Olov Oscarsson (1931-1996) of Lund University, a Pioneer in Cerebellar Neurobiology.

The present Cerebellar Classic highlights the experimental work of the Swedish neurophysiologist Olov Oscarsson (1931-1996) on the afferent innervation of the cerebellum by axons emanating from neurons in the spinal cord and the inferior olive. Historically, the schemes of cerebellar division had been principally based on the external morphology of lobules and fissures. However, the macroscopic anatomical division of the cerebellum does not coincide with its pattern of functional organization. By defining a system of longitudinal somatotopy, Oscarsson contributed to the much needed plan of cerebellar division that correlates experimental information on axonal connections with physiology. His contribution has ultimately led to the currently accepted microzonal modular scheme of cerebellar corticonuclear microcomplexes.

Hernias of the Cerebellum.

The present Cerebellar Classic highlights a paper published in 1908 by the American pathologist Simeon Burt Wolbach (1880-1954), in which he reported multiple hernias of the cerebellum for the first time in 9 cases of increased intracranial pressure. The importance of the meninges and the anatomy of involved compartments is emphasized.

The Discovery of the Monoaminergic Innervation of the Cerebellum: Convergence of Divergent and Point-to-Point Systems.

This Cerebellar Classic highlights the landmark discovery of the innervation of the cerebellar cortex and cerebellar nuclei by noradrenergic and serotoninergic axons emanating, respectively, from the locus coeruleus and the raphé nuclei. Since then, modulation of the activity of cerebellar neurons by the monoamine systems has been studied extensively, as well as their reorganization and modifications during development, plasticity, and disease. The discovery of noradrenergic and serotoninergic innervation of the cerebellum has been a crucial step in understanding the neurochemical relationships between brainstem nuclei and the cerebellum, and the attempts to treat cerebellar ataxias pharmacologically. The large neurochemical repertoire of the cerebellum represents one of the complexities and challenges in the modern appraisal of cerebellar disorders.

Nothnagel Syndrome.

The internist Hermann Nothnagel (1841-1905) took a special interest in the cerebellum. In an early experimental study on rabbits conducted in 1876, he demonstrated the involvement of the vermis in the pathophysiology of motor ataxia. Between 1879 and 1889, he reported four cases of tectal tumors that clinically manifested with bilateral ophthalmoplegia and unilateral gait ataxia, culminating in the Cerebellar Classic highlighted here. Nothnagel attributed this clinical syndrome to lesions of the colliculi ("quadrigeminal bodies") and compression of the nuclei of the third cranial nerves, but also left open the possibility of the involvement of neighboring structures, such as the cerebellar vermis. Today, the ataxic component of Nothnagel syndrome is explained by a dorsal midbrain abnormality of either neoplastic or vascular origin, involving the superior cerebellar peduncles, besides the oculomotor nerves.

Paraneoplastic Ataxia: Antibodies at the Forefront Have Become Routine Biomarkers.

Paraneoplastic cerebellopathies are immune-mediated disorders targeting primarily the cerebellar circuitry, often presenting in a subacute course. The syndrome often develops before the cancer. Therefore, its identification often leads secondarily to a diagnosis of cancer, a critical step to stabilize symptoms. Two categories of antibodies have been identified these last 30 years: (a) onconeuronal antibodies which are directed against intracellular antigens, and (b) antibodies which are directed against synaptic and cell surface proteins. These latter impact on the location and function of the antigens, causing a genuine neuronal dysfunction. Appropriate and fast tumor screening has emerged as a recommendation facing a subacute cerebellar syndrome suspected to be paraneoplastic. Search for antibodies is now a milestone for the diagnosis.

"A Great Reinforcing Organ": the Cerebellum According to Silas Weir Mitchell.

This Cerebellar Classic highlights a work by the physician and novelist, Silas Weir Mitchell (1829-1914), a pupil of Claude Bernard and a founding father of American neurology. Published in the aftermath of the American Civil War, the article reported observations on cerebellar physiology based on ablation and tissue freezing experiments in pigeons, rabbits, and guinea pigs. Mitchell communicated his results before the Academy of Natural Sciences of Philadelphia, and proposed a general theory of the cerebellum as an augmenting and reinforcing organ to the cerebrospinal motor system. After reviewing and contrasting previous theories of Flourens and Bouillaud, Mitchell formulated his own theory, which was in line with the views of Rolando and Luys. The theory emphasized the necessity, initially suggested by Brown-Séquard, of distinguishing between phenomena due to loss of function and those due to irritation as a central principle that should guide any physiological research.

