Pioneers of cortical cytoarchitectonics: the forgotten contribution of Herbert Major.

The study of cortical cytoarchitectonics and the histology of the human cerebral cortex was pursued by many investigators in the second half of the nineteenth century, such as Jacob Lockhart Clarke, Theodor Meynert, and Vladimir Betz. Another of these pioneers, whose name has largely been lost to posterity, is considered here: Herbert Coddington Major (1850-1921). Working at the West Riding Asylum in Wakefield, United Kingdom, Major's thesis of 1875 described and illustrated six-layered cortical structure in both non-human primates and man, as well as "giant nerve cells" which corresponded to those cells previously described, but not illustrated, by Betz. Further journal publications by Major in 1876 and 1877 confirmed his finding of six cortical strata. However, Major's work was almost entirely neglected by his contemporaries, including his colleague and sometime pupil at the West Riding Asylum, William Bevan-Lewis (1847-1929), who later (1878) reported the presence of both pentalaminar and hexalaminar cortices. Bevan-Lewis's work was also later credited with the first illustration of Betz cells.

Herbert Major on the insula: An early depiction of von Economo neurones?

Herbert Major (1850-1921) undertook histopathological studies of human and non-human primate brains at the West Riding Lunatic Asylum in Wakefield, England, during the 1870s. Two of his papers specifically investigated the structure of the island of Reil, or insula, "with the view of ascertaining its exact structure". In addition to describing and illustrating its lamination as six-layered, Major also identified "spindle-shaped" cells in the lower layers of human brains, but not in non-human primates. His written description, including measurements of cell body size, and illustration are suggestive that these were the neurones later described in the frontoinsular and anterior cingulate cortex by Constantin von Economo and Georg N. Koskinas and which were subsequently given the eponym "von Economo neurones". von Economo noted that this special neuronal type had been previously seen by Betz (1881), Hammarberg (1895), and Ramón y Cajal (1899-1904), but he did not mention Major's works. Major also ascribed linguistic functions to the insula. Hence, with respect to both anatomical and physiological features, Major may have pre-empted the findings of later research on this structure.

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.

Neurobiological and pathophysiological concepts of Christfried Jakob (1866-1956) on language and aphasia: An English translation of two communications [1910,1932] and a modern perspective.

The aim of the present article is to preserve, in English translation, two historical communications on aphasia and the pathophysiology of language by the neurobiologist Christfried Jakob (1866-1956) of Buenos Aires, and to place them in a modern perspective. The morphofunctional basis of human language and its pathology occupied Jakob's mind over three decades. His synthetic conclusions were based on the neuropathological examination of dozens of aphasic cases from the Hospital de Las Mercedes and the National Women's Psychiatric Hospital between 1906 and 1936. Special mention is made of the role of the cerebellum, the thalamus, and their connections with the cerebral cortex, and the language network. Current research and imaging studies support and elaborate that which Jacob presented so many years ago; many of his analyses and ideas are informative and remain relevant today.

The Pioneer Neuropharmacologist Alfred Fröhlich (1871-1953) and the Origins of Neuroendocrinology: A Sesquicentennial Remembrance.

The birth of neuroendocrinology as a scientific discipline is traced back to 1900-1901, when Joseph Babinski, Alfred Fröhlich, and Harvey Cushing independently identified adiposogenital dystrophy (Fröhlich syndrome), and related gonadal underdevelopment and obesity to a tumor near the pituitary gland. This discovery prompted decades of research into the brain mechanisms responsible for the control of peripheral metabolism and endocrine functions. On the occasion of the 150th anniversary of Fröhlich's birth, this study traces the origins of his intellectual formation and his association with renowned contemporaries in Austria, England, Italy, and finally Cincinnati, Ohio, where he sought refuge after Austria's annexation by Nazi Germany. Fröhlich interacted with seminal figures in biomedicine, including Lothar von Frankl-Hochwart, Hans Horst Meyer, Ernst Peter Pick, Harvey Cushing, John Newport Langley, and the Nobel laureates Charles Scott Sherrington and Otto Loewi. Alfred Fröhlich, one of the 20th century's most emblematic physicians, left his mark on neurophysiology and neuropharmacology with important works, and published authoritative manuals of drug dispensing and clinical therapy. He confronted the calamities of two World Wars with remarkable resilience like many of his Viennese colleagues who, overcoming the constraints of National Socialism, settled overseas to fulfil their calling as physicians, researchers, and teachers.

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.

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.

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.

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.