience these explanations have been replaced by views that the treatment works through suggestion and placebo. Discomfort with these conclusions has in the past discouraged ongoing development of electrical treatments, even if the end result for patients has been encouraging. In Edwards's Bayesian model, functional motor and sensory symptoms are hypothesized to arise when 'pathologically precise prior beliefs' mediated by attentional processes cause experience of symptoms via a hierarchy of false inferences (Edwards, 2012). It can be argued that use of TMS or peripheral stimulation to produce movement of a functionally weak limb has the specific potential to modulate pathological expectations. To reject these treatments as no more than placebo may mean missing an unusual opportunity to manipulate key elements in the mechanism of the disorder. However, changes to these 'priors' may also be dependent upon patient expectations, and as we see through history, this may only happen if the patient believes there is an actual neuromodulatory effect. This may give rise to significant ethical issues in that the treatment may well directly benefit patients but only if they are (mis)informed that there is an underlying biological rationale. We conclude that modern trials of TMS in functional disorders are part of a repeating cycle of experimentation recurring since the mid-18th century. We suspect that emerging technology, including transcranial direct current stimulation, will follow a similar pattern of experimentation, speculation and marginalization. We suggest that considering our modern efforts in a historical context could aid our ability to further expand and maintain our use of electrical therapies that have proven helpful in the past for patients with functional disorders.

The cruelty and failings of therapies for neurological diseases in French literature.

In this chapter, excerpts from famous or little-known works of French literature are used to illustrate how eighteenth- and nineteenth-century physicians tried to treat neuropsychiatric illnesses. Although the causes were unknown to them, they did not hesitate to inflict suffering on their patients, who were often in an appalling condition to begin with. Novelists such as Gustave Flaubert, Alphonse Daudet, the Goncourt brothers, Georges Siménon, and Céline applied their writing talents to describing the use of leeches, bloodletting, vibratory treatments, suspension of the body, multiple painful injections, and brutal electrotherapy. These writers reveal how physicians used their imaginations not only boundlessly but also without pity, to treat their patients. Each literary work is presented with the medical justifications of the time, for example, the explanations of Cruveilhier, Charcot, Brown-Sequard, Sollier, Vincent, and Roussy.

La neurología en los regimina sanitatis medievales / Neurology in medieval regimina sanitatis

Introducción: En la literatura médica medieval destacan unas obras sobre dietética, entendida como alimentación, así como otros factores presentes en el entorno de las personas y que pueden influir en su salud. Se conocen bajo el término de regimina sanitatis o salutis, regímenes de la salud y conocieron un especial desarrollo en el occidente cristiano. Atienden, por lo general, al equilibrio entre las ‘seis cosas no naturales’, factores para regular la salud e impedir que se pierda: ambiente, ejercicio, alimentos, sueño, evacuaciones y emociones. Metodos:Tras revisar las fuentes de estas obras y definir las etapas evolutivas de este género literario, nos centramos en tres de los más destacados regimina medievales, el anónimo Regimen sanitatis salernitanum, el Regimen sanitatis ad regem aragonum de Arnaldo de Villanova y el Tractatus de conservatione vite humane de Bernardo de Gordon. En ellos revisamos las referencias hechas a patologías en la esfera de la neurología. Resultados: La presencia de la neurología en los regimina, aunque no considerada de forma independiente, es destacada. Así, los textos revisados proponen medidas dietéticas para preservar el funcionamiento de la memoria, los nervios, la vista o el oído, así como para el tratamiento de cefalea, epilepsia, apoplejía o vértigos. Conclusiones: Los regimina, textos muy representativos de esta época, nos ofrecen la visión de las enfermedades neurológicas del médico medieval occidental, y cómo este recurría a la dietética para preservar la salud, y a los remedios ofrecidos por la naturaleza para combatir la enfermedad (AU)