Postnatal Neurogenesis Beyond Rodents: the Groundbreaking Research of Joseph Altman and Gopal Das.

An integral component of neural ontogeny and plasticity is the ongoing generation of new neurons from precursor cells throughout the lifespan in virtually all animals with a nervous system. In mammals, postnatal neurogenesis has been documented in the cerebellum, olfactory bulb, hippocampus, striatum, substantia nigra, hypothalamus, and amygdala. Germinal centers of new neuron production in the adult brain have been identified in the neuroepithelium of the subventricular zone and the dentate gyrus. One of the earliest lines of evidence gathered came from studies on the production of cerebellar microneurons in the external germinal layer of rodents and carnivores in the 1960s and 1970s. The undeniable pioneer of that research was the insightful developmental neurobiologist Joseph Altman (1925-2016). This Cerebellar Classic is devoted to the groundbreaking work of Altman and his graduate student and, subsequently, fellow faculty member, Gopal Das (1933-1991), on postnatal neurogenesis using tritiated thymidine autoradiography to tag newly formed neurons in the cerebellum of cats. Perseverant to their ideas and patiently working in West Lafayette (Indiana), they were the founders of two fields that brought about paradigm shifts and led to an explosive growth in brain research: adult neurogenesis and neural tissue transplantation.

The Significance of the Granular Layer of the Cerebellum, by Professor Heinrich Obersteiner (English Translation).

The paper is an English translation of Heinrich Obersteiner's lecture on the significance of the granular layer of the cerebellum, rendered from the original German text that was published under the title Über die Bedeutung der Körnerschichte des Kleinhirns in the Jahrbücher für Psychiatrie und Neurologie (the official organ of the Society for Psychiatry and Neurology in Vienna), volume 30, pages 192-200, 1909, communicated on 21 September 1909 before the Session on Neurology and Psychiatry at the 81st meeting of the Society of German Natural Scientists and Physicians held in Salzburg, Austria.

Commentary on "The Significance of the Granular Layer of the Cerebellum: a Communication by Heinrich Obersteiner (1847-1922) Before the 81st Meeting of the Society of German Natural Scientists and Physicians in Salzburg, September 1909".

This commentary highlights a "cerebellar classic" by Heinrich Obersteiner (1847-1922), the founder of Vienna's Neurological Institute. Obersteiner had a long-standing interest in the cerebellar cortex, its development, and pathology, having provided one of the early accurate descriptions of the external germinal layer (sometimes called the "marginal zone of Obersteiner" or "Obersteiner layer"). In his communication before the 81st meeting of the Society of German Natural Scientists and Physicians in Salzburg in September 1909, Obersteiner placed special emphasis on the histophysiology of the granule cell layer of the cerebellum and covered most of the fundamental elements of the cerebellar circuitry, on the basis of Ramón y Cajal's neuronism. Those elements are discussed in a historic and a modern perspective, including some recent ideas about the role of granule cells, beyond the mere relay of sensorimotor information from mossy fibers to the Purkinje cells, in learning and cognition.

Exploring Subcellular Cerebellar Fractions with the Electron Microscope.

Differential ultracentrifugation and subcellular fractionation historically helped to study the components of the cell, to discover new cellular organelles, and to decipher their morphological and molecular properties. In neuroscience, the technique has yielded important results on neuron biochemistry and the mechanisms of synaptic transmission. This Cerebellar Classic is devoted to the pioneering work of Manuel del Cerro, Ray S. Snider, and Mary Lou Oster-Granite, who isolated purified fractions after successive centrifugations of the rat cerebellum from birth to adulthood and studied them under the electron microscope.

From Cerebellar Apoplexy in 1849 to Cerebellar Stroke in the 2020s: Robert Dunn's Contribution.

Stroke of the cerebellum represents about 10% of strokes of the brain. Both infarction and hemorrhage manifest with symptoms related to the location and extent of the lesion(s). Bilateral cerebellar infarcts constitute up to one third of all cerebellar infarctions. The leading cause of cerebellar infarcts is emboli of cardiac origin or from intra-arterial sources. Potential complications include brainstem compression and hydrocephalus. Malignant cerebellar edema is a life-threatening complication of ischemic posterior circulation stroke requiring urgent management. The advent of MRI has revolutionized the early diagnosis in vivo, showing small and large territorial infarcts, hemorrhages, and venous infarcts. Endovascular procedures are growingly applied and are impacting on the prognosis of stroke, although cerebellar stroke from occlusion of small cerebellar arteries is currently not accessible to thrombectomy. Surgical procedures of space-occupying stroke include external ventricular drainage, suboccipital craniotomy, or combined procedures. In 1849, Robert Dunn (1799-1877), an English surgeon, reported the details of a case of apoplexy of the cerebellum in a 52-year-old man, pointing to the importance of post-mortem studies of patients followed meticulously during lifetime. Dunn discussed inflammation surrounding hemorrhage as a source of cerebral degeneration, linking for the first time cerebellar stroke, neuroinflammation, and atherosclerosis.

Part I: The Complex Spikes as One of the Cerebellar Secrets.

The olivocerebellar tract has unique morphological, physiological, and developmental properties. Olivocerebellar axons are the source of multiple climbing fibers (CFs). The synapse between CFs and the Purkinje neuron is one of the most powerful excitatory in the central nervous system. Complex spikes are composed of an initial large amplitude spike followed by spikelets. The spatiotemporal patterns of complex/simple spikes complement the rate coding to enhance the accuracy of motor and cognitive processing, and to improve predictions related to internal models. Understanding the role of complex spikes is essential in clarifying how the cerebellar cortex contributes to learning, motor control, cognitive tasks, and the processing of emotions. This Cerebellar Classic is devoted to the pioneering work of Eccles, Llinás, and Sasaki on complex spikes using intracellular recordings from Purkinje neurons.

Sven Ingvar (1889-1947) of Lund University and the Centennial of His Landmark Dissertation on Cerebellar Phylo-Ontogeny.

In January 1919, Sven Ingvar (1889-1947) defended his doctoral dissertation (required for the M.D. degree) on cerebellar phylogeny, development, and function at Lund University, Sweden. The work was supervised by Cornelius U. Ariëns Kappers (1877-1946) in Amsterdam and by Karl Petrén (1868-1927) in Lund. A physician of many interests, Ingvar became professor of Practical Medicine in his alma mater. His cerebellar papers, spanning over a decade, are the contributions that gained him international recognition in the neurological sciences. A key discovery was the demonstration, with the Marchi method, of the primary vestibulocerebellar afferent fibers. The merits of his work rest with the use of connections to compare lobes and lobules in different species, and the introduction of the idea of vestibular, spinal, and corticopontine storeys; on the other hand, based on current knowledge, one might take a more critical stance toward the proposition of a posterior lobe as a phylogenetically old structure, and the homolog of the human tonsil. Nonetheless, Ingvar was an early pioneer of the "evo-devo" synthesis (or the field of Evolutionary Developmental Biology, which aims at understanding how developmental processes evolve across species). He studied the comparative anatomy of the cerebellum in over 50 species of reptiles, birds, and mammals and theorized about the spatial relations of phylogenetically older and more recent acquisitions in both the cerebellar and the thalamocortical systems.

The physiological experiments of Constantin von Economo on the central pathways of mastication and deglutition.