Introduction: In medical medieval literature some works about dietetics stand out. Dietetics, as a separate branch of medicine, includes not only food or drinks, but other environmental factors influencing on health. They are known as regimina sanitatis or salutis, and specially developed in the Christian west. They generally consisted of a balance between the Galenic ‘‘six non-natural things’’; factors regulating health and its protection: environment, exercise, food, sleep, bowel movements and emotions. Methods: After reviewing the sources and defining the different stages of this genre, we have considered three of the most out-standing medieval regimina, the anonymous Regimen sanitatis salernitanum, Arnaldo de Vilanova’s Regimen sanitatis ad regem aragonum and Bernardo de Gordon’s Tractatus of conservatione vite humane. In them we review references to neurological disease. Results: Though not independently considered, there is a significant presence of neurological diseases in the regimina. Dietetics measures are proposed to preserve memory, nerves, or hearing, as well as for the treatment of migraine, epilepsy, stroke or dizziness. Conclusion: Regimina are quiet representative among medical medieval literature, and they show medieval physicians vision of neurological diseases. Dietetics was considered useful to preserve health, and therapeutics was based on natural remedies (AU)

Chapter 2: mesopotamia.

No treatise of ancient Mesopotamian clinical neurology has yet been written, although much groundbreaking work on medical or medically-related texts from this area (modern Iraq) has been performed in recent years. All through Mesopotamian civilization (c. 3000-100 BC), literary and erudite knowledge, recorded on clay tablets in cuneiform script, thrived; within the scholarly collections of medical texts, signs and symptoms of many afflictions were referred back to external agents entering in contact with the patient's body, albeit invisibly. This external etiological sphere pertained to the supernatural, although the Mesopotamians viewed it as a constituent part of reality. A similar deterministic approach may be traced in the earliest layers of Greek medicine, but it was repudiated by Hippocratic medical thought. The 40-tablet series of sakikku ("Symptoms") shows a vast number of entries on neurological symptoms and syndromes pertaining to: headache, motor and sensory impairments, coma, seizure and epilepsy, cranial trauma, spinal cord trauma, brain tumors and abscesses, strokes, pediatric neurology, basal ganglia disorders, (perhaps) Gilles de la Tourette syndrome, rabies, tetanus, and cerebral malaria. Recurring sets of supernatural agents are behind these afflictions: possibly they had become, over time, mere "labels" for a technical pinpointing of the disorders themselves.

Chapter 29: historical aspects of the major neurological vitamin deficiency disorders: overview and fat-soluble vitamin A.

The vitamine doctrine: Although diseases resulting from vitamin deficiencies have been known for millennia, such disorders were generally attributed to toxic or infectious causes until the "vitamin doctrine" was developed in the early 20th century. In the late-19th century, a physiologically complete diet was believed to require only sufficient proteins, carbohydrates, fats, inorganic salts, and water. From 1880-1912, Lunin, Pekelharing, and Hopkins found that animals fed purified mixtures of known food components failed to grow or even lost weight and died, unless the diet was supplemented with small amounts of milk, suggesting that "accessory food factors" are required in trace amounts for normal growth. By this time, Funk suggested that deficiencies of trace dietary factors, which he labeled "vitamines" on the mistaken notion that they were "vital amines," were responsible for such diseases as beriberi, scurvy, rickets, and pellagra. Vitamin A deficiency eye disease: Night blindness was recognized by the ancient Egyptians and Greeks, and many authorities from Galen onward advocated liver as a curative. Outbreaks of night blindness were linked to nutritional causes in the 18th and 19th centuries by von Bergen, Schwarz, and others. Corneal ulceration was reported in 1817 by Magendie among vitamin A-deficient dogs fed for several weeks on a diet limited to sugar and water, although he erroneously attributed this to a deficiency of dietary nitrogen (i.e. protein). Subsequently, corneal epithelial defects, often in association with night blindness, were recognized in malnourished individuals subsisting on diets now recognizable as deficient in vitamin A by Budd, Livingstone, von Hubbenet, Bitot, Mori, Ishihari, and others. During World War I, Bloch conducted a controlled clinical trial of different diets among malnourished Danish children with night blindness and keratomalacia and concluded that whole milk, butter, and cod-liver oil contain a fat-soluble substance that protects against xerophthalmia. Early retinal photochemistry: In the 1870s, Boll found that light causes bleaching of the retinal pigment, and suggested that the outer segments of the rods contain a substance that conveys an impression of light to the brain by a photochemical process. Shortly thereafter, Kühne demonstrated that the bleaching process depends upon light, and was reversible if the retinal pigment epithelium was intact. Kühne proposed an "optochemical hypothesis," a prescient concept of photochemical transduction, attributing vision to a photochemical change in visual purple (rhodopsin) with resulting chemical products stimulating the visual cells and thereby conveying a visual image. Vitamin A: In 1913, Ishihara proposed that a "fatty substance" in blood is necessary for synthesis of both rhodopsin and the surface layer of the cornea, and that night blindness and keratomalacia develop when this substance is deficient. That year McCollum and Davis (and almost simultaneously Mendel and Osborne) discovered a fat-soluble accessory food factor (later called "fat-soluble A") distinct from the water-soluble anti-beriberi factor (later called "fat-soluble B"). By 1922 McCollum and colleagues distinguished two vitamins within the fat-soluble fraction, later named vitamins A and D. In 1925 Fridericia and Holm directly linked vitamin A to night blindness in animal experiments using rats, and in 1929 Holm demonstrated the presence of vitamin A in retinal tissue. In the 1930s, Moore, Karrer, Wald, and others established the provitamin role of beta-carotene. Karrer and colleagues isolated beta-carotene (the main dietary precursor of vitamin A) and retinol (vitamin A), and determined their chemical structures. In 1947, Isler and colleagues completed the full chemical synthesis of vitamin A. Modern retinal photochemistry: Beginning in the 1930s, Wald and colleagues greatly elaborated the photochemistry of vision, with the discovery of the visual cycle of vitamin A, demonstration that rhodopsin is decomposed by light into retinal (the aldehyde form of vitamin A) and a protein (opsin), elaboration of the enzymatic conversions of various elements in the rhodopsin system, and discovery that the rhodopsin system is dependent on a photoisomerization of retinal. In 1942, Hecht and colleagues demonstrated that a single photon could trigger excitation in a rod. In 1965, Wald suggested that a large chemical amplification was necessary for this degree of light sensitivity, likely by a cascade of enzymatic reactions. Later studies elaborated this cascade and found that an intermediary in the photoisomerization of retinal interacts with transducin, a G-protein, to activate phosphodiesterases that control cyclic GMP levels, which in turn modulate the release of neurotransmitter from the rod cell. Public health: Although the availability of vitamin A through food fortification and medicinal supplements virtually eliminated ocular vitamin A deficiency from developed countries by the second half of the 20th century, vitamin A deficiency remains a serious problem in developing countries as indicated by global surveys beginning in the 1960s. Millions of children were shown to be vitamin A deficient, with resultant blindness, increased susceptibility to infection, and increased childhood mortality. Beginning in the 1960s, intervention trials showed that vitamin A deficiency disorders could be prevented in developing countries with periodic vitamin A dosing, and in the 1980s and 1990s, large randomized, double-blind, placebo-controlled clinical trials demonstrated the marked efficacy of vitamin A supplementation in reducing childhood mortality.

Chapter 30: historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins.