The first study of Constantin von Economo on the mammalian brain was published in 1902. Experiments were carried out in rabbits at the Physiological Institute headed by Siegmund von Exner-Ewarten in Vienna to investigate the central pathways of chewing and swallowing. After placing cortical lesions, Economo applied cortical and subcortical electrical stimulation to obtain masticatory movements, and tracked degenerated fibers by means of the Marchi method. He traced fibers through the internal capsule, ventral nucleus of the thalamus, subthalamic nucleus, substantia nigra and its connections with the motor nucleus of the trigeminal nerve, and nucleus solitarius. He suggested that the substantia nigra is responsible for coordinating alimentation movements, with the involvement of cranial nerves V, VII, IX and X as well. We discuss these findings in a historical and a modern perspective, including the concept of a central pattern generator in the pontine reticular formation and its interaction with the nucleus solitarius. Today we understand that mastication is a voluntary action controlled by motor cortical areas, by motoneurons of the trigeminal, and by a neural pattern generator in the pons. On the other hand, deglutition comprises 'reflex swallowing' triggered by sensory fibers of cranial nerves V, IX and X, and 'voluntary swallowing' which may be controlled by both cortical fields and subcortical areas, such as the internal capsule, the hypothalamus and the mesencephalic reticular formation.

Women neuropsychiatrists on Wagner-Jauregg's staff in Vienna at the time of the Nobel award: ordeal and fortitude.

This article profiles the scientific lives of six women physicians on the staff of the Clinic of Neurology and Psychiatry at the University of Vienna in 1927, the year when its Director, Julius Wagner-Jauregg, was awarded the Nobel Prize in Physiology or Medicine. They were all of Jewish descent and had to leave Austria in the 1930s to escape from the National Socialist regime. With a solid background in brain science and mental disorders, Alexandra Adler, Edith Klemperer, Annie Reich, Lydia Sicher and Edith Vincze pursued academic careers in the USA, while Fanny Halpern spent 18 years in Shanghai, where she laid the foundations of modern Chinese psychiatry, before going to Canada. At the dawn of their medical careers, they were among the first women to practise neurology and psychiatry, both in Austria and overseas.

The Fifth International Neurological Congress in Lisbon, 1953.

We present an overview of the International Neurological Congress that was held in Lisbon, Portugal, on September 7-12, 1953, the fifth in the series of meetings that became a tradition and helped to establish Neurology and Neurosurgery as independent medical specialties in the mid-twentieth century. Four main symposia focused on vascular and metabolic diseases of the brain and on the parietal lobe. An additional 345 papers were read on diverse topics. The Congress was attended by 982 delegates from 39 countries. A central figure was Egas Moniz (1874-1955), the pioneer of cerebral angiography, who was awarded the Nobel Prize in Physiology or Medicine in 1949 for applying prefrontal leukotomy to manage certain forms of psychosis. Special tributes were paid to Constantin von Monakow (1853-1930) and Santiago Ramón y Cajal (1852-1934) on the occasion of the centennial anniversary of their births. A satellite meeting was held in Madrid immediately after the Lisbon conference; speakers including John F. Fulton (1899-1960), Sir Walter Russell Brain (1895-1966) and Fernando de Castro (1896-1967) praised the discoveries of Cajal, the neuron theory, and their impact on the medical sciences and on the future of Neurology.

Constantin Tsiminakis (1875-1942): Neurologist, Neuropathologist, Statesman.

The article is a 75-year memorial tribute to the Greek neurologist, Constantin Tsiminakis (1875-1942). Coming from a family of physicians, Tsiminakis graduated from the University of Athens in 1897, and trained in Vienna under Nothnagel, Frankl-Hochwart, and Obersteiner. In 1905, he was appointed Reader in Neurology and Psychiatry at his alma mater. He published over 40 articles on topics of neurology and neuropathology, including megalencephaly, hydrocephalus, progressive paralysis, epidemic encephalitis, dengue fever, and narcolepsy. However, his main focus of interest was epilepsy, including post-encephalitic forms. To differentially diagnose true from feigned epilepsy, he devised a method of compressing the carotids, which became known as the "Tsiminakis maneuver". A cultivated man and a talented poet, he rebutted the Freudian interpretation of artistic creativity. Finally, in the national legislative election in 1923, Tsiminakis was elected a Plenipotentiary Member of the Hellenic Parliament under the Liberal Party and served until 1925.

The Cerebellar System and What it Signifies from a Biological Perspective, by Professor Christofredo Jakob (English Translation).

The paper is an English translation of Christofredo Jakob's 1938 lecture on cerebellar neurobiology, rendered from the original Spanish text. Communicated at the special sessions of the Society of Neurology and Psychiatry of Buenos Aires, December 1938.