This historical review addresses major neurological disorders associated with deficiencies of water-soluble B vitamins: beriberi, Wernicke-Korsakoff syndrome, pellagra, neural tube defects, and subacute combined degeneration of the spinal cord. Beriberi: Beriberi was known for millennia in Asia, but was not described by a European until the 17th century when Brontius in the Dutch East Indies reported the progressive sensorimotor polyneuropathy. The prevalence of beriberi increased greatly in Asia with a change in the milling process for rice in the late 19th century. In the 1880s, Takaki demonstrated the benefits of dietary modification in sailors, and later instituted dietary reforms in the Japanese Navy, which largely eradicated beriberi from the Japanese Navy by 1887. In 1889 Eijkman in Java serendipitously identified dietary factors as a major contributor to "chicken polyneuritis," which he took to be an animal model for beriberi; the polyneuritis could be cured or prevented by feeding the chickens either unpolished rice or rice polishings. By 1901, Grijns, while continuing studies of beriberi in Java, suggested a dietary deficiency explanation for beriberi after systematically eliminating deficiencies of known dietary components and excluding a toxic effect. Wernicke-Korsakoff syndrome: In the late 1870s, Wernicke identified a clinicopathological condition with ophthalmoparesis, nystagmus, ataxia, and encephalopathy, associated with punctate hemorrhages symmetrically arranged in the grey matter around the third and fourth ventricles and the aqueduct of Sylvius. In the late 1880s, Korsakoff described a spectrum of cognitive disorders, including a confabulatory amnestic state following an agitated delirium, occurring in conjunction with peripheral polyneuropathy. Beginning around 1900, investigators recognized the close relationship between Korsakoff's psychosis, delirium tremens, and Wernicke's encephalopathy, but not until several decades later were Wernicke's encephalopathy, Korsakoff's psychosis, and beriberi all linked to the deficiency of a specific dietary factor, i.e. thiamin. Thiamin: Thiamin was crystallized from rice polishings by Jansen and Donath in 1926, and synthesized by Williams and Cline in 1936. In the late 1930s and early 1940s, characteristic pathological changes of Wernicke-Korsakoff syndrome were produced in animal models, the biochemical roles of thiamin in intermediary carbohydrate metabolism were elaborated by Peters and others, and the therapeutic benefits of thiamin for Wernicke-Korsakoff syndrome and beriberi were demonstrated. By the 1950s synthetic forms of the vitamin were produced cheaply, allowing both therapeutic administration and prevention with food enrichment. Pellagra and niacin: Pellagra was unknown prior to the introduction of maize into Europe from the New World. In the 18th century, Casàl and Frapolli described the clinical features of pellagra in Europe, and linked it with poverty and subsistence on nutritionally marginal corn-based diets. In the United States, pellagra became epidemic among poor Southerners in the early 20th century, in part because of economically-driven reliance on monotonous, nutritionally inadequate diets, combined with new manufacturing methods that removed vitamins from processed grain. From 1914-1929, Goldberger completed well-designed epidemiologic investigations, tested theories with human experiments, and utilized an animal model ("black tongue" in dogs) - all strongly supporting a dietary deficiency explanation for pellagra over prevailing toxic and infectious theories. Initial prevention and treatment approaches proved inadequate because of complex social issues linked to poverty, even after Goldberger and colleagues established that dried brewer's yeast could cure or prevent pellagra less expensively than dietary modification. During the depression, the collapse of cotton as an economically viable crop facilitated crop diversification, which contributed to an abrupt decline in pellagra mortality in the early 1930s. In 1937 Elvehjem isolated the P-P (pellagra preventive) factor, identified it as nicotinic acid (niacin), and demonstrated that nicotinic acid and nicotinic acid amide cure black tongue in dogs. Although clinical trials soon confirmed dramatic therapeutic effects in individual people, therapeutic administration of niacin had relatively little impact on population-level morbidity and mortality. Vitamin fortification of foodstuffs during World War II ultimately eradicated endemic pellagra in the United States. In the 1940s and 1950s, with expanded biochemical knowledge, pellagra was reformulated as a deficiency disease due to inadequate niacin and its amino acid precursor tryptophan. Neural tube defects and folate: Folate deficiency was initially recognized clinically as a macrocytic anemia in the 1920s, and only clearly separated from pernicious anemia by the mid-20th century. When folic acid was isolated and synthesized in the 1940s, it was shown to correct the macrocytic anemia associated with pernicious anemia, while the neurological manifestations progressed. In the 1950s and 1960s, the biochemical role of folates in transferring single carbon units was elucidated. Beginning in the 1960s, folate deficiency was increasingly recognized as the major cause of preventable neural tube defects. In the early 1990s well-designed randomized trials established that folate supplementation could prevent neural tube defects. Trial data, collectively indicating that periconceptual folate administration reduces both the occurrence and recurrence risks of neural tube defects by at least 70%, helped establish governmental recommendations concerning folic acid intake and health policy concerning vitamin fortification of foodstuffs. When dietary modification and supplementation strategies proved inadequate, folic acid food fortification was legally mandated in the US in the late 1990s, which significantly improved population folate status and produced an abrupt decline (20%-27%) in the prevalence of neural tube defects at birth. Recent studies have established genetic predispositions for neural tube defects, including both infant and maternal gene polymorphisms for enzymes involved in folate-dependent homocysteine metabolism, which help explain how the genotype of the mother, the genotype of the unborn child, and environmental factors (e.g. folate intake) can all impact on the risk of neural tube defects. Subacute combined degeneration and B(12) deficiency: Pernicious anemia was recognized clinically in the mid-19th century by Addison, but the most important neurological manifestation - subacute combined degeneration of the spinal cord - was not recognized clinically and linked with pernicious anemia until the end of the 19th century, particularly by Lichtheim, Putnam, and Dana. At the beginning of the 20th century, pernicious anemia and the associated subacute combined degeneration of the spinal cord were considered, by many investigators, to result from infectious or toxic causes. During the first quarter of the 20th century, various therapies were employed, but, with the possible exception of transfusion, were largely ineffective. In the 1920s, Minot and Murphy showed that large quantities of ingested liver could be used to effectively treat pernicious anemia, and specifically could improve or prevent progression of neurological manifestations, and could extend life expectancy beyond 2 years. Beginning in the late 1920s, Castle demonstrated that a substance elaborated by the gastric mucosa ("intrinsic factor") was essential for the absorption of a dietary factor ("extrinsic factor," later shown to be vitamin B(12)) needed to prevent pernicious anemia. Over two decades, from the late 1920s until the late 1940s, increasingly potent liver extracts were manufactured that could be given either intramuscularly or intravenously. In 1947, vitamin B(12) was isolated by Folkers and colleagues, and nearly simultaneously by Smith. Shortly thereafter the therapeutic efficacy of vitamin B(12) on subacute combined degeneration was demonstrated by West and Reisner and others. By 1955, Hodgkin determined the molecular structure of cyanocobalamin using computer-assisted x-ray crystallography, allowing complete chemical synthesis of vitamin B(12) in 1960 by an international consortium. Beginning in the late 1950s, the absorption and biochemistry of vitamin B(12) were elaborated, and several lines of evidence converged to support an autoimmune basis for pernicious anemia.

Chapter 41: the history of neurology in Scandinavia.

Neurology is well developed in Scandinavia (Denmark, Finland, Iceland, Norway, and Sweden) with a large number of clinical departments and specialists. The care for neurological patients is fairly equally organized even if neurology has evolved from different sources, from psychiatry in Denmark and Finland, internal medicine in Sweden and electrotherapy in Norway. Evidence of diagnostic activity and treatment of neurological diseases can be found in Scandinavia for more than 5000 years. The oldest are trepanned skulls. Written documentation exists from the Viking era, describing treatment of seizures and possibly also the effect of ergotamine. The methods were in concordance with medical practice in the rest of Europe. Scandinavian neurobiologists have produced important contributions to neuroscience during the last 300 or 400 years. Their names can be recognized as eponyms and Nobel prize laureates. Examples are Niels Stensen (Nicolaus Stenoni), the Bartholin family and Knud Krabbe of Denmark, Ragnar Granit of Finland, Bjørn Sigurdsson (the concept of slow virus infections) of Iceland, Asbjørn Følling and Sigvald Refsum of Norway and Gunnar Wohlfart, Eric Kugelberg, Lisa Welander and Arvid Carlsson of Sweden. In addition, well known neurological diseases were described in Scandinavia long before those neuroscientists that today have their names attached to them: Otto Christian Stengel, Norway (1826: Batten-Spielmayer-Vogt's disease), Johan Christian Lund, Norway (1860: Huntington's chorea) and Ernst Alexander Homén, Finland (1889: Wilson's disease